Salivary Protein Cyclin-Dependent Kinase-like from Grain Aphid Sitobion avenae Suppresses Wheat Defense Response and Enhances Aphid Adaptation.

Aphids are insect pests that suck phloem sap and introduce salivary proteins into plant tissues through saliva secretion. The effector of salivary proteins plays a key role in the modulation of host plant defense responses and enhancing aphid host adaptation. Based on previous transcriptome sequencing results, a candidate effector cyclin-dependent kinase-like (CDK) was identified from the grain aphid Sitobion avenae. In this study, the function of SaCDK in wheat defense response and the adaptation of S. avenae was investigated. Our results showed that the transient overexpression of SaCDK in tobacco Nicotiana benthamiana suppressed cell death triggered by mouse pro-apoptotic protein-BAX or Phytophthora infestans PAMP-INF1. SaCDK, delivered into wheat cells through a Pseudomonas fluorescens-mediated bacterial type III secretion system, suppressed callose deposition in wheat seedlings, and the overexpression of SaCDK in wheat significantly decreased the expression levels of salicylic acid and jasmonic acid signaling pathway-related genes phenylalanine ammonia lyase (PAL), pathogenesis-related 1 protein (PR1), lipoxygenase (LOX) and Ω-3 fatty acid desaturase (FAD). In addition, aphid bioassay results showed that the survival and fecundity of S. avenae were significantly increased while feeding on the wheat plants carrying SaCDK. Taken together, our findings demonstrate that the salivary protein SaCDK is involved in inhibiting host defense response and improving its host adaptation, which lays the foundation to uncover the mechanism of the interaction of cereal aphids and host plants.

Autologous Hematopoietic Cell Transplantation Consolidation for First Response is Associated With Longer Survival Among Patients With Nodal Peripheral T Cell Lymphoma.

Nodal peripheral T cell lymphomas (PTCLs) are challenging subsets of non-Hodgkin lymphomas characterized by their heterogeneity and aggressive clinical behavior. Given the mixed outcomes reported in previous studies, the efficacy of autologous hematopoietic cell transplantation (auto-SCT) as a consolidation strategy following initial chemotherapy response remains uncertain. This study aims to evaluate the impact of upfront auto-SCT consolidation on overall survival (OS) and event-free survival (EFS) among patients with nodal PTCL who achieved a complete or partial response to initial chemotherapy. A retrospective cohort study was conducted at Moffitt Cancer Center, involving 123 patients with nodal PTCL treated between February 2005 and February 2021. Patients were stratified into 2 groups based on whether they received auto-SCT as part of their initial treatment strategy. Kaplan-Meier method and Cox proportional hazard models were used for statistical analysis to compare OS and EFS between groups. Patients undergoing auto-SCT after first response demonstrated significantly longer median OS (12.3 versus 4.3 yr; P = .035) and EFS (6.2 versus 2.2 yr; P = .003) compared to those who did not. Multivariate analyses indicated that auto-SCT at first response and younger age at diagnosis were favorable prognostic factors. The findings suggest that upfront auto-SCT consolidation can significantly improve long-term outcomes in patients with nodal PTCL, supporting the strategy of early auto-SCT consideration and referral following initial chemotherapy response. These results underscore the importance of integrating upfront auto-SCT into the treatment paradigm for nodal PTCL, emphasizing early referral to transplantation services to optimize patient outcomes.

Characteristics of lipid metabolism after treatment of colon cancer mice with American ginseng vesicles.

