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Phenotypic variation within the skeleton has biological, behavioral, and biomedical functional implications for individuals and species. Thus, it is critical to understand how genomic, environmental, and mediating regulatory factors combine and interact to drive skeletal trait development and evolution. Recent research efforts to clarify these mechanisms have been made possible by expanded collections of genomic and phenotypic data from in vivo skeletal tissues, as well as the development of relevant in vitro skeletal cell culture systems. This review outlines this current work and recommends that continued exploration of this complexity should include an increased focus on how interactions between genomic and physiologically relevant contexts contribute to skeletal trait variation at population and evolutionary scales., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Osteogenic differentiation is essential for bone development and metabolism, but the underlying gene regulatory networks have not been well investigated. We differentiated mesenchymal stem cells, derived from 20 human induced pluripotent stem cell lines, into preosteoblasts and osteoblasts, and performed systematic RNA-seq analyses of 60 samples for differential gene expression. We noted a highly significant correlation in expression patterns and genomic proximity among transcription factor (TF) and long noncoding RNA (lncRNA) genes. We identified TF-TF regulatory networks, regulatory roles of lncRNAs on their neighboring coding genes for TFs and splicing factors, and differential splicing of TF, lncRNA, and splicing factor genes. TF-TF regulatory and gene co-expression network analyses suggested an inhibitory role of TF KLF16 in osteogenic differentiation. We demonstrate that in vitro overexpression of human KLF16 inhibits osteogenic differentiation and mineralization, and in vivo Klf16 +/- mice exhibit increased bone mineral density, trabecular number, and cortical bone area. Thus, our model system highlights the regulatory complexity of osteogenic differentiation and identifies novel osteogenic genes., Competing Interests: Competing interests The authors declare no competing interests

Nonhuman primates provide unique evolutionary and comparative insight into the human phenotype. Genome assemblies are now available for nearly half of the species in the primate order, expanding our understanding of genetic variation within and between species and making important contributions to evolutionary biology, evolutionary anthropology, and human genetics., Competing Interests: Declaration of interests The authors have no interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Clonal hematopoiesis (CH) represents clonal expansion of mutated hematopoietic stem cells detectable in the peripheral blood or bone marrow through next generation sequencing. The current prevailing model posits that CH mutations detected in the peripheral blood mirror bone marrow mutations with clones widely disseminated across hematopoietic compartments. We sought to test the hypothesis that all clones are disseminated throughout hematopoietic tissues by comparing CH in hip vs peripheral blood specimens collected at the time of hip replacement surgery. Here, we show that patients with osteoarthritis have a high prevalence of CH, which involve genes encoding epigenetic modifiers and DNA damage repair pathway proteins. Importantly, we illustrate that CH, including clones with variant allele frequencies >10%, can be confined to specific bone marrow spaces and may be eliminated through surgical excision. Future work will define whether clones with somatic mutations in particular genes or clonal fractions of certain sizes are either more likely to be localized or are slower to disseminate into the peripheral blood and other bony sites., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Changes in potential regulatory elements are thought to be key drivers of phenotypic divergence. However, identifying changes to regulatory elements that underlie human-specific traits has proven very challenging. Here, we use 63 reconstructed and experimentally measured DNA methylation maps of ancient and present-day humans, as well as of six chimpanzees, to detect differentially methylated regions that likely emerged in modern humans after the split from Neanderthals and Denisovans. We show that genes associated with face and vocal tract anatomy went through particularly extensive methylation changes. Specifically, we identify widespread hypermethylation in a network of face- and voice-associated genes (SOX9, ACAN, COL2A1, NFIX and XYLT1). We propose that these repression patterns appeared after the split from Neanderthals and Denisovans, and that they might have played a key role in shaping the modern human face and vocal tract.

The evolution of complex skeletal traits in primates was likely influenced by both genetic and environmental factors. Because skeletal tissues are notoriously challenging to study using functional genomic approaches, they remain poorly characterized even in humans, let alone across multiple species. The challenges involved in obtaining functional genomic data from the skeleton, combined with the difficulty of obtaining such tissues from nonhuman apes, motivated us to consider an alternative in vitro system with which to comparatively study gene regulation in skeletal cell types. Specifically, we differentiated six human (Homo sapiens) and six chimpanzee (Pan troglodytes) induced pluripotent stem cell lines (iPSCs) into mesenchymal stem cells (MSCs) and subsequently into osteogenic cells (bone cells). We validated differentiation using standard methods and collected single-cell RNA sequencing data from over 100,000 cells across multiple samples and replicates at each stage of differentiation. While most genes that we examined display conserved patterns of expression across species, hundreds of genes are differentially expressed (DE) between humans and chimpanzees within and across stages of osteogenic differentiation. Some of these interspecific DE genes show functional enrichments relevant in skeletal tissue trait development. Moreover, topic modeling indicates that interspecific gene programs become more pronounced as cells mature. Overall, we propose that this in vitro model can be used to identify interspecific regulatory differences that may have contributed to skeletal trait differences between species., Competing Interests: The authors have declared that no competing interests exist.

Bone strength and the incidence and severity of skeletal disorders vary significantly among human populations, due in part to underlying genetic differentiation. While clinical models predict that this variation is largely deleterious, natural population variation unrelated to disease can go unnoticed, altering our perception of how natural selection has shaped bone morphologies over deep and recent time periods. Here, we conduct the first comparative population-based genetic analysis of the main bone structural protein gene, collagen type I α 1 ( COL1A1 ), in clinical and 1000 Genomes Project datasets in humans, and in natural populations of chimpanzees. Contrary to predictions from clinical studies, we reveal abundant COL1A1 amino acid variation, predicted to have little association with disease in the natural population. We also find signatures of positive selection associated with intron haplotype structure, linkage disequilibrium, and population differentiation in regions of known gene expression regulation in humans and chimpanzees. These results recall how recent and deep evolutionary regimes can be linked, in that bone morphology differences that developed among vertebrates over 450 million years of evolution are the result of positive selection on subtle type I collagen functional variation segregating within populations over time.

