India's rising twin birth rate, driven by assisted reproductive technologies and delayed childbearing, generates approximately 30,000-40,000 twin pairs annually, yet this invaluable research resource remains systematically underutilized. While established twin registries in the United Kingdom, Australia, and Nordic countries have transformed understanding of disease heritability and gene-environment interactions, India, despite its 1.4 billion population and exceptional genetic diversity, lacks a coordinated infrastructure to capitalize on this scientific opportunity. Twin studies provide nature's ideal control experiment, enabling researchers to disentangle genetic predisposition from environmental influences through comparison of monozygotic and dizygotic pairs, with discordant twins offering particularly powerful insights into modifiable risk factors. India's extraordinary genetic heterogeneity, encompassing over 4600 distinct population groups, coupled with rapid environmental transitions including urbanization, dietary shifts, and pollution exposure, creates unparalleled natural experiments for investigating conditions demonstrating marked interpopulation variation such as type 2 diabetes, cardiovascular disease, and neuropsychiatric disorders. Establishing a National Twin Registry through a federated model linking existing birth registries with opt-in research participation, leveraging digital health infrastructure like Ayushman Bharat Digital Mission, would require modest investment while generating insights applicable across the disease spectrum. Initiating pilot registries in states with robust health systems such as Kerala, Tamil Nadu or Karnataka would enable iterative refinement before national expansion. International collaborations with established registries could accelerate development while preserving data sovereignty through robust governance frameworks. A National Twin Registry represents a strategic imperative for transitioning India from a research subject pool to a research leader in precision medicine, enabling Indian investigators to drive discovery addressing India-specific health priorities.

Short-read sequencing (SRS) has been the cornerstone of cancer genomics for nearly two decades; however, its inherent limitations in read length have restricted comprehensive characterisation of complex genomic features. Long-read sequencing (LRS) represents not merely a technical increment but a conceptual shift from computational inference of genomic structure to its direct observation. It enables 3-4-fold greater sensitivity for structural variant detection, unambiguous full-length transcript characterisation, native DNA methylation profiling without bisulfite conversion, and high-resolution HLA typing at 8-digit allele resolution. In haematological malignancies, these capabilities have identified cryptic rearrangements in 10-15

Abstract Air particulate matter (PM2.5 and PM10), can cross the placental barrier, triggering oxidative stress and inflammation that compromise fetal development. These insults lead to placental dysfunction and complications including preterm birth, low birth weight, and preeclampsia. In cell line and placental explant models, urban particulate matter (UPM) increased pro-inflammatory cytokines and oxidative stress pathways, impairing trophoblast invasion, angiogenesis, and nutrient transport, while also altering epigenetic modifications and endoplasmic reticulum function. Rodent studies revealed reduced litter size, placental abnormalities, and fetal growth arrest along with postnatal neurodevelopmental alterations. Human cohorts from high-exposure regions showed elevated low birth weight rates. Proteomic and transcriptomic analyses of rat placenta revealed an inflammatory signature and altered metabolic networks, while gut microbiome dysbiosis suggested links to metabolic disturbances. Importantly, transcriptomic analysis identified IGFBP3 as a major downregulated gene following UPM exposure. IGFBP3, a key regulator of IGF bioavailability, was suppressed by IL1β, establishing inflammation-driven repression as the mechanism. These findings underscore UPM’s multidimensional impact on maternal–fetal health and highlight preventive strategies as urgent priorities.

BackgroundBiliary Tract Cancers (BTCs), including cholangiocarcinoma and gallbladder cancer, are aggressive malignancies characterized by late diagnosis, high mortality, and intrinsic resistance to standard chemotherapeutic regimens like gemcitabine and cisplatin. A critical barrier to improving therapeutic outcomes is the historical reliance on 2D monolayer cultures. These conventional models fail to recapitulate the complex Tumor Microenvironment (TME), leading to poor predictive validity and high attrition rates in drug discovery.ScopeThis review critically examines the paradigm shift from reductionist 2D cultures to advanced 3D tumor models—as superior in vitro platforms for decoding drug resistance and apoptosis evasion in BTCs, while acknowledging that 2D model limitations represent only one component of a broader translational pipeline that includes animal models, biomarker gaps, and anatomical challenges.Key InsightsThe article highlights that 3D architectures uniquely recapitulate physiological barriers absent in monolayers, including hypoxia-driven metabolic reprogramming, dense Extracellular Matrix (ECM) shielding, and drug distribution gradients. These models reveal specific “multicellular resistance” (MCR) mechanisms, such as the dysregulation of the Bcl-2 rheostat (particularly Bcl-xL and Mcl-1 dependence). Furthermore, 3D systems provide a more accurate context for investigating alternative cell death pathways, including ferroptosis and necroptosis, and for identifying quiescent cancer stem cell populations protected by the niche.Conclusion3D tumor models, particularly PDOs, serve as high-fidelity “clinical avatars” that bridge the translational gap between preclinical screening and precision oncology. While challenges regarding standardization, immune component integration, and scalability remain, the adoption of these physiologically relevant systems is imperative for developing effective combinatorial therapies and overcoming the profound chemoresistance inherent to BTCs.

