Resistance Signaling Research Articles

First-line durvalumab with arterial chemotherapy in major portal invaded hepatocellular carcinoma: The phase 2 DurHope study with biomolecular analyses.

576 Background: Current clinical trials for advanced hepatocellular carcinoma (HCC) significantly underrepresent patients (pts) with Vp4 portal vein tumor thrombus (PVTT), a poor prognostic factor, including only 0–15% despite their real-world prevalence of 24–49%. Previous FOHAIC-1 study indicated the favorable efficacy of arterial FOLFOX chemotherapy in this population. Preclinical evidence suggested that oxaliplatin in the FOLFOX regimen can induce immunogenic cell death. The DurHope study is a biomolecular exploratory, phase 2 trial of first-line durvalumab combined with arterial FOLFOX in pts with Vp4 PVTT. Methods: This trial enrolled 30 HCC pts with Vp4 (n = 24, 80.0%) or Vp3 (n = 6, 20.0%) PVTT. Arterial FOLFOX was given on day 1–3, plus durvalumab (1120 mg) intravenously on day 7 (± 2) of each 21-day cycle up to 8 cycles. Maintenance durvalumab (1500 mg) was administered every 28 days thereafter until disease progression, unacceptable toxicity, or death. Primary endpoint was 1-year OS rate. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) per RECIST v1.1, and safety. Single-cell RNA sequencing (scRNA-seq) was performed on pre-treatment biopsies and peripheral blood mononuclear cells (PBMCs) collected at baseline and during treatment from responders (CR/PR) and nonresponders (SD/PD). Results: With a median follow-up of 21.6 months, the 1-year OS rate was 63.3%, median OS was 13.9 months (95% CI, 10.7–NR), and median PFS was 9.0 months (95% CI, 4.5–12.2). ORR was 53.3% (CR: 5/30 [16.7%]; PR: 11/30 [36.7%]), and median duration of response was 9.1 months (> 6 months: 11/16 [68.8%]; > 12 months: 4/16 [25%]). Grade ≥ 3 TRAEs occurred in 43.3% of patients, with no unexpected safety events beyond those of each agent. ScRNA-seq of biopsies revealed enrichment of chemotherapy resistance and immune escape signatures in non-responders, while responders exhibited higher immune cell infiltration and stronger immune-malignant cell interaction. Dynamic scRNA-seq of serial PBMCs demonstrated expanded T cell subsets and increased expression of cytotoxicity-related genes (e.g., GZMB, GNLY, and IFNG) and proliferation marker (MKI67) after treatment, which was more pronounced in responders. This was accompanied by decreased non-classical monocyte frequency and reduced M2-directed monocyte polarization in responders. In vivo mouse models further showed enhanced efficacy of the combination of chemotherapy and PD-L1 blockade, indicating the synergistic effects of this therapeutic approach. Conclusions: Durvalumab plus arterial FOLFOX showed promising efficacy and manageable toxicities in advanced HCC with Vp4 PVTT. Biomolecular exploratory analyses revealed enhanced cellular immune responses triggered by treatment, along with novel molecular biomarkers that may help predict therapeutic response. Clinical trial information: NCT04945720 .

Identification and validation of a prognostic signature of drug resistance and mitochondrial energy metabolism-related differentially expressed genes for breast cancer

