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PubMed2026

Co-targeting Deregulated WNT and MAPK Signaling Pathways Limits Phenotypic Reprogramming of Intestinal Stem Cell Progeny in KRAS-Hyperactivated Colorectal Cancer.

In their recent article, Moore and colleagues demonstrate that, upon KRAS hyperactivation, colorectal cancer growth is driven by a reprogramming of Lgr5+ intestinal stem cell (ISC) progeny towards the acquisition of a regenerative phenotype. They find that this phenotype is regulated by a balance between WNT-related ISCs and MAPK-related regenerative and proliferative transcriptional programs. By targeting both pathways, they are able to suppress this dynamic plasticity and achieve tumor regression in cell line and mouse models. The antagonistic relationship between these central pathways defined here provides key insights into genomic patterns of colorectal cancer and targeted therapy strategies.

Colorectal Neoplasms↗

PubMed2026

A minimal three-arm oral regimen for healthspan: mechanistic alignment with transcriptomic signals from a large parental-lifespan GWAS.

A large genome-wide association study of parental lifespan was reported in 2019. A later transcriptome-wide association study (TWAS) based on those summary statistics identified a set of transcriptional programs associated with longer genetically predicted survival, including increased brain NAD + salvage, especially NMNAT2, reduced glucose-stimulated insulin secretion, a shift toward synaptic pruning with less broad plasticity, and a glial pattern characterized by relatively greater microglial and lower astrocytic signatures, with only weak pan-tissue senescence signals. Building on those directional findings, this short communication proposes a minimal three-arm oral regimen with unequal evidentiary weight: first, the Cheung Glutamatergic Regimen, consisting of low-dose dextromethorphan potentiated by a CYP2D6 inhibitor together with piracetam and L-glutamine, as an exploratory adjunct aimed at preserving residual functional connectivity; second, daily nicotinamide mononucleotide and N-acetylcysteine with pulsed senolytics for NAD + salvage and senescence modulation; and third, GLP-1 receptor agonism for metabolic reprogramming. The NAD+/senescence arm is the primary mechanistic anchor, GLP-1 receptor agonism provides secondary metabolic support, and the glutamatergic arm is exploratory. Each arm targets a separate node within the pruning-plasticity-metabolic triad. The regimen is fully oral, uses conservative dosing, and draws on prior therapeutic or human-exposure data, although the proposed combination has no established safety profile. Although direct combination data are lacking and the foundational TWAS remains a preprint, the components show plausible but uneven mechanistic alignment with the TWAS signals and may justify carefully designed, safety-focused pilot evaluation.

GLP-1↗

PubMed2026

Altered Excitation-Inhibition Balance and mGluR1/5-Driven Plasticity in the Motor Cortical Surface in a Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by progressive dopaminergic degeneration and maladaptive motor cortical plasticity. However, the cellular pathways underlying cortical surface activity in the primary motor cortex (M1) remain unclear, despite serving as a potential target for electrotherapy. We investigated the excitatory-inhibitory (E-I) balance and synaptic plasticity of superficial M1 circuits in a unilateral 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Using extracellular local field potential and whole-cell patch recordings from the contralateral and ipsilateral M1 hemispheres of hemi-parkinsonian rats, we observed a significantly elevated field excitatory postsynaptic potential (fEPSP) input-output function but unchanged intrinsic neuronal excitability in the M1 superficial layer. An altered relative contribution between alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and N-methyl-D-aspartate receptor (NMDAR)-mediated transmission was reflected by a significantly increased AMPA/NMDA ratio. Markedly reduced inhibitory synaptic tone was also evidenced by the decreased amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), supporting an E-I imbalance favoring excitation in PD. Furthermore, group I metabotropic glutamate receptor (mGluR1/5)-dependent long-term depression (LTD) was abolished in the ipsilateral PD hemisphere, whereas NMDAR-dependent LTD remained intact. In summary, dopamine depletion appears to enhance network excitation and disrupt mGluR1/5-mediated control of M1 surface circuitry. Our findings identify altered cortical surface mGluR-dependent plasticity in the hemi-parkinsonian model; however, the relationship between these electrophysiological alterations and individual motor outcomes remains to be determined.

Animals↗

PubMed1977

Enhancing effect of low dose cyclophosphamide treatment on the in vitro antibody response.