Gallbladder cancer (GBC) is a rare yet highly aggressive malignancy and remains the most prevalent cancer of the biliary tract. The pathogenesis is multifactorial, involving chronic inflammation, gallstone disease, genetic predisposition, and environmental and lifestyle determinants. Notably, GBC exhibits pronounced disparities across multiple dimensions, including sex, geography, ethnicity, and others which altogether shape disease incidence and outcomes. Using protein–protein interaction and gene ontology analyses, we identify candidate molecular pathways and genes implicated in GBC pathogenesis that may differentially operate across biological contexts, some of which are supported by prior experimental findings. This review examines the varied disparities in GBC, emphasising variations in incidence, pathophysiology, risk profiles, and therapeutic responses.

Coronary artery disease (CAD) remains one of the leading causes of mortality worldwide, driven by complex gene regulatory mechanisms. Non coding RNAs such as microRNAs (miRNAs) act as pivotal regulators of CAD pathogenesis. This study employed a multi-omics in silico approach to uncover microRNA (miRNA)-mediated regulatory networks in CAD. Differentially expressed miRNAs were identified from patient cohorts and mapped to target genes. Overlapping common genes (OCGs) between predicted targets and CAD-associated DEGs were used to construct a regulatory network. Hub miRNAs were prioritized, identifying 20 key regulators, including 11 novel hub-level regulatory candidates not previously prioritized as master regulators in integrated CAD miRNA network analyses. Functional enrichment confirmed the involvement of these OCGs in atherosclerosis and cardiomyopathy. A competing endogenous miRNA-lncRNA network was built to explore multi-layered regulation. Possible drug targets were analyzed to assess therapeutic potential for the results. This integrative pipeline offers insights into miRNA-driven CAD mechanisms and highlights novel biomarkers and targets for clinical implementation.

The emergence of digital twin technology represents a paradigm shift in precision oncology, offering unprecedented opportunities to transform how we diagnose, treat, and monitor cancer patients. Originally conceived in aerospace and manufacturing industries, digital twins – dynamic virtual replicas that evolve with real-time data inputs – are now poised to revolutionize cancer care by enabling truly personalized therapeutic strategies. THE DIGITAL TWIN PARADIGM IN CANCER A cancer patient digital twin integrates multiscale, multimodal patient data – including genomics, proteomics, imaging, clinical records, and real-time monitoring – to create a computational model that mirrors an individual patient’s disease trajectory. Unlike static predictive models, digital twins continuously assimilate new data, enabling dynamic adaptation as a patient’s condition evolves. This real-time learning capability addresses a fundamental limitation of traditional clinical approaches, where treatment decisions are often based on population averages rather than individual characteristics. The global digital twin market in healthcare is experiencing explosive growth, projected to reach USD 21.1 billion by 2028 with a compound annual growth rate exceeding 25%. In oncology specifically, research output has surged dramatically since 2020, with major initiatives from institutions including the National Cancer Institute, MD Anderson Cancer Center, and European Union-funded consortia driving innovation. TRANSFORMATIVE APPLICATIONS Digital twins offer transformative potential across multiple domains of cancer care. In personalized treatment planning, they enable simulation of tumor responses across treatment modalities – immunotherapy, chemotherapy, radiation – allowing clinicians to develop bespoke treatment plans that optimize outcomes while minimizing adverse effects. Early clinical applications have demonstrated success, including evolution-based mathematical models that significantly prolonged time-to-progression in metastatic castrate-resistant prostate cancer through adaptive therapy strategies. In clinical trial design, digital twins enable in silico simulation of trial outcomes, optimizing study designs and accelerating drug development. Virtual patient populations can be generated to test hypotheses, identify potential biomarkers for patient stratification, and predict treatment responses before human exposure – potentially reducing the time and cost associated with traditional clinical trials.9 Recent validation studies comparing virtual trials with conventional outcomes have demonstrated remarkable concordance, supporting the reliability of this approach. For real-time monitoring and adaptation, digital twins continuously integrate data from clinical encounters, imaging, and even wearable devices to track disease progression and treatment response. This enables clinicians to adjust protocols dynamically – critical in oncology where tumor biology and treatment responsiveness vary significantly over time and between individuals. Despite their promise, significant challenges remain. Data integration across heterogeneous sources presents substantial technical hurdles, requiring robust frameworks for harmonizing genomic, imaging, and clinical data under findability, accessibility, interoperability, reusability principles. The complexity of cancer biology – including mechanisms of drug resistance, immune responses, and inter-patient heterogeneity – poses challenges for mechanistic modeling, particularly in immuno-oncology, where treatment mechanisms are not fully understood. Regulatory frameworks remain underdeveloped. Bodies, including the Food and Drug Administration and European Medicines Agency will need to establish clear guidelines for validating and deploying digital twins in clinical settings, similar to existing frameworks for medical devices. Furthermore, ethical considerations regarding data privacy, algorithmic bias, and equitable access needs careful attention to ensure this technology benefits all patients. Digital twins represent more than incremental technological advancement – they embody a fundamental reconceptualization of cancer care from population-based medicine to truly individualized therapy. As computational capabilities expand, data integration improves, and validation studies accumulate, we stand at the threshold of an era where virtual experiments on patient-specific models may guide clinical decisions with unprecedented precision. The convergence of artificial intelligence, mathematical modeling, and clinical oncology in digital twin technology offers hope for a future where each cancer patient receives care optimized specifically for their unique disease biology. Realizing this vision will require sustained collaboration across computational, experimental, and clinical communities, but the potential to transform cancer outcomes makes this a challenge worth embracing.