INTRODUCTION: Lipid molecules are present in tumours and play an important role in the anti-inflammatory response as well as in antiviral protection. Changes in the type and location of lipids in the intestine following exposure to environmental stressors play an important role in several disorders, including ulcerative colitis (UC), inflammatory bowel disease (IBD), and colorectal cancer. OBJECTIVES: The aim of this work is to provide a new theoretical basis for tumour initiation and development by accurately measuring the spatial distribution of lipids and metabolites in intestinal tissue. Spatial metabolomics allows the detection of samples with minimal sample volume by label-free imaging of complex samples in their original state. The distribution of lipid molecules in tumours has not been reported, although the distribution of lipid molecules in intestinal tissue has been reported in the literature. METHODS: The range of lipid profiles in colon cancer mouse tumour tissue was compiled using a spatial metabolomics: lipid extraction method. The changes in lipid distribution in two regions after oral administration of American Ginseng (Panax quinquefolius L.) vesicles were also compared. Tumour tissue samples were extracted with 80% methanol-20% formic acid in water. RESULTS: The resulting spatial metabolic profile allowed the identification of seven lipid classes in mouse tumours. The distribution of fibre tissue cells was 23.2% higher than tumour tissue cells, with the exception of the fatty acid (FA) species.

MiR-146a reduces fibrosis after glaucoma filtration surgery in rats.

PURPOSE: To explore the impact of microRNA 146a (miR-146a) and the underlying mechanisms in profibrotic changes following glaucoma filtering surgery (GFS) in rats and stimulation by transforming growth factor (TGF)-ß1 in rat Tenon's capsule fibroblasts. METHODS: Cultured rat Tenon's capsule fibroblasts were treated with TGF-ß1 and analyzed with microarrays for mRNA profiling to validate miR-146a as the target. The Tenon's capsule fibroblasts were then respectively treated with lentivirus-mediated transfection of miR-146a mimic or inhibitor following TGF-ß1 stimulation in vitro, while GFS was performed in rat eyes with respective intraoperative administration of miR-146a, mitomycin C (MMC), or 5-fluorouracil (5-FU) in vivo. Profibrotic genes expression levels (fibronectin, collagen Iα, NF-KB, IL-1ß, TNF-α, SMAD4, and α-smooth muscle actin) were determined through qPCR, Western blotting, immunofluorescence staining and/or histochemical analysis in vitro and in vivo. SMAD4 targeting siRNA was further used to treat the fibroblasts in combination with miR-146a intervention to confirm its role in underlying mechanisms. RESULTS: Upregulation of miR-146a reduced the proliferation rate and profibrotic changes of rat Tenon's capsule fibroblasts induced by TGF-ß1 in vitro, and mitigated subconjunctival fibrosis to extend filtering blebs survival after GFS in vivo, where miR-146a decreased expression levels of NF-KB-SMAD4-related genes, such as fibronectin, collagen Iα, NF-KB, IL-1ß, TNF-α, SMAD4, and α-smooth muscle actin(α-SMA). Additionally, SMAD4 is a key target gene in the process of miR-146a inhibiting fibrosis. CONCLUSIONS: MiR-146a effectively reduced TGF-ß1-induced fibrosis in rat Tenon's capsule fibroblasts in vitro and in vivo, potentially through the NF-KB-SMAD4 signaling pathway. MiR-146a shows promise as a novel therapeutic target for preventing fibrosis and improving the success rate of GFS.

ent-8(14),15-Pimaradiene-2ß,19-diol, a diterpene from Aleuritopteris albofusca, inhibits growth and induces protective autophagy in hepatocellular carcinoma cells.

