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Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immunemediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.

Mutations in the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of fumarate caused by the inactivation of FH leads to oxidative stress that is mediated by the formation of succinicGSH, a covalent adduct between fumarate and glutathione. Chronic succination of GSH, caused by the loss of FH, or by exogenous fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo . Importantly, the ablation of p21, a key mediator of senescence, in Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that fumarate-induced senescence needs to be bypassed for the initiation of renal cancers. Fumarate hydratase (FH) mutations are associated with renal cancer. Here, Zheng et al . use metabolomic and analytical chemistry approaches to reveal that fumarate accumulated due to FH loss covalently modifies intracellular glutathione, leading to oxidative stress and senescence.

Tumor plasticity, the capacity of malignant cells to undergo reversible phenotypic switching, is a fundamental driver of lineage diversion and therapeutic resistance. While the bacterial microbiome is a recognized modulator of the tumor microenvironment (TME), the non-bacterial oncobiome, comprising the mycobiome (fungi) and virome (viruses), represents a critical but under-explored frontier in cellular adaptability. This review synthesizes current evidence regarding the mechanistic contributions of fungal and viral constituents to tumor plasticity and characterizes the molecular cross-talk that facilitates host cell reprogramming. We conducted a structured narrative synthesis of literature indexed in PubMed, Scopus, and Web of Science (2020-2026), focusing on high-throughput studies such as ITS sequencing, metagenomics NGS (mNGS), and single-cell network analyses. We specifically evaluated evidence concerning the activation of host pattern recognition receptors and the subsequent transcriptional rewiring of lineage-defining markers. Emerging data indicate that fungal dysbiosis, particularly involving Candida and Malassezia species, triggers the Dectin-1/STAT3 signaling axis, a known inducer of epithelial-mesenchymal transition (EMT). Concurrently, the virome, ranging from integrated oncoviruses to reactivated endogenous retroviruses (ERVs), is shown to hijack the Wnt/ -catenin pathway, enforcing a progenitor-like stemness state. This inter-kingdom synergy promotes an immune-excluded niche, effectively shielding plastic sub-populations from cytotoxic stress and targeted therapies. The non-bacterial oncobiome provides genomic momentum and inflammatory cues necessary to lower the threshold for phenotypic switching. This review highlights that stabilizing the TME ecosystem through ecologically targeted therapy may be a prerequisite for overcoming drug resistance and improving clinical outcomes in refractory cancers.

The Ran GTPase regulates nuclear import and export by controlling the assembly state of transport complexes. This involves the direct action of RanGTP, which is generated in the nucleus by the chromatin‐associated nucleotide exchange factor, RCC1. Ran interactions with RCC1 contribute to formation of a nuclear:cytoplasmic (N:C) Ran protein gradient in interphase cells. In previous work, we showed that the Ran protein gradient is disrupted in fibroblasts from Hutchinson–Gilford progeria syndrome (HGPS) patients. The Ran gradient disruption in these cells is caused by nuclear membrane association of a mutant form of Lamin A, which induces a global reduction in heterochromatin marked with Histone H3K9me3 and Histone H3K27me3. Here, we have tested the hypothesis that heterochromatin controls the Ran gradient. Chemical inhibition and depletion of the histone methyltransferases (HMTs) G9a and GLP in normal human fibroblasts reduced heterochromatin levels and caused disruption of the Ran gradient, comparable to that observed previously in HGPS fibroblasts. HMT inhibition caused a defect in nuclear localization of TPR, a high molecular weight protein that, owing to its large size, displays a Ran‐dependent import defect in HGPS. We reasoned that pathways dependent on nuclear import of large proteins might be compromised in HGPS. We found that nuclear import of ATM requires the Ran gradient, and disruption of the Ran gradient in HGPS causes a defect in generating nuclear γ‐H2AX in response to ionizing radiation. Our data suggest a lamina–chromatin–Ran axis is important for nuclear transport regulation and contributes to the DNA damage response.

