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Increased levels and activation of the IL-17 receptor in microglia contribute to enhanced neuroinflammation in cerebellum of hyperammonemic rats

Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with mild cognitive impairment and motor incoordination. Rats with chronic hyperammonemia reproduce these alterations. Motor incoordi...

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Identification and expression analysis of two steamer-like retrotransposons in the Chilean blue mussel ( Mytilus chilensis )

Disseminated neoplasia (DN) is a proliferative cell disorder of the circulatory system of bivalve mollusks. The disease is transmitted between individuals and can also be induced by external chemical agents su...

Noncoding RNAs in skeletal development and disorders

Protein-encoding genes only constitute less than 2% of total human genomic sequences, and 98% of genetic information was previously referred to as “junk DNA”. Meanwhile, non-coding RNAs (ncRNAs) consist of app...

Cx43 hemichannels and panx1 channels contribute to ethanol-induced astrocyte dysfunction and damage

Alcohol, a widely abused drug, significantly diminishes life quality, causing chronic diseases and psychiatric issues, with severe health, societal, and economic repercussions. Previously, we demonstrated that...

Galectins in epithelial-mesenchymal transition: roles and mechanisms contributing to tissue repair, fibrosis and cancer metastasis

Galectins are soluble glycan-binding proteins that interact with a wide range of glycoproteins and glycolipids and modulate a broad spectrum of physiological and pathological processes. The expression and subc...

Glutaminolysis regulates endometrial fibrosis in intrauterine adhesion via modulating mitochondrial function

Endometrial fibrosis, a significant characteristic of intrauterine adhesion (IUA), is caused by the excessive differentiation and activation of endometrial stromal cells (ESCs). Glutaminolysis is the metabolic...

The long-chain flavodoxin FldX1 improves the biodegradation of 4-hydroxyphenylacetate and 3-hydroxyphenylacetate and counteracts the oxidative stress associated to aromatic catabolism in Paraburkholderia xenovorans

Bacterial aromatic degradation may cause oxidative stress. The long-chain flavodoxin FldX1 of Paraburkholderia xenovorans LB400 counteracts reactive oxygen species (ROS). The aim of this study was to evaluate the...

MicroRNA-148b secreted by bovine oviductal extracellular vesicles enhance embryo quality through BPM/TGF-beta pathway

Extracellular vesicles (EVs) and their cargoes, including MicroRNAs (miRNAs) play a crucial role in cell-to-cell communication. We previously demonstrated the upregulation of bta-mir-148b in EVs from oviductal...

YME1L-mediated mitophagy protects renal tubular cells against cellular senescence under diabetic conditions

The senescence of renal tubular epithelial cells (RTECs) is crucial in the progression of diabetic kidney disease (DKD). Accumulating evidence suggests a close association between insufficient mitophagy and RT...

Effects of latroeggtoxin-VI on dopamine and α-synuclein in PC12 cells and the implications for Parkinson’s disease

Parkinson’s disease (PD) is characterized by death of dopaminergic neurons leading to dopamine deficiency, excessive α-synuclein facilitating Lewy body formation, etc. Latroeggtoxin-VI (LETX-VI), a proteinaceo...

Glial-restricted progenitor cells: a cure for diseased brain?

The central nervous system (CNS) is home to neuronal and glial cells. Traditionally, glia was disregarded as just the structural support across the brain and spinal cord, in striking contrast to neurons, alway...

Carbapenem-resistant hypervirulent ST23 Klebsiella pneumoniae with a highly transmissible dual-carbapenemase plasmid in Chile

The convergence of hypervirulence and carbapenem resistance in the bacterial pathogen Klebsiella pneumoniae represents a critical global health concern. Hypervirulent K. pneumoniae (hvKp) strains, frequently from...

Endometrial mesenchymal stromal/stem cells improve regeneration of injured endometrium in mice

The monthly regeneration of human endometrial tissue is maintained by the presence of human endometrial mesenchymal stromal/stem cells (eMSC), a cell population co-expressing the perivascular markers CD140b an...

Embryo development is impaired by sperm mitochondrial-derived ROS

Basal energetic metabolism in sperm, particularly oxidative phosphorylation, is known to condition not only their oocyte fertilising ability, but also the subsequent embryo development. While the molecular pat...

Fibroblasts inhibit osteogenesis by regulating nuclear-cytoplasmic shuttling of YAP in mesenchymal stem cells and secreting DKK1

Fibrous scars frequently form at the sites of bone nonunion when attempts to repair bone fractures have failed. However, the detailed mechanism by which fibroblasts, which are the main components of fibrous sc...

MSC-derived exosomes protect auditory hair cells from neomycin-induced damage via autophagy regulation

Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as ...

Alpha-synuclein dynamics bridge Type-I Interferon response and SARS-CoV-2 replication in peripheral cells

Increasing evidence suggests a double-faceted role of alpha-synuclein (α-syn) following infection by a variety of viruses, including SARS-CoV-2. Although α-syn accumulation is known to contribute to cell toxic...

Lactadherin immunoblockade in small extracellular vesicles inhibits sEV-mediated increase of pro-metastatic capacities

Tumor-derived small extracellular vesicles (sEVs) can promote tumorigenic and metastatic capacities in less aggressive recipient cells mainly through the biomolecules in their cargo. However, despite recent ad...

Integration of ATAC-seq and RNA-seq identifies MX1-mediated AP-1 transcriptional regulation as a therapeutic target for Down syndrome

Growing evidence has suggested that Type I Interferon (I-IFN) plays a potential role in the pathogenesis of Down Syndrome (DS). This work investigates the underlying function of MX1, an effector gene of I-IFN,...

The novel roles of YULINK in the migration, proliferation and glycolysis of pulmonary arterial smooth muscle cells: implications for pulmonary arterial hypertension

Abnormal remodeling of the pulmonary vasculature, characterized by the proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) along with dysregulated glycolysis, is a pathognomonic feat...

Electroacupuncture promotes neurogenesis in the dentate gyrus and improves pattern separation in an early Alzheimer's disease mouse model

Impaired pattern separation occurs in the early stage of Alzheimer’s disease (AD), and hippocampal dentate gyrus (DG) neurogenesis participates in pattern separation. Here, we investigated whether spatial memo...

Role of SYVN1 in the control of airway remodeling in asthma protection by promoting SIRT2 ubiquitination and degradation

Asthma is a heterogenous disease that characterized by airway remodeling. SYVN1 (Synoviolin 1) acts as an E3 ligase to mediate the suppression of endoplasmic reticulum (ER) stress through ubiquitination and de...

Advances towards the use of gastrointestinal tumor patient-derived organoids as a therapeutic decision-making tool

In December 2022 the US Food and Drug Administration (FDA) removed the requirement that drugs in development must undergo animal testing before clinical evaluation, a declaration that now demands the establish...

Melatonin alleviates pyroptosis by regulating the SIRT3/FOXO3α/ROS axis and interacting with apoptosis in Atherosclerosis progression

Atherosclerosis (AS), a significant contributor to cardiovascular disease (CVD), is steadily rising with the aging of the global population. Pyroptosis and apoptosis, both caspase-mediated cell death mechanism...

Prenatal ethanol exposure and changes in fetal neuroendocrine metabolic programming

Prenatal ethanol exposure (PEE) (mainly through maternal alcohol consumption) has become widespread. However, studies suggest that it can cause intrauterine growth retardation (IUGR) and multi-organ developmen...

Autologous non-invasively derived stem cells mitochondria transfer shows therapeutic advantages in human embryo quality rescue

The decline in the quantity and quality of mitochondria are closely associated with infertility, particularly in advanced maternal age. Transferring autologous mitochondria into the oocytes of infertile female...

Development of synthetic modulator enabling long-term propagation and neurogenesis of human embryonic stem cell-derived neural progenitor cells

Neural progenitor cells (NPCs) are essential for in vitro drug screening and cell-based therapies for brain-related disorders, necessitating well-defined and reproducible culture systems. Current strategies em...

Heat-responsive microRNAs participate in regulating the pollen fertility stability of CMS-D2 restorer line under high-temperature stress

Anther development and pollen fertility of cytoplasmic male sterility (CMS) conditioned by Gossypium harknessii cytoplasm (CMS-D2) restorer lines are susceptible to continuous high-temperature (HT) stress in sum...

Chemogenetic inhibition of NTS astrocytes normalizes cardiac autonomic control and ameliorate hypertension during chronic intermittent hypoxia

Obstructive sleep apnea (OSA) is characterized by recurrent episodes of chronic intermittent hypoxia (CIH), which has been linked to the development of sympathoexcitation and hypertension. Furthermore, it has ...

SARS-CoV-2 spike protein S1 activates Cx43 hemichannels and disturbs intracellular Ca 2+ dynamics

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the ongoing coronavirus disease 2019 (COVID-19). An aspect of high uncertainty is whether the SARS-CoV-2 per se or the systemic inflammation ...

The effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats treated with the ACE2 inhibitor MLN-4760

Angiotensin converting enzyme 2 (ACE2) plays a crucial role in the infection cycle of SARS-CoV-2 responsible for formation of COVID-19 pandemic. In the cardiovascular system, the virus enters the cells by bind...

Two murine models of sepsis: immunopathological differences between the sexes—possible role of TGFβ1 in female resistance to endotoxemia

Endotoxic shock (ExSh) and cecal ligature and puncture (CLP) are models that induce sepsis. In this work, we investigated early immunologic and histopathologic changes induced by ExSh or CLP models in female a...

An intracellular, non-oxidative factor activates in vitro chromatin fragmentation in pig sperm

In vitro incubation of epididymal and vas deferens sperm with Mn 2+ induces Sperm Chromatin Fragmentation (SCF), a mechanism that causes double-stranded breaks in toroid-linker regions (TLRs). Whether this mechani...

Focal ischemic stroke modifies microglia-derived exosomal miRNAs: potential role of mir-212-5p in neuronal protection and functional recovery

Ischemic stroke is a severe type of stroke with high disability and mortality rates. In recent years, microglial exosome-derived miRNAs have been shown to be promising candidates for the treatment of ischemic ...

S -Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis

Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationa...

Identifying pyroptosis- and inflammation-related genes in intracranial aneurysms based on bioinformatics analysis

Intracranial aneurysm (IA) is the most common cerebrovascular disease, and subarachnoid hemorrhage caused by its rupture can seriously impede nerve function. Pyroptosis is an inflammatory mode of cell death wh...

Drosophila Atlastin regulates synaptic vesicle mobilization independent of bone morphogenetic protein signaling

The endoplasmic reticulum (ER) contacts endosomes in all parts of a motor neuron, including the axon and presynaptic terminal, to move structural proteins, proteins that send signals, and lipids over long dist...

Mucin1 induced trophoblast dysfunction in gestational diabetes mellitus via Wnt/β-catenin pathway

To elucidate the role of Mucin1 (MUC1) in the trophoblast function (glucose uptake and apoptosis) of gestational diabetes mellitus (GDM) women through the Wnt/β-catenin pathway.

Human umbilical cord mesenchymal stem cells (hUC-MSCs) alleviate paclitaxel-induced spermatogenesis defects and maintain male fertility

Chemotherapeutic drugs can cause reproductive damage by affecting sperm quality and other aspects of male fertility. Stem cells are thought to alleviate the damage caused by chemotherapy drugs and to play role...

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians

The genomes of present-day non-Africans are composed of 1–3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50–60 thousand years ago. Ne...

Identification and analysis of key hypoxia- and immune-related genes in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM), an autosomal dominant genetic disease, is the main cause of sudden death in adolescents and athletes globally. Hypoxia and immune factors have been revealed to be related to ...

How do prolonged anchorage-free lifetimes strengthen non-small-cell lung cancer cells to evade anoikis? – A link with altered cellular metabolomics

Malignant cells adopt anoikis resistance to survive anchorage-free stresses and initiate cancer metastasis. It is still unknown how varying periods of anchorage loss contribute to anoikis resistance, cell migr...

Single nucleotide polymorphisms associated with wine fermentation and adaptation to nitrogen limitation in wild and domesticated yeast strains

For more than 20 years, Saccharomyces cerevisiae has served as a model organism for genetic studies and molecular biology, as well as a platform for biotechnology (e.g., wine production). One of the important eco...

Investigating the dark-side of the genome: a barrier to human disease variant discovery?

The human genome contains regions that cannot be adequately assembled or aligned using next generation short-read sequencing technologies. More than 2500 genes are known contain such ‘dark’ regions. In this st...