A new pimarane-type diterpene, ent-8(14),15-pimaradiene-2ß,19-diol (JXE-23), was isolated from the fern plant Aleuritopteris albofusca by our previous work; however, the biological activity of this diterpene remains unclear. In the present study, the anti-cancer potential of JXE-23 in various cancer cells was investigated. Among MCF-7 breast cancer cells, A549 lung cancer cells, and HepG2 liver cancer cells, JXE-23 displayed significant cytotoxicity to HepG2 cells with an IC50 value of 17.20 ± 1.73 µM, while showing no obvious toxicity in normal hepatocytes HL7702. JXE-23 inhibited cell growth and colony formation in HepG2 cells. A cell cycle distribution analysis showed that JXE-23 caused G2/M cell cycle arrest. Besides, JXE-23 also suppressed the migration of HepG2 cells. Interestingly, an increase of light chain 3 II (LC3II) and Beclin 1 and a decrease of P62 have occurred in JXE-23-treated cells, as well as the formation of GFP-LC3 dots, indicative of autophagy induction by JXE-23. When combined with autophagy inhibitor 3-methyladenine and chloroquine, the cell viability was significantly reduced, suggesting that JXE-23 triggered protective autophagy in hepatoma cells. Further study showed that JXE-23 inactivated the CIP2A/p-AKT/c-Myc signaling axis in HepG2 cells. Our data provided evidence that JXE-23 inhibited cell growth, arrested cells at the G2/M phase, and induced protective autophagy in HepG2 hepatocellular carcinoma cells. JXE-23 may be a potential lead compound for anti-cancer drug development, and autophagy inhibitor treatment may provide an effective strategy for improving its anti-cancer effect.

Fangji Huangqi Decoction alleviates rheumatoid arthritis through regulating HIF-1α mediated the angiogenesis and the balance between autophagy and apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Fangji Huangqi Decoction (FHD) is frequently prescribed for the clinical treatment of wind-cold and wind-dampness pathogenic superficial deficiency syndrome. It also has a notable curative effect on rheumatoid arthritis (RA). AIM OF THE STUDY: The study aimed to explore the possible mechanism of FHD against RA and provided a theoretical basis for alternative therapies for RA. MATERIALS AND METHODS: We used UPLC-Q-TOF-MS to analysis the ingredients and absorbed blood components of FHD. At the same time, the collagen-induced arthritis (CIA) rat model was established to estimate the therapeutic effects on FHD by considering body weight, arthritis score, paw swelling, autonomous movement ability, and synovial microvessel counts. Subsequently, immunofluorescence, immunohistochemistry, and Western blot were employed to detect the anti-angiogenic capacity of FHD in vivo, as well as the levels of apoptosis and autophagy in the synovial tissue. In addition, flow cytometry and Western blot were used to assess the effects of FHD on apoptosis and autophagy in MH7A cells. The effects of FHD on the proliferation and migration of MH7A cells were measured by CCK8 assay, cell migration and, invasion experiments. Finally, a tube formation assay was performed to evaluate the angiogenic capacity of FHD in co-cultures of MH7A cells and HUVEC cells. RESULTS: Through testing of FHD's original formula, a total of 26 active ingredients have been identified, with 17 of them being absorbed into the bloodstream. FHD significantly improved the pathological symptoms and synovial hyperplasia of CIA rats. FHD could suppress the expression of HIF-1α, promote apoptosis in CIA rat synovial tissue, and suppress autophagy and angiogenesis. In vitro experiments showed that serum containing FHD inhibited the proliferation, migration, and invasion of MH7A cells, and also suppressed the expression of autophagy-related proteins while promoting apoptosis. FHD markedly repressed the expression of HIF-1α protein in TNF-α-stimulated MH7A cells and inhibited the tube formation capacity induced by MH7A cells in HUVEC cells. CONCLUSIONS: The study had proven that FHD played an excellent anti-RA role, which may be attributed to its potential mechanism of regulating the balance between autophagy and apoptosis in RA FLS by suppressing the HIF-1α, thus contributing to its anti-angiogenic activities.

Comprehensive pan-cancer analysis of 33 human cancers reveals immunotherapeutic value of focal adhesion tyrosine kinase.