BackgroundDrug resistance constitutes one of the principal causes of poor prognosis in breast cancer patients. Although cancer cells can maintain viability independently of mitochondrial energy metabolism, they remain reliant on mitochondrial functions for the synthesis of new DNA strands. This dependency underscores a potential link between mitochondrial energy metabolism and drug resistance. Hence, drug resistance and mitochondrial energy metabolism-related differentially expressed genes (DMRDEGs) may emerge as candidates for novel cancer biomarkers. This study endeavors to assess the viability of DMRDEGs as biomarkers or therapeutic targets for breast cancer.MethodsWe utilized the DRESIS database and MSigDB to identify genes related to drug resistance. Additionally, we sourced genes associated with mitochondrial energy metabolism from GeneCards and extant literature. By merging these genes with differentially expressed genes observed in normal and tumor tissues from the TCGA-BRCA and GEO databases, we successfully identified the DMRDEGs. Employing unsupervised consensus clustering, we divided breast cancer patients into two distinct groups based on the DMRDEGs. Consequently, we identified four hub genes to formulate a prognostic model, applying Cox regression, LASSO regression, and Random Forest methods. Furthermore, we examined immune infiltration and tumor mutation burden of the genes within our model and scrutinized divergences in the immune microenvironment between high- and low-risk groups. Small hairpin RNA and lentiviral plasmids were designed for stable transfection of breast cancer cell lines MDA-MB-231 and HCC1806. By conducting clone formation, scratch test, transwell assays, cell viability assay and measurement of oxygen consumption we initiated a preliminary investigation into mechanistic roles of AIFM1.ResultsWe utilized DMRDEGs to develop a prognostic model that includes four mRNAs for breast cancer. This model combined with various clinical features and critical breast cancer facets, demonstrated remarkable efficacy in predicting patient outcomes. AIFM1 appeared to enhance the proliferation, migration, and invasiveness of breast cancer cell lines MDA-MB-231 and HCC1806. Moreover, by reducing oxygen consumption, it aids in the cancer cells' acquisition of drug resistance.ConclusionsDMRDEGs hold promise as diagnostic markers and therapeutic targets for breast cancer. Among the associated mutated genes, ATP7B, FUS, AIFM1, and PPARG could serve as early diagnostic indicators, and notably, AIFM1 may present itself as a promising therapeutic target.

Clinical significance of stratifying prostate cancer patients through specific circulating genes.

Patient stratification remains a challenge for optimal treatment of prostate cancer (PCa). This clinical heterogeneity implies intra-tumoural heterogeneity, with different prostate epithelial cell subtypes not all targeted by current treatments. We reported that such cell subtypes are traceable in liquid biopsies through representative transcripts. Expanding on this concept, we included 57 genes representing cell subtypes, drug targets and relevant to resistance as non-invasive biomarkers for stratification. This panel was tested by RT-qPCR (quantitative reverse transcription polymerase chain reaction) in blood of controls and different categories of PCa patients. Overall, circulating transcripts showed predictive value throughout the disease. Those with aggressive pathological features such as intra-ductal carcinoma at diagnosis showed more genes over-expressed. In metastatic patients, signatures of subtypes or resistance were associated with treatments, progression-free survival and overall survival. Altogether, testing markers of cell diversity, an intrinsic feature of tumours, and drug targets via liquid biopsies represents a valuable means to stratify patients and predict responses to current or new therapeutic modalities. Over-expressed drug target genes suggest potential benefit from targeted treatments, justifying new clinical trials to offer patient-tailored strategies to eventually impact on PCa mortality.

Molecular hallmarks of excitatory and inhibitory neuronal resilience and resistance to Alzheimer's disease.

A significant proportion of individuals maintain healthy cognitive function despite having extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals can identify therapeutic targets for AD dementia. This study aims to define molecular and cellular signatures of cognitive resilience, protection and resistance, by integrating genetics, bulk RNA, and single-nucleus RNA sequencing data across multiple brain regions from AD, resilient, and control individuals. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk (n=631) and multi-regional single nucleus (n=48) RNA sequencing. Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition distribution. Transcriptomic results, supported by GWAS-derived polygenic risk scores, place cognitive resilience as an intermediate state in the AD continuum. Tissue-level analysis revealed 43 genes enriched in nucleic acid metabolism and signaling that were differentially expressed between AD and resilience. Only GFAP (upregulated) and KLF4 (downregulated) showed differential expression in resilience compared to controls. Cellular resilience involved reorganization of protein folding and degradation pathways, with downregulation of Hsp90 and selective upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. Excitatory neuronal subpopulations in the entorhinal cortex (ATP8B1+ and MEF2Chigh) exhibited unique resilience signaling through neurotrophin (modulated by LINGO1) and angiopoietin (ANGPT2/TEK) pathways. We identified MEF2C, ATP8B1, and RELN as key markers of resilient excitatory neuronal populations, characterized by selective vulnerability in AD. Protective rare variant enrichment highlighted vulnerable populations, including somatostatin (SST) inhibitory interneurons, validated through immunofluorescence showing co-expression of rare variant associated RBFOX1 and KIF26B in SST+ neurons in the dorsolateral prefrontal cortex. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. We identified molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preservation of neuronal function, maintenance of excitatory/inhibitory balance, and activation of protective signaling pathways. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable SST interneurons likely provide compensation against AD-associated dysregulation. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Fecal propionate is a signature of insulin resistance in polycystic ovary syndrome.