Epigenetic factors, such as DNA methylation, play an influential role in the development of the degenerative joint disease osteoarthritis (OA). These molecular mechanisms have been heavily studied in humans, and although OA affects several other animals in addition to humans, few efforts have taken an evolutionary perspective. This study explores the evolution of OA epigenetics by assessing the relationship between DNA methylation variation and knee OA development in baboons (Papio spp.) and by comparing these findings to human OA epigenetic associations. Genome-wide DNA methylation patterns were identified in bone and cartilage of the right distal femora from 56 pedigreed, adult baboons (28 with and 28 without knee OA) using the Illumina Infinium MethylationEPIC BeadChip. Several significantly differentially methylated positions (DMPs) and regions were found between tissue types. Substantial OA-related differential methylation was also identified in cartilage, but not in bone, suggesting that cartilage epigenetics may be more influential in OA than bone epigenetics. Additionally, some genes containing OA-related DMPs overlap with and display methylation patterns similar to those previously identified in human OA, revealing a mixture of evolutionarily conserved and divergent OA-related methylation patterns in primates. Overall, these findings reinforce the current etiological perspectives of OA and enhance our evolutionary understanding of epigenetic mechanisms associated with OA. This study further establishes baboons as a valuable nonhuman primate model of OA, and continued investigations in baboons will help to disentangle the molecular mechanisms contributing to OA and their evolutionary histories., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

We provide here a current overview of marmoset (Callithrix) evolution, hybridization, species biology, basic/biomedical research, and conservation initiatives. Composed of 2 subgroups, the aurita group (C aurita and C flaviceps) and the jacchus group (C geoffroyi, C jacchus, C kuhlii, and C penicillata), this relatively young primate radiation is endemic to the Brazilian Cerrado, Caatinga, and Atlantic Forest biomes. Significant impacts on Callithrix within these biomes resulting from anthropogenic activity include (1) population declines, particularly for the aurita group; (2) widespread geographic displacement, biological invasions, and range expansions of C jacchus and C penicillata; (3) anthropogenic hybridization; and (4) epizootic Yellow Fever and Zika viral outbreaks. A number of Brazilian legal and conservation initiatives are now in place to protect the threatened aurita group and increase research about them. Due to their small size and rapid life history, marmosets are prized biomedical models. As a result, there are increasingly sophisticated genomic Callithrix resources available and burgeoning marmoset functional, immuno-, and epigenomic research. In both the laboratory and the wild, marmosets have given us insight into cognition, social group dynamics, human disease, and pregnancy. Callithrix jacchus and C penicillata are emerging neotropical primate models for arbovirus disease, including Dengue and Zika. Wild marmoset populations are helping us understand sylvatic transmission and human spillover of Zika and Yellow Fever viruses. All of these factors are positioning marmosets as preeminent models to facilitate understanding of facets of evolution, hybridization, conservation, human disease, and emerging infectious diseases., (© The Author(s) 2021. Published by Oxford University Press on behalf of the National Academies of Sciences, Engineering, and Medicine 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Epigenetic mechanisms influence the development and maintenance of complex phenotypes and may also contribute to the evolution of species-specific phenotypes. With respect to skeletal traits, little is known about the gene regulation underlying these hard tissues or how tissue-specific patterns are associated with bone morphology or vary among species. To begin exploring these topics, this study evaluates one epigenetic mechanism, DNA methylation, in skeletal tissues from five nonhuman primate species which display anatomical and locomotor differences representative of their phylogenetic groups., Materials and Methods: First, we test whether intraspecific variation in skeletal DNA methylation is associated with intraspecific variation in femur morphology. Second, we identify interspecific differences in DNA methylation and assess whether these lineage-specific patterns may have contributed to species-specific morphologies. Specifically, we use the Illumina Infinium MethylationEPIC BeadChip to identify DNA methylation patterns in femur trabecular bone from baboons (n = 28), macaques (n = 10), vervets (n = 10), chimpanzees (n = 4), and marmosets (n = 6)., Results: Significant differentially methylated positions (DMPs) were associated with a subset of morphological variants, but these likely have small biological effects and may be confounded by other variables associated with morphological variation. Conversely, several species-specific DMPs were identified, and these are found in genes enriched for functions associated with complex skeletal traits., Discussion: Overall, these findings reveal that while intraspecific epigenetic variation is not readily associated with skeletal morphology differences, some interspecific epigenetic differences in skeletal tissues exist and may contribute to evolutionarily distinct phenotypes. This work forms a foundation for future explorations of gene regulation and skeletal trait evolution in primates., (© 2020 Wiley Periodicals, Inc.)

Functional genomics research is continually improving our understanding of genotype-phenotype relationships in humans, and comparative genomics perspectives can provide additional insight into the evolutionary histories of such relationships. To specifically identify conservation or species-specific divergence in humans, we must look to our closest extant evolutionary relatives. Primate functional genomics research has been steadily advancing and expanding, in spite of several limitations and challenges that this field faces. New technologies and cheaper sequencing provide a unique opportunity to enhance and expand primate comparative studies, and we outline possible paths going forward. The potential human-specific insights that can be gained from primate functional genomics research are substantial, and we propose that now is a prime time to expand such endeavors., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Osteoarthritis (OA) affects humans and several other animals. Thus, the mechanisms underlying this disorder, such as specific skeletal tissue DNA methylation patterns, may be evolutionary conserved. However, associations between methylation and OA have not been readily studied in nonhuman animals. Baboons serve as important models of disease and develop OA at rates similar to those in humans. Therefore, this study investigated the associations between methylation and OA in baboons to advance the evolutionary understanding of OA., Design: Trabecular bone and cartilage was collected from the medial condyles of adult female baboon femora, 5 with and 5 without knee OA. The Infinium HumanMethylation450 BeadChip (450K array) was used to identify DNA methylation patterns in these tissues., Results: Approximately 44% of the 450K array probes reliably align to the baboon genome, contain a CpG site of interest, and maintain a wide distribution throughout the genome. Of the 2 filtering methods tested, both identified significantly differentially methylated positions (DMPs) between healthy and OA individuals in cartilage tissues, and some of these patterns overlap with those previously identified in humans. Conversely, no DMPs were found between tissue types or between disease states in bone tissues., Conclusions: Overall, the 450K array can be used to measure genome-wide DNA methylation in baboon tissues and identify significant associations with complex traits. The results of this study indicate that some DNA methylation patterns associated with OA are evolutionarily conserved, while others are not. This warrants further investigation in a larger and more phylogenetically diverse sample set.