Small-cell lung cancer (SCLC) has long been characterized by its aggressive clinical course and a deceptive initial sensitivity to chemotherapy that almost invariably yields to recalcitrant disease. Recent genomic and transcriptomic profiling has dismantled the historical view of SCLC as a monolithic entity, revealing a complex landscape of inter- and intra-tumoral heterogeneity defined by the differential expression of key transcription factors—ASCL1, NEUROD1, POU2F3, and YAP1. Central to this heterogeneity is the phenomenon of lineage infidelity, a form of cellular plasticity where SCLC cells transit between molecularly distinct states to evade physiological and therapeutic pressures. In this review, we decode the epigenetic and transcriptional networks that govern these subtype transitions, highlighting how the loss of canonical lineage markers drives the emergence of variant phenotypes with altered metabolic and tumor profiles. We argue that this plasticity is not merely a byproduct of tumor evolution but a fundamental engine of chemoresistance. Crucially, we identify the acquired therapeutic vulnerabilities inherent to each state, proposing a transition from broad-spectrum cytotoxic regimens to a trajectory-based precision medicine framework. By targeting the gatekeepers of lineage identity and exploiting the transient weakness of emerging subtypes, we outline a roadmap for overcoming the historical stalemate in SCLC treatment and achieving sustained clinical responses.

Accumulation of fumarate resulting from mutations in fumarate hydratase,which are associated with renal and other cancers, is shown to induce epithelial-to-mesenchymal transition—a process associated with cancer initiation. Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer 1 . Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome 2 . Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite 3 . Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation 4 , 5 . However, the link between fumarate accumulation, epigenetic changes, and tumorigenesis is unclear. Here we show that loss of fumarate hydratase and the subsequent accumulation of fumarate in mouse and human cells elicits an epithelial-to-mesenchymal-transition (EMT), a phenotypic switch associated with cancer initiation, invasion, and metastasis 6 . We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster 6 mir-200ba429 , leading to the expression of EMT-related transcription factors and enhanced migratory properties. These epigenetic and phenotypic changes are recapitulated by the incubation of fumarate hydratase-proficient cells with cell-permeable fumarate. Loss of fumarate hydratase is associated with suppression of miR-200 and the EMT signature in renal cancer and is associated with poor clinical outcome. These results imply that loss of fumarate hydratase and fumarate accumulation contribute to the aggressive features of fumarate hydratase-deficient tumours.

Background Personalised medicine strategies may improve outcomes in pancreatic ductal adenocarcinoma (PDAC), but validation of predictive biomarkers is required. Having developed a clinical trial to assess the ATR inhibitor, AZD6738, in combination with gemcitabine (ATRi/gem), we investigated ATM loss as a predictive biomarker of response to ATRi/gem in PDAC. Methods Through kinase inhibition, siRNA depletion and CRISPR knockout of ATM, we assessed how ATM targeting affected the sensitivity of PDAC cells to ATRi/gem. Using flow cytometry, immunofluorescence and immunoblotting, we investigated how ATRi/gem synergise in ATM-proficient and ATM-deficient cells, before assessing the impact of ATM loss on ATRi/gem sensitivity in vivo. Results Complete loss of ATM function (through pharmacological inhibition or CRISPR knockout), but not siRNA depletion, sensitised to ATRi/gem. In ATM-deficient cells, ATRi/gem-induced replication catastrophe was augmented, while phospho-Chk2-T68 and phospho-KAP1-S824 persisted via DNA-PK activity. ATRi/gem caused growth delay in ATM-WT xenografts in NSG mice and induced regression in ATM-KO xenografts. Conclusions ATM loss augments replication catastrophe-mediated cell death induced by ATRi/gem and may predict clinical responsiveness to this combination. ATM status should be carefully assessed in tumours from patients with PDAC, since distinction between ATM-low and ATM-null could be critical in maximising the success of clinical trials using ATM expression as a predictive biomarker.