To investigate the roles of fecal short-chain fatty acids (SCFAs) in polycystic ovary syndrome (PCOS). The levels of SCFAs (acetate, propionate, and butyrate) in 83 patients with PCOS and 63 controls were measured, and their relationships with various metabolic parameters were analyzed. Intestinal microbiome analysis was conducted to identify relevant bacteria. The study took place at the Center for Reproductive Medicine at Shengjing Hospital of China Medical University in Shenyang, from 5 February to 23 May 2023. Logistic regression analyses were used to investigate the relationships between SCFAs, PCOS, and PCOS-related insulin resistance (IR). Differences in bacterial populations between women with PCOS-IR and those with PCOS-non-insulin resistance (NIR) were identified using linear discriminant analysis effect Size (LEfSe). The relationships between bacteria and fecal propionate levels were explored through linear regression analyses. The potential of fecal propionate and microbial profiles as biomarkers for insulin resistance in PCOS patients was assessed using receiver operating characteristic (ROC) curve analysis. Higher fecal propionate levels were observed in patients with PCOS compared to controls (p = 0.042) and in PCOS-IR compared to PCOS-NIR (p = 0.009). There was no significant difference in fecal propionate levels between the IR and NIR subgroups of women in the control group (p > 0.05). Additionally, higher fecal propionate levels were associated with IR in PCOS (p = 0.039; OR, 1.115; 95% CI, 1.006-1.237). The abundance of Prevotella copri and Megamonas funiformis was higher in PCOS-IR women compared to PCOS-NIR women (LDA score > 3) and correlated with fecal propionate levels (adjusted R² = 0.145, p < 0.001). The area under the curve (AUC) for propionate and the combined presence of P. copri and M. funiformis in predicting PCOS was 78.0%, with a sensitivity of 78.5% and a specificity of 72.4%. Pathways related to carbohydrate metabolism were significantly enriched in the microbiota of the PCOS-IR population but not in the control IR group. Higher fecal propionate levels correlate with PCOS-related insulin resistance. P. copri and M. funiformis might be key functional bacteria. Therefore, the combination of propionate levels and the abundance of these two bacteria may serve as a potential biomarker for insulin resistance in PCOS patients. Regulation of the intestinal microbiome might be beneficial for the metabolic health of women with PCOS.

An early, transient Interferon-associated innate immune response associates with protection from SARS-CoV-2 infection