Leprosy is caused by the bacterial pathogens Mycobacterium leprae and Mycobacterium lepromatosis. Apart from humans, animals such as nine-banded armadillos in the Americas and red squirrels in the British Isles are naturally infected with M. leprae. Natural leprosy has also been reported in certain nonhuman primates, but it is not known whether these occurrences are due to incidental infections by human M. leprae strains or by M. leprae strains specific to nonhuman primates. In this study, complete M. leprae genomes from three naturally infected nonhuman primates (a chimpanzee from Sierra Leone, a sooty mangabey from West Africa, and a cynomolgus macaque from The Philippines) were sequenced. Phylogenetic analyses showed that the cynomolgus macaque M. leprae strain is most closely related to a human M. leprae strain from New Caledonia, whereas the chimpanzee and sooty mangabey M. leprae strains belong to a human M. leprae lineage commonly found in West Africa. Additionally, samples from ring-tailed lemurs from the Bezà Mahafaly Special Reserve, Madagascar, and chimpanzees from Ngogo, Kibale National Park, Uganda, were screened using quantitative PCR assays, to assess the prevalence of M. leprae in wild nonhuman primates. However, these samples did not show evidence of M. leprae infection. Overall, this study adds genomic data for nonhuman primate M. leprae strains to the existing M. leprae literature and finds that this pathogen can be transmitted from humans to nonhuman primates as well as between nonhuman primate species. While the prevalence of natural leprosy in nonhuman primates is likely low, nevertheless, future studies should continue to explore the prevalence of leprosy-causing pathogens in the wild.

Background: Only a small portion of human long non-coding RNAs (lncRNAs) appear to be conserved outside of mammals, but the events underlying the birth of new lncRNAs in mammals remain largely unknown. One potential source is remnants of protein-coding genes that transitioned into lncRNAs., Results: We systematically compare lncRNA and protein-coding loci across vertebrates, and estimate that up to 5% of conserved mammalian lncRNAs are derived from lost protein-coding genes. These lncRNAs have specific characteristics, such as broader expression domains, that set them apart from other lncRNAs. Fourteen lncRNAs have sequence similarity with the loci of the contemporary homologs of the lost protein-coding genes. We propose that selection acting on enhancer sequences is mostly responsible for retention of these regions. As an example of an RNA element from a protein-coding ancestor that was retained in the lncRNA, we describe in detail a short translated ORF in the JPX lncRNA that was derived from an upstream ORF in a protein-coding gene and retains some of its functionality., Conclusions: We estimate that ~ 55 annotated conserved human lncRNAs are derived from parts of ancestral protein-coding genes, and loss of coding potential is thus a non-negligible source of new lncRNAs. Some lncRNAs inherited regulatory elements influencing transcription and translation from their protein-coding ancestors and those elements can influence the expression breadth and functionality of these lncRNAs.

Background: Ovarian cancer is difficult to treat due to absence of selective drugs and tendency of platinum drugs to promote resistance. Combination therapy using epigenetic drugs is predicted to be a beneficial alternative., Materials and Methods: This study investigated the effects of combination therapies using two structurally different histone deacetylase (HDAC) inhibitors (HDACi), sodium butyrate and suberanilohydroxamic acid (SAHA), with the calpain inhibitor calpeptin on two characteristically different ovarian cancer cell lines, CAOV-3 and SKOV-3., Results: Suboptimal doses of HDACi and calpeptin produced several effects. Growth inhibition was enhanced and the epigenetically silenced tumor suppressor genes ARHI, p21 and RARβ2 were re-expressed. Methylation of specific CpG residues in ARHI were reduced. Cell-cycle progression was inhibited and apoptosis, as well as autophagy, were induced. The phosphorylation of ERK and Akt were differentially effected by these inhibitors., Conclusion: The re-expression of tumor suppressors may sensitize ovarian cancer cells, which then undergo apoptosis and autophagy for cell death., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Breast cancer persists as the most common cause of cancer death in women worldwide. Ovarian cancer is also a significant source of morbidity and mortality, as the fifth leading cause of cancer death among women. This reflects the continued need for further understanding and innovation in cancer treatment. Though breast and ovarian cancer usually present as distinct clinical entities, the recent explosion of large-scale -omics research has uncovered many overlaps, particularly with respect to genetic and epigenetic alterations. We compared genetic, microenvironmental, stromal, and epigenetic changes common between breast and ovarian cancer cells, as well as the clinical relevance of these changes. Some of the most striking commonalities include genetic alterations of BRCA1 and 2, TP53, RB1, NF1, FAT3, MYC, PTEN, and PIK3CA; down regulation of miRNAs 9, 100, 125a, 125b, and 214; and epigenetic alterations such as H3K27me3, H3K9me2, H3K9me3, H4K20me3, and H3K4me. These parallels suggest shared features of pathogenesis. Furthermore, preliminary evidence suggests a shared epigenetic mechanism of oncogenesis. These similarities, warrant further investigation in order to ultimately inform development of more effective chemotherapeutics, as well as strategies to circumvent drug resistance.