Gallbladder cancer (GBC) is a rare but aggressive biliary tract malignancy. This study explores the transcriptomic profile of GBC to identify differentially expressed genes (DEGs) and dysregulated pathways involved in its pathogenesis. RNA sequencing was performed on 13 GBC tumors and 6 matched controls. Functional enrichment analysis (FEA) as well as weighted gene co-expression network analysis (WGCNA) were used to identify dysregulated pathways, functionally relevant gene modules and hub genes. Key targets were validated in patient tissues and cell lines. A total of 1319 DEGs were identified (528 upregulated, 791 downregulated). Gene set enrichment analysis revealed activation of E2F targets and G2/M checkpoint, with downregulation of bile acid metabolism and estrogen response pathways. A tumor grade-correlated gene module was identified by WGCNA. FEA of the gene module highlighted pathways related to cell cycle and cell division. Co-expression analysis identified TPX2 as a central hub gene. Inhibitors of aurora kinase, TPX2 dependent enzyme, significantly reduced proliferation, migration, and invasion in GBC cells. Elevated Aurora kinases expression was also observed in GBC. This first transcriptomic analysis of GBC in South-East Asian Indians uncovers key drivers like TPX2 and Aurora kinases in disease progression. The study highlights cell cycle dysregulation and sex-linked signatures, offering insights for biomarker discovery and targeted therapies.

Gallbladder cancer (GBC) is a major malignancy of the hepato-biliary tract, often detected at advanced, inoperable stages with limited therapeutic options. Nuclear receptors (NRs), a family of ligand-dependent transcription factors, play key roles in cancer biology and represent promising drug targets. mRNA expression of 48 NRs was profiled in GBC (n = 13) and chronic cholecystitis tissues using the Nanostring nCounter platform, identifying NR4A1 as significantly downregulated. NR4A1 activity was modulated in GBC cell lines using the agonist Cytosporone B (CSNB) or siRNA knockdown, and effects on proliferation, invasion, and cell cycle were assessed by qPCR, flow cytometry, and functional assays. NR4A1 was markedly downregulated in GBC tissues and NOZ cells. CSNB treatment increased NR4A1 expression, reduced migration and invasion, and induced G0/G1 arrest. RNA-seq following CSNB treatment highlighted downregulation of pathways related to cell proliferation. NR4A1 knockdown lead to reduction in epithelial markers and increase in proliferation markers like mki67. NR4A1 loss was also associated with adverse survival outcomes. Our findings highlight NR4A1 as a key tumor suppressor in GBC, whose loss confers proliferative and invasive advantages. Pharmacological activation of NR4A1 effectively counteracts these oncogenic traits, highlighting its potential as a therapeutic target, especially for advanced GBC.