A proportion of individuals exposed to respiratory viruses avoid contracting detectable infection. We tested the hypothesis that early innate immune responses associate with resistance to detectable infection in close contacts of COVID-19 cases. 48 recently-exposed household contacts of symptomatic COVID-19 cases were recruited in London, UK between May 2020 and March 2021 through a prospective, longitudinal observational study. Blood and nose and throat swabs were collected during the acute period of index case viral shedding and longitudinally thereafter. Magnitude of SARS-CoV-2 exposure was quantified, and serial PCR and serological assays used to determine infection status of contacts. Whole-blood RNA-seq was performed and analysed to identify transcriptomic signatures of early infection and resistance to infection. 24 highly-exposed household contacts became PCR-positive and seropositive whilst 24 remained persistently PCR-negative and seronegative. A 96-gene transcriptomic signature of early SARS-CoV-2 infection was identified using RNA-seq of longitudinal blood samples from PCR-positive contacts. This signature was dominated by interferon-associated genes and expression correlated positively with viral load. Elevated expression of this 96-gene signature was also observed during exposure in 25% (6/24) of persistently PCR-negative, seronegative contacts. PCR-negative contacts with elevated signature expression had higher-magnitude SARS-CoV-2 exposure compared to those with low signature expression. We validated this signature in SARS-CoV-2-infected individuals in two independent cohorts. In naturally-exposed healthcare workers (HCWs) we found that 7/58 (12%) PCR-negative HCWs exhibited elevated signature expression. Comparing gene-signature expression in SARS-CoV-2 Controlled Human Infection Model (CHIM) volunteers pre- and post-inoculation, we observed that 14 signature genes were transiently upregulated as soon as 6hr post-inoculation in PCR-negative volunteers, while in PCR-positive volunteers gene-signature upregulation did not occur until 3 days later. Our interferon-associated signature of early SARS-CoV-2 infection characterises a subgroup of exposed, uninfected contacts in three independent cohorts who may have successfully aborted infection prior to induction of adaptive immunity. The earlier transient upregulation of signature genes in PCR-negative compared to PCR-positive CHIM volunteers suggests that ultra-early interferon-associated innate immune responses correlate with, and may contribute to, protection against SARS-CoV-2 infection. This work was supported by the NIHR Health Protection Research Unit in Respiratory Infections, United Kingdom, NIHR Imperial College London, United Kingdom (Grant number: NIHR200927; AL) in partnership with the UK Health Security Agency and the NIHR Medical Research Council (MRC), United Kingdom (Grant number: MR/X004058/1). Support for sequencing was provided by the Imperial BRC Genomics Facility which is funded by the NIHR, United Kingdom. The development of the hybrid DABA assay used for quantification of SARS-CoV-2 anti-Spike RBD antibodies was supported by the MRC (MC_PC_19078).

Identification of SETD4 as an Onco-Immunological Biomarker Encompassing the Tumor Microenvironment, Prognoses, and Therapeutic Responses in Various Human Cancers.

SET domain-containing protein 4 (SETD4) is a histone methyltransferase that has been shown to modulate cell proliferation, differentiation, and inflammatory responses by regulating histone H4 trimethylation (H4K20me3). Previous reports have demonstrated its function in the quiescence of cancer stem cells as well as drug resistance in several cancers. A limited number of systematic studies have examined SETD4's role in the tumor microenvironment, pathogenesis, prognosis, and therapeutic response. Utilizing The Cancer Genome Atlas database, and other publicly accessible platforms, we comprehensively analyzed SETD4 gene expression, methylation patterns, and prognostic significance. Furthermore, we investigated its association with cancer-related pathways, the immune microenvironment, immunotherapy markers, and drug resistance signatures of chemotherapy. Additionally, qRT-PCR was performed to validate SETD4 expression in clinical specimens. The expression of SETD4 was abnormal across a variety of cancer types and the expression of SETD4 in colorectal cancer tissues was verified in clinical specimens. The upregulation of SETD4 may be a prognostic risk factor predicting poor overall survival and progression-free survival. The analysis revealed that the mRNA level of SETD4 was modulated by promoter methylation, and patients with lower methylation levels showed shorter survival times. Pathway analysis showed that SETD4 influenced several key cell cycle pathways, including the G2M checkpoint, and mitotic spindle pathways. In addition, SETD4 negatively affects immune cell infiltration in most cancers, including B cells, CD8 T cells, and macrophages. The correlation between SETD4 and cancer stemness as well as homologous recombination deficiency varied across tumor types, suggesting that SETD4 may play a multifaceted role in tumor resistance. Notably, we identified several potential agents targeting SETD4. This study demonstrates that SETD4 is an immune-oncogenic molecule in multiple cancers, with the potential to be a diagnosis, prognosis, and targeted therapy marker.

Systems-level liquid biopsy in advanced prostate cancer.