Long noncoding RNAs (lncRNAs) are a diverse class of RNAs with increasingly appreciated functions in vertebrates, yet much of their biology remains poorly understood. In particular, it is unclear to what extent the current catalog of over 10,000 annotated lncRNAs is indeed devoid of genes coding for proteins. Here we review the available computational and experimental schemes for distinguishing between coding and noncoding transcripts and assess the conclusions from their recent genome-wide applications. We conclude that the model most consistent with the available data is that a large number of mammalian lncRNAs undergo translation, but only a very small minority of such translation events results in stable and functional peptides. The outcomes of the majority of the translation events and their potential biological purposes remain an intriguing topic for future investigation. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Zoonotic pathogens that cause leprosy (Mycobacterium leprae) and tuberculosis (Mycobacterium tuberculosis complex, MTBC) continue to impact modern human populations. Therefore, methods able to survey mycobacterial infection in potential animal hosts are necessary for proper evaluation of human exposure threats. Here we tested for mycobacterial-specific single- and multi-copy loci using qPCR. In a trial study in which armadillos were artificially infected with M. leprae, these techniques were specific and sensitive to pathogen detection, while more traditional ELISAs were only specific. These assays were then employed in a case study to detect M. leprae as well as MTBC in wild marmosets. All marmosets were negative for M. leprae DNA, but 14 were positive for the mycobacterial rpoB gene assay. Targeted capture and sequencing of rpoB and other MTBC genes validated the presence of mycobacterial DNA in these samples and revealed that qPCR is useful for identifying mycobacterial-infected animal hosts.

EMT and MET comprise the processes by which cells transit between epithelial and mesenchymal states, and they play integral roles in both normal development and cancer metastasis. This article reviews these processes and the molecular pathways that contribute to them. First, we compare embryogenesis and development with cancer metastasis. We then discuss the signaling pathways and the differential expression and down-regulation of receptors in both tumor cells and stromal cells, which play a role in EMT and metastasis. We further delve into the clinical implications of EMT and MET in several types of tumors, and lastly, we discuss the role of epigenetic events that regulate EMT/MET processes. We hypothesize that reversible epigenetic events regulate both EMT and MET, and thus, also regulate the development of different types of metastatic cancers.

Background: Colorectal cancer (CRC) is one of thes most prevalent malignant tumors worldwide. Current therapeutic strategies for CRC have limitations, while nanomaterials show significant potential for diagnosing and treating CRC. This study utilizes bibliometric analysis to evaluate the current status and trends in this field. Methods: Research on nanomaterials in CRC from 2003 to 2024 was retrieved from the Web of Science Core Collection (WOSCC). Tools such as CiteSpace, VOSviewer, RStudio, GraphPad Prism, and Excel were used to analyze trends and hotspots, covering publication trends, countries, institutions, authors, journals, co-citation analysis, and keywords. Visual maps were created to forecast future developments. Results: The analysis includes 3,683 publications by 17,261 authors from 3,721 institutions across 100 countries/regions, published in 840 journals. Global publications have steadily increased, particularly since 2018. China leads in publication volume and citations, with six of the top ten research institutions and seven of the ten most cited authors, while the United States excels in citation impact and academic centrality. Both countries currently dominate the field, underscoring the urgent need for enhanced international collaboration. Ramezani M and Abnous K lead in publication volume and H-index, while Siegel RL is highly cited. The International Journal of Nanomedicine has the highest publication volume, while the Journal of Controlled Release is the most cited. In addition to "colorectal cancer" and "nanoparticles," the most common keyword is "drug delivery." Emerging research areas such as "metal-organic frameworks (MOFs)" and "green synthesis" are gaining attention as leading hotspots. Conclusion: This study offers an in-depth analysis of the application of nanomaterials in CRC, promoting interdisciplinary collaboration and advancing scientific progress in this field. [ABSTRACT FROM AUTHOR]

Many human diseases are the result of early developmental defects. As most paediatric diseases and disorders are rare, children are critically underrepresented in research. Functional genomics studies primarily rely on adult tissues and lack critical cell states in specific developmental windows. In parallel, little is known about the conservation of developmental programmes across non-human primate (NHP) species, with implications for human evolution. Here we introduce the developmental Genotype-Tissue Expression (dGTEx) projects, which span humans and NHPs and aim to integrate gene expression, regulation and genetics data across development and species. The dGTEx cohort will consist of 74 tissue sites across 120 human donors from birth to adulthood, and developmentally matched NHP age groups, with additional prenatal and adult animals, with 126 rhesus macaques (Macaca mulatta) and 72 common marmosets (Callithrix jacchus). The data will comprise whole-genome sequencing, extensive bulk, single-cell and spatial gene expression profiles, and chromatin accessibility data across tissues and development. Through community engagement and donor diversity, the human dGTEx study seeks to address disparities in genomic research. Thus, dGTEx will provide a reference human and NHP dataset and tissue bank, enabling research into developmental changes in expression and gene regulation, childhood disorders and the effect of genetic variation on development.The developmental Genotype-Tissue Expression (dGTEx) projects will catalogue and integrate gene expression, regulation and genetics data across 120 human donors from birth to adulthood with developmentally matched non-human primates, including 126 rhesus macaques and 72 common marmosets. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats. [ABSTRACT FROM AUTHOR]