Hyperbaric oxygen treatment increases intestinal stem cell proliferation through the mTORC1/S6K1 signaling pathway in Mus musculus

Hyperbaric oxygen treatment (HBOT) has been reported to modulate the proliferation of neural and mesenchymal stem cell populations, but the molecular mechanisms underlying these effects are not completely unde...

Polar microalgae extracts protect human HaCaT keratinocytes from damaging stimuli and ameliorate psoriatic skin inflammation in mice

Polar microalgae contain unique compounds that enable them to adapt to extreme environments. As the skin barrier is our first line of defense against external threats, polar microalgae extracts may possess res...

Correction: Utility of melatonin in mitigating ionizing radiation‑induced testis injury through synergistic interdependence of its biological properties

The original article was published in Biological Research 2022 55 :33

Beyond energy provider: multifunction of lipid droplets in embryonic development

Since the discovery, lipid droplets (LDs) have been recognized to be sites of cellular energy reserves, providing energy when necessary to sustain cellular life activities. Many studies have reported large num...

Retraction Note: Tridax procumbens flavonoids: a prospective bioactive compound increased osteoblast differentiation and trabecular bone formation

Electroacupuncture protective effects after cerebral ischemia are mediated through mir-219a inhibition.

Electroacupuncture (EA) is a complementary and alternative therapy which has shown protective effects on vascular cognitive impairment (VCI). However, the underlying mechanisms are not entirely understood.

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Biological Research

ISSN: 0717-6287

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Page 1 of 6

Endothelial adherens junctions and the actin cytoskeleton: an 'infinity net'?

A recent paper in BMC Biology reports that actin stress fibers in adjacent cultured endothelial cells are linked through adherens junctions. This organization might provide a super-cellular network that could ena...

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Robust and specific inhibition of microRNAs in Caenorhabditis elegans

MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of numerous target genes. Yet, while hundreds of miRNAs have been identified, little is known about their functions. In a recent report...

Genome of a songbird unveiled

An international collaborative effort has recently uncovered the genome of the zebra finch, a songbird model that has provided unique insights into an array of biological phenomena.

The mathematics of sexual attraction

Pollen tubes follow attractants secreted by the ovules. In a recent paper in BMC Plant Biology , Stewman and colleagues have quantified the parameters of this attraction and used them to calibrate a mathematical m...

Diversity lost: are all Holarctic large mammal species just relict populations?

Population genetic analyses of Eurasian wolves published recently in BMC Evolutionary Biology suggest that a major genetic turnover took place in Eurasian wolves after the Pleistocene. These results add to the gr...

Hybridization and speciation in angiosperms: arole for pollinator shifts?

The majority of convincingly documented cases of hybridization in angiosperms has involved genetic introgression between the parental species or formation of a hybrid species with increased ploidy; however, ho...

Evolution underground: shedding light on the diversification of subterranean insects

A recent study in BMC Evolutionary Biology has reconstructed the molecular phylogeny of a large Mediterranean cave-dwelling beetle clade, revealing an ancient origin and strong geographic structuring. It seems li...

A modern circadian clock in the common angiosperm ancestor of monocots and eudicots

The circadian clock enhances fitness through temporal organization of plant gene expression, metabolism and physiology. Two recent studies, one in BMC Evolutionary Biology , demonstrate through phylogenetic analys...

Scale-eating cichlids: from hand(ed) to mouth

Two recent studies in BMC Biology and Evolution raise important questions about a textbook case of frequency-dependent selection in scale-eating cichlid fishes. They also suggest a fascinating new line of researc...

Top dogs: wolf domestication and wealth

A phylogeographic analysis of gene sequences important in determining body size in dogs, recently published in BMC Biology , traces the appearance of small body size to the Neolithic Middle East. This finding stre...

No better time to FRET: shedding light on host pathogen interactions

Understanding the spatio-temporal subversion of host cell signaling by bacterial virulence factors is key to combating infectious diseases. Following a recent study by Buntru and co-workers published in BMC Biolo...

Making progress in genetic kin recognition among vertebrates

A recent study in BMC Evolutionary Biology has shown that genetically similar individual ring-tailed lemurs are also more similar in their scent composition, suggesting a possible mechanism of kin recognition. Th...

Regeneration review reprise

There have been notable advances in the scientific understanding of regeneration within the past year alone, including two recently published in BMC Biology . Increasingly, progress in the regeneration field is be...

Acoel and platyhelminth models for stem-cell research

Acoel and platyhelminth worms are particularly attractive invertebrate models for stem-cell research because their bodies are continually renewed from large pools of somatic stem cells. Several recent studies,...

Madm (Mlf1 adapter molecule) cooperates with Bunched A to promote growth in Drosophila

The TSC-22 domain family (TSC22DF) consists of putative transcription factors harboring a DNA-binding TSC-box and an adjacent leucine zipper at their carboxyl termini. Both short and long TSC22DF isoforms are ...

Bunched and Madm: a novel growth-regulatory complex?

By combining Drosophila genetics and proteomics Gluderer et al. report in this issue of Journal of Biology the isolation of a novel growth-regulatory complex consisting of Bunched and Madm. Future study of this c...

Q&A: What can microfluidics do for stem-cell research?

Regulation of metabolism in caenorhabditis elegans longevity.

The nematode Caenorhabditis elegans is a favorite model for the study of aging. A wealth of genetic and genomic studies show that metabolic regulation is a hallmark of life-span modulation. A recent study in BMC ...

Reprogramming of the non-coding transcriptome during brain development

A recent global analysis of gene expression during the differentiation of neuronal stem cells to neurons and oligodendrocytes indicates a complex pattern of changes in the expression of both protein-coding tra...

The THO complex as a key mRNP biogenesis factor in development and cell differentiation

The THO complex is a key component in the co-transcriptional formation of messenger ribonucleoparticles that are competent to be exported from the nucleus, yet its precise function is unknown. A recent study in B...

SnoPatrol: how many snoRNA genes are there?

Small nucleolar RNAs (snoRNAs) are among the most evolutionarily ancient classes of small RNA. Two experimental screens published in BMC Genomics expand the eukaryotic snoRNA catalog, but many more snoRNAs remain...

Sometimes one just isn't enough: do vertebrates contain an H2A.Z hyper-variant?

How much functional specialization can one component histone confer on a single nucleosome? The histone variant H2A.Z seems to be an extreme example. Genome-wide distribution maps show non-random (and evolutio...

Apical polarity in three-dimensional culture systems: where to now?

Delineation of the mechanisms that establish and maintain the polarity of epithelial tissues is essential to understanding morphogenesis, tissue specificity and cancer. Three-dimensional culture assays provide...

The water flea Daphnia - a 'new' model system for ecology and evolution?

Daphnia pulex is the first crustacean to have its genome sequenced. Availability of the genome sequence will have implications for research in aquatic ecology and evolution in particular, as addressed by a series...

Top ten in Journal of Biology in 2009: stem cells, influenza, pit bulls, Darwin, and more

The bacterial pathogen listeria monocytogenes : an emerging model in prokaryotic transcriptomics.

A major challenge in bacterial pathogenesis is understanding the molecular basis of the switch from saprophytism to virulence. Following a recent whole-genome transcriptomic analysis using tiling arrays, an ar...

Forward genetics in Tribolium castaneum : opening new avenues of research in arthropod biology

A recent paper in BMC Biology reports the first large-scale insertional mutagenesis screen in a non-drosophilid insect, the red flour beetle Tribolium castaneum . This screen marks the beginning of a non-biased, '...

Mapping the protistan 'rare biosphere'

The use of cultivation-independent approaches to map microbial diversity, including recent work published in BMC Biology , has now shown that protists, like bacteria/archaea, are much more diverse than had been re...

Scribble at the crossroads

Although proteins involved in determining apical-basal cell polarity have been directly linked to tumorigenesis, their precise roles in this process remain unclear. A recent report in BMC Biology clarifies the si...

Q&A: Quantitative approaches to planar polarity and tissue organization

Gene regulation, evolvability and the limits of genomics, the transcriptome of human monocyte subsets begins to emerge.

Human monocytes can be divided into subsets according to their expression or lack of the cell-surface antigen CD16. In papers published recently in the Journal of Proteome Research and in BMC Genomics , two groups...

Chromatin 'programming' by sequence - is there more to the nucleosome code than %GC?

The role of genomic sequence in directing the packaging of eukaryotic genomes into chromatin has been the subject of considerable recent debate. A new paper from Tillo and Hughes shows that the intrinsic therm...

Fishing for the signals that pattern the face

Zebrafish are a powerful system for studying the early embryonic events that form the skull and face, as a model for human craniofacial birth defects such as cleft palate. Signaling pathways that pattern the p...

Coordinated gene expression by post-transcriptional regulons in African trypanosomes

The regulation of gene expression in trypanosomes is unique. In the absence of transcriptional control at the level of initiation, a subset of Trypanosoma brucei genes form post-transcriptional regulons in which ...

Promoter architecture and the evolvability of gene expression

Evolutionary changes in gene expression are a main driver of phenotypic evolution. In yeast, genes that have rapidly diverged in expression are associated with particular promoter features, including the prese...

Adaptations of proteins to cellular and subcellular pH

Bioinformatics-based searches for correlations between subcellular localization and pI or charge distribution of proteins have failed to detect meaningful correlations. Recent work published in BMC Biology finds ...

TBP2 is a general transcription factor specialized for female germ cells

The complexity of the core promoter transcription machinery has emerged as an additional level of transcription regulation that is used during vertebrate development. Recent studies, including one published in BM...

Generalized immune activation as a direct result of activated CD4 + T cell killing

In addition to progressive CD4 + T cell immune deficiency, HIV infection is characterized by generalized immune activation, thought to arise from increased microbial exposure resulting from diminishing immunity.

Life and death as a T lymphocyte: from immune protection to HIV pathogenesis

Detailed analysis of T cell dynamics in humans is challenging and mouse models can be important tools for characterizing T cell dynamic processes. In a paper just published in Journal of Biology , Marques et al . s...

What we still don't know about AIDS

The gene complement of the ancestral bilaterian - was urbilateria a monster.

Expressed sequence tag analyses of the annelid Pomatoceros lamarckii , recently published in BMC Evolutionary Biology , are consistent with less extensive gene loss in the Lophotrochozoa than in the Ecdysozoa, but ...

The nature of cell-cycle checkpoints: facts and fallacies

The concept of checkpoint controls revolutionized our understanding of the cell cycle. Here we revisit the defining features of checkpoints and argue that failure to properly appreciate the concept is leading ...

An expanded evolutionary role for flower symmetry genes

CYCLOIDEA (CYC) -like TCP genes are critical for flower developmental patterning. Exciting recent breakthroughs, including a study by Song et al. published in BMC Evolutionary Biology , demonstrate that CYC -like ge...

Mechanisms of ubiquitin transfer by the anaphase-promoting complex

The anaphase-promoting complex (APC) is a ubiquitin-protein ligase required for the completion of mitosis in all eukaryotes. Recent mechanistic studies reveal how this remarkable enzyme combines specificity in...

Targeting TNF-α for cancer therapy

As the tumor vasculature is a key element of the tumor stroma, angiogenesis is the target of many cancer therapies. Recent work published in BMC Cell Biology describes a fusion protein that combines a peptide pre...

TEs or not TEs? That is the evolutionary question

Transposable elements (TEs) have contributed a wide range of functional sequences to their host genomes. A recent paper in BMC Molecular Biology discusses the creation of new transcripts by transposable element i...

Molecular machines or pleiomorphic ensembles: signaling complexes revisited

Signaling complexes typically consist of highly dynamic molecular ensembles that are challenging to study and to describe accurately. Conventional mechanical descriptions misrepresent this reality and can be a...

Ockham's broom: A new series

Adaptation by introgression.

Both selective and random processes can affect the outcome of natural hybridization. A recent analysis in BMC Evolutionary Biology of natural hybridization between an introduced and a native salamander reveals th...

Journal of Biology

ISSN: 1475-4924

April 15, 2024

Symbiosis across the tree of life

Symbiosis research has become a holistic and pervasive field with a mature theoretical basis. This collection of 10 articles aims to showcase the extraordinary diversity in symbiotic relationships across the tree of life, exploring their evolutionary basis and underlying mechanisms.