In the received wisdom of molecular biology, stop codons, UAA, UAG, and UGA, are inviolable signals: The full stops at which the ribosome releases its nascent polypeptide and dissociates from the messenger RNA (mRNA). Yet biology, as ever, resists absolutes. A growing body of evidence reveals that in select bacteria, ribosomes can be programmed to decode stop codons as sense codons, incorporating an amino acid and continuing elongation to yield C-terminally extended protein isoforms, a phenomenon termed programmed stop-codon readthrough (SCR). Far from being a translational accident, SCR is increasingly understood as a context-dependent regulatory mechanism that expands the functional proteome, modulates protein activity, and contributes to adaptive responses – all without altering a single nucleotide of the genome. The molecular decision between termination and readthrough is a kinetic one. Release factors RF1 (cognate for UAA and UAG) and RF2 (cognate for UAA and UGA) must compete with near-cognate aminoacyl-transfer RNAs (aa-tRNAs) for occupancy of the ribosomal A-site when a stop codon is presented. Several cis-acting features tip this competition toward read-through. The nucleotide immediately 3′ of the stop codon – position +4 – exerts a dominant influence: A cytidine at this position markedly reduces RF binding efficiency and promotes aa-tRNA incorporation, while uridine has the opposite effect. Downstream mRNA secondary structures, including pseudoknots and stem-loops, can stall the translocating ribosome, prolonging A-site dwell time and providing near-cognate tRNAs an extended window for decoding. The intracellular ratios of competing aa-tRNA isoacceptors to release factors, modulated by growth phase and nutritional state, further tune readthrough efficiency across a dynamic range of ~0.1–>10%. The canonical example of programmed bacterial readthrough is found in the RNA bacteriophages Qβ and MS2, where the UGA stop codon of the coat protein cistron is read through at ~5% efficiency to produce a minor readthrough protein, the A1 protein, whose incorporation into the virion capsid is strictly required for infectivity. This elegant system established the principle that readthrough-derived protein isoforms need not be low-level noise but can be indispensable functional products. Genome-wide ribosome profiling, which maps ribosome density at single-codon resolution, has since uncovered dozens of endogenous readthrough loci in Escherichia coli and Bacillus subtilis, encompassing metabolic enzymes, membrane transport proteins, and virulence-associated regulators. These observations imply that the bacterial proteome contains a previously uncharacterized layer of C-terminal protein diversity generated without alternative splicing or transcriptional reprogramming. The most molecularly elaborate instances of programmed bacterial SCR are the co-translational insertions of the 21st amino acid selenocysteine (Sec), encoded by UGA, and the 22nd amino acid pyrrolysine, encoded by UAG. Selenoprotein synthesis in E. coli – typified by formate dehydrogenase H requires the concerted action of a dedicated elongation factor (SelB), a specialized Sec-tRNASec, and a cis-acting selenocysteine insertion sequence hairpin element immediately 3′ of the recoded UGA. The existence of this dedicated molecular machinery demonstrates that bacteria have evolved sophisticated solutions to exploit stop codons as sense codons in a precisely controlled, codon-context-dependent manner, blurring the once-sharp boundary between termination and elongation. The implications of bacterial SCR reverberate across evolutionary biology, stress physiology, and antimicrobial pharmacology. Evolutionarily, readthrough-generated C-terminal extensions provide cryptic sequence variation that can be recruited by natural selection for novel functions without the immediate fitness cost of stop codon mutation. Under stress conditions – including oxidative stress, amino acid starvation, and antibiotic exposure alterations in tRNA modification, release factor abundance, and codon occupancy can collectively elevate genome-wide readthrough frequencies, potentially rewiring the proteome in ways that facilitate survival. Pharmacologically, aminoglycoside antibiotics promote ribosomal misreading and readthrough as part of their mechanistic repertoire, a property now being deliberately harnessed to suppress pathogenic premature termination codons in strategies targeting nonsense-mutation harboring bacteria and, by extension, in human genetic disease. As cryo-EM structural analyses of read through competent ribosomes and single-molecule translation imaging approaches mature, the mechanistic grammar of stop-codon recoding will be written with ever greater precision. What is already clear, however, is that the stop codon is not the end of the story – it is, in select contexts, the beginning of a new one.

Syncytins are envelope proteins of retroviral origin that have been evolutionarily co-opted to play essential roles in placental biology. Primarily recognized for mediating the fusion of cytotrophoblasts into the syncytiotrophoblast, a multinucleated epithelium, critical for nutrient transport and maternal-fetal immune tolerance. Syncytins also contribute to broader aspects of placental development through diverse mechanistic pathways. This review focuses on the evolutionary origins and functional mechanisms of Syncytin-1 (encoded by HERV-W) and Syncytin-2 (encoded by HERV-FRD) in orchestrating placental morphogenesis and homeostasis. We further discuss the clinical significance of aberrant syncytin expression, which is associated with adverse pregnancy outcomes including preeclampsia, intrauterine growth restriction, gestational diabetes mellitus, and trophoblastic disease. Additionally, we examine how exogenous viral infections, such as cytomegalovirus and SARS-CoV-2, may disrupt syncytin transcriptional regulation and compromise placental integrity. Collectively, syncytins represent a paradigm of evolutionary viral domestication, wherein pathogenic genetic elements have been repurposed into indispensable mediators of human reproduction. Their precise spatiotemporal regulation is paramount for optimal placental function and maternal-fetal health. Future research leveraging advanced omics technologies and placental organoid systems will be instrumental in elucidating underlying molecular mechanisms and developing targeted therapeutic interventions for pregnancy-related disorders.