Cancer remains a leading cause of mortality globally and a major health burden, with chemotherapy often serving as the primary therapeutic option for patients with advanced-stage disease, partially compensating for the limitations of non-curative treatments. However, the emergence of chemotherapy resistance significantly limits its efficacy, posing a major clinical challenge. Moreover, heterogeneity of resistance mechanisms across cancer types complicates the development of universally effective diagnostic and therapeutic approaches. Understanding the molecular mechanisms of chemoresistance and identifying strategies to overcome it are current research focal points. This review provides a comprehensive analysis of the key molecular mechanisms underlying chemotherapy resistance, including drug efflux, enhanced DNA damage repair (DDR), apoptosis evasion, epigenetic modifications, altered intracellular drug metabolism, and the role of cancer stem cells (CSCs). We also examine specific causes of resistance in major cancer types and highlight various molecular targets involved in resistance. Finally, we discuss current strategies aiming at overcoming chemotherapy resistance, such as combination therapies, targeted treatments, and novel drug delivery systems, while proposing future directions for research in this evolving field. By addressing these molecular barriers, this review lays a foundation for the development of more effective cancer therapies aimed at mitigating chemotherapy resistance. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is one of the most prevalent forms of head and neck squamous cell carcinomas (HNSCC) with a poor overall survival rate (about 50%), particularly in cases of metastasis. RNA-based cancer biomarkers are a relatively advanced concept, and non-coding RNAs currently have shown promising roles in the detection and treatment of various malignancies. This review underlines the function of long non-coding RNAs (lncRNAs) in the OSCC and its subsequent clinical implications. LncRNAs, a class of non-coding RNAs, are larger than 200 nucleotides and resemble mRNA in numerous ways. However, unlike mRNA, lncRNA regulates multiple druggable and non-druggable signaling molecules through simultaneous interaction with DNA, RNA, proteins, or microRNAs depending on concentration and localization in cells. Upregulation of oncogenic lncRNAs and down-regulation of tumor suppressor lncRNAs are evident in OSCC tissues and body fluids such as blood and saliva indicating their potential as valuable biomarkers. Targeted inhibition of candidate oncogenic lncRNAs or over-expression of tumor suppressor lncRNAs showed potential therapeutic roles in in-vivo animal models. The types of lncRNAs that are expressed differentially in OSCC tissue and bodily fluids have been systematically documented with specificity and sensitivity. This review thoroughly discusses the biological functions of such lncRNAs in OSCC cell survival, proliferation, invasion, migration, metastasis, angiogenesis, metabolism, epigenetic modification, tumor immune microenvironment, and drug resistance. Subsequently, we addressed the diagnostic and therapeutic importance of lncRNAs in OSCC pre-clinical and clinical systems, providing details on ongoing research and outlining potential future directions for advancements in this field. In essence, this review could be a valuable resource by offering comprehensive and current insights into lncRNAs in OSCC for researchers in fundamental and clinical domains. [ABSTRACT FROM AUTHOR]

Violent crimes are often pigeon-holed by bloodstain found at the crime scene. The science of analysing the bloodstains found at the crime scene is referred to as bloodstain pattern analysis (BPA). The bloodstain pattern analysis embraces analysts recognising and interpreting bloodstain patterns to uncover how they were bent, when they were created, who created them and what object was used. Bloodstain pattern analysis is an important technique for determining what happened at the crime scene and presenting answers to the crime that occurred. Bloodstain pattern analysis is a subfield of forensic science that utilises blood evidence to dive a conclusion about a crime and to illustrate the shadows of violent crimes. Though violent crime scenes that involve bloodshed often provide a prosperity of data in the form of the patterns, location, and possible causes of the bloodshed, it is unfortunate that such critical information can be missed and/or evidence demolished due to futile ways of protecting and preserving bloodstain patterns at the crime scene by the crime scene investigators from the Local Criminal Record Centre. The article took qualitative empirical approach where participants were interviewed with the permission obtain from South African police Services and ethical clearance acquired from the University of South Africa. Findings and recommendations in this article were significant for implementation by the police. [ABSTRACT FROM AUTHOR]

Leukaemia, a group of haematological malignancies, presents ongoing diagnosis, prognosis, and treatment challenges. A major obstacle in treating this disease is the development of drug resistance. Overcoming drug resistance poses a significant barrier to effective leukaemia treatment. The emergence of exosome research has unveiled new insights into the probable theragnostic implementations in leukaemia. Various research has exhibited the diagnostic possibilities of exosomes in identifying leukaemia‐specific biomarkers, including genetic mutations and fusion transcripts. Additionally, exosomes have been implicated in disease progression and treatment response, rendering them appealing targets for therapeutics. Exosomes, originating from diverse cell types, are instrumental in intercellular communication as they participate in the functional transportation of molecules like proteins, nucleic acids and lipids across space. Exosomes have a dual role in immune regulation, mediating immune suppression and modulating anti‐leukaemia immune responses. Interestingly, exosomes can even act as drug transport vehicles. This review delves into the intricate process of exosome biogenesis, shedding light on their formation and release from donor cells. The key mechanisms engaged in exosome biogenesis, for instance, the endosomal sorting complexes required for transport (ESCRT) machinery and ESCRT‐independent pathways, are thoroughly discussed. Looking ahead, future approaches that leverage innovative technologies hold the promise of revolutionizing disease management and improving patient outcomes. [ABSTRACT FROM AUTHOR]

This review investigates the therapeutic potential of butyrate, a short-chain fatty acid (SCFA) produced by gut microbiota, in the prevention and treatment of various gynecological diseases, including polycystic ovary syndrome (PCOS), endometriosis, and gynecologic cancers like cervical and ovarian cancer. These conditions often pose treatment challenges, with conventional therapies offering limited and temporary relief, significant side effects, and a risk of recurrence. Emerging evidence highlights butyrate's unique biological activities, particularly its role as a histone deacetylase (HDAC) inhibitor, which allows it to modulate gene expression, immune responses, and inflammation. In PCOS, butyrate aids in restoring hormonal balance, enhancing insulin sensitivity, and reducing chronic inflammation. For endometriosis, butyrate appears to suppress immune dysregulation and minimize lesion proliferation. Additionally, in cervical and ovarian cancers, butyrate demonstrates anticancer effects through mechanisms such as cell cycle arrest, apoptosis induction, and suppression of tumor progression. Dietary interventions, particularly high-fiber and Mediterranean diets, that increase butyrate production are proposed as complementary approaches, supporting natural microbiota modulation to enhance therapeutic outcomes. However, butyrate's short half-life limits its clinical application, spurring interest in butyrate analogs and probiotics to maintain stable levels and extend its benefits. This review consolidates current findings on butyrate's multifaceted impact across gynecological health, highlighting the potential for microbiota-centered therapies in advancing treatment strategies and improving women's reproductive health. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) remains a significant global health issue, necessitating advanced molecular approaches for early detection and prevention. This review delves into the roles of microRNAs (miRNAs) and circular RNAs (circRNAs) in BC, highlighting their potential as non-invasive biomarkers. Utilizing in silico tools and databases, we propose a novel methodology to establish mRNA/circRNA/miRNA axes possibly indicative of early detection and possible prevention. We propose that during early tumor initiation, some changes in oncogene or tumor suppressor gene expression (mRNA) are mirrored by alterations in corresponding circRNAs and reciprocal changes in sponged miRNAs affecting tumorigenesis pathways. We used two Gene Expression Omnibus (GEO) datasets and identified five mRNA/circRNA/miRNA axes as early possible tumor initiation biomarkers. We further validated the proposed axes through a Kaplan–Meier (KM) plot and enrichment analysis of miRNA expression using patient data. Evaluating coupled differential expression of circRNAs and miRNAs in body fluids or exosomes provides greater confidence than assessing either, with more axes providing even greater confidence. The proposed methodology not only improves early BC detection reliability but also has applications for other cancers, enhancing preventive measures. [ABSTRACT FROM AUTHOR]