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Research Article

Role of chromatin factor CFDP1 in mitotic spindle formation

CFDP1 is a chromatin factor that has been shown to regulate cell proliferation and maintain higher-order chromatin structure, but its mechanistic role in mitotic spindle assembly is unclear. Gokul Gopinathan, Qian Xu, Xianghong Luan and Thomas Diekwisch show that CFDP1 is essential for the structural stability of centromeric heterochromatin, which in turn influences microtubule nucleation during mitotic spindle formation.

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Recently Published Articles

• Drosophila ">Mrj is a chaperone of the Hsp40 family that regulates Orb2 oligomerization and long-term memory in Drosophila
• Identifying causes and consequences of rhizosphere microbiome heritability
• The genotype of barley cultivars influences multiple aspects of their associated microbiota via differential root exudate secretion

Current Issue March 2024

Short Reports

Why older males succeed in the mating game

Male reproductive performance typically improves over time, but is this due to competition with older males or inherent to younger males? This study of blue tits by Emmi Schlicht, Bart Kempenaers and colleagues suggests that older males outcompete yearling males via sperm competition or differences in attractiveness to females.

Image credit: Unsplash user Amee Fairbank-Brown

Confounding in GWAS

GWASs aim to estimate direct effects of genotype on an individual's phenotype, but this can be subject to genetic and environmental confounds and "indirect" genetic effects of relatives' genotypes. Carl Veller and Graham Coop present a theoretical analysis of the influence of confounders in population-based and within-family GWASs, showing that, while family-based studies are more rigorous, they still carry subtle issues that arise from confounding. Also read the accompanying Primer by Alexander Young.

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Formal Comment

Realism when studying both sexes

A recent article claimed that researchers need not increase the overall sample size for a study that includes both sexes. Szymon Drobniak, Shinichi Nakagawa and colleagues point out that that study assumed two sexes to have the same variance, and explains why this is a unrealistic assumption. Also read the response by Benjamin Phillips, Timo Haschler and Natasha Karp.

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Hsp70 reduces protein synthesis in stressed Salmonella

Hsp70 chaperones preserve protein synthesis by promoting protein folding and preventing its aggregation. Carissa Chan and Eduardo Groisman report a new role of Hsp70 in Salmonella enterica survival during low Mg 2+ conditions by binding to the ribosome and reducing protein synthesis.

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Perceiving memorable images

How does the processing of images with high and low memorability differ in the brain? Benjamin Lahner, Yalda Mohsenzadeh, Caitlin Mullin and Aude Oliva combine fMRI and MEG to show that only images with high memorability scores undergo extended processing late in time throughout the ventral visual stream, including early visual cortex.

Image credit: pbio.3002564

Unsolved Mystery

How do endosymbionts work with so few genes?

This Unsolved Mystery article explores how genome reduction alters endosymbiont biology and highlights a ‘tipping point’ where the loss of the ability to build a cell envelope coincides with a marked erosion of translation-related genes.

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Symbiosis: In search of a deeper understanding

Thomas Richards and Nancy Moran discuss our new collection of articles exploring emerging themes in symbiosis research, as researchers exploit modern research tools and new models to unravel how symbiotic interactions function and evolve.

Perspective

Fungal holobionts to inform synthetic endosymbioses

Rhizopus microsporus is a fungal holobiont, harboring bacterial and viral endosymbionts. Laila Partida-Martínez explores how these microbial allies increase pathogenicity and defense and control reproduction in the fungus.

Image credit: pbio.3002587

Fitness trade-offs and the origins of endosymbiosis

Endosymbiosis is common and has played an important role in the evolution of complex life. Michael Brockhurst, Duncan Cameron and Andrew Beckerman explore the theory and experimental evidence for trade-offs in the early-stage evolution of endosymbiosis.

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Symbiosis research has become a holistic and pervasive field with a mature theoretical basis. This collection showcases symbiotic relationships across the tree of life, exploring their evolutionary basis and underlying mechanisms.

PLOS Biology 20th Anniversary

PLOS Biology is 20 and we are celebrating with a collection that contains articles that look back at landmark studies that we published, others that look past and future, and others discussing how publishing and open science have evolved and what is to come.

Engineering plants for a changing climate

This collection explores engineering strategies to help us adapt plants to a changing climate, including breeding techniques, genome engineering, synthetic biology and microbiome engineering.

Going for green

The green collection explores biological solutions that could be applied to reduce CO2 emissions, get rid of non-degradable plastics, produce food in a sustainable manner or generate energy.

Ocean solutions for a sustainable, healthy and inclusive future

This collection explores potential solutions to mitigate the impacts of human activity on ocean ecosystems to minimize or reverse degradation.

RS: Vaccines and antimicrobial resistance: from science to policy

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GRC: Enhancing Public Health, Food Security and Biodiversity

May 19 - 24

Meet Editor in Chief Nonia Pariente ([email protected])

CSHL: Brain Body Physiology

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Meet Senior Editor Luke Smith ([email protected])

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Page 1 of 17

PSMD1 and PSMD2 regulate HepG2 cell proliferation and apoptosis via modulating cellular lipid droplet metabolism

Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC). The lipid-rich environment enhances the proliferation and metastasis abilities of tumor cells. Pre...

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The effect of BACE1-AS on β-amyloid generation by regulating BACE1 mRNA expression

The BACE1 antisense transcript (BACE1-AS) is a conserved long noncoding RNA (lncRNA). The level of BACE1-AS is significantly increased and the level of the BACE1 mRNA is slightly increased in subjects with AD....

Overlapping transcriptional expression response of wheat zinc-induced facilitator-like transporters emphasize important role during Fe and Zn stress

Hexaploid wheat is an important cereal crop that has been targeted to enhance grain micronutrient content including zinc (Zn) and iron (Fe). In this direction, modulating the expression of plant transporters i...

MiR-32-5p influences high glucose-induced cardiac fibroblast proliferation and phenotypic alteration by inhibiting DUSP1

The current study aimed to investigate the effects of miR-32-5p on cardiac fibroblasts (CFs) that were induced with high levels of glucose; we also aimed to identify the potential mechanisms involved in the re...

Correction to: A protocol for custom CRISPR Cas9 donor vector construction to truncate genes in mammalian cells using pcDNA3 backbone

The original article [1] contains three erroneous mentions of usage of a restriction enzyme— Bst Z17I—in the Methods section as displayed in the following sentences.

The original article was published in BMC Molecular Biology 2018 19 :3

Comparison of miRNA - 101a - 3p and miRNA - 144a - 3p regulation with the key genes of alpaca melanocyte pigmentation

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Correction to: MicroRNA-325-3p protects the heart after myocardial infarction by inhibiting RIPK3 and programmed necrosis in mice

The original article [1] contains an error whereby Fig. 7 displays incorrect results; the correct version of Fig. 7 can be viewed ahead in this Correction article and should be considered in place of the origi...

The original article was published in BMC Molecular Biology 2019 20 :17

MicroRNA-325-3p protects the heart after myocardial infarction by inhibiting RIPK3 and programmed necrosis in mice

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Targeting miR-9 in gastric cancer cells using locked nucleic acid oligonucleotides

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Physical shearing imparts biological activity to DNA and ability to transmit itself horizontally across species and kingdom boundaries

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• Cancer Control
• v.28; Jan-Dec 2021

Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective

Patricia piña-sánchez.

1 Oncology Research Unit, Oncology Hospital, Mexican Institute of Social Security, Mexico

Antonieta Chávez-González

Martha ruiz-tachiquín, eduardo vadillo, alberto monroy-garcía, juan josé montesinos, rocío grajales.

2 Department of Medical Oncology, Oncology Hospital, Mexican Institute of Social Security, Mexico

Marcos Gutiérrez de la Barrera

3 Clinical Research Division, Oncology Hospital, Mexican Institute of Social Security, Mexico

Hector Mayani

Since the second half of the 20th century, our knowledge about the biology of cancer has made extraordinary progress. Today, we understand cancer at the genomic and epigenomic levels, and we have identified the cell that starts neoplastic transformation and characterized the mechanisms for the invasion of other tissues. This knowledge has allowed novel drugs to be designed that act on specific molecular targets, the immune system to be trained and manipulated to increase its efficiency, and ever more effective therapeutic strategies to be developed. Nevertheless, we are still far from winning the war against cancer, and thus biomedical research in oncology must continue to be a global priority. Likewise, there is a need to reduce unequal access to medical services and improve prevention programs, especially in countries with a low human development index.

Introduction

During the last one hundred years, our understanding of the biology of cancer increased in an extraordinary way. 1 - 4 Such a progress has been particularly prompted during the last few decades because of technological and conceptual progress in a variety of fields, including massive next-generation sequencing, inclusion of “omic” sciences, high-resolution microscopy, molecular immunology, flow cytometry, analysis and sequencing of individual cells, new cell culture techniques, and the development of animal models, among others. Nevertheless, there are many questions yet to be answered and many problems to be solved regarding this disease. As a consequence, oncological research must be considered imperative.

Currently, cancer is one of the illnesses that causes more deaths worldwide. 5 According to data reported in 2020 by the World Health Organization (WHO), cancer is the second cause of death throughout the world, with 10 million deaths. 6 Clearly, cancer is still a leading problem worldwide. With this in mind, the objective of this article is to present a multidisciplinary and comprehensive overview of the disease. We will begin by analyzing cancer as a process, focusing on the current state of our knowledge on 4 specific aspects of its biology. Then, we will look at cancer as a global health problem, considering some epidemiological aspects, and discussing treatment, with a special focus on novel therapies. Finally, we present our vision on some of the challenges and perspectives of cancer in the 21 st century.

The Biology of Cancer

Cancer is a disease that begins with genetic and epigenetic alterations occurring in specific cells, some of which can spread and migrate to other tissues. 4 Although the biological processes affected in carcinogenesis and the evolution of neoplasms are many and widely different, we will focus on 4 aspects that are particularly relevant in tumor biology: genomic and epigenomic alterations that lead to cell transformation, the cells where these changes occur, and the processes of invasion and metastasis that, to an important degree, determine tumor aggressiveness.

Cancer Genomics

The genomics of cancer can be defined as the study of the complete sequence of DNA and its expression in tumor cells. Evidently, this study only becomes meaningful when compared to normal cells. The sequencing of the human genome, completed in 2003, was not only groundbreaking with respect to the knowledge of our gene pool, but also changed the way we study cancer. In the post-genomic era, various worldwide endeavors, such as the Human Cancer Genome Project , the Cancer Genome ATLAS (TCGA), the International Cancer Genome Consortium, and the Pan-Cancer Analysis Working Group (PCAWG), have contributed to the characterization of thousands of primary tumors from different neoplasias, generating more than 2.5 petabytes (10 15 ) of genomic, epigenomic, and proteomic information. This has led to the building of databases and analytical tools that are available for the study of cancer from an “omic” perspective, 7 , 8 and it has helped to modify classification and treatment of various neoplasms.

Studies in the past decade, including the work by the PCAWG, have shown that cancer generally begins with a small number of driving mutations (4 or 5 mutations) in particular genes, including oncogenes and tumor-suppressor genes. Mutations in TP53, a tumor-suppressor gene, for example, are found in more than half of all cancer types as an early event, and they are a hallmark of precancerous lesions. 9 - 12 From that point on, the evolution of tumors may take decades, throughout which the mutational spectrum of tumor cells changes significantly. Mutational analysis of more than 19 000 exomes revealed a collection of genomic signatures, some associated with defects in the mechanism of DNA repair. These studies also revealed the importance of alterations in non-coding regions of DNA. Thus, for example, it has been observed that various pathways of cell proliferation and chromatin remodeling are altered by mutations in coding regions, while pathways, such as WNT and NOTCH, can be disrupted by coding and non-coding mutations. To the present date, 19 955 genes that codify for proteins and 25 511 genes for non-coding RNAs have been identified ( https://www.gencodegenes.org/human/stats.html ). Based on this genomic catalogue, the COSMIC (Catalogue Of Somatic Mutations In Cancer) repository, the most robust database to date, has registered 37 288 077 coding mutations, 19 396 fusions, 1 207 190 copy number variants, and 15 642 672 non-coding variants reported up to August 2020 (v92) ( https://cosmic-blog.sanger.ac.uk/cosmic-release-v92/ ).