We have studied the effect of cyclophosphamide (CY) administration on the subsequent in vitro antibody response in the mouse. Treatment with a low dose (20 mg/kg) of CY four days before culture results in an increased IgM response to the T-independent antigen trinitrophenylated polyacrylamide (TNP-PAA), without affecting the background response of unstimulated cultures. This suggests that CY treatment eliminates a short-lived suppressor cell, involved in the regulation of the in vitro B cell response. In contrast, the same regimen decreases the ability of nude mouse spleen cells to respond to TNP-PAA, showing that the target of CY-enhancing effect is a mature T cell. The increased response observed in conventional mice should be the result of a balance between the direct suppressive effect of CY on B cells and the elimination of a suppresor T cell, the latter phenomenon being of predominant significance in our conditions. The target of CY-enhancing effect is nonadherent to plastic, but adherent to Sephadex G-10 columns.

Acrylamides↗

PubMed2025

Druggable genome CRISPRi screen in 3D hydrogels reveals regulators of cortactin-driven actin remodeling in invading glioblastoma cells.

To identify new therapeutic targets that limit glioblastoma (GBM) invasion, we applied druggable-genome CRISPR screens to patient-derived GBM cells in micro-dissectible biomimetic 3D hydrogel platforms that permit separation and independent analysis of core vs. invasive fractions. We identified 12 targets whose suppression limited invasion, of which ACP1 (LMW-PTP) and Aurora Kinase B (AURKB) were validated in neurosphere assays. Proximity labeling analysis identified cortactin as an ACP1-AURKB link, as cortactin undergoes serine phosphorylation by AURKB and tyrosine dephosphorylation by ACP1. Suppression of ACP1 or AURKB in culture and in vivo shifted the balance of cortactin phosphorylation in GBM and reduced actin polymerization and actin-cortactin co-localization. Additional biophysical analysis implicated AURKB in GBM cell adhesion and cortical stiffness, and ACP1 in resistance to mechanical stress and shape plasticity needed for 3D migration. These findings reveal a novel targetable axis that balances kinase and phosphatase activities to regulate actin polymerization during GBM invasion.

CRISPR↗

PubMed1979

Autoimmune interaction measured in a postlabelling microcytostasis assay.

A postlabelling microcytostasis assay was developed to assess primary immune interaction between normal rat lymphocytes and autologous testis cells. In this vitro model of experimental autoimmune orchitis (EAO) unprimed T cells respond to a Sertoli-like subpopulation of testis cells during a 4 day culture period. The T effector cells exert a cytostatic effect on the monolayer-forming target cells. The number of remaining target cells, which inversely correlates with the intensity of the autoimmune reaction, is quantified by 51Cr incorporation. The assay is performed in multiple well plastic plates which allow rapid harvesting by cutting off the bottoms of each well. The attached labelled target cells are directly measured on the bottoms without any further transfer step. The method is adapted for the EAO model but may be useful to study primary T cell interaction with any other monolayer-forming target cells.

Animals↗

PubMed1977

Effect of chemotherapy and immunotherapy on tumor-specific immunity in melanoma.

The effects of chemotherapy, with nitrosoureas or dimethyl-triazeno-imidazole-carboxamide (DTIC), or immunotherapy with Bacillus Calmette-Guérin (BCG), on cell-mediated immunity (CMI), and serum blocking factor (BF) to melanoma cells were studied in 23 patients. Studies were performed with autologous or allogenic melanoma target cells obtained from recent biopsy, in 16 mm diameter plastic wells. Assays for lymphocyte-mediated cytotoxicity and BF were performed at weekly intervals over the course of 3-4 mo, with some studies extending beyond 3 yr. The specificity of cytotoxicity was good with these methods. Nine patients given nitrosoureas, predominantly methyl-chloroethyl-cyclohexyl-nitrosourea, showed a transient decline in CMI from 42.2 to 14% 3 wk after administration of a single dose of the agent, with a rapid recovery within 1 week. 10 patients given 5-day courses of DTIC at 3-wk intervals showed no decline in CMI after two courses, and 7 of the 10 had no decline even after three courses. Three of the four patients who achieved a remission lost BF previously present: BF reappeared in both patients studied during a subsequent relapse. BCG intradermally or intralesionally elevated CMI within 2 mo after initiation of therapy, but despite continuation of the injections CMI returned to base line in all but two of the nine patients studied. These results indicate that chemotherapy for melanoma with nitrosoureas or DTIC at these schedules is not profoundly immunosuppressive towards tumor-specific immunity, as measured by our procedures. Putative immunotherapy with BCG at these schedules was likewise only transiently stimulatory.

Adult↗

PubMed2026

Non-coding RNAs in cancer: multi-omics insights, liquid biopsy advances, drug resistance mechanisms, and the road to clinical translation.