The identification of novel biomarkers for coronary artery disease (CAD) risk stratification remains a critical priority in cardiovascular medicine. While natriuretic peptides – specifically atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) – have long been established as diagnostic and prognostic markers in heart failure, emerging evidence suggests their potential utility extends to CAD risk assessment. Natriuretic peptides are secreted by cardiac myocytes in response to ventricular wall stress and volume overload. ANP, primarily released from atrial tissue, and BNP, predominantly from ventricular myocardium, exert natriuretic, diuretic, and vasodilatory effects while antagonizing the renin-angiotensin-aldosterone system. Recent studies have demonstrated that elevated levels of these peptides are independently associated with increased cardiovascular mortality and incident CAD events, even in patients without overt heart failure. The mechanistic link between natriuretic peptides and CAD is multifaceted. Myocardial ischemia induces left ventricular dysfunction and wall stress, triggering neurohormonal activation and natriuretic peptide release even before clinical symptoms manifest. Furthermore, chronic elevation of these biomarkers may reflect subclinical atherosclerotic burden and endothelial dysfunction. Data from the Framingham Heart Study revealed that BNP levels correlate with CAD risk independent of traditional risk factors, suggesting its potential as an additive risk marker. The clinical implications are substantial. Incorporating ANP and BNP into existing risk assessment algorithms could enhance the identification of high-risk individuals who may benefit from aggressive preventive strategies. The cost-effectiveness and widespread availability of these assays make them attractive candidates for routine screening. However, standardization of measurement techniques and establishment of population-specific reference ranges remain essential prerequisites for clinical implementation. As we advance toward precision cardiovascular medicine, natriuretic peptides represent promising tools for CAD risk stratification. Future research should focus on prospective validation studies, optimal threshold determination, and integration of these biomarkers into comprehensive risk prediction models. The journey from biomarker discovery to clinical utility requires rigorous investigation, but the potential to improve cardiovascular outcomes makes this pursuit worthwhile.

The 2025 Nobel Prize in Physiology or Medicine, awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their ground breaking discoveries concerning peripheral immune tolerance, represents a triumphant vindication of scientific persistence against prevailing dogma and a milestone achievement with profound clinical implications. When Sakaguchi et al., first identified regulatory T cells in 1995, challenging the entrenched belief that immune tolerance was solely established through central mechanisms in the thymus, he faced considerable skepticism from the scientific community. His courage to swim against the tide, combined with the elegant molecular genetics work of Brunkow et al., and Blair et al., in identifying the FOXP3 gene through studies of the “scurfy” mutant mouse, ultimately unveiled the immune system’s sophisticated peripheral security apparatus that prevents autoimmune catastrophe. These discoveries have transformed our understanding of immunological self-recognition and laid the foundation for an entire field of research now yielding promising therapeutic interventions. The implications extend across the spectrum of human disease – from enhancing regulatory T cell function to combat autoimmune disorders, such as type 1 diabetes and rheumatoid arthritis, to selectively dampening their immunosuppressive effects in cancer immunotherapy, to preventing transplant rejection. Perhaps most remarkably, this recognition arrives at a moment when regulatory T cell-based therapeutics are transitioning from pre-clinical promise to clinical reality, with multiple trials evaluating cellular therapies and targeted interventions aimed at modulating FOXP3 expression. The laureates’ work exemplifies how fundamental mechanistic insights into biological systems, pursued with rigor and conviction even in the face of scientific resistance, can ultimately revolutionize medicine and offer hope to millions of patients worldwide suffering from immune-mediated diseases. As we celebrate this achievement, it serves as a powerful reminder that paradigm-shifting discoveries often emerge from challenging established assumptions and that the most transformative advances in medicine frequently arise from understanding the elegant regulatory mechanisms that nature has evolved to maintain homeostasis within complex biological systems.

Zika and Dengue viruses are arboviral pathogens capable of crossing the placental barrier, representing major global health risks for maternal and fetal outcomes. In this narrative review, we compare their epidemiology, clinical consequences in pregnancy, and underlying mechanisms of vertical transmission. Emerging molecular insights are highlighted, including disruptions to placental signaling pathways such as JAK/STAT and mTOR, and strategies to evade Hofbauer cells and the immune system. A comparative analysis of these processes underscores a critical need for improved understanding of placental pathophysiology, immune regulation, and molecular pathways of transmission. Identifying such mechanisms may promote vaccine development, improved diagnostics, and therapies to reduce adverse outcomes in the mother-infant dyad during maternal infection.