The genomic approach has accelerated the development of new cancer drugs. Indeed, two of the most relevant initiatives in recent years are ATOM (Accelerating Therapeutics for Opportunities in Medicine), which groups industry, government and academia, with the objective of accelerating the identification of drugs, 13 and the Connectivity Map (CMAP), a collection of transcriptional data obtained from cell lines treated with drugs for the discovery of functional connections between genes, diseases, and drugs. The CMAP 1.0 covered 1300 small molecules and more than 6000 signatures; meanwhile, the CMAP 2.0 with L1000 assay profiled more than 1.3 million samples and approximately 400 000 signatures. 14

The genomic study of tumors has had 2 fundamental contributions. On the one hand, it has allowed the confirmation and expansion of the concept of intratumor heterogeneity 15 , 16 ; and on the other, it has given rise to new classification systems for cancer. Based on the molecular classification developed by expression profiles, together with mutational and epigenomic profiles, a variety of molecular signatures have been identified, leading to the production of various commercial multigene panels. In breast cancer, for example, different panels have been developed, such as Pam50/Prosigna , Blue Print , OncotypeDX , MammaPrint , Prosigna , Endopredict , Breast Cancer Index , Mammostrat, and IHC4 . 17

Currently, the genomic/molecular study of cancer is more closely integrated with clinical practice, from the classification of neoplasms, as in tumors of the nervous system, 18 to its use in prediction, as in breast cancer. 17 Improvement in molecular methods and techniques has allowed the use of smaller amounts of biological material, as well as paraffin-embedded samples for genomic studies, both of which provide a wealth of information. 19 In addition, non-invasive methods, such as liquid biopsies, represent a great opportunity not only for the diagnosis of cancer, but also for follow-up, especially for unresectable tumors. 20

Research for the production of genomic information on cancer is presently dominated by several consortia, which has allowed the generation of a great quantity of data. However, most of these consortia and studies are performed in countries with a high human development index (HDI), and countries with a low HDI are not well represented in these large genomic studies. This is why initiatives such as Human Heredity and Health in Africa (H3Africa) for genomic research in Africa are essential. 21 Generation of new information and technological developments, such as third-generation sequencing, will undoubtedly continue to move forward in a multidisciplinary and complex systems context. However, the existing disparities in access to genomic tools for diagnosis, prognosis, and treatment of cancer will continue to be a pressing challenge at regional and social levels.

Cancer Epigenetics

Epigenetics studies the molecular mechanisms that produce hereditable changes in gene expression, without causing alterations in the DNA sequence. Epigenetic events are of 3 types: methylation of DNA and RNA, histone modification (acetylation, methylation, and phosphorylation), and the expression of non-coding RNA. Epigenetic aberrations can drive carcinogenesis when they alter chromosome conformation and the access to transcriptional machinery and to various regulatory elements (promoters, enhancers, and anchors for interaction with chromatin, for example). These changes may activate oncogenesis and silence tumor-suppressor mechanisms when they modulate coding and non-coding sequences (such as micro-RNAs and long-RNAs). This can then lead to uncontrolled growth, as well as the invasion and metastasis of cancer cells.

While genetic mutations are stable and irreversible, epigenetic alterations are dynamic and reversible; that is, there are several epigenomes, determined by space and time, which cause heterogeneity of the “epigenetic status” of tumors during their development and make them susceptible to environmental stimuli or chemotherapeutic treatment. 22 Epigenomic variability creates differences between cells, and this creates the need to analyze cells at the individual level. In the past, epigenetic analyses measured “average states” of cell populations. These studies revealed general mechanisms, such as the role of epigenetic marks on active or repressed transcriptional states, and established maps of epigenetic composition in a variety of cell types in normal and cancerous tissue. However, these approaches are difficult to use to examine events occurring in heterogeneous cell populations or in uncommon cell types. This has led to the development of new techniques that permit marking of a sequence on the epigenome and improvement in the recovery yield of epigenetic material from individual cells. This has helped to determine changes in DNA, RNA, and histones, chromatin accessibility, and chromosome conformation in a variety of neoplasms. 23 , 24

In cancer, DNA hypomethylation occurs on a global scale, while hypermethylation occurs in specific genomic loci, associated with abnormal nucleosome positioning and chromatin modifications. This information has allowed epigenomic profiles to be established in different types of neoplasms. In turn, these profiles have served as the basis to identify new neoplasm subgroups. For example, in triple negative breast cancer (TNBC), 25 and in hepatocellular carcinoma, 26 DNA methylation profiles have helped to the identification of distinct subgroups with clinical relevance. Epigenetic approaches have also helped to the development of prognostic tests to assess the sensitivity of cancer cells to specific drugs. 27

Epigenetic traits could be used to characterize intratumoral heterogeneity and determine the relevance of such a heterogeneity in clonal evolution and sensitivity to drugs. However, it is clear that heterogeneity is not only determined by genetic and epigenetic diversity resulting from clonal evolution of tumor cells, but also by the various cell populations that form the tumor microenvironment (TME). 28 Consequently, the epigenome of cancer cells is continually remodeled throughout tumorigenesis, during resistance to the activity of drugs, and in metastasis. 29 This makes therapeutic action based on epigenomic profiles difficult, although significant advances in this area have been reported. 30

During carcinogenesis and tumor progression, epigenetic modifications are categorized by their mechanisms of regulation ( Figure 1A ) and the various levels of structural complexity ( Figure 1B ). In addition, the epigenome can be modified by environmental stimuli, stochastic events, and genetic variations that impact the phenotype ( Figure 1C ). 31 , 32 The molecules that take part in these mechanisms/events/variations are therapeutic targets of interest with potential impact on clinical practice. There are studies on a wide variety of epidrugs, either alone or in combination, which improve antitumor efficacy. 33 However, the problems with these drugs must not be underestimated. For a considerable number of epigenetic compounds still being under study, the main challenge is to translate in vitro efficacy of nanomolar (nM) concentrations into well-tolerated and efficient clinical use. 34 The mechanisms of action of epidrugs may not be sufficiently controlled and could lead to diversion of the therapeutic target. 35 It is known that certain epidrugs, such as valproic acid, produce unwanted epigenetic changes 36 ; thus the need for a well-established safety profile before these drugs can be used in clinical therapy. Finally, resistance to certain epidrugs is another relevant problem. 37 , 38

Epigenetics of cancer. (A) Molecular mechanisms. (B) Structural hierarchy of epigenomics. (C) Factors affecting the epigenome. Modified from Refs. 31 and 32 .

As we learn about the epigenome of specific cell populations in cancer patients, a door opens to the evaluation of sensitivity tests and the search for new molecular markers for detection, prognosis, follow-up, and/or response to treatment at various levels of molecular regulation. Likewise, the horizon expands for therapeutic alternatives in oncology with the use of epidrugs, such as pharmacoepigenomic modulators for genes and key pathways, including methylation of promoters and regulation of micro-RNAs involved in chemoresponse and immune response in cancer. 39 There is no doubt that integrated approaches identifying stable pharmagenomic and epigenomic patterns and their relation with expression profiles and genetic functions will be more and more valuable in our fight against cancer.

Cancer Stem Cells

Tumors consist of different populations of neoplastic cells and a variety of elements that form part of the TME, including stromal cells and molecules of the extracellular matrix. 40 Such intratumoral heterogeneity becomes even more complex during clonal variation of transformed cells, as well as influence the elements of the TME have on these cells throughout specific times and places. 41 To explain the origin of cancer cell heterogeneity, 2 models have been put forward. The first proposes that mutations occur at random during development of the tumor in individual neoplastic cells, and this promotes the production of various tumor populations, which acquire specific growth and survival traits that lead them to evolve according to intratumor mechanisms of natural selection. 42 The second model proposes that each tumor begins as a single cell that possess 2 functional properties: it can self-renew and it can produce several types of terminal cells. As these 2 properties are characteristics of somatic stem cells, 43 the cells have been called cancer stem cells (CSCs). 44 According to this model, tumors must have a hierarchical organization, where self-renewing stem cells produce highly proliferating progenitor cells, unable to self-renew but with a high proliferation potential. The latter, in turn, give rise to terminal cells. 45 Current evidence indicates that both models may coexist in tumor progression. In agreement with this idea, new subclones could be produced as a result of a lack of genetic stability and mutational changes, in addition to the heterogeneity derived from the initial CSC and its descendants. Thus, in each tumor, a set of neoplastic cells with different genetic and epigenetic traits may be found, which would provide different phenotypic properties. 46

The CSC concept was originally presented in a model of acute myeloid leukemia. 47 The presence of CSCs was later proved in chronic myeloid leukemia, breast cancer, tumors of the central nervous system, lung cancer, colon cancer, liver cancer, prostate cancer, pancreatic cancer, melanoma, and cancer of the head and neck, amongst others. In all of these cases, detection of CSCs was based on separation of several cell populations according to expression of specific surface markers, such as CD133, CD44, CD24, CD117, and CD15. 48 It is noteworthy that in some solid tumors, and even in some hematopoietic ones, a combination of specific markers that allow the isolation of CSCs has not been found. Interestingly, in such tumors, a high percentage of cells with the capacity to start secondary tumors has been observed; thus, the terms Tumor Initiating Cells (TIC) or Leukemia Initiating Cells (LIC) have been adopted. 46

A relevant aspect of the biology of CSCs is that, just like normal stem cells, they can self-renew. Such self-renewal guarantees the maintenance or expansion of the tumor stem cell population. Another trait CSCs share with normal stem cells is their quiescence, first described in chronic myeloid leukemia. 49 The persistence of quiescent CSCs in solid tumors has been recently described in colorectal cancer, where quiescent clones can become dominant after therapy with oxaliplatin. 50 In non-hierarchical tumors, such as melanoma, the existence of slow-cycling cells that are resistant to antimitogenic agents has also been proved. 51 Such experimental evidence supports the idea that quiescent CSCs or TICs are responsible for both tumor resistance to antineoplastic drugs and clinical relapse after initial therapeutic success.

In addition to quiescence, CSCs use other mechanisms to resist the action of chemotherapeutic drugs. One of these is their increased numbers: upon diagnosis, a high number of CSCs are observed in most analyzed tumors, making treatment unable to destroy all of them. On the other hand, CSCs have a high number of molecular pumps that expulse drugs, as well as high numbers of antiapoptotic molecules. In addition, they have very efficient mechanisms to repair DNA damage. In general, these cells show changes in a variety of signaling pathways involved in proliferation, survival, differentiation, and self-renewal. It is worth highlighting that in recent years, many of these pathways have become potential therapeutic targets in the elimination of CSCs. 52 Another aspect that is highly relevant in understanding the biological behavior of CSCs is that they require a specific site for their development within the tissue where they are found that can provide whatever is needed for their survival and growth. These sites, known as niches, are made of various cells, both tumor and non-tumor, as well as a variety of non-cellular elements (extracellular matrix [ECM], soluble cytokines, ion concentration gradients, etc.), capable of regulating the physiology of CSCs in order to promote their expansion, the invasion of adjacent tissues, and metastasis. 53

It is important to consider that although a large number of surface markers have been identified that allow us to enrich and prospectively follow tumor stem cell populations, to this day there is no combination of markers that allows us to find these populations in all tumors, and it is yet unclear if all tumors present them. In this regard, it is necessary to develop new purification strategies based on the gene expression profiles of these cells, so that tumor heterogeneity is taken into account, as it is evident that a tumor can include multiple clones of CSCs that, in spite of being functional, are genetically different, and that these clones can vary throughout space (occupying different microenvironments and niches) and time (during the progression of a range of tumor stages). Such strategies, in addition to new in vitro and in vivo assays, will allow the development of new and improved CSC elimination strategies. This will certainly have an impact on the development of more efficient therapeutic alternatives.

Invasion and Metastasis

Nearly 90% of the mortality associated with cancer is related to metastasis. 54 This consists of a cascade of events ( Figure 2 ) that begins with the local invasion of a tumor into surrounding tissues, followed by intravasation of tumor cells into the blood stream or lymphatic circulation. Extravasation of neoplastic cells in areas distant from the primary tumor then leads to the formation of one or more micrometastatic lesions which subsequently proliferate to form clinically detectable lesions. 4 The cells that are able to produce metastasis must acquire migratory characteristics, which occur by a process known as epithelial–mesenchymal transition (EMT), that is, the partial loss of epithelial characteristics and the acquirement of mesenchymal traits. 55

Invasion and metastasis cascade. Invasion and metastasis can occur early or late during tumor progression. In either case, invasion to adjacent tissues is driven by stem-like cells (cancer stem cells) that acquire the epithelial–mesenchymal transition (EMT) (1). Once they reach sites adjacent to blood vessels, tumor cells (individually or in clusters) enter the blood (2). Tumor cells in circulation can adhere to endothelium and extravasation takes place (3). Other mechanisms alternative to extravasation can exist, such as angiopelosis, in which clusters of tumor cells are internalized by the endothelium. Furthermore, at certain sites, tumor cells can obstruct microvasculature and initiate a metastatic lesion right there. Sometimes, a tumor cells that has just exit circulation goes into an MET in order to become quiescent (4). Inflammatory signals can activate quiescent metastatic cells that will proliferate and generate a clinically detectable lesion (5).