Treatment for castration-resistant prostate cancer (CRPC) primarily involves suppression of androgen receptor (AR) activity using androgen receptor signaling inhibitors (ARSIs). While ARSIs have extended patient survival, resistance inevitably develops. Mechanisms of resistance include genomic aberrations at the AR locus that reactivate AR signaling or lineage plasticity that drives emergence of AR-independent phenotypes. Given the diverse mechanisms of ARSI resistance in CRPC, there is a need for more effective monitoring strategies that detect signs of resistance to inform prognosis and guide use of alternative therapies. Liquid biopsy is a blood test that has emerged as a powerful, minimally invasive tool for investigating advanced cancer. In CRPC, liquid biopsy has been shown to reflect genomic and transcriptomic features in tumor tissue and has been utilized to detect an array of resistance signatures. Liquid biopsy is uninhibited by spatial restrictions and allows for longitudinal monitoring of disease progression. However, current clinical liquid biopsy tests provide limited actionable information. This review highlights recent advancements to the understanding of mechanisms driving treatment resistance in CRPC through research-grade liquid biopsy assays. We explore novel methods of disease characterization developed using liquid biopsy and emphasize the clinical potential of a multi-omics molecular profiling approach to comprehensively detect emerging therapeutic resistance. Routine assessment of therapy resistance using a liquid biopsy assay has the potential to enhance prognostication and improve outcomes of men with CRPC.

Resistance Signatures to Oncolytic Vesiculoviruses in Pancreatic Ductal Adenocarcinoma

Resistance Signatures to Oncolytic Vesiculoviruses in Pancreatic Ductal Adenocarcinoma

All-trans retinoic acid sensitizes epithelial ovarian cancer to PARP inhibition after exposure to cisplatin.

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Notably, Platinum-based chemotherapy induces resistance of EOC to poly (ADP-ribose) polymerase (PARP) inhibition. However, therapeutic approaches targeting PARP inhibitors (PARPi) resistance remain to be explored. Here, we show that all-trans retinoic acid (ATRA) reduces PARPi resistance-associated EOC cells induced by cisplatin (CDDP) treatment. Clinically applicable ATRA suppressed the outgrowth of CDDP-treated EOC cells both in vitro and in vivo. Moreover, a CDDP treatment followed by niraparib maintenance therapy in combination with ATRA improved the survival of EOC-bearing mice. These phenotypes correlated with PARPi resistant EOC signature, which consists of elevated expression of ALDH1A1, NAMPT, PARP1 and Chk1, as well as elevated NAD+ level-mediated high activity of ALDH1A1 and PARP1. Mechanistically, ATRA down-regulates the expression of these genes and level of intracellular NAD+. Our results suggest that ATRA in conjunction with PARPi represents a promising maintenance therapeutic strategy for EOC.

Insecticide Resistance of Xenopsylla cheopis in Madagascar: Revision of Diagnostic Doses for Bioassay and Exploration of Biochemical Mechanisms.

The Oriental rat flea, Xenopsylla cheopis, is known worldwide as an efficient plague vector, including in Madagascar, where the disease remains a public health concern. Chemical control is the primary response method against X. cheopis in Madagascar. Previous bioassays focusing on different flea populations from Madagascar showed phenotypic resistance to various insecticides, including deltamethrin and fenitrothion, which, respectively, represent the previous and current chemicals for flea vector control. Despite apparent insecticide resistance, the associated mechanisms of this resistance remain poorly known. The aims of this study were to adjust diagnostic doses of deltamethrin and fenitrothion and to investigate the metabolism-based insecticide resistance of X. cheopis in Madagascar. Five available laboratory-reared flea strains of X. cheopis were selected, and their susceptibility statuses to deltamethrin and fenitrothion were determined using the WHO standard bioassay. Diagnostic doses of each insecticide were determined by the probit method, in accordance with concentration gradients. Biochemical microplate-based assays were performed to detect overproduction of cytochrome P450, alpha-/beta-esterases, and glutathione S-transferase (GST), which are signatures of metabolic resistance. The five tested strains showed different susceptibility statuses against deltamethrin and fenitrothion. The diagnostic doses were estimated to be 0.07% for deltamethrin and 1.56% for fenitrothion. Increased activities of cytochrome P450, beta-esterase, and GST enzymes in the resistant strains were revealed in comparison with those of the susceptible strain. In conclusion, readjusted diagnostic doses will help to better understand the susceptibility status of X. cheopis to deltamethrin and fenitrothion. The overproduction of cytochrome P450, beta-esterase, and GST observed on deltamethrin-resistant flea strains suggests metabolic resistance.