Chemoresistance – the acquired or intrinsic ability of a tumor to evade cytotoxic therapy – has long been attributed to tumor-cell-intrinsic factors: Genomic mutations, epigenetic plasticity, and pro-survival signaling. Yet a mounting body of evidence compels a fundamental reassessment: Bacteria residing within tumor tissues are active and mechanistically sophisticated contributors to treatment failure, operating through direct drug catabolism, epigenetic reprogramming of cell-death pathways, and immunological subversion of the tumor microenvironment. The existence of a resident intratumoral microbiome, distinct from the gut flora and detectable across pancreatic, colorectal, breast, lung, and ovarian cancers, is now firmly established by microbial sequencing, fluorescence in situ hybridization, and culture-based approaches. The most biochemically direct mechanism is enzymatic inactivation of chemotherapy agents by bacterial enzymes expressed within the tumor itself. The landmark demonstration by Geller et al., in Science, showed that Gammaproteobacteria – detectable in 76% of human pancreatic ductal adenocarcinoma (PDAC) specimens – express a long isoform of the bacterial cytidine deaminase enzyme that converts gemcitabine into its inactive metabolite 2′,2′-difluorodeoxyuridine, rendering the cornerstone of PDAC chemotherapy ineffective before it ever reaches the tumor cell. This resistance was abrogated by co-treatment with ciprofloxacin in murine models, directly validating the therapeutic potential of antibiotic co-administration – an approach now being evaluated clinically. Analogous enzymatic biotransformation of fludarabine, cladribine, and the prodrug CB1954 by intratumoral Escherichia coli strains establishes that bacterial drug inactivation is neither species-specific nor confined to a single chemotherapy class. Perhaps no single organism better encapsulates the bacterial threat to chemotherapy than Fusobacterium nucleatum (Fn), an oral anaerobe that ectopically colonizes colorectal, esophageal, breast, and pancreatic tumors and whose elevated intratumoral burden independently predicts poor chemotherapy response and reduced survival. Its resistance mechanisms span multiple programmed cell-death pathways: Fn activates autophagic flux in colorectal cancer (CRC) cells via its surface adhesin FadA – engaging E-cadherin to trigger Wnt/β-catenin signaling – and through lipopolysaccharide-mediated TLR4/MyD88/NF-κB activation that upregulates miR-21, shielding tumor cells from 5-fluorouracil- and oxaliplatin-induced apoptosis. Beyond autophagy, Fn inhibits pyroptosis via the Hippo pathway and suppresses ferroptosis, functioning as a broad-spectrum antagonist of chemotherapy-triggered tumor cell death. A striking cell-nonautonomous mechanism involves Fn-infected cancer cells releasing exosomes laden with specific circular RNAs that transfer resistance to neighboring, uninfected tumor cells by alleviating endoplasmic reticulum stress-dependent apoptosis – demonstrating that bacterial chemoresistance can propagate across the tumor without requiring direct bacterial contact. The broader intratumoral bacterial community compounds these individual species-level effects through several additional mechanisms. Polymicrobial biofilms construct physical barriers that impede drug penetration, while simultaneously generating hypoxic, acidic niches intrinsically refractory to conventional cytotoxics.10 Bacteria actively remodel tumor immune tone: Fn recruits myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages while suppressing NK cell and cytotoxic T-lymphocyte activity, blunting the immune effectors that facilitate clearance of chemotherapy-damaged cells and underpin immunotherapy efficacy. Lactobacillus iners in cervical cancer confers chemo-radioresistance by reprogramming tumor metabolism toward elevated lactate production, while Peptostreptococcus anaerobius in CRC abrogates anti-PD-1 immunotherapy response by activating intratumoral immunosuppressive MDSCs. From the gut, microbiome-derived metabolites – including indoles that impair innate immune activation within the tumor milieu – extend bacterial influence on drug efficacy far beyond the immediate tumor microenvironment. The translational implications are substantial and increasingly actionable. Antibiotic-chemotherapy co-administration, precision intratumoral antibacterial nanomedicine, and fecal microbiota transplantation from chemotherapyresponder donors each represent therapeutic strategies under active investigation, while intratumoral microbiome profiling is emerging as an independent predictor of treatment response that may refine precision oncology protocols. Yet a necessary caution applies: The intratumoral microbiome is not uniformly deleterious, with certain bacterial populations sensitizing tumors to immunotherapy, and indiscriminate antibiotic strategies risk disrupting both systemic microbiome homeostasis and the very immune competence that underpins therapeutic response. Bacteria, long absent from the canonical models of chemoresistance, are microbial saboteurs operating at the heart of treatment failure. Decoding and strategically disrupting their contribution– through enzymatic drug metabolism, cell-death pathway subversion, and immune remodeling – is no longer a frontier curiosity but a clinical imperative that may prove decisive in overcoming one of oncology’s most enduring challenges.