Although several of the factors involved in this process are currently known, many issues are still unsolved. For instance, it has not yet been possible to monitor in vivo the specific moment when it occurs 54 ; the microenvironmental factors of the primary tumor that promote such a transition are not known with precision; and the exact moment during tumor evolution in which one cell or a cluster of cells begin to migrate to distant areas, is also unknown. The wide range of possibilities offered by intra- and inter-tumoral heterogeneity 56 stands in the way of suggesting a generalized strategy that could resolve this complication.

It was previously believed that metastasis was only produced in late stages of tumor progression; however, recent studies indicate that EMT and metastasis can occur during the early course of the disease. In pancreatic cancer, for example, cells going through EMT are able to colonize and form metastatic lesions in the liver in the first stages of the disease. 52 , 57 Metastatic cell clusters circulating in peripheral blood (PB) are prone to generate a metastatic site, compared to individual tumor cells. 58 , 59 In this regard, novel strategies, such as the use of micro-RNAs, are being assessed in order to diminish induction of EMT. 60 It must be mentioned, however, that the metastatic process seems to be even more complex, with alternative pathways that do not involve EMT. 61 , 62

A crucial stage in the process of metastasis is the intravasation of tumor cells (alone or in clusters) towards the blood stream and/or lymphatic circulation. 63 These mechanisms are also under intensive research because blocking them could allow the control of spreading of the primary tumor. In PB or lymphatic circulation, tumor cells travel to distant parts for the potential formation of a metastatic lesion. During their journey, these cells must stand the pressure of blood flow and escape interaction with natural killer (NK) cells . 64 To avoid them, tumor cells often cover themselves with thrombocytes and also produce factors such as VEGF, angiopoietin-2, angiopoietin-4, and CCL2 that are involved in the induction of vascular permeability. 54 , 65 Neutrophils also contribute to lung metastasis in the bloodstream by secreting IL-1β and metalloproteases to facilitate extravasation of tumor cells. 64

The next step in the process of metastasis is extravasation, for which tumor cells, alone or in clusters, can use various mechanisms, including a recently described process known as angiopellosis that involves restructuring the endothelial barrier to internalize one or several cells into a tissue. 66 The study of leukocyte extravasation has contributed to a more detailed knowledge of this process, in such a way that some of the proposed strategies to avoid extravasation include the use of integrin inhibitors, molecules that are vital for rolling, adhesion, and extravasation of tumor cells. 67 , 68 Another strategy that has therapeutic potential is the use of antibodies that strengthen vascular integrity to obstruct transendothelial migration of tumor cells and aid in their destruction in PB. 69

Following extravasation, tumor cells can return to an epithelial phenotype, a process known as mesenchymal–epithelial transition and may remain inactive for several years. They do this by competing for specialized niches, like those in the bone marrow, brain, and intestinal mucosa, which provide signals through the Notch and Wnt pathways. 70 Through the action of the Wnt pathway, tumor cells enter a slow state of the cell cycle and induce the expression of molecules that inhibit the cytotoxic function of NK cells. 71 The extravasated tumor cell that is in a quiescent state must comply with 2 traits typical of stem cells: they must have the capacity to self-renew and to generate all of the cells that form the secondary tumor.

There are still several questions regarding the metastatic process. One of the persisting debates at present is if EMT is essential for metastasis or if it plays a more important role in chemoresistance. 61 , 62 It is equally important to know if there is a pattern in each tumor for the production of cells with the capacity to carry out EMT. In order to control metastasis, it is fundamental to know what triggers acquisition of the migratory phenotype and the intrinsic factors determining this transition. Furthermore, it is essential to know if mutations associated with the primary tumor or the variety of epigenetic changes are involved in this process. 55 It is clear that metastatic cells have affinity for certain tissues, depending on the nature of the primary tumor (seed and soil hypothesis). This may be caused by factors such as the location and the direction of the bloodstream or lymphatic fluid, but also by conditioning of premetastatic niches at a distance (due to the large number of soluble factors secreted by the tumor and the recruitment of cells of the immune system to those sites). 72 We have yet to identify and characterize all of the elements that participate in this process. Deciphering them will be of upmost importance from a therapeutic point of view.

Epidemiology of Cancer

Cancer is the second cause of death worldwide; today one of every 6 deaths is due to a type of cancer. According to the International Agency for Research on Cancer (IARC), in 2020 there were approximately 19.3 million new cases of cancer, and 10 million deaths by this disease, 6 while 23.8 million cases and 13.0 million deaths are projected to occur by 2030. 73 In this regard, it is clear the increasing role that environmental factors—including environmental pollutants and processed food—play as cancer inducers and promoters. 74 The types of cancer that produce the greatest numbers of cases and deaths worldwide are indicated in Table 1 . 6

Total Numbers of Cancer Cases and Deaths Worldwide in 2020 by Cancer Type (According to the Global Cancer Observatory, IARC).

Data presented on this table were obtained from Ref. 6.

As shown in Figure 3 , lung, breast, prostate, and colorectal cancer are the most common throughout the world, and they are mostly concentrated in countries of high to very high human development index (HDI). Although breast, prostate, and colorectal cancer have a high incidence, the number of deaths they cause is proportionally low, mostly reflecting the great progress made in their control. However, these data also reveal the types of cancer that require further effort in prevention, precise early detection avoiding overdiagnosis, and efficient treatment. This is the case of liver, lung, esophageal, and pancreatic cancer, where the difference between the number of cases and deaths is smaller ( Figure 3B ). Social and economic transition in several countries has had an impact on reducing the incidence of neoplasms associated with infection and simultaneously produced an increase in the types related to reproductive, dietary, and hormonal factors. 75

Incidence and mortality for some types of cancer in the world. (A) Estimated number of cases and deaths in 2020 for the most frequent cancer types worldwide. (B) Incidence and mortality rates, normalized according to age, for the most frequent cancer types in countries with very high/& high (VH&H; blue) and/low and middle (L&M; red) Human Development Index (HDI). Data include both genders and all ages. Data according to https://gco.iarc.fr/today , as of June 10, 2021.

In the past 3 decades, cancer mortality rates have fallen in high HDI countries, with the exception of pancreatic cancer, and lung cancer in women. Nevertheless, changes in the incidence of cancer do not show the same consistency, possibly due to variables such as the possibility of early detection, exposure to risk factors, or genetic predisposition. 76 , 77 Countries such as Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the United Kingdom have reported a reduction in incidence and mortality in cancer of the stomach, colon, lung, and ovary, as well as an increase in survival. 78 Changes in modifiable risk factors, such as the use of tobacco, have played an important role in prevention. In this respect, it has been estimated that decline in tobacco use can explain between 35% and 45% of the reduction in cancer mortality rates, 79 while the fall in incidence and mortality due to stomach cancer can be attributed partly to the control of Helicobacter pylori infection. 80 Another key factor in the fall of mortality rates in developed countries has been an increase in early detection as a result of screening programs, as in breast and prostate cancer, which have had their mortality rates decreased dramatically in spite of an increase in their incidence. 76

Another important improvement observed in recent decades is the increase in survival rates, particularly in high HDI countries. In the USA, for example, survival rates for patients with prostate cancer at 5 years after initial diagnosis was 28% during 1947–1951; 69% during 1975–1977, and 100% during 2003–2009. Something similar occurred with breast cancer, with a 5-year survival rate of 54% in 1947–1951, 75% in 1975–1977, and 90% in 2003–2009. 81 In the CONCORD 3 version, age-standardize 5-year survival for patients with breast cancer in the USA during 2010–2014 was 90%, and 97% for prostate cancer patients. 82 Importantly, even among high HDI countries, significant differences have been identified in survival rates, being stage of disease at diagnosis, time for access to effective treatment, and comorbidities, the main factors influencing survival in these nations. 78 Unfortunately, survival rates in low HDI countries are significantly lower due to several factors, including lack of information, deficient screening and early detection programs, limited access to treatment, and suboptimal cancer registration. 82 It should be noted that in countries with low to middle HDI, neoplasms with the greatest incidence are those affecting women (breast and cervical cancer), which reflects not only a problem with access to health services, but also a serious inequality issue that involves social, cultural, and even religious obstacles. 83

Up to 42% of incident cases and 47% of deaths by cancer in the USA are due to potentially modifiable risk factors such as use of tobacco, physical activity, diet, and infection. 84 It has been calculated that 2.4 million deaths by cancer, mostly of the lung, can be attributed to tobacco. 73 In 2020, the incidence rate of lung cancer in Western Africa was 2.2, whereas in Polynesia and Eastern Asia was 37.3 and 34.4, respectively. 6 In contrast, the global burden of cancer associated with infection was 15.4%, but in Sub-Saharan Africa it was 30%. 85 Likewise, the incidence of cervical cancer in Eastern Africa was 40.1, in contrast with the USA and Canada that have a rate of 6.2. This makes it clear that one of the challenges we face is the reduction of the risk factors that are potentially modifiable and associated with specific types of cancer.

Improvement of survival rates and its disparities worldwide are also important challenges. Five-year survival for breast cancer—diagnosed during 2010-2014— in the USA, for example, was 90%, whereas in countries like South Africa it was 40%. 82 Childhood leukemia in the USA and several European countries shows a 5-year survival of 90%, while in Latin-American countries it is 50–76%. 86 Interestingly, there are neoplasms, such as pancreatic cancer, for which there has been no significant increase in survival, which remains low (5–15%) both in developed and developing countries. 82

Although data reported on global incidence and mortality gives a general overview on the epidemiology of cancer, it is important to note that there are great differences in coverage of cancer registries worldwide. To date, only 1 out of every 3 countries reports high quality data on the incidence of cancer. 87 For the past 50 years, the IARC has supported population-based cancer registries; however, more than one-third of the countries belonging to the WHO, mainly countries of low and middle income (LMIC), have no data on more than half of the 18 indicators of sustainable development goals. 88 High quality cancer registries only cover 4% of the population in Africa, 8% in Asia, and 7% in Latin America, contrasting with 83% in the USA and Canada, and 33% in Europe. 89 In response to this situation, the Global Initiative for Cancer Registry Development was created in 2012 to generate improved infrastructure to permit greater coverage and better quality registries, especially in countries with low and middle HDI. 88 It is expected that initiatives of this sort in the coming years will allow more and better information to guide strategies for the control of cancer worldwide, especially in developing regions. This will enable survival to be measured over longer periods of time (10, 15, or 20 years), as an effective measure in the control of cancer. The WHO has established as a target for 2025 to reduce deaths by cancer and other non-transmissible diseases by 25% in the population between the ages of 30–69; such an effort requires not only effective prevention measures to reduce incidence, but also more efficient health systems to diminish mortality and increase survival. At the moment, it is an even greater challenge because of the effects of the COVID-19 pandemic which has negatively impacted cancer prevention and health services. 90

Oncologic Treatments

A general perspective.