CtDNA-based liquid biopsy reveals wider mutational profile with therapy resistance and metastasis susceptibility signatures in early-stage breast cancer patients

ctDNA-based liquid biopsy reveals wider mutational profile with therapy resistance and metastasis susceptibility signatures in early-stage breast cancer patients

Integrated multi-omics and machine learning reveal a gefitinib resistance signature for prognosis and treatment response in lung adenocarcinoma.

Gefitinib resistance (GR) presents a significant challenge in treating lung adenocarcinoma (LUAD), highlighting the need for alternative therapies. This study explores the genetic basis of GR to improve prediction, prevention, and treatment strategies. We utilized public databases to obtain GR gene sets, single-cell data, and transcriptome data, applying univariate and multivariate regression analyses alongside machine learning to identify key genes and develop a predictive signature. The signature's performance was evaluated using survival analysis and time-dependent ROC curves on internal and external datasets. Enrichment and tumor immune microenvironment analyses were conducted to understand the mechanistic roles of the signature genes in GR. Our analysis identified a robust 22-gene signature with strong predictive performance across validation datasets. This signature was significantly associated with chromosomal processes, DNA replication, immune cell infiltration, and various immune scores based on enrichment and tumor microenvironment analyses. Importantly, the signature also showed potential in predicting the efficacy of immunotherapy in LUAD patients. Moreover, we identified alternative agents to gefitinib that could offer improved therapeutic outcomes for high-risk and low-risk patient groups, thereby guiding treatment strategies for gefitinib-resistant patients. In conclusion, the 22-gene signature not only predicts prognosis and immunotherapy efficacy in gefitinib-resistant LUAD patients but also provides novel insights into non-immunotherapy treatment options.

From Structure to Performance: Insights into the Role of Porous Transport Layers in PEM Water Electrolysis via Electrode Engineering

Proton Exchange Membrane Water Electrolyzers (PEMWEs) are a promising technology to combat the deleterious effects of climate change [1]. It uses intermittent electricity from sustainable energy sources to electrochemically generate green hydrogen – a carbon-free energy carrier. Most importantly, the integration of water electrolyzers with fuel cells into a single reversible system is an enabler to achieving hydrogen-based long-duration energy storage. To make PEMWE systems more cost-competitive and technologically viable, it is essential to control the ohmic and mass transport limitations, a significant contribution of which stems from the fibrous porous transport layers (PTLs). In this work, we present a multiscale framework to investigate the effect of PTL electrode parameters on the electrochemical response of the PEMWE. Our starting point is stochastically generated PTL configurations with a host of microstructural features such as fiber diameter, porosity, fiber orientation, etc. The salient morphology-dependent transport properties like tortuosities, effective electronic conductivities, and two-phase permeabilities are then evaluated by employing pore-network modeling [2]. These are subsequently deployed to a physics-based multiphase reactive transport model [3] of the electrolyzer to quantify the concomitant overpotential modes. The interplay of operating regimes and PTL structural parameters on the resistive signature is further delineated. An optimization of the PTL architecture along with its pore size distribution investigated in this study can guide the design of experiments towards high-performing PEMWEs with enhanced catalyst utilization and mass transport.

Polyploid cancer cells reveal signatures of chemotherapy resistance.

Therapeutic resistance in cancer significantly contributes to mortality, with many patients eventually experiencing recurrence after initial treatment responses. Recent studies have identified therapy-resistant large polyploid cancer cells in patient tissues, particularly in late-stage prostate cancer, linking them to advanced disease and relapse. Here, we analyzed bone marrow aspirates from 44 advanced prostate cancer patients and found the presence of circulating tumor cells with increased genomic content (CTC-IGC) was significantly associated with poorer progression-free survival. Single cell copy number profiling of CTC-IGC displayed clonal origins with typical CTCs, suggesting complete polyploidization. Induced polyploid cancer cells from PC3 and MDA-MB-231 cell lines treated with docetaxel or cisplatin were examined through single cell DNA sequencing, RNA sequencing, and protein immunofluorescence. Novel RNA and protein markers, including HOMER1, TNFRSF9, and LRP1, were identified as linked to chemotherapy resistance. These markers were also present in a subset of patient CTCs and are associated with recurrence in public gene expression data. This study highlights the prognostic significance of large polyploid tumor cells, their role in chemotherapy resistance, and the expression of markers tied to cancer relapse, offering new potential avenues for therapeutic development.