For most of the twentieth century, the transcriptional output of the human genome was thought to be biologically inert-a characterization that has been proven wrong in almost every important respect. Non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), small nucleolar RNAs (snoRNAs) and PIWI-interacting RNAs (piRNAs) are now thought of as vital regulators of gene expression in all the stages of cancer pathogenesis, including the initial epigenetic changes, metastatic spread and the development of therapeutic resistance. This review highlights four areas where the clinical potential of ncRNAs is most promising: reconstruction of ncRNA regulatory networks by multi-omics integration; circulating ncRNAs as minimally invasive cancer biomarkers; causal roles of ncRNAs in drug resistance through epithelial-mesenchymal plasticity, metabolic reprogramming, and stromal communication; and translation of ncRNA targeting strategies to clinical trials. We will need to invest equally in mechanistic rigor and translational infrastructure to move forward.

antisense oligonucleotides↗

PubMed2026

Genome-wide mapping of stress-responsive lncRNA, uc.104, reveals the chromatin-mediated regulation of stress and plasticity-related genes in the hippocampus of chronic restraint rats.

Chronic stress significantly impacts hippocampal function through transcriptional and epigenetic mechanisms. While the roles of lncRNAs in stress-related transcriptional and epigenetic regulation have recently been recognized, their genome-wide functions controlling the transcriptional network remain largely unclear. Evidence indicates that the lncRNA uc.104 is involved in stress responses; however, its genome-wide chromatin interactions and gene regulatory effects are yet to be explored. To examine this, we combined chromatin isolation by RNA purification sequencing (ChIRP-seq) and RNA sequencing (RNA-seq) in the hippocampus from handled control and chronic restraint stress (CRS) rats. ChIRP-seq identified 6,664 uc.104 binding peaks under CRS, including 6,517 enriched and 149 reduced. Many peaks were mapped to intronic and promoter-proximal regions of protein-coding genes. Integration of ChIRP-seq with RNA-seq data revealed 1,839 differentially expressed genes associated with uc.104 binding sites, with 106 high-confidence overlaps. Several genes (Gabra3, Htr7, Irs1, Gpr37, Clu, Hspa1b, Ppp3r2, Nfasc, Pcdhac2, and Cysltr2) identified as regulatory targets of uc.104, have been directly implicated in stress responses, synaptic plasticity, and neuroinflammation. Gene ontology and Synapse GO (SynGO) analyses revealed significant enrichment for processes involving dendritic spine formation, synapse organization, and pre- and postsynaptic signaling. Protein-protein interaction analysis identified hub genes, including EGFR, CDC42, IGF1R, CTNNB1, CALM1, CALM3, POLR2A, MDM2, TBP, and CSNK1E, several of which have been linked to stress-responsive pathways. Together, our findings reveal that uc.104 binding to chromatin near stress- and synapse-related genes may act as a regulator of stress-responsive transcriptional networks in the hippocampus. By linking uc.104 occupancy to stress and synaptic responsive genes, this study highlights uc.104 as a potential mediator of stress-induced hippocampal malfunctions.

Animals↗

PubMed2026

The genomic alchemist's arsenal: A comprehensive review of gene recruitment, regulatory rewiring, and the evolutionary arms race in snake envenomation.

Snake venom represents a striking example of evolutionary innovation, in which ancestral physiological gene networks have been co-opted into potent biochemical weapons. Advances in multi-omics, single-cell genomics, and structural bioinformatics have catalyzed a conceptual shift from descriptive toxin cataloging to a systems-level understanding of venom evolution, regulation, and function. This Review integrates genomic, cellular, and structural perspectives to delineate the molecular architecture underpinning venom diversification and target-site co-evolution. Emphasis is placed on regulatory mechanisms driving rapid expression plasticity, including super-enhancer activity, transposable element insertion, spatial heterogeneity within the venom gland, and non-coding RNA-mediated modulation. At the protein level, the review examines how hypervariable toxins engage in structural arms races with prey targets, and how multi-toxin complex formation, functional synergy, and molecular dynamics simulations inform models of lethality and resistance. A comparative framework is provided by contrasting high-potency predatory snake venoms with low-potency defensive venoms of hymenopterans such as bees and wasps, revealing how ecological selective pressures shape toxin potency, composition, and target specificity across taxa. Finally, current translational strategies are evaluated, with a focus on the relative merits of recombinant human monoclonal antibodies versus catalytic-site small-molecule inhibitors as deployable interventions for snakebite. By synthesizing evolutionary genomics, structural biology, comparative toxinology, and synthetic antivenomics, this Review outlines a predictive framework for anticipating venom evolutionary trajectories and for designing broad-spectrum, next-generation therapeutics.