At the beginning of the 20th century, cancer treatment, specifically treatment of solid tumors, was based fundamentally on surgical resection of tumors, which together with other methods for local control, such as cauterization, had been used since ancient times. 91 At that time, there was an ongoing burst of clinical observations along with interventions sustained on fundamental knowledge about physics, chemistry, and biology. In the final years of the 19 th century and the first half of the 20th, these technological developments gave rise to radiotherapy, hormone therapy, and chemotherapy. 92 - 94 Simultaneously, immunotherapy was also developed, although usually on a smaller scale, in light of the overwhelming progress of chemotherapy and radiotherapy. 95

Thus began the development and expansion of disciplines based on these approaches (surgery, radiotherapy, chemotherapy, hormone therapy, and immunotherapy), with their application evolving ever more rapidly up to their current uses. Today, there is a wide range of therapeutic tools for the care of cancer patients. These include elements that emerged empirically, arising from observations of their effects in various medical fields, as well as drugs that were designed to block processes and pathways that form part of the physiopathology of one or more neoplasms according to knowledge of specific molecular alterations. A classic example of the first sort of tool is mustard gas, originally used as a weapon in war, 96 but when applied for medical purposes, marked the beginning of the use of chemicals in the treatment of malignant neoplasms, that is, chemotherapy. 94 A clear example of the second case is imatinib, designed specifically to selectively inhibit a molecular alteration in chronic myeloid leukemia: the Bcr-Abl oncoprotein. 97

It is on this foundation that today the 5 areas mentioned previously coexist and complement one another. The general framework that motivates this amalgam and guides its development is precision medicine, founded on the interaction of basic and clinical science. In the forecasts for development in each of these fields, surgery is expected to continue to be the fundamental approach for primary tumors in the foreseeable future, as well as when neoplastic disease in the patient is limited, or can be limited by applying systemic or regional elements, before and/or after surgical resection, and it can be reasonably anticipated for the patient to have a significant period free from disease or even to be cured. With regards to technology, intensive exploration of robotic surgery is contemplated. 98

The technological possibilities for radiotherapy have progressed in such a way that it is now possible to radiate neoplastic tissue with an extraordinary level of precision, and therefore avoid damage to healthy tissue. 99 This allows administration of large doses of ionizing radiation in one or a few fractions, what is known as “radiosurgery.” The greatest challenges to the efficacy of this approach are related to radio-resistance in certain neoplasms. Most efforts regarding research in this field are concentrated on understanding the underlying biological mechanisms of the phenomenon and their potential control through radiosensitizers. 100

“Traditional” chemotherapy, based on the use of compounds obtained from plants and other natural products, acting in a non-specific manner on both neoplastic and healthy tissues with a high proliferation rate, continues to prevail. 101 The family of chemotherapeutic drugs currently includes alkylating agents, antimetabolites, anti-topoisomerase agents, and anti-microtubules. Within the pharmacologic perspective, the objective is to attain a high concentration or activity of such molecules in specific tissues while avoiding their accumulation in others, in order to achieve an increase in effectiveness and a reduction in toxicity. This has been possible with the use of viral vectors, for example, that are able to limit their replication in neoplastic tissues, and activate prodrugs of normally nonspecific agents, like cyclophosphamide, exclusively in those specific areas. 102 More broadly, chemotherapy also includes a subgroup of substances, known as molecular targeted therapy, that affect processes in a more direct and specific manner, which will be mentioned later.

There is no doubt that immunotherapy—to be explored next—is one of the therapeutic fields where development has been greatest in recent decades and one that has produced enormous expectation in cancer treatment. 103 Likewise, cell therapy, based on the use of immune cells or stem cells, has come to complement the oncologic therapeutic arsenal. 43 Each and every one of the therapeutic fields that have arisen in oncology to this day continue to prevail and evolve. Interestingly, the foreseeable future for the development of cancer treatment contemplates these approaches in a joint and complementary manner, within the general framework of precision medicine, 104 and sustained by knowledge of the biological mechanisms involved in the appearance and progression of neoplasms. 105 , 106

Immunotherapy

Stimulating the immune system to treat cancer patients has been a historical objective in the field of oncology. Since the early work of William Coley 107 to the achievements reached at the end of the 20 th century, scientific findings and technological developments paved the way to searching for new immunotherapeutic strategies. Recombinant DNA technology allowed the synthesis of cytokines, such as interferon-alpha (IFN-α) and interleukin 2 (IL-2), which were authorized by the US Food and Drug Administration (FDA) for the treatment of hairy cell leukemia in 1986, 108 as well as kidney cancer and metastatic melanoma in 1992 and 1998, respectively. 109

The first therapeutic vaccine against cancer, based on the use of autologous dendritic cells (DCs), was approved by the FDA against prostate cancer in 2010. However, progress in the field of immunotherapy against cancer was stalled in the first decade of the present century, mostly due to failure of several vaccines in clinical trials. In many cases, application of these vaccines was detained by the complexity and cost involved in their production. Nevertheless, with the coming of the concept of immune checkpoint control, and the demonstration of the relevance of molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), and programmed cell death molecule-1 (PD-1), immunotherapy against cancer recovered its global relevance. In 2011, the monoclonal antibody (mAb) ipilimumab, specific to the CTLA-4 molecule, was the first checkpoint inhibitor (CPI) approved for the treatment of advanced melanoma. 110 Later, inhibitory mAbs for PD-1, or for the PD-1 ligand (PD-L1), 111 as well as the production of T cells with chimeric receptors for antigen recognition (CAR-T), 112 which have been approved to treat various types of cancer, including melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, bladder cancer, renal cell carcinoma (RCC), and hepatocellular carcinoma, among others, have changed the paradigm of cancer treatment.

In spite of the current use of anti-CTLA-4 and anti-PD-L1 mAbs, only a subgroup of patients has responded favorably to these CPIs, and the number of patients achieving clinical benefit is still small. It has been estimated that more than 70% of patients with solid tumors do not respond to CPI immunotherapy because either they show primary resistance, or after responding favorably, develop resistance to treatment. 113 In this regard, it is important to mention that in recent years very important steps have been taken to identify the intrinsic and extrinsic mechanisms that mediate resistance to CPI immunotherapy. 114 Intrinsic mechanisms include changes in the antitumor immune response pathways, such as faulty processing and presentation of antigens by APCs, activation of T cells for tumor cell destruction, and changes in tumor cells that lead to an immunosuppressive TME. Extrinsic factors include the presence of immunosuppressive cells in the local TME, such as regulatory T cells, myeloid-derived suppressor cells (MDSC), mesenchymal stem/stromal cells (MSCs), and type 2 macrophages (M2), in addition to immunosuppressive cytokines.

On the other hand, classification of solid tumors as “hot,” “cold,” or “excluded,” depending on T cell infiltrates and the contact of such infiltrates with tumor cells, as well as those that present high tumor mutation burden (TMB), have redirected immunotherapy towards 3 main strategies 115 ( Table 2 ): (1) Making T-cell antitumor response more effective, using checkpoint inhibitors complementary to anti-CTLA-4 and anti-PD-L1, such as LAG3, Tim-3, and TIGT, as well as using CAR-T cells against tumor antigens. (2) Activating tumor-associated myeloid cells including monocytes, granulocytes, macrophages, and DC lineages, found at several frequencies within human solid tumors. (3) Regulating the biochemical pathways in TME that produce high concentrations of immunosuppressive molecules, such as kynurenine, a product of tryptophan metabolism, through the activity of indoleamine 2,3 dioxygenase; or adenosine, a product of ATP hydrolysis by the activity of the enzyme 5’nucleotidase (CD73). 116

Current Strategies to Stimulate the Immune Response for Antitumor Immunotherapy.

Abbreviations: TME, tumor microenvironment; IL, interleukin; TNF, Tumor Necrosis Factor; TNFR, TNF-receptor; CD137, receptor–co-stimulator of the TNFR family; OX40, member number 4 of the TNFR superfamily; CD27/CD70, member of the TNFR superfamily; CD40/CD40L, antigen-presenting cells (APC) co-stimulator and its ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; STING, IFN genes-stimulator; RIG-I, retinoic acid inducible gene-I; MDA5, melanoma differentiation-associated protein 5; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high mobility group B1 protein; TLR, Toll-like receptor; HVEM, Herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic T lymphocyte antigen 4; PD-L1, programmed death ligand-1; TIGIT, T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibition motives; CSF1/CSF1R, colony-stimulating factor-1 and its receptor; CCR2, Type 2 chemokine receptor; PI3Kγ, Phosphoinositide 3-Kinase γ; CXCL/CCL, chemokine ligands; LFA1, lymphocyte function-associated antigen 1; ICAM1, intercellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indolamine 2,3-dioxigenase; TGF, transforming growth factor; LAG-3, lymphocyte-activation gene 3 protein; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; CD73, 5´nucleotidase; ARs, adenosine receptors; Selectins, cell adhesion molecules; CAR-T, chimeric antigen receptor T cell; TCR-T, T-cell receptor engineered T cell.

Apart from the problems associated with its efficacy (only a small group of patients respond to it), immunotherapy faces several challenges related to its safety. In other words, immunotherapy can induce adverse events in patients, such as autoimmunity, where healthy tissues are attacked, or cytokine release syndrome and vascular leak syndrome, as observed with the use of IL-2, both of which lead to serious hypotension, fever, renal failure, and other adverse events that are potentially lethal. The main challenges to be faced by immunotherapy in the future will require the combined efforts of basic and clinical scientists, with the objective of accelerating the understanding of the complex interactions between cancer and the immune system, and improve treatment options for patients. Better comprehension of immune phenotypes in tumors, beyond the state of PD-L1 and TME, will be relevant to increase immunotherapy efficacy. In this context, the identification of precise tumor antigenicity biomarkers by means of new technologies, such as complete genome sequencing, single cell sequencing, and epigenetic analysis to identify sites or subclones typical in drug resistance, as well as activation, traffic and infiltration of effector cells of the immune response, and regulation of TME mechanisms, may help define patient populations that are good candidates for specific therapies and therapeutic combinations. 117 , 118 Likewise, the use of agents that can induce specific activation and modulation of the response of T cells in tumor tissue, will help improve efficacy and safety profiles that can lead to better clinical results.

Molecular Targeted Therapy

For over 30 years, and based on the progress in our knowledge of tumor biology and its mechanisms, there has been a search for therapeutic alternatives that would allow spread and growth of tumors to be slowed down by blocking specific molecules. This approach is known as molecular targeted therapy. 119 Among the elements generally used as molecular targets there are transcription factors, cytokines, membrane receptors, molecules involved in a variety of signaling pathways, apoptosis modulators, promoters of angiogenesis, and cell cycle regulators. 120

Imatinib, a tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, became the first targeted therapy in the final years of the 1990s. 97 From then on, new drugs have been developed by design, and today more than 60 targeted therapies have been approved by the FDA for the treatment of a variety of cancers ( Table 3 ). 121 This has had a significant impact on progression-free survival and global survival in neoplasms such as non-small cell lung cancer, breast cancer, renal cancer, and melanoma.

FDA Approved Molecular Targeted Therapies for the Treatment of Solid Tumors.

Abbreviations: mAb, monoclonal antibody; ALK, anaplastic lymphoma kinase; CDK, cyclin-dependent kinase; CTLA-4, cytotoxic lymphocyte antigen-4; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GIST, gastrointestinal stroma tumor; mTOR, target of rapamycine in mammal cells; NSCLC, non-small cell lung carcinoma; PARP, poli (ADP-ribose) polimerase; PD-1, programmed death protein-1; PDGFR, platelet-derived growth factor receptor; PD-L1, programmed death ligand-1; ER, estrogen receptor; PR, progesterone receptor; TKR, tyrosine kinase receptors; SERM, selective estrogen receptor modulator; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. Modified from Ref. [ 127 ].

Most drugs classified as targeted therapies form part of 2 large groups: small molecules and mAbs. The former are defined as compounds of low molecular weight (<900 Daltons) that act upon entering the cell. 120 Targets of these compounds are cell cycle regulatory proteins, proapoptotic proteins, or DNA repair proteins. These drugs are indicated based on histological diagnosis, as well as molecular tests. In this group there are multi-kinase inhibitors (RTKs) and tyrosine kinase inhibitors (TKIs), like sunitinib, sorafenib, and imatinib; cyclin-dependent kinase (CDK) inhibitors, such as palbociclib, ribociclib and abemaciclib; poli (ADP-ribose) polimerase inhibitors (PARPs), like olaparib and talazoparib; and selective small-molecule inhibitors, like ALK and ROS1. 122

As for mAbs, they are protein molecules that act on membrane receptors or extracellular proteins by interrupting the interaction between ligands and receptors, in such a way that they reduce cell replication and induce cytostasis. Among the most widely used mAbs in oncology we have: trastuzumab, a drug directed against the receptor for human epidermal growth factor-2 (HER2), which is overexpressed in a subgroup of patients with breast and gastric cancer; and bevacizumab, that blocks vascular endothelial growth factor and is used in patients with colorectal cancer, cervical cancer, and ovarian cancer. Other mAbs approved by the FDA include pembolizumab, atezolizumab, nivolumab, avelumab, ipilimumab, durvalumab, and cemiplimab. These drugs require expression of response biomarkers, such as PD-1 and PD-L1, and must also have several resistance biomarkers, such as the expression of EGFR, the loss of PTEN, and alterations in beta-catenin. 123

Because cancer is such a diverse disease, it is fundamental to have precise diagnostic methods that allow us to identify the most adequate therapy. Currently, basic immunohistochemistry is complemented with neoplastic molecular profiles to determine a more accurate diagnosis, and it is probable that in the near future cancer treatments will be based exclusively on molecular profiles. In this regard, it is worth mentioning that the use of targeted therapy depends on the existence of specific biomarkers that indicate if the patient will be susceptible to the effects of the drug or not. Thus, the importance of underlining that not all patients are susceptible to receive targeted therapy. In certain neoplasms, therapeutic targets are expressed in less than 5% of the diagnosed population, hindering a more extended use of certain drugs.