The immune environment in tumors is the key factor affecting the survival and immunotherapeutic response of patients. This research aimed to explore the underlying association between focal adhesion tyrosine kinase (FAK/PTK2) and cancer immunotherapy in 33 human cancers. Gene expression data and clinical features of 33 cancers were retrieved from the Cancer Genome Atlas Database. The immunotherapy cohorts included GSE67501, GSE78220, and IMVIGOR210, which were derived from the comprehensive gene expression database or from previous studies. Clinical parameters including patient age, gender, survival rate, and tumor stage were analyzed to evaluate the prognostic value of FAK/PTK2. FAK/PTK2 activity was detected by single-sample gene set enrichment analysis and used to compare the difference between FAK/PTK2 transcriptome and protein expression levels. To better understand the role of FAK/PTK2 in cancer immunotherapy, we analyzed its correlations with tumor microenvironment and with immune processes/elements (e.g., immune cell infiltration, immunosuppressants, and stimulants) and major histocompatible complexes. Potential pathways associated with FAK/PTK2 signaling in cancers were also explored. Correlations between FAK/PTK2 and 2 immunotherapeutic biomarkers (tumor mutation load and microsatellite instability) were studied. Finally, the 3 independent immunotherapy cohorts were used to study the relationship between FAK/PTK2 and immunotherapeutic response. Although FAK/PTK2 is not closely associated with age (13/33), gender (5/33), or tumor stage (5/33) in any of the studied human cancers, it has potential prognostic value for predicting patient survival. Consistency between FAK/PTK2 activity and expression exists in some cancers (3/33). Generally, FAK/PTK2 is robustly correlated with immune cell infiltration, immune modulators, and immunotherapeutic markers. Moreover, high FAK/PTK2 expression is significantly related to immune-relevant pathways. However, FAK/PTK2 is not significantly correlated with the immunotherapeutic response. Research on the immunotherapeutic value of FAK/PTK2 in 33 human cancers provides evidence regarding the function of FAK/PTK2 and its role in clinical treatment. However, given the use of a bioinformatics approach, our results are preliminary and require further validation.

High Pretreatment DHEA Is Associated with Inferior Immunotherapy Response in Metastatic Non-Small Cell Lung Cancer.

Background: Sex difference in the immune response may influence patients' response to immune checkpoint inhibitors (ICIs). We conducted a prospective observation study to determine the correlation between pretreatment sex hormone levels and response to ICIs in metastatic non-small cell lung cancer (NSCLC). Method: Pretreatment plasma samples from 61 patients with newly diagnosed NSCLC prior to ICI therapy were collected. Six sex hormone levels [pyrazole triol, 17 ß-estradiol, 5-androstenediol, 3ß-androstenediol, dehydroepiandrosterone (DHEA), and S-equol] were measured using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Overall survival (OS) and progression-free survival (PFS) were compared between the high- and low-level groups in the whole cohort. Result: Among the six sex hormones measured, DHEA levels were significantly higher among patients without clinical benefits in the discovery cohort; the remaining sex hormones did not differ significantly. In the whole cohort, median PFS was 22 months for patients with low DHEA levels vs. 3.8 months for those with high DHEA [hazard ratio, 14.23 (95% CI, 4.7-43); p < 0.001]. A significant association was also observed for OS [hazard ratio, 8.2 (95% CI, 2.89-23.35); p < 0.0001]. Conclusions: High pretreatment plasma DHEA levels were associated with poor clinical outcomes for patients with metastatic NSCLC treated with ICIs.

Interactome Analysis of ClpX Reveals Its Regulatory Role in Metabolism and Photosynthesis in Cyanobacteria.