Metabolic signature of insulin resistance and risk of Alzheimer's disease.

Substantial evidence supports the relationship between peripheral insulin resistance (IR) and the development of Alzheimer's disease (AD)-dementia. However, the mechanisms explaining these associations are only partly understood. We aimed to identify a metabolic signature of IR associated with the progression from mild cognitive impairment (MCI) to AD-dementia. This is a case-control study on 400 MCI subjects, free of type 2 diabetes, within the ACE cohort, including individuals ATN+ and ATN-. After a median of 2.1 years follow-up, 142 subjects converted to AD-dementia. IR was assessed using the HOMA-IR. A targeted multi-platform approach profiled over 600 plasma metabolites. Elastic net penalized linear regression with 10-fold cross-validation was employed to select those metabolites associated with HOMA-IR. The prediction ability of the signature was assessed using support vector machine and performance metrics. The metabolic signature was associated with AD-dementia risk using a multivariable Cox regression model. Using counterfactual-based mediation analysis we investigated the mediation role of the metabolic signature between HOMA-IR and AD-dementia. The metabolic pathways in which the metabolites were involved were identified using MetaboAnalyst. The metabolic signature comprised 18 metabolites correlated with HOMA-IR. After adjustments by confounders, the signature was associated with increased AD-dementia risk (HR 1.234; 95%CI 1.019-1.494; p<0.05). The metabolic signature mediated 35% of the total effect of HOMA-IR on AD-dementia risk. Significant metabolic pathways were related to glycerophospholipid and tyrosine metabolism. We have identified a blood-based metabolic signature that reflects IR and may enhance our understanding of the biological mechanisms through which IR affects AD-dementia.

Microglia induce an interferon-stimulated gene expression profile in glioblastoma and increase glioblastoma resistance to temozolomide.

Glioblastoma is the most malignant primary brain tumour. Even with standard treatment comprising surgery followed by radiation and concomitant temozolomide (TMZ) chemotherapy, glioblastoma remains incurable. Almost all patients with glioblastoma relapse owing to various intrinsic and extrinsic resistance mechanisms of the tumour cells. Glioblastomas are densely infiltrated with tumour-associated microglia and macrophages (TAMs). These immune cells affect the tumour cells in experimental studies and are associated with poor patient survival in clinical studies. The aim of the study was to investigate the impact of microglia on glioblastoma chemo-resistance. We co-cultured patient-derived glioblastoma spheroids with microglia at different TMZ concentrations and analysed cell death. In addition, we used RNA sequencing to explore differentially expressed genes after co-culture. Immunostaining was used for validation. Co-culture experiments showed that microglia significantly increased TMZ resistance in glioblastoma cells. RNA sequencing revealed upregulation of a clear interferon-stimulated gene (ISG) expression signature in the glioblastoma cells after co-culture with microglia, including genes such as IFI6, IFI27, BST2, MX1 and STAT1. This ISG expression signature is linked to STAT1 signalling, which was confirmed by immunostaining. The ISG expression profile observed in glioblastoma cells with enhanced TMZ resistance corresponded to the interferon-related DNA damage resistance signature (IRDS) described in different solid cancers. Here, we show that the IRDS signature, linked to chemo-resistance in other cancers, can be induced in glioblastoma by microglia. ISG genes and the microglia inducing the ISG expression could be promising novel therapeutic targets in glioblastoma.

Polyploid cancer cells reveal signatures of chemotherapy resistance.

Therapeutic resistance in cancer significantly contributes to mortality, with many patients eventually experiencing recurrence after initial treatment responses. Recent studies have identified therapy-resistant large polyploid cancer cells in patient tissues, particularly in late-stage prostate cancer, linking them to advanced disease and relapse. Here, we analyzed bone marrow aspirates from 44 advanced prostate cancer patients and found the presence of CTC-IGC was significantly associated with poorer progression-free survival. Single cell copy number profiling of CTC-IGC displayed clonal origins with typical CTCs, suggesting complete polyploidization. Induced polyploid cancer cells from PC3 and MDA-MB-231 cell lines treated with docetaxel or cisplatin were examined through single cell DNA sequencing, RNA sequencing, and protein immunofluorescence. Novel RNA and protein markers, including HOMER1, TNFRSF9, and LRP1, were identified as linked to chemotherapy resistance. These markers were also present in a subset of patient CTCs and associated with recurrence in public gene expression data. This study highlights the prognostic significance of large polyploid tumor cells, their role in chemotherapy resistance, and their expression of markers tied to cancer relapse, offering new potential avenues for therapeutic development.