The identification of biomarkers and the use of new generation sequencing on tumor cells has shown predictive and prognostic relevance. Likewise, mutation analysis has allowed monitoring of tumor clone evolution, providing information on changes in canonic gene sequences, such as TP53, GATA3, PIK3CA, AKT1, and ERBB2; infrequent somatic mutations developed after primary treatments, like SWI-SNF and JAK2-STAT3; or acquired drug resistance mutations such as ESR1. 124 The study of mutations is vital; in fact, many of them already have specific therapeutic indications, which have helped select adequate treatments. 125

There is no doubt that molecular targeted therapy is one of the main pillars of precision medicine. However, it faces significant problems that often hinder obtaining better results. Among these, there is intratumor heterogeneity and differences between the primary tumor and metastatic sites, as well as intrinsic and acquired resistance to these therapies, the mechanisms of which include the presence of heterogeneous subclones, DNA hypermethylation, histone acetylation, and interruption of mRNA degradation and translation processes. 126 Nonetheless, beyond the obstacles facing molecular targeted therapy from a biological and methodological point of view, in the real world, access to genomic testing and specific drugs continues to be an enormous limitation, in such a way that strategies must be designed in the future for precision medicine to be possible on a global scale.

Cell Therapy

Another improvement in cancer treatment is the use of cell therapy, that is, the use of specific cells as therapeutic agents. This clinical procedure has 2 modalities: the first consists of replacing and regenerating functional cells in a specific tissue by means of stem/progenitor cells of a certain kind, 43 while the second uses immune cells as effectors to eliminate malignant cells. 127

Regarding the first type, we must emphasize the development of cell therapy based on hematopoietic stem and progenitor cells. 128 For over 50 years, hematopoietic cell transplants have been used to treat a variety of hematologic neoplasms (different forms of leukemia and lymphoma). Today, it is one of the most successful examples of cell therapy, including innovative modalities, such as haploidentical transplants, 129 as well as application of stem cells expanded ex vivo . 130 There are also therapies that have used immature cells that form part of the TME, such as MSCs. The replication potential and cytokine secretion capacity of these cells make them an excellent option for this type of treatment. 131 Neural stem cells can also be manipulated to produce and secrete apoptotic factors, and when these cells are incorporated into primary neural tumors, they cause a certain degree of regression. They can even be transfected with genes that encode for oncolytic enzymes capable of inducing regression of glioblastomas. 132

With respect to cell therapy using immune cells, several research groups have manipulated cells associated with tumors to make them effector cells and thus improve the efficacy and specificity of the antitumor treatment. PB leckocytes cultured in the presence of IL-2 to obtain activated lymphocytes, in combination with IL-2 administration, have been used in antitumor clinical protocols. Similarly, infiltrating lymphocytes from tumors with antitumor activity have been used and can be expanded ex vivo with IL-2. These lymphocyte populations have been used in immunomodulatory therapies in melanoma, and pancreatic and kidney tumors, producing a favorable response in treated patients. 133 NK cells and macrophages have also been used in immunotherapy, although with limited results. 134 , 135

One of the cell therapies with better projection today is the use of CAR-T cells. This strategy combines 2 forms of advanced therapy: cell therapy and gene therapy. It involves the extraction of T cells from the cancer patient, which are genetically modified in vitro to express cell surface receptors that will recognize antigens on the surface of tumor cells. The modified T cells are then reintroduced in the patient to aid in an exacerbated immune response that leads to eradication of the tumor cells ( Figure 4 ). Therapy with CAR-T cells has been used successfully in the treatment of some types of leukemia, lymphoma, and myeloma, producing complete responses in patients. 136

CAR-T cell therapy. (A) T lymphocytes obtained from cancer patients are genetically manipulated to produce CAR-T cells that recognize tumor cells in a very specific manner. (B) Interaction between CAR molecule and tumor antigen. CAR molecule is a receptor that results from the fusion between single-chain variable fragments (scFv) from a monoclonal antibody and one or more intracellular signaling domains from the T-cell receptor. CD3ζ, CD28 and 4-1BB correspond to signaling domains on the CAR molecule.

Undoubtedly, CAR-T cell therapy has been truly efficient in the treatment of various types of neoplasms. However, this therapeutic strategy can also have serious side effects, such as release of cytokines into the bloodstream, which can cause different symptoms, from high fever to multiorgan failure, and even neurotoxicity, leading to cerebral edema in many cases. 137 Adequate control of these side effects is an important medical challenge. Several research groups are trying to improve CAR-T cell therapy through various approaches, including production of CAR-T cells directed against a wider variety of tumor cell-specific antigens that are able to attack different types of tumors, and the identification of more efficient types of T lymphocytes. Furthermore, producing CAR-T cells from a single donor that may be used in the treatment of several patients would reduce the cost of this sort of personalized cell therapy. 136

Achieving wider use of cell therapy in oncologic diseases is an important challenge that requires solving various issues. 138 One is intratumor cell heterogeneity, including malignant subclones and the various components of the TME, which results in a wide profile of membrane protein expression that complicates finding an ideal tumor antigen that allows specific identification (and elimination) of malignant cells. Likewise, structural organization of the TME challenges the use of cell therapy, as administration of cell vehicles capable of recognizing malignant cells might not be able to infiltrate the tumor. This results from low expression of chemokines in tumors and the presence of a dense fibrotic matrix that compacts the inner tumor mass and avoids antitumor cells from infiltrating and finding malignant target cells.

Further Challenges in the 21st Century

Beyond the challenges regarding oncologic biomedical research, the 21 st century is facing important issues that must be solved as soon as possible if we truly wish to gain significant ground in our fight against cancer. Three of the most important have to do with prevention, early diagnosis, and access to oncologic medication and treatment.

Prevention and Early Diagnosis

Prevention is the most cost-effective strategy in the long term, both in low and high HDI nations. Data from countries like the USA indicate that between 40-50% of all types of cancer are preventable through potentially modifiable factors (primary prevention), such as use of tobacco and alcohol, diet, physical activity, exposure to ionizing radiation, as well as prevention of infection through access to vaccination, and by reducing exposure to environmental pollutants, such as pesticides, diesel exhaust particles, solvents, etc. 74 , 84 Screening, on the other hand, has shown great effectiveness as secondary prevention. Once population-based screening programs are implemented, there is generally an initial increase in incidence; however, in the long term, a significant reduction occurs not only in incidence rates, but also in mortality rates due to detection of early lesions and timely and adequate treatment.

A good example is colon cancer. There are several options for colon cancer screening, such as detection of fecal occult blood, fecal immunohistochemistry, flexible sigmoidoscopy, and colonoscopy, 139 , 140 which identify precursor lesions (polyp adenomas) and allow their removal. Such screening has allowed us to observe 3 patterns of incidence and mortality for colon cancer between the years 2000 and 2010: on one hand, an increase in incidence and mortality in countries with low to middle HDI, mainly countries in Asia, South America, and Eastern Europe; on the other hand, an increase in incidence and a fall in mortality in countries with very high HDI, such as Canada, the United Kingdom, Denmark, and Singapore; and finally a fall in incidence and mortality in countries like the USA, Japan, and France. The situation in South America and Asia seems to reflect limitations in medical infrastructure and a lack of access to early detection, 141 while the patterns observed in developed countries reveal the success, even if it may be partial, of that which can be achieved by well-structured prevention programs.

Another example of success, but also of strong contrast, is cervical cancer. The discovery of the human papilloma virus (HPV) as the causal agent of cervical cancer brought about the development of vaccines and tests to detect oncogenic genotypes, which modified screening recommendations and guidelines, and allowed several developed countries to include the HPV vaccine in their national vaccination programs. Nevertheless, the outlook is quite different in other areas of the world. Eighty percent of the deaths by cervical cancer reported in 2018 occurred in low-income nations. This reveals the urgency of guaranteeing access to primary and secondary prevention (vaccination and screening, respectively) in these countries, or else it will continue to be a serious public health problem in spite of its preventability.

Screening programs for other neoplasms, such as breast, prostate, lung, and thyroid cancer have shown outlooks that differ from those just described, because, among other reasons, these neoplasms are highly diverse both biologically and clinically. Another relevant issue is the overdiagnosis of these neoplasms, that is, the diagnosis of disease that would not cause symptoms or death in the patient. 142 It has been calculated that 25% of breast cancer (determined by mammogram), 50–60% of prostate cancer (determined by PSA), and 13–25% of lung cancer (determined by CT) are overdiagnosed. 142 Thus, it is necessary to improve the sensitivity and specificity of screening tests. In this respect, knowledge provided by the biology of cancer and “omic” sciences offers a great opportunity to improve screening and prevention strategies. All of the above shows that prevention and early diagnosis are the foundations in the fight against cancer, and it is essential to continue to implement broader screening programs and better detection methods.

Global Equity in Oncologic Treatment

Progress in cancer treatment has considerably increased the number of cancer survivors. Nevertheless, this tendency is evident only in countries with a very solid economy. Indeed, during the past 30 years, cancer mortality rates have increased 30% worldwide. 143 Global studies indicate that close to 70% of cancer deaths in the world occur in nations of low to middle income. But even in high-income countries, there are sectors of society that are more vulnerable and have less access to cancer treatments. 144 Cancer continues to be a disease of great social inequality.

In Europe, the differences in access to cancer treatment are highly marked. These treatments are more accessible in Western Europe than in its Eastern counterpart. 145 Furthermore, highly noticeable differences between high-income countries have been detected in the cost of cancer drugs. 146 It is interesting to note that in many of these cases, treatment is too costly and the clinical benefit only marginal. Thus, the importance of these problems being approached by competent national, regional, and global authorities, because if these new drugs and therapeutic programs are not accessible to the majority, progress in biomedical, clinical and epidemiological research will have a limited impact in our fight against cancer. We must not forget that health is a universal right, from which low HDI countries must not be excluded, nor vulnerable populations in nations with high HDI. The participation of a well-informed society will also be fundamental to achieve a global impact, as today we must fight not only against the disease, but also against movements and ideas (such as the anti-vaccine movement and the so-called miracle therapies) that can block the medical battle against cancer.

Final Comments

From the second half of the 20th century to the present day, progress in our knowledge about the origin and development of cancer has been extraordinary. We now understand cancer in detail in genomic, molecular, cellular, and physiological terms, and this knowledge has had a significant impact in the clinic. There is no doubt that a patient who is diagnosed today with a type of cancer has a better prospect than a patient diagnosed 20 or 50 years ago. However, we are still far from winning the war against cancer. The challenges are still numerous. For this reason, oncologic biomedical research must be a worldwide priority. Likewise, one of the fundamental challenges for the coming decades must be to reduce unequal access to health services in areas of low- to middle income, and in populations that are especially vulnerable, as well as continue improving prevention programs, including public health programs to reduce exposure to environmental chemicals and improve diet and physical activity in the general population. 74 , 84 Fostering research and incorporation of new technological resources, particularly in less privileged nations, will play a key role in our global fight against cancer.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Hector Mayani https://orcid.org/0000-0002-2483-3782

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Molecular Biosciences Theses and Dissertations

Theses/dissertations from 2023 2023.