Background: Hepatic metastasis is the primary cause of colorectal cancer (CRC)-induced death. Our previous results showed the anti-metastatic effects of Coptidis rhizoma using in vitro model. Aim: The present study aimed to investigate whether berberine, the main active compound of C. rhizoma, inhibits colon–liver metastasis in an animal model, and to elucidate the underlying mechanisms. Methods: Murine colon carcinoma (CT26) tumor tissue was implanted into the cecum of balb/c mice with/without oral administration of berberine (100 mg/kg) for 21 days, after which liver metastasis was evaluated. In addition, the pharmacological actions of berberine were explored using 5-fluorouracil-resistant human colon cancer cells (HCT116/R). Result: The administration of berberine significantly decreased the number of tumor nodules in the liver, while significant activation of E-cadherin (an epithelial marker), and suppression of vimentin, Snail and TGF-β (mesenchymal markers) were observed in primary colon tumor tissues. Berberine treatment also notably lowered the levels of inflammatory cytokines (TGF-β, TNF- α, IL-6 and IL-1β) in the blood. In HCT116/R cells, berberine significantly inhibited migration and invasion and modulated the expression of TGF-β and representative molecules related to its pathway. The results obtained with a TGF-β inhibitor (SB431542) and a TGF-β siRNA, strongly suggest that the mechanism of action of berberine is linked to TGF-β signaling. Conclusion: In conclusion, berberine evidently possess an anti-colon–liver metastatic effect, and its underlying mechanisms involve the inhibition of epithelial–mesenchymal transition (EMT) through the TGF-β signaling pathway. Thus, we cautiously propose the pharmacological potential of berberine in drug research studies targeting hepatic metastasis from CRC. [ABSTRACT FROM AUTHOR]

Cancer, the world's second leading cause of death after cardiovascular diseases, is characterized by hallmarks such as uncontrolled cell growth, metastasis, angiogenesis, hypoxia, and resistance to therapy. Autophagy, a cellular process that can both support and inhibit cancer progression, plays a critical role in cancer development and progression. This process involves the formation of autophagosomes that ultimately fuse with lysosomes to degrade cellular components. A key regulator of this process is Sirtuin 1 (SIRT1), which significantly influences autophagy. This review delves into the role of SIRT1 in modulating autophagy and its broader impacts on carcinogenesis. SIRT1 regulates crucial autophagy mediators, such as AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), effectively promoting or suppressing autophagy. Beyond its direct effects on autophagy, SIRT1's regulatory actions extend to other cell death processes, including apoptosis and ferroptosis, thereby influencing tumor cell proliferation, metastasis, and chemotherapy responses. These insights underscore the complex interplay between SIRT1 and autophagy, with significant implications for cancer therapy. Targeting SIRT1 and its associated pathways presents a promising strategy to manipulate autophagy in cancer treatment. This review underscores the potential of SIRT1 as a therapeutic target, opening new avenues for enhancing cancer treatment efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Non-small cell lung cancer (NSCLC) is a prominent lung cancer disease worldwide. Currently, commonly used methods, such as surgery and radiotherapy, have significant side effects. Traditional Chinese medicine (TCM) has become a research hotspot because of its safe and effective characteristics. The branches and leaves of Taxus media are abundant in antitumor active compounds, and there has been no research conducted as yet regarding its anti–lung cancer molecular mechanism. Objective: The aim of this study is to investigate the antitumor activity of two samples before and after fermentation of T. media , and to research the molecular mechanism of its inhibitory effect on NSCLC. Methods: The chemical composition of pre-fermentation T. media (TM) and post-fermentation T. media qu (TMQ) were investigated using UHPLC-Q-Qrbitrap HRMS and high-performance liquid chromatography (HPLC). The anti-lung cancer activities of TM and TMQ were compared using an A549-induced tumor mouse model. An enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (H&E) staining, immunohistochemistry, and immunofluorescence were used to determine the of TMQ mechanism of action. Results: The results indicated that TM and TMQ contained 83 compounds, consisting primarily of flavonoids, organic acids, and taxanes. Both taxanes and flavonoids in TMQ were higher than that in TM. Both TM and TMQ effectively inhibited the tumor growth in non-small cell lung cancer (NSCLC), and the inhibition rate was greater in TMQ (57.24%) than in TM (49.62%). TMQ administration downregulated the tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and the glutathione (GSH) level and upregulated interferon-γ (IFN-γ), reactive oxygen species (ROS), and malondialdehyde (MDA) levels in the serum of tumor mice. TMQ treatment also increased the protein expression of Bax, Caspase-3, and Beclin-1 in tumor tissues. In contrast, the bcl-2, PI3K, Ki67, ULK1, and mTOR protein levels were suppressed by TMQ. Protein assay analyses reemphasized the superior antitumor effect of TMQ over TM. These cumulative findings demonstrated that the mechanism of action of TMQ was closely related to the activation of transcriptional misregulation in the cancer pathway that inhibited the cholinergic synaptic, AMPK, and PI3K/Akt/mTOR signaling pathways. Conclusion: This study demonstrated that fermentation increased the active ingredient contents and antitumor effects of T. media. In addition, post-fermentation TMQ was superior to TM as a herbal medicine for NSCLC treatment. [ABSTRACT FROM AUTHOR]