Maternal nutrition is a cornerstone of a healthy pregnancy and birth outcomes, influencing everything from fetal development to neonatal survival. Ensuring adequate and balanced nutrition during pregnancy is not just a personal health choice – it is a public health imperative. Maternal nutrition plays a pivotal role in shaping the health trajectory of both mother and child. The “first 1000 days” – from conception to a child’s second birthday – are widely recognized as a critical window for growth and development. During this period, nutritional adequacy directly impacts fetal growth, birth weight, and long-term cognitive and physical outcomes. Undernutrition in pregnant women has been linked to increased risks of anemia, preterm labor, low birth weight, and cesarean delivery. A recent study found that neonates born to undernourished mothers were significantly more likely to have lower Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) scores and delayed breastfeeding initiation. These outcomes not only affect immediate survival but also predispose children to chronic diseases later in life. Micronutrient deficiencies – particularly in iron, folate, iodine, and Vitamin D – are common in low-resource settings and contribute to poor maternal and neonatal health. For instance, iron deficiency anemia is associated with increased maternal mortality and impaired fetal oxygenation, whereas folate deficiency raises the risk of neural tube defects. Conversely, adequate maternal nutrition supports optimal placental function, gestational weight gain, and fetal tissue accretion. Balanced diets rich in fruits, vegetables, whole grains, lean proteins, and essential fats are universally recommended. Supplementation programs and nutritional counseling during antenatal care have shown promising results in improving outcomes, especially in vulnerable populations. In conclusion, maternal nutrition is not merely a biological necessity – it is a determinant of equity, survival, and human potential. Governments and healthcare systems must prioritize nutritional education, access to supplements, and food security for pregnant women. The health of future generations begins with the nourishment of mothers.

Nasopharyngeal carcinoma (NPC) are geographically restricted malignancies, exhibiting significantly higher incidence in specific regions and among certain ethnic groups, indicating strong genetic and region-specific etiological influences. The pathogenesis of these malignancies illustrates a multifaceted interaction involving host genetic predisposition, viral infections, as well as various environmental and lifestyle factors. This mini review brings together existing evidence regarding the molecular genetic factors influencing both EBV and HR-HPV-associated NPC, focusing on gene polymorphisms, viral biomarkers, and risk modifiers that vary across populations. Recurrent genetic associations involved polymorphisms in GSTM1, CYP1A1, XRCC1, TNF, HLA microsatellites, and xenobiotic metabolism genes, particularly CYP2A6. Markers linked to EBV, including LMP1, EBNA1, and circulating plasma EBV DNA, exhibited a consistent association with NPC susceptibility. Similarly, HR-HPV markers including E6 and E7 oncoproteins, p16INK4a overexpression, and HPV DNA detection serve as critical biomarkers for HPV-driven HNCs, but categorically these associations haven’t yet been discovered in regard to NPC. These findings classify NPC as a genetically modified, virus-related cancer and highlight the necessity for population-specific genetic risk assessment, EBV/HPV-derived biomarkers, and targeted preventative efforts.