Exploring strain variation and bacteriophage predation in the gut microbiome of Ciona robusta , Celine Grace F. Atkinson

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression , Janine M. DeBlasi

Thermodynamic frustration of TAD2 and PRR contribute to autoinhibition of p53 , Emily Gregory

Utilization of Detonation Nanodiamonds: Nanocarrier for Gene Therapy in Non-Small Cell Lung Cancer , Allan E. Gutierrez

Role of HLA-DRB1 Fucosylation in Anti-Melanoma Immunity , Daniel K. Lester

Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML , Christopher T. Letson

Regulated Intramembrane Proteolysis by M82 Peptidases: The Role of PrsS in the Staphylococcus aureus Stress Response , Baylie M. Schott

Histone Deacetylase 8 is a Novel Therapeutic Target for Mantle Cell Lymphoma and Preserves Natural Killer Cell Cytotoxic Function , January M. Watters

Theses/Dissertations from 2022 2022

Regulation of the Heat Shock Response via Lysine Acetyltransferase CBP-1 and in Neurodegenerative Disease in Caenorhabditis elegans , Lindsey N. Barrett

Determining the Role of Dendritic Cells During Response to Treatment with Paclitaxel/Anti-TIM-3 , Alycia Gardner

Cell-free DNA Methylation Signatures in Cancer Detection and Classification , Jinyong Huang

The Role Of Eicosanoid Metabolism in Mammalian Wound Healing and Inflammation , Kenneth D. Maus

A Holistic Investigation of Acidosis in Breast Cancer , Bryce Ordway

Characterizing the Impact of Postharvest Temperature Stress on Polyphenol Profiles of Red and White-Fruited Strawberry Cultivars , Alyssa N. Smith

Theses/Dissertations from 2021 2021

Multifaceted Approach to Understanding Acinetobacter baumannii Biofilm Formation and Drug Resistance , Jessie L. Allen

Cellular And Molecular Alterations Associated with Ovarian and Renal Cancer Pathophysiology , Ravneet Kaur Chhabra

Ecology and diversity of boletes of the southeastern United States , Arian Farid

CircREV1 Expression in Triple-Negative Breast Cancer , Meagan P. Horton

Microbial Dark Matter: Culturing the Uncultured in Search of Novel Chemotaxonomy , Sarah J. Kennedy

The Multifaceted Role of CCAR-1 in the Alternative Splicing and Germline Regulation in Caenorhabditis elegans , Doreen Ikhuva Lugano

Unraveling the Role of Novel G5 Peptidase Family Proteins in Virulence and Cell Envelope Biogenesis of Staphylococcus aureus , Stephanie M. Marroquin

Cytoplasmic Polyadenylation Element Binding Protein 2 Alternative Splicing Regulates HIF1α During Chronic Hypoxia , Emily M. Mayo

Transcriptomic and Functional Investigation of Bacterial Biofilm Formation , Brooke R. Nemec

A Functional Characterization of the Omega (ω) subunit of RNA Polymerase in Staphylococcus aureus , Shrushti B. Patil

The Role Of Cpeb2 Alternative Splicing In TNBC Metastasis , Shaun C. Stevens

Screening Next-generation Fluorine-19 Probe and Preparation of Yeast-derived G Proteins for GPCR Conformation and Dynamics Study , Wenjie Zhao

Theses/Dissertations from 2020 2020

Understanding the Role of Cereblon in Hematopoiesis Through Structural and Functional Analyses , Afua Adutwumwa Akuffo

To Mid-cell and Beyond: Characterizing the Roles of GpsB and YpsA in Cell Division Regulation in Gram-positive Bacteria , Robert S. Brzozowski

Spatiotemporal Changes of Microbial Community Assemblages and Functions in the Subsurface , Madison C. Davis

New Mechanisms That Regulate DNA Double-Strand Break-Induced Gene Silencing and Genome Integrity , Dante Francis DeAscanis

Regulation of the Heat Shock Response and HSF-1 Nuclear Stress Bodies in C. elegans , Andrew Deonarine

New Mechanisms that Control FACT Histone Chaperone and Transcription-mediated Genome Stability , Angelo Vincenzo de Vivo Diaz

Targeting the ESKAPE Pathogens by Botanical and Microbial Approaches , Emily Dilandro

Succession in native groundwater microbial communities in response to effluent wastewater , Chelsea M. Dinon

Role of ceramide-1 phosphate in regulation of sphingolipid and eicosanoid metabolism in lung epithelial cells , Brittany A. Dudley

Allosteric Control of Proteins: New Methods and Mechanisms , Nalvi Duro

Microbial Community Structures in Three Bahamian Blue Holes , Meghan J. Gordon

A Novel Intramolecular Interaction in P53 , Fan He

The Impact of Myeloid-Mediated Co-Stimulation and Immunosuppression on the Anti-Tumor Efficacy of Adoptive T cell Therapy , Pasquale Patrick Innamarato

Investigating Mechanisms of Immune Suppression Secondary to an Inflammatory Microenvironment , Wendy Michelle Kandell

Posttranslational Modification and Protein Disorder Regulate Protein-Protein Interactions and DNA Binding Specificity of p53 , Robin Levy

Mechanistic and Translational Studies on Skeletal Malignancies , Jeremy McGuire

Novel Long Non-Coding RNA CDLINC Promotes NSCLC Progression , Christina J. Moss

Genome Maintenance Roles of Polycomb Transcriptional Repressors BMI1 and RNF2 , Anthony Richard Sanchez IV

The Ecology and Conservation of an Urban Karst Subterranean Estuary , Robert J. Scharping

Biological and Proteomic Characterization of Cornus officinalis on Human 1.1B4 Pancreatic β Cells: Exploring Use for T1D Interventional Application , Arielle E. Tawfik

Evaluation of Aging and Genetic Mutation Variants on Tauopathy , Amber M. Tetlow

Theses/Dissertations from 2019 2019

Investigating the Proteinaceous Regulome of the Acinetobacter baumannii , Leila G. Casella

Functional Characterization of the Ovarian Tumor Domain Deubiquitinating Enzyme 6B , Jasmin M. D'Andrea

Integrated Molecular Characterization of Lung Adenocarcinoma with Implications for Immunotherapy , Nicholas T. Gimbrone

The Role of Secreted Proteases in Regulating Disease Progression in Staphylococcus aureus , Brittney D. Gimza

Advanced Proteomic and Epigenetic Characterization of Ethanol-Induced Microglial Activation , Jennifer Guergues Guergues

Understanding immunometabolic and suppressive factors that impact cancer development , Rebecca Swearingen Hesterberg

Biochemical and Proteomic Approaches to Determine the Impact Level of Each Step of the Supply Chain on Tomato Fruit Quality , Robert T. Madden

Enhancing Immunotherapeutic Interventions for Treatment of Chronic Lymphocytic Leukemia , Kamira K. Maharaj

Characterization of the Autophagic-Iron Axis in the Pathophysiology of Endometriosis and Epithelial Ovarian Cancers , Stephanie Rockfield

Understanding the Influence of the Cancer Microenvironment on Metabolism and Metastasis , Shonagh Russell

Modeling of Interaction of Ions with Ether- and Ester-linked Phospholipids , Matthew W. Saunders

Novel Insights into the Multifaceted Roles of BLM in the Maintenance of Genome Stability , Vivek M. Shastri

Conserved glycine residues control transient helicity and disorder in the cold regulated protein, Cor15a , Oluwakemi Sowemimo

A Novel Cytokine Response Modulatory Function of MEK Inhibitors Mediates Therapeutic Efficacy , Mengyu Xie

Novel Strategies on Characterizing Biologically Specific Protein-protein Interaction Networks , Bi Zhao

Theses/Dissertations from 2018 2018

Characterization of the Transcriptional Elongation Factor ELL3 in B cells and Its Role in B-cell Lymphoma Proliferation and Survival , Lou-Ella M.m. Alexander

Identification of Regulatory miRNAs Associated with Ethanol-Induced Microglial Activation Using Integrated Proteomic and Transcriptomic Approaches , Brandi Jo Cook

Molecular Phylogenetics of Floridian Boletes , Arian Farid

MYC Distant Enhancers Underlie Ovarian Cancer Susceptibility at the 8q24.21 Locus , Anxhela Gjyshi Gustafson

Quantitative Proteomics to Support Translational Cancer Research , Melissa Hoffman

A Systems Chemical Biology Approach for Dissecting Differential Molecular Mechanisms of Action of Clinical Kinase Inhibitors in Lung Cancer , Natalia Junqueira Sumi

Investigating the Roles of Fucosylation and Calcium Signaling in Melanoma Invasion , Tyler S. Keeley

Synthesis, Oxidation, and Distribution of Polyphenols in Strawberry Fruit During Cold Storage , Katrina E. Kelly

Investigation of Alcohol-Induced Changes in Hepatic Histone Modifications Using Mass Spectrometry Based Proteomics , Crystina Leah Kriss

Off-Target Based Drug Repurposing Using Systems Pharmacology , Brent M. Kuenzi

Investigation of Anemarrhena asphodeloides and its Constituent Timosaponin-AIII as Novel, Naturally Derived Adjunctive Therapeutics for the Treatment of Advanced Pancreatic Cancer , Catherine B. MarElia

The Role of Phosphohistidine Phosphatase 1 in Ethanol-induced Liver Injury , Daniel Richard Martin

Theses/Dissertations from 2017 2017

Changing the Pathobiological Paradigm in Myelodysplastic Syndromes: The NLRP3 Inflammasome Drives the MDS Phenotype , Ashley Basiorka

Modeling of Dynamic Allostery in Proteins Enabled by Machine Learning , Mohsen Botlani-Esfahani

Uncovering Transcriptional Activators and Targets of HSF-1 in Caenorhabditis elegans , Jessica Brunquell

The Role of Sgs1 and Exo1 in the Maintenance of Genome Stability. , Lillian Campos-Doerfler

Mechanisms of IKBKE Activation in Cancer , Sridevi Challa

Discovering Antibacterial and Anti-Resistance Agents Targeting Multi-Drug Resistant ESKAPE Pathogens , Renee Fleeman

Functional Roles of Matrix Metalloproteinases in Bone Metastatic Prostate Cancer , Jeremy S. Frieling

Disorder Levels of c-Myb Transactivation Domain Regulate its Binding Affinity to the KIX Domain of CREB Binding Protein , Anusha Poosapati

Role of Heat Shock Transcription Factor 1 in Ovarian Cancer Epithelial-Mesenchymal Transition and Drug Sensitivity , Chase David Powell

Cell Division Regulation in Staphylococcus aureus , Catherine M. Spanoudis

A Novel Approach to the Discovery of Natural Products From Actinobacteria , Rahmy Tawfik

Non-classical regulators in Staphylococcus aureus , Andy Weiss

Theses/Dissertations from 2016 2016

In Vitro and In Vivo Antioxidant Capacity of Synthetic and Natural Polyphenolic Compounds Identified from Strawberry and Fruit Juices , Marvin Abountiolas

Quantitative Proteomic Investigation of Disease Models of Type 2 Diabetes , Mark Gabriel Athanason

CMG Helicase Assembly and Activation: Regulation by c-Myc through Chromatin Decondensation and Novel Therapeutic Avenues for Cancer Treatment , Victoria Bryant

Computational Modeling of Allosteric Stimulation of Nipah Virus Host Binding Protein , Priyanka Dutta

Cell Cycle Arrest by TGFß1 is Dependent on the Inhibition of CMG Helicase Assembly and Activation , Brook Samuel Nepon-Sixt

Gene Expression Profiling and the Role of HSF1 in Ovarian Cancer in 3D Spheroid Models , Trillitye Paullin

VDR-RIPK1 Interaction and its Implications in Cell Death and Cancer Intervention , Waise Quarni

Regulation of nAChRs and Stemness by Nicotine and E-cigarettes in NSCLC , Courtney Schaal

Targeting Histone Deacetylases in Melanoma and T-cells to Improve Cancer Immunotherapy , Andressa Sodre De Castro Laino

Nonreplicative DNA Helicases Involved in Maintaining Genome Stability , Salahuddin Syed

Theses/Dissertations from 2015 2015

Functional Analysis of the Ovarian Cancer Susceptibility Locus at 9p22.2 Reveals a Transcription Regulatory Network Mediated by BNC2 in Ovarian Cells , Melissa Buckley

Exploring the Pathogenic and Drug Resistance Mechanisms of Staphylococcus aureus , Whittney Burda

Regulation and Targeting of the FANCD2 Activation in DNA Repair , Valentina Celeste Caceres

Mass Spectrometry-Based Investigation of APP-Dependent Mechanisms in Neurodegeneration , Dale Chaput

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Title: automated text mining of experimental methodologies from biomedical literature.

Abstract: Biomedical literature is a rapidly expanding field of science and technology. Classification of biomedical texts is an essential part of biomedicine research, especially in the field of biology. This work proposes the fine-tuned DistilBERT, a methodology-specific, pre-trained generative classification language model for mining biomedicine texts. The model has proven its effectiveness in linguistic understanding capabilities and has reduced the size of BERT models by 40\% but by 60\% faster. The main objective of this project is to improve the model and assess the performance of the model compared to the non-fine-tuned model. We used DistilBert as a support model and pre-trained on a corpus of 32,000 abstracts and complete text articles; our results were impressive and surpassed those of traditional literature classification methods by using RNN or LSTM. Our aim is to integrate this highly specialised and specific model into different research industries.

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