The TRIM (tripartite motif) family, with TRIM28 as a key member, plays a vital role in regulating health and disease. TRIM28 contains various functional domains essential for transcriptional regulation, primarily through its interaction with KRAB‐ZNF proteins, which influence chromatin remodeling and gene expression. Despite extensive research, the precise mechanisms by which TRIM28 impacts health and disease remain elusive. This review delves into TRIM28's multifaceted roles in maintaining health, contributing to a variety of diseases, and influencing cancer progression. In cancers, TRIM28 exhibits a dual nature, functioning as both a tumor promoter and suppressor depending on the cellular context and cancer type. The review also explores its critical involvement in processes such as DNA repair, cell cycle regulation, epithelial‐to‐mesenchymal transition, and the maintenance of stem cell properties. By uncovering TRIM28's complex roles across different cancers and other diseases, this review underscores its potential as a therapeutic target. The significance of TRIM28 as a versatile regulator opens the door to innovative therapeutic strategies, particularly in cancer treatment and the management of other diseases. Ongoing research into TRIM28 may yield key insights into disease progression and novel treatment options. [ABSTRACT FROM AUTHOR]

Bruton's Tyrosine Kinase (BTK), a soluble tyrosine kinase plays an essential role in the growth, development, and signalling of B cells. It is a non-receptor kinase that is crucial for leukemic cell survival, proliferation, and oncogenic signalling in many B cell malignancies. The enhanced metastasis caused by BTK expression may be reduced by BTK inhibitors, which also have powerful therapeutic effects. The goal of the study is to identify potential inhibitors which have good binding affinity with BTK. The current study also aims to investigate the expression pattern and the prognostic significance of BTK across all cancer types. Interestingly, it was found that BTK was highly overexpressed in numerous cancer types including; clear cell renal carcinoma, glioblastoma, head and neck, liver and breast cancer. BTK was found to reduce the relapse-free and overall survival rate. Furthermore, using in silico approach two structural analogues of Pirtobrutinib namely; 163207918 and 129269825 that bind to BTK with higher affinity were identified. Using drug-likeness analysis the therapeutic possibility of screened Pirtobrutinib analogues were evaluated. The Molecular docking and dynamic analysis revealed that the new Pirtobrutinib analogues could be potent inhibitors with higher binding affinity and stability in comparison with the parent compound. In conclusion, after preclinical and clinical research, the identified analogues may open the door for their prospective use in cancer therapy. [ABSTRACT FROM AUTHOR]

Since the mid-1970s, increasingly innovative methods to detect DNA methylation provided detailed information about its distribution, functions, and dynamics. As a result, new concepts were formulated and older ones were revised, transforming our understanding of the associated biology and catalyzing unprecedented advances in biomedical research, drug development, anthropology, and evolutionary biology. In this review, we discuss a few of the most notable advances, which are intimately intertwined with the study of DNA methylation, with a particular emphasis on the past three decades. Examples of these strides include elucidating the intricacies of 5-methylcytosine (5-mC) oxidation, which are at the core of the reversibility of this epigenetic modification; the three-dimensional structural characterization of eukaryotic DNA methyltransferases, which offered insights into the mechanisms that explain several disease-associated mutations; a more in-depth understanding of DNA methylation in development and disease; the possibility to learn about the biology of extinct species; the development of epigenetic clocks and their use to interrogate aging and disease; and the emergence of epigenetic biomarkers and therapies. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is associated with a generally poor prognosis due to its highly aggressive and metastatic nature, lack of targetable receptors, as well as the frequent development of resistance to chemotherapy. We previously reported that AU1, a small molecule developed as an inhibitor of BPTF (bromodomain PHD finger-containing transcription factor), was capable of sensitizing preclinical models of TNBC to chemotherapy in part via the promotion of autophagy. In studies reported here, we identify an additional property of this compound, specifically that sensitization is associated with the inhibition of the P-glycoprotein (P-gp) efflux pump. In silico molecular docking studies indicate that AU1 binds to active regions of the efflux pump in a manner consistent with the inhibition of the pump function. This work identifies a novel chemical structure that can influence multidrug efflux, an established mechanism of drug resistance in TNBC, that has not yet been successfully addressed by clinical efforts. [ABSTRACT FROM AUTHOR]

Cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. This paper outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and the epithelial-mesenchymal transition, as well as how inherent tumor cell heterogeneity plays a role in drug resistance. It also describes the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies. Lastly, this review concludes with a discussion on the best treatment options for existing drug resistant cancers, ways to prevent the formation of drug resistant cancers and cancer progenitor cells, and future directions of study.

Molecular-based characterizations of Andean peoples are traditionally conducted in the service of elucidating continent-level evolutionary processes in South America. Consequently, genetic variation among "western" Andean populations is often represented in relation to variation among "eastern" Amazon and Orinoco River Basin populations. This west-east contrast in patterns of population genetic variation is typically attributed to large-scale phenomena, such as dual founder colonization events or differing long-term microevolutionary histories. However, alternative explanations that consider the nature and causes of population genetic diversity within the Andean region remain underexplored. Here we examine population genetic diversity in the Peruvian Central Andes using data from the mtDNA first hypervariable region and Y-chromosome short tandem repeats among 17 newly sampled populations and 15 published samples. Using this geographically comprehensive data set, we first reassessed the currently accepted pattern of western versus eastern population genetic structure, which our results ultimately reject: mtDNA population diversities were lower, rather than higher, within Andean versus eastern populations, and only highland Y-chromosomes exhibited significantly higher within-population diversities compared with eastern groups. Multiple populations, including several highland samples, exhibited low genetic diversities for both genetic systems. Second, we explored whether the implementation of Inca state and Spanish colonial policies starting at about ad 1400 could have substantially restructured population genetic variation and consequently constitute a primary explanation for the extant pattern of population diversity in the Peruvian Central Andes. Our results suggest that Peruvian Central Andean population structure cannot be parsimoniously explained as the sole outcome of combined Inca and Spanish policies on the region's population demography: highland populations differed from coastal and lowland populations in mtDNA genetic structure only; highland groups also showed strong evidence of female-biased gene flow and/or effective sizes relative to other Peruvian ecozones. Taken together, these findings indicate that population genetic structure in the Peruvian Central Andes is considerably more complex than previously reported and that characterizations of and explanations for genetic variation may be best pursued within more localized regions and defined time periods.