Animals↗

PubMed1975

The calculation of charged particle fluence and LET spectra for the irradiation of biologically significant materials by neutrons.

As a preliminary step to evaluating recent theories concerning the biological effect of ionizing radiation, the charged particle fluence distributions and the dose distribution in linear energy transfer have been computed analytically for targets of biological and dosimetric interest irradiated by neutrons. Specifically, 14.7 MeV neutrons, the 252Cf neutron spectrum and a cyclotron generated neutron spectrum are considered to irradiate water, tissue-equivalent plastic and standard man tissue and results are given for all these cases. From a knowledge of the target composition, and the cross-sections and kinetics of all the possible neutron induced reactions in the elements hydrogen, carbon, nitrogen and oxygen, the secondary particle spectrum is calculated. By combining with stopping power data for the ions in the target, the charged particle fluence spectra and dose distribution in linear energy transfer are derived. Secondary quantities computed are kerma, energy expended as nuclear elastic scattering, specific ionization and mean quality factor. Stopping powers have been derived from published atomic stopping powers by summing according to the Bragg rule. A comparison between tissue-equivalent plastic and standard man tissue had been made for each of the neutron spectra.

Californium↗

PubMed2026

Overcoming cancer resistance in pancreatic cancer: toward dynamic precision oncology.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, largely because of its profound and evolving therapeutic resistance. Resistance is not determined by a single molecular alteration but arises from interconnected mechanisms, including intrinsic resistance, treatment-induced adaptive resistance, acquired resistance, genomic evolution, clonal selection, cancer stemness, phenotypic plasticity, metabolic adaptation, and tumor microenvironment-mediated effects. Emerging therapeutic approaches targeting KRAS/RAS signaling, stromal and immune components, metabolic dependencies, and DNA damage repair pathways offer opportunities to address these mechanisms, although durable efficacy remains limited by biological heterogeneity and adaptive responses. In this review, we examine therapeutic resistance as an evolutionary and multidimensional process and summarize emerging strategies for overcoming resistance. We further propose a Dynamic Precision Oncology (DPO) framework that extends conventional precision oncology beyond baseline molecular profiling by integrating longitudinal assessment of tumor genomics, circulating tumor DNA, CA19-9, imaging, radiomics, and clinical characteristics. This framework emphasizes iterative detection and characterization of emerging resistance, mechanism-informed treatment adaptation, and subsequent reassessment rather than automatic treatment modification based on a single biomarker. DPO may provide a conceptual framework for integrating evolving tumor biology into treatment decision-making, while prospective studies are needed to validate biomarkers, define actionable thresholds, and determine whether longitudinal resistance-guided strategies improve clinical outcomes in PDAC.

Humans↗

PubMed1977

Spontaneous, augmentable cell-mediated cytotoxicity with limited target cell specificity in human blood.

Nonadherent and nonphagocytic lymphoid cells from human peripheral blood became strongly cytotoxic against 51Cr-labeled chicken red blood cells and cells from an established human myeloma cell line when subjected to repeated cycles of washing in phosphate buffered saline or treated with trypsin or lecithinase. Prior to augmentation the effector cells pass nylon wool columns that remove practically all surface IgG-positive cells, but after augmentation they are retained in such columns. Augmentation does not make them phagocytic or adherent to plastic surfaces. Incubation at 37 degrees C of augmented cells prior to addition on the target cells restores the original nonaggressive state. Morphologically the cells making contact with the target cells are small or intermediate-sized mononuclear cells.

Animals↗

PubMed2026

MicroRNA-driven regulatory networks in aphid ecological adaptation: integrating stress tolerance, dispersal plasticity, and population expansion.

Aphids (Hemiptera: Aphididae) are important agricultural pests and exhibit strong ecological adaptability, allowing them to persist under stress, disperse to new habitats, and rapidly increase population size. Recent advances in functional genomics have identified microRNAs (miRNAs) as key post-transcriptional regulators involved in these processes, yet their roles have remained fragmented across studies. Here, we synthesize current evidence into a "three-stage framework", encompassing population maintenance under stress, dispersal to new habitats, and population expansion upon establishment. We highlight how miRNAs regulate detoxification pathways (e.g., P450s, UGTs, ABC transporters), mediate interactions with host plants and symbionts, and integrate hormonal signaling networks including insulin, juvenile hormone, and ecdysteroid pathways. This framework identifies candidate miRNAs, target genes, and signaling pathways that may recur across different ecological contexts, including stress responses, dispersal-related plasticity, and reproductive regulation. However, direct evidence demonstrating that candidate shared miRNA regulators coordinate multiple life-history stages remains limited and requires further experimental validation. We critically evaluate the strength of functional evidence, distinguishing experimentally validated miRNA-target interactions from prediction- or expression-based associations. Finally, we discuss emerging applications of miRNA-based pest control, including artificial miRNAs, RNAi technologies, and nanocarrier delivery systems. By linking molecular mechanisms with ecological outcomes, this review provides a synthesis and highlights miRNAs as important regulators of aphid adaptation and candidate targets for sustainable management strategies.