For over a century, the architecture of glucose homeostasis has been understood through a canonical triad: Insulin secretion from pancreatic β-cells, hepatic glucose production, and uptake by insulin-sensitive peripheral tissues, principally skeletal muscle and adipose tissue. Red blood cells (RBCs), long regarded as metabolically inert oxygen carriers, have rarely featured in this framework. A landmark study by Martí-Mateos et al., published in Cell Metabolism in February 2026, fundamentally disrupts this paradigm. Employing a convergence of mouse models, positron emission tomography/computed tomography (PET/CT) imaging, isotope-tracing metabolomics, and pharmacological intervention, the investigators establish that RBCs function as a primary, hypoxia-activated glucose sink capable of dramatically lowering circulating blood glucose independently of insulin signaling. This finding invites a wholesale re-evaluation of the cellular contributors to systemic glycemic control. The epidemiological observation that high-altitude populations exhibit markedly lower rates of type 2 diabetes mellitus and improved glucose tolerance has been documented across diverse geographies, from the Andean altiplano to the Himalayan plateau. Early reports from the Harvard Fatigue Laboratory in the 1930s documented improved glucose tolerance in lowlanders transported to high altitude in the Chilean Andes, yet the mechanistic basis of this phenomenon remained elusive for nearly nine decades. Hypoxia robustly suppresses blood glucose in murine models, and PET/CT imaging routinely used to trace glucose uptake in solid tumors revealed a striking anomaly in hypoxic animals: glucose was disappearing from the circulation at rates that could not be accounted for by uptake in any major organ. The glucose was, in the words of the investigators, vanishing into an invisible sink. Mature erythrocytes are uniquely positioned to fulfill this role. As anucleate, mitochondria-devoid cells, they are entirely dependent on anaerobic glycolysis for adenosine triphosphate (ATP) production. This metabolic constraint makes them constitutively reliant on glucose. Under normoxic conditions, however, their contribution to whole-body glucose disposal is limited by the relatively modest circulating RBC mass. Hypoxia changes this equation in two critical ways. First, chronic hypoxia nearly doubles the circulating RBC mass through erythropoietin-driven polycythemia, expanding the total glycolytic capacity of the blood compartment substantially. Second and more mechanistically compelling, individual RBCs in hypoxia undergo a profound metabolic reprogramming: The study reports a sustained ~3-fold increase in glucose uptake per cell, accompanied by a ~2-fold upregulation of glucose transporter 1 (GLUT1), the primary erythrocyte glucose transporter, selectively in newly synthesized RBCs. The mechanistic pivot is deoxyhemoglobin. In low-oxygen conditions, deoxyhemoglobin competitively displaces glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from its inhibitory binding site on band 3 protein, an integral membrane anion exchanger, liberating GAPDH into the cytoplasm and amplifying glycolytic flux. Critically, this redirected glycolysis is channeled not toward lactate, but toward 2,3-diphosphoglycerate (2,3-DPG) through the Luebering–Rapoport shunt. Elevated 2,3-DPG reduces hemoglobin–oxygen affinity, facilitating oxygen delivery to hypoxic tissues and simultaneously consuming glucose in the process. The glucose sink and the oxygen delivery mechanism are therefore two faces of a single adaptive response. The authors provide compelling evidence that RBCs are not merely coincidentally associated with glucose clearance but are causally responsible. The translational implications are considerable. The investigators tested HypoxyStat, a small-molecule inhibitor of prolyl hydroxylase domain enzymes that stabilizes hypoxia-inducible factor signaling under normoxic conditions, as a pharmacological hypoxia mimetic. Strikingly, HypoxyStat rescued hyperglycemia in murine models of both type 1 and type 2 diabetes, recapitulating the glycemic benefit of altitude without the need for actual hypoxic exposure. Whether erythrocyte metabolic reprogramming can be selectively activated, decoupled from the polycythemic response that may carry cardiovascular risk, will be a critical determinant of therapeutic feasibility in diabetic populations. The study by Martí-Mateos et al. compels a conceptual expansion of the glucose homeostasis framework to incorporate a hematological dimension. The 30 trillion erythrocytes in the human circulation, collectively representing the most abundant cell type in the body, have been hiding in plain sight as metabolic regulators, invisible to PET imaging and excluded from insulincentric models of glucose disposal. Their rehabilitation as active participants in glycemic control is not merely an academic revision; it identifies an entirely new class of therapeutic targets and a novel physiological axis that may prove particularly relevant in populations where conventional antidiabetic strategies have failed to achieve adequate control. The erythrocyte, it would seem, has significantly more to offer physiology than the delivery of oxygen.

The pharmaceutical industry continues to face a critical translational bottleneck, with the majority of drug candidates failing in clinical trials despite promising preclinical results, largely due to the limited predictive power of conventional in vitro systems and animal models. Microphysiological systems (MPS), including organ-on-chip and organoid-on-chip platforms, have emerged as transformative human-relevant technologies capable of recapitulating organ-level structure, function, and disease dynamics under precisely controlled microenvironments. By integrating advances in microfabrication, biomaterials, stem cell and organoid biology, microfluidics, and real-time sensing, MPS enables physiologically faithful modeling of tissue interfaces, mechanical forces, metabolic processes, and inter-organ communication. Recent progress has led to robust organ-specific platforms, interconnected multi-organ systems, and body-on-chip models that support systemic pharmacokinetic and pharmacodynamic studies. Concurrently, regulatory recognition through the FDA Modernization Acts and accelerating international standardization efforts have positioned MPS as a validated new approach for drug development and safety assessment. Despite these advances, challenges related to cell sourcing, tissue heterogeneity, scalability, statistical rigor, and protocol standardization remain. This review synthesizes the technological foundations, biological applications, regulatory landscape, and emerging challenges of MPS, emphasizing the need to quantify and harness biological heterogeneity rather than eliminate it.