Integrated Geophysical Investigation using Aero-radiometric and Electrical Methods for Potential Gold mineralization within Yauri/Zuru Schist Belts, Kebbi State NW Nigeria

This study used aero-radiometric, 2D electrical resistivity tomography (ERT), and induced polarization (IP) methods to delineate gold mineralization potential. The study also confirmed and followed-up on regions with major structural features identified in previous aeromagnetic studies in the area. A half-degree airborne radiometric data of sheet 118_Yelwa from the NGSA, which contains three radioelements (%K, eTh, and eU) were used in this study. These datasets were processed and analyzed with Oasis Montaj Grid Math expression builder to obtain the %K_ratio_eTh and Ternary grid anomalies. The results identified zones E and F as hydrothermally altered regions that may harbour gold mineralization. These findings were consistent with the regions of major structural features identified in previous aeromagnetic studies in the area. The zones were located in the eastern parts of Ngaski, Yauri (Yelwa), Shanga, and Agwara, as well as Magama's northwest region. However, zone F1 (the eastern portion of Ngaski/Yauri) has been further investigated using 2ERT and IP detailed geophysical methods in a dipole-dipole configuration. The results of geoelectric techniques along profiles 1, 2, and 3 identified the major gold mineralization potential zones, which were labeled A1, A, and C. These regions have low/high resistivity and chargeability signatures, and could thus be interpreted as potential target zones for metallic mineral exploration, particularly gold mineralization. The regions are located in the northern part of Mararraba and southwest of the Jinsani areas of Kebbi State.

Metabolomic characterization of human glioblastomas and patient plasma: a pilot study

Background Glioblastoma (GBM) is a clinically challenging primary brain tumor with poor survival outcome despite surgical resection and intensive chemoradiation. The metabolic heterogeneity of GBM can become biomarkers for treatment response, resistance, and outcome prediction. The aim of the study is to investigate metabolic distinctions between primary and recurrent GBM tissue and patient plasma to establish feasibility for metabolic profiling. Methods A single-center cohort study analyzed tissue and blood samples from 15 patients with GBM using untargeted metabolomic/lipidomic assays. Metabolomic, lipidomic, and biogenic amine analyses were conducted on GBM tissue and patient plasma at diagnosis and recurrence using untargeted mass spectrometry. The study utilized a small but longitudinally collected cohort to evaluate alteration in metabolites, lipids, and biogenic amines between specimens at diagnosis and recurrence. Results Exploratory analysis revealed significant alteration in metabolites, lipids, and biogenic amines between diagnostic and recurrent states in both tumor and plasma specimens. Notable metabolites differed at recurrence, including N-alpha-methylhistamine, glycerol-3-phosphate, phosphocholine, and succinic acid in tissue, and indole-3-acetate, and urea in plasma. Principal component analysis revealed distinct metabolomic profiles between tumor tissue and patient plasma. Distinct metabolic profiles were observed in GBM tissue and patient plasma at recurrence, demonstrating the feasibility of using metabolomic methodologies for longitudinal studies. One patient exhibited a unique tumor resistance signature at diagnosis, possibly indicating a high-risk metabolomic phenotype. Conclusions In this small cohort, the findings suggest the potential of metabolomic signatures of GBM tissue and patient plasma for risk stratification, outcome prediction, and the development of novel adjuvant metabolic-targeting therapies. The findings suggest metabolic discrepancies at diagnosis and recurrence in tissue and plasma, highlighting potential implications for evaluation of clinical response. The identification of significant changes in metabolite abundance emphasizes the need for larger studies using targeted metabolomics to validate and further explore these profiles.