Developing new label-free paradigms for functional assays in biomedical research has the potential to catalyze efforts in drug discovery and improve the understanding of complex disorders. Mitochondria are an essential organelle in nearly every eukaryotic organism that perform vital functions such as adenosine triphosphate (ATP) production, redox signaling, reactive oxygen species (ROS) homeostasis and regulation of programmed cell death. These activities are regulated by electrophysiological processes that occur in the inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM) in response to metabolic demands, making them an important physiological marker for bioenergetic studies. Mitochondria dysfunction is an early pathological biomarker of complex diseases, such as diabetes, neurodegeneration, myopathy, cancer, and cardiovascular disease. Built atop a novel microfabrication strategy for 3D Microelectrode Arrays (MEAs), we demonstrate a 3D mitochondria biosensor capable of bimodal sensing of mitochondrial electrophysiology from the OMM and IMM using electrochemical impedance spectroscopy (EIS) and electrophysiology recordings. Data obtained using EIS displays impedance magnitude and phase characterization of mitochondria isolated from NIH3T3 and induced pluripotent stem cells (iPSC) models, these measurements represent the major functional outputs of cellular respiration and electron transport chain (ETC) activity through the detection of conductive and capacitive properties of the IMM. Additionally, time-resolved electrophysiological recordings from an NIH3T3 derived mitochondrial pellet captured sub-millisecond voltage transients, establishing a complementary real-time electrophysiological profile of mitochondrial membrane activity that can be attributed voltage dependent anion channel (VDAC) gating or IMM potential dynamics.

Plotter cutters in stencil mask prototyping are underutilized but have several advantages over traditional MEMS techniques. In this paper we investigate the use of a conventional plotter cutter as a highly effective benchtop tool for the rapid prototyping of stencil masks in the sub-250 μm range and characterize patterned layers of organic/inorganic materials. Furthermore, we show a new diagnostic monitoring application for use in healthcare, and a potential replacement of the Standard Kirby-Bauer Diffusion Antibiotic Resistance tests was developed and tested on both Escherichia coli and Xanthomonas alfalfae as pathogens with Oxytetracycline, Streptomycin and Kanamycin. We show that the reduction in area required for the minimum inhibitory concentration tests; allow for three times the number of tests to be performed within the same nutrient agar Petri dish, demonstrated both theoretically and experimentally resulting in correlations of R ≈ 0.96 and 0.985, respectively for both pathogens.

There are many events in the lives of insects where rapid, effective stress reactions are needed, including fighting conspecifics to defend territories, evading predators, and responding to wounds. A key element of the stress reaction is elevation of heartrate (HR), for enhancing distribution of blood (hemolymph) to body compartments. We conducted two experiments designed to improve understanding of the insect stress reaction and how it is influenced by parasitism in a common beetle species (Odontotaenius disjunctus). By non-destructively observing heartbeat frequency before, during and after applying a stressor (physical restraint) for 10 min, we sought to determine: (1) the exact timing of the cardiac stress reaction; (2) the magnitude of heartrate elevation during stress; and (3) if the physiological response is affected by a naturally-occurring nematode parasite, Chondronema passali. Restraint caused a dramatic increase in heartrate, though not immediately; maximum HR was reached after approximately 8 min. Average heartrate went from 65.5 beats/min to a maximum of 81.5 (24.5% increase) in adults raised in the lab (n = 19). Using wild-caught adults (n = 77), average heartrates went from 54.9 beats/min to 74.2 (35.5% increase). When restraint was removed, HR declined after ~5 min, and reached baseline 50 min later. The nematode parasite did not affect baseline heartrates in either experiment, but in one, it retarded the heartrate elevation during stress, and in the other, it reduced the overall magnitude of the elevation. While we acknowledge that our results are based on comparisons of beetles with naturally-occurring parasite infections, these results indicate this parasite causes a modest reduction in host cardiac output during acute stress conditions.