Protein homeostasis is essential for cyanobacteria to maintain proper cellular function under adverse and fluctuating conditions. The AAA+ superfamily of proteolytic complexes in cyanobacteria plays a critical role in this process, including ClpXP, which comprises a hexameric ATPase ClpX and a tetradecameric peptidase ClpP. Despite the physiological effects of ClpX on growth and photosynthesis, its potential substrates and underlying mechanisms in cyanobacteria remain unknown. In this study, we employed a streptavidin-biotin affinity pull-down assay coupled with label-free proteome quantitation to analyze the interactome of ClpX in the model cyanobacterium Synechocystis sp. PCC 6803 (hereafter Synechocystis). We identified 503 proteins as potential ClpX-binding targets, many of which had novel interactions. These ClpX-binding targets were found to be involved in various biological processes, with particular enrichment in metabolic processes and photosynthesis. Using protein-protein docking, GST pull-down, and biolayer interferometry assays, we confirmed the direct association of ClpX with the photosynthetic proteins, ferredoxin-NADP+ oxidoreductase (FNR) and phycocyanin subunit (CpcA). Subsequent functional investigations revealed that ClpX participates in the maintenance of FNR homeostasis and functionality in Synechocystis grown under different light conditions. Overall, our study provides a comprehensive understanding of the extensive functions regulated by ClpX in cyanobacteria to maintain protein homeostasis and adapt to environmental challenges.

Pathological image profiling identifies onco-microbial, tumor immune microenvironment, and prognostic subtypes of colorectal cancer.

Histology slide, tissue microbes, and the host gene expression can be independent prognostic factors of colorectal cancer (CRC), but the underlying associations and biological significance of these multimodal omics remain unknown. Here, we comprehensively profiled the matched pathological images, intratumoral microbes, and host gene expression characteristics in 527 patients with CRC. By clustering these patients based on histology slide features, we classified the patients into two histology slide subtypes (HSS). Onco-microbial community and tumor immune microenvironment (TIME) were also significantly different between the two subtypes (HSS1 and HSS2) of patients. Furthermore, variation in intratumoral microbes-host interaction was associated with the prognostic heterogeneity between HSS1 and HSS2. This study proposes a new CRC classification based on pathological image features and elucidates the process by which tumor microbes-host interactions are reflected in pathological images through the TIME.

EBV DNA methylation profiles and its application in distinguishing nasopharyngeal carcinoma and nasal NK/T-cell lymphoma.

BACKGROUND: As an oncovirus, EBV is associated with multiple cancers, including solid tumors and hematological malignancies. EBV methylation plays an important role in regulating tumor occurrence. However, the EBV methylation profiles in EBV-associated tumor tissues are poorly understood. RESULTS: In this study, EBV methylation capture sequencing was conducted in several different tumor tissue samples, including NPC, EBVaGC, lung LELC and parotid LELC. Besides, EBV capture sequencing and following qMSP were performed on nasopharyngeal brushing samples from NPC and nasal NKTCL patients. Our results showed that the EBV genome among different types of tumors displayed specific methylation patterns. Among the four types of tumors from epithelial origin (NPC, EBVaGC, lung LELC and parotid LELC), the most significant differences were found between EBVaGC and the others. For example, in EBVaGC, all CpG sites within 1,44,189-1,45,136 bp of the EBV genome sequence on gene RPMS1 were hyper-methylated compared to the others. Differently, significant differences of EBV CpG sites, particularly those located on gene BILF2, were observed between NPC and nasal NKTCL patients in nasopharyngeal brushing samples. Further, the methylated level of BILF2 was further detected using qMSP, and a diagnostic model distinguishing NPC and nasal NKTCL was established. The AUC of the model was 0.9801 (95% CI 0.9524-1.0000), with the sensitivity and specificity of 98.81% (95% CI 93.63-99.94%) and 76.92% (95% CI 49.74-91.82%), respectively. CONCLUSIONS: Our study reveals more clues for further understanding the pathogenesis of EBV, and provides a possibility for distinguishing EBV-related tumor by detecting specific EBV CpG sites.

Prognostic factors affecting long-term outcomes in patients with concurrent IgA nephropathy and membranous nephropathy.