Aphids↗

PubMed1977

Natural cell-mediated immunity to lymphoma cells. I. Characteristics of effector cells in a cytostasis assay in vitro.

Spleen cells from normal, nonimmune, CBA or (CBA X AKR)F1 mice markedly and rapidly inhibited the incorporation of [3H]thymidine by two different T-cell lymphomas in an in vitro cytostasis assay. These were the I-529 lymphoma of spontaneous AKR origin and the Moloney murine leukemia virus-induced YAC lymphoma of A mouse origin. Spleen cells were the most efficient inhibitors for both types of target cells, whereas lymph node cells were much less active and thymus cells showed little or no activity. Granulocytes, as well as conventional T- and B-lymphocytes, were excluded as important contributors to the cytostatic cell population. Spleen cells were separated on nylon wool, Sephadex G-10 columns, or plastic petri dishes and tested for activity in the cytostasis assay or for cytotoxicity against 51Cr-labeled lymphoma target cells. Adherent cells carried almost all cytostatic activity against the AKR lymphoma but also showed significant cytotoxic activity against these target cells. In addition, the cytostatic activity against the YAC lymphoma was mainly due to adherent spleen cells, but nonadherent cells were relatively more active against this target than against I-529 cells. Such nonadherent spleen cells further showed increased cytotoxic activity, compared to the whole spleen cell population.

Animals↗

PubMed2026

Exploiting DNA damage tolerance for precision oncology.

Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein-protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.

DDT↗

PubMed1978

Cell-mediated cytotoxicity of desialylated human lymphocytes induced by a mitogenic mammalian liver protein.

The ability of a purified rabbit liver membrane protein that selectively binds desialylated glycoproteins to induce desialylated human peripheral blood lymphocytes to mediate mitogen-induced cellular cytotoxicity has been determined. After short term exposure to purified hepatic binding protein, desialylated, but not intact, lymphocytes exhibited mitogen-induced cellular cytotoxicity against Chang target cells, which do not have exposed hepatic binding protein on their surface membrane. Furthermore, desialylated lymphocytes, in the absence of purified hepatic binding protein, reduced the proportion of isolated rabbit hepatocytes that adhered to plastic to a significantly greater extent than did intact lymphocytes, suggesting that the exposed hepatic binding protein demonstrated on the surface membrane of these target cells is capable of inducing mitogen-induced cellular cytotoxicity. The specific inhibition of this effect by asialo-orosomucoid, but not by intact orosomucoid, indicates that the site involved in the binding of asialo-glycoproteins to hepatic binding protein is probably also responsible for the induction of mitogen-induced cellular cytoxocity. The demonstration that hepatic binding protein, a normal constituent of the surface, membrane of mammalian hepatocytes, can induce mitogen-induced cellular cytotoxicity, suggests that mitogen-induced cellular cytotoxicity may be a mechanism of cellular injury in vivo.

Animals↗

PubMed1979

Interaction between T cells and non-T cells in suppression of cytotoxic lymphocyte responses.

Generation of cytotoxic T lymphocytes (CTL) in mixed leukocyte cultures was suppressed by a factor elaborated by alloantigen-activated T cells. This suppressor factor, CTL-TsF, in contrast to a factor that suppresses proliferative responses in mixed leukocyte reactions (MLR-TsF), was effective only when added during the first 24 hr of a 6-day-culture period. Moreover, removal of CTL-TsF 24 hr after culture initiation failed to restore CTL responses. CTL activity could be rescued from suppressed cultures, however, by addition of 2-mercaptoethanol on days 3 or 4. Similarly, transfer of nonadherent cells at 3 or 4 days from cultures treated with CTL-TsF to cultures of adherent cells initiated in control factor restored CTL responses. Mixing experiments with cells pulsed with CTL-TsF for 4 hr at culture initiation identified a target of CTL-TsF as a Thy-1 negative cell that was adherent to plastic and to Sephadex G-10. Suppression was not due to interference with physiologic accessory cell function, but more likely was accomplished via a negative signal from CTL-TsF-pulsed cells. The results thus suggest that CTL-TsF acts early, but reversibly, in the CTL differentiative process via a second suppressor effector cell, possibly a macrophage.

Animals↗