Although breast cancer is a heterogeneous disease that is challenging to characterize and treat, the recent explosion of genetic and epigenetic research may help improve these endeavors. In the present review, we use genetic diversity to characterize and classify different types of breast cancer. We also discuss genetic and epigenetic changes that are involved in the development of different breast cancer types and examine how these changes affect prognosis. It appears that while a combination of mutations and copy number changes determine the type of breast cancer, epigenetic alterations may be the primary initiators of cancer development. Understanding these critical biomarkers and molecular changes will advance our ability to effectively treat breast cancer. Next, we examine potential drug therapies directed at epigenetic changes, as such epigenetic drug treatments may prove useful for treating patient-specific tumors, breast cancer progenitor cells, and drug-resistant cells. Lastly, we discuss on mechanisms of carcinogenesis, including a novel hypothesis outlining the role of epigenetics in the development of cancer progenitor cells and metastasis. Overall, breast cancer subtypes may have a similar epigenetic signal that promotes cancer development, and treatment may be most effective if both epigenetic and genetic differences are targeted.

Competing Interests: The authors have declared that no competing interests exist.

Development of new breast cancer therapies is needed, particularly as cells become refractory or develop increased drug resistance. In an effort to develop such treatments, class I and II histone deacetylases (HDACs), alone and in combination with other cytotoxic agents, are currently in clinical trial. Herein, we discuss the effects of histone deacetylase inhibitors (HDACi) when used in combination with calpeptin, an inhibitor of the regulatory protease, calpain. We present results of study in two breast cancer cells lines with distinct characteristics: MDA-MB-231 and MCF-7. When used in combination with calpeptin, two chemically distinct HDACi significantly inhibited growth and increased cell death by inducing cell-cycle arrest and apoptosis. MCF-7 cells exhibited a greater proportion of arrest at the G(1) phase, whereas triple-negative MDA-MB-231 cells exhibited increased cell cycle arrest at the S phase. Methylation of the imprinted and silenced proapoptoic tumor suppressor gene aplasia Ras homolog member I (ARHI) was reduced in both cell lines after treatment with HDACi. However, it was only re-expressed on such treatment in MDA-MB-231 cells, suggesting that re-expression operates under differential mechanisms in these two cell lines. Collectively, these results showed that the combination of HDACi and calpeptin inhibited the growth of two distinctly different types of breast cancer cells and could have wide clinical applications, though the mechanisms of inhibition are possibly different.

COMBREX (http://combrex.bu.edu) is a project to increase the speed of the functional annotation of new bacterial and archaeal genomes. It consists of a database of functional predictions produced by computational biologists and a mechanism for experimental biochemists to bid for the validation of those predictions. Small grants are available to support successful bids.

Simple Summary: Cancer is one of the leading causes of death, with one out of six deaths worldwide. Breast cancer has the highest occurrence of other cancers, although, in terms of the number of deaths, breast cancer ranks fifth among all cancers. Depending on the nature of the cells and the associated cellular environment, different types of breast cancer are possible. Many breast cancer types are highly challenging to treat, and even if treatable, the treatments involve several side effects. Antibody–drug conjugates (ADCs) comprise monoclonal antibodies that explicitly target the tumor-specific antigens and cytotoxic drugs (mainly small molecules) that act as payloads to kill the malignant cells/tumor. As a result, the healthy cells are not affected by the toxic drugs, which potentially reduces the side effects. These target-specific chemo-biologic drugs (ADCs) have shed new light on hopes in cancer therapy. Currently, three ADCs have been approved for breast cancer treatment, and many are in clinical trials. A detailed discussion on the biochemical nature, mechanism of action, and current status of ADCs in breast cancer treatments has been accomplished in this article. While we made every effort to include all the related developments in this field, any omission is truly unintentional. Cancer is a significant health challenge globally, with millions of people affected every year, resulting in high morbidity and mortality. Although other treatment options are available with limitations, chemotherapy, either standalone or combined with other therapeutic procedures, is the most commonly used practice of treating cancer. In chemotherapy, cancer cells/malignant tumors are targeted; however, due to less target specificity, along with malignant cells, normal cells are also affected, which leads to various off-target effects (side effects) that impact the patient quality of life. Out of all the different types of cancers, breast cancer is the most common type of cancer in humans worldwide. Current anticancer drug discovery research aims to develop therapeutics with higher potency and lower toxicity, which is only possible through target-specific therapy. Antibody–drug conjugates (ADCs) are explicitly designed to target malignant tumors and minimize off-target effects by reducing systemic cytotoxicity. Several ADCs have been approved for clinical use and have shown moderate to good efficacy so far. Considering various aspects, chemotherapy and ADCs are useful in treating cancer. However, ADCs provide a more focused and less toxic approach, which is especially helpful in cases where resistance to chemotherapy (drug resistance) occurs and in the type of malignancies in which specific antigens are overexpressed. Ongoing ADC research aims to develop more target-specific cancer treatments. In short, this study presents a concise overview of ADCs specific to breast cancer treatment. This study provides insight into the classifications, mechanisms of action, structural aspects, and clinical trial phases (current status) of these chemo-biologic drugs (ADCs). [ABSTRACT FROM AUTHOR]