Background: The incidence of concurrent immunoglobulin A nephropathy and membranous nephropathy (cIgAN/MN) is low and rarely reported, and the prognosis of patients with cIgAN/MN remains unclear. This study was designed to compare the clinical and prognostic characteristics of cIgAN/MN with IgAN and MN and to identify crucial factors influencing the outcomes of patients with cIgAN/MN. Methods: We included biopsy-proven cIgAN/MN patients between December 2012 and December 2020 at Xijing Hospital. In the same period, propensity score matching was employed to select an equal number of IgAN and MN patients according to the following criteria: age, sex, and follow-up time. The primary endpoint was defined as a composite of eGFR decline ≥30 %, end-stage renal disease, or death. The patient survival rate was examined using Kaplan-Meier survival curves. Univariate and multivariate Cox regression analysis models were utilized to identify the risk factors affecting renal prognosis. Results: A total of 135 patients were finally included in this study and 35 (25.9 %) reached the primary endpoint. The median follow-up time of cIgAN/MN was 45.9 (24.0, 72.0) months. Compared to the IgAN group, the cIgAN/MN group exhibited a lower cumulative incidence rate of composite renal endpoints (P = 0.044), while no significant difference was found between MN and cIgAN/MN patients (P = 0.211). Univariate Cox analysis revealed that mean arterial pressure, serum potassium, blood urea nitrogen, serum IgA, segmental glomerulosclerosis (S1), and MN staging were associated with an increased risk of renal composite endpoints. The multivariate Cox regression analysis of clinical variables plus histological lesion scoring demonstrated that potassium (HR = 14.350, 95 % CI 2.637-78.090, P = 0.002), serum IgA (HR = 1.870, 95 % CI 1.109-3.153, P = 0.019), and S1 (HR = 11.965, 95 % CI 2.166-66.105, P = 0.004) were independent risk factors influencing renal outcomes in cIgAN/MN patients. Conclusion: The prognosis of cIgAN/MN patients may exhibit an intermediate pattern between IgAN and MN, leaning towards being more similar to MN in certain aspects. Within the cIgAN/MN cohort, potassium, and serum IgA may be more predictive of rapid progression of renal endpoints, and S1 may indicate a more aggressive disease course.

Toward Accurate Simulation of Coupling between Protein Secondary Structure and Phase Separation.

Intrinsically disordered proteins (IDPs) frequently mediate phase separation that underlies the formation of a biomolecular condensate. Together with theory and experiment, efficient coarse-grained (CG) simulations have been instrumental in understanding the sequence-specific phase separation of IDPs. However, the widely used Cα-only models are limited in capturing the peptide nature of IDPs, particularly backbone-mediated interactions and effects of secondary structures, in phase separation. Here, we describe a hybrid resolution (HyRes) protein model toward a more accurate description of the backbone and transient secondary structures in phase separation. With an atomistic backbone and coarse-grained side chains, HyRes can semiquantitatively capture the residue helical propensity and overall chain dimension of monomeric IDPs. Using GY-23 as a model system, we show that HyRes is efficient enough for the direct simulation of spontaneous phase separation and, at the same time, appears accurate enough to resolve the effects of single His to Lys mutations. HyRes simulations also successfully predict increased ß-structure formation in the condensate, consistent with available experimental CD data. We further utilize HyRes to study the phase separation of TPD-43, where several disease-related mutants in the conserved region (CR) have been shown to affect residual helicities and modulate the phase separation propensity as measured by the saturation concentration. The simulations successfully recapitulate the effect of these mutants on the helicity and phase separation propensity of TDP-43 CR. Analyses reveal that the balance between backbone and side chain-mediated interactions, but not helicity itself, actually determines phase separation propensity. These results support that HyRes represents an effective protein model for molecular simulation of IDP phase separation and will help to elucidate the coupling between transient secondary structures and phase separation.

Alterations of the gut microbiota in the lupus nephritis: a systematic review.

BACKGROUND: Emerging evidence suggests that gut microbiota dysbiosis may play a critical role in the development of lupus nephritis (LN). However, the specific characteristics of the gut microbiota in individuals with LN have not been fully clarified. METHODS: The PubMed, Web of Science, and Embase databases were systematically searched for clinical and animal studies related to the relationship between LN and gut microbiota from inception until October 1, 2023. A semiquantitative analysis was used to assess the changes in gut microbial profiles. RESULTS: A total of 15 clinical studies were selected for analysis, which included 138 LN patients, 441 systemic lupus erythematosus patients, and 1526 healthy controls (HCs). Five different types of LN mouse models were included in 5 animal studies. The alpha diversity was decreased in LN patients compared to HCs. A significant decrease in the Firmicutes/Bacteroidetes (F/B) ratio is considered a hallmark of pathological conditions. Specifically, alterations in the abundance of the phylum Proteobacteria, genera Streptococcus and Lactobacillus, and species Ruminococcus gnavus and Lactobacillus reuteri may play a critical role in the pathogenesis of LN. Remarkably, the gut taxonomic chain Bacteroidetes-Bacteroides-Bacteroides thetaiotaomicron was enriched in LN patients, which could be a crucial characteristic of LN patients. The increased level of interleukin-6, imbalance of regulatory T cells and T helper 17 cells, and decreased level of the intestinal tight junction proteins zonula occludens-1 and claudin-1 also might be related to the pathogenesis of LN. CONCLUSIONS: Specific changes in the abundance of gut microbiota such as decreased F/B ratio, and the level of inflammatory indicators, and markers of intestinal barrier dysfunction may play a crucial role in the pathogenesis of LN. These factors could be effective diagnostic and potential therapeutic targets for LN.

Mfat-1 ameliorates cachexia after hypoxic-ischemic brain damage in mice by protecting the hypothalamus-pituitary-adrenal axis.

AIMS: Cachexia, a metabolic syndrome, affects 21 % of patients suffering from ischemic encephalopathy. However, the specific mechanism and prevention measures are still unclear. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been proven to reduce inflammatory cytokine levels during ischemic events, but whether they have a protective effect against cachexia after hypoxic-ischemic brain damage (HIBD) remains unclear. MAIN METHODS: C57BL/6J wild-type and mfat-1 transgenic male mice were treated with and without HIBD. One day after HIBD, the epididymal white fat, gastrocnemius muscle and hypothalamus were weighed and analyzed the phenotypic changes. RNA sequencing was applied to gastrocnemius muscle to identify differential genes and pathways in HIBD groups. The effect of HPA axis on cachexia post-HIBD was examined via adrenalectomy, dexamethasone (0.1 mg/kg), and corticosterone injection (100 mg/kg). KEY FINDINGS: The results showed that the incidence of cachexia in mfat-1 mice, which produce high proportion of n-3 PUFAs, was significantly lower than that in wild-type mice post-HIBD. Cachexia-related factors, such as inflammation, muscle atrophy and lipid metabolism were significantly improved in mfat-1 HIBD. RNA sequencing revealed that catabolic and proteasome pathways were significantly downregulated. In hypothalamus, inflammatory cytokines, lipid peroxidation levels were reduced. Corticosterone, glucocorticoid receptor, and dexamethasone suppression test all showed that mfat-1 improved the dysfunction of the HPA axis post-HIBD. The present study elucidated for the first time that mfat-1 reduced HIBD-induced hyperactivation of the HPA axis in mice by reducing inflammation and oxidative stress and contributed to the reduction of metabolic imbalance in peripheral tissues. SIGNIFICANCE: Our study provides mechanistic information for the development of intervention strategies to prevent cachexia.

Pan-cancer analyses reveal the stratification of patient prognosis by viral composition in tumor tissues.

The associations between cancer and bacteria/fungi have been extensively studied, but the implications of cancer-associated viruses have not been thoroughly examined. In this study, we comprehensively characterized the cancer virome of tissue samples across 31 cancer types, as well as blood samples from 23 cancer types. Our findings demonstrated the presence of viral DNA at low abundances in both tissue and blood across major human cancers, with significant differences in viral community composition observed among various cancer types. Furthermore, Cox regression analyses conducted on four cancers, including Head and Neck squamous cell carcinoma (HNSC), Kidney renal clear cell carcinoma (KIRC), Stomach adenocarcinoma (STAD), and Uterine Corpus Endometrial Carcinoma (UCEC), revealed strong correlation between viral composition/abundance in tissues and patient survival. Additionally, we identified virus-associated prognostic signatures (VAPS) for these four cancers, and discerned differences in the interplay between VAPS and dominant bacteria in tissues among patients with varying survival risks. Notably, clinically relevant analyses revealed prognostic capacities of the VAPS in these four cancers. Taken together, our study provides novel insights into the role of viruses in tissue in the prognosis of multiple cancers and offers guidance on the use of tissue viruses to stratify prognosis for patients with cancer.

Deciphering the Role of p60AmotL2 in Epithelial Extrusion and Cell Detachment.

Preserving an accurate cell count is crucial for maintaining homeostasis. Apical extrusion, a process in which redundant cells are eliminated by neighboring cells, plays a key role in this regard. Recent studies have revealed that apical extrusion can also be triggered in cells transformed by oncogenes, suggesting it may be a mechanism through which tumor cells escape their microenvironment. In previous work, we demonstrated that p60AmotL2 modulates the E-cadherin function by inhibiting its connection to radial actin filaments. This isoform of AmotL2 is expressed in invasive breast and colon tumors and promotes invasion in vitro and in vivo. Transcriptionally regulated by c-Fos, p60AmotL2 is induced by local stress signals such as severe hypoxia. In this study, we investigated the normal role of p60AmotL2 in epithelial tissues. We found that this isoform is predominantly expressed in the gut, where cells experience rapid turnover. Through time-lapse imaging, we present evidence that cells expressing p60AmotL2 are extruded by their normal neighboring cells. Based on these findings, we hypothesize that tumor cells exploit this pathway to detach from normal epithelia and invade surrounding tissues.

A MRI-based radiomics model for predicting the response to anlotinb combined with temozolomide in recurrent malignant glioma patients.

OBJECTIVE: Anlotinib is a multitarget anti-angiogenic drug that combined with temozolomide (TMZ) can effectively prolongs the overall survival (OS) of recurrent malignant glioma(rMG),but some patients do not respond to anlotinib combined with TMZ. These patients were associated with a worse prognosis and lack effective identification methods. Therefore, it is necessary to differentiate patients who may have good response to anlotinb in combination with TMZ from those who are not, in order to provide personalized targeted therapies. METHODS: Fifty three rMG patients (42 in training cohort and 11 in testing cohort) receiving anlotinib combined with TMZ were enrolled. A total of 3668 radiomics features were extracted from the recurrent MRI images. Radiomics features are reduced and filtered by hypothesis testing and Least Absolute Shrinkage And Selection (LASSO) regression. Eight machine learning models construct the radiomics model, and then screen out the optimal model. The performance of the model was assessed by its discrimination, calibration, and clinical usefulness with validation. RESULTS: Fifty three patients with rMG were enrolled in our study. Thirty four patients displayed effective treatment response, showed a higher survival benefits than non-response group, the median progression-free survival(PFS) was 8.53 months versus 5.33 months (p = 0.06) and the median OS was 19.9 months and 7.33 months (p = 0.029), respectively. Three radiomics features were incorporated into the model construction as final variables after LASSO regression analysis. In testing cohort, Logistic Regression (LR) model has the best performance with an Area Under the Curve (AUC) of 0.93 compared with other models, which can effectively predict the response of rMG patients to anlotinib in combination with TMZ. The calibration curve confirmed the agreement between the observed actual and prediction probability. Within the reasonable threshold probability range (0.38-0.88), the radiomics model shows good clinical utility. CONCLUSIONS: The above-described radiomics model performed well, which can serve as a clinical tool for individualized prediction of the response to anlotinb combined with TMZ in rMG patients.