Dissection of triple-negative breast cancer microenvironment and identification of potential therapeutic drugs using single-cell RNA sequencing analysis.

Breast cancer remains a leading cause of mortality in women worldwide. Triple-negative breast cancer (TNBC) is a particularly aggressive subtype characterized by rapid progression, poor prognosis, and lack of clear therapeutic targets. In the clinic, delineation of tumor heterogeneity and development of effective drugs continue to pose considerable challenges. Within the scope of our study, high heterogeneity inherent to breast cancer was uncovered based on the landscape constructed from both tumor and healthy breast tissue samples. Notably, TNBC exhibited significant specificity regarding cell proliferation, differentiation, and disease progression. Significant associations between tumor grade, prognosis, and TNBC oncogenes were established via pseudotime trajectory analysis. Consequently, we further performed comprehensive characterization of the TNBC microenvironment. A crucial epithelial subcluster, E8, was identified as highly malignant and strongly associated with tumor cell proliferation in TNBC. Additionally, epithelial-mesenchymal transition (EMT)-associated fibroblast and M2 macrophage subclusters exerted an influence on E8 through cellular interactions, contributing to tumor growth. Characteristic genes in these three cluster cells could therefore serve as potential therapeutic targets for TNBC. The collective findings provided valuable insights that assisted in the screening of a series of therapeutic drugs, such as pelitinib. We further confirmed the anti-cancer effect of pelitinib in an orthotopic 4T1 tumor-bearing mouse model. Overall, our study sheds light on the unique characteristics of TNBC at single-cell resolution and the crucial cell types associated with tumor cell proliferation that may serve as potent tools in the development of effective anti-cancer drugs.

High-Flux Steady-State Demulsification of Oil-In-Water Emulsions by Superhydrophilic-Oleophobic Copper Foams with Ultra-Small Pores Under Pressure.

3D superwetting materials struggle to maintain high-flux steady-state demulsification for oil-in-water emulsions because the accumulated oil within the material is difficult to discharge rapidly. The water flow shear force can swiftly remove the oil from the anti-fouling surface. In this study, by introducing nanofibers and carbon nanotubes and chemical modification, a superhydrophilic-oleophobic copper foam with pores of several micrometers is prepared, which can achieve a continuous demulsification process with steady-state flux over 57000 L m-2 h-1 for oil-in-water emulsions and rapid hydraulic-driven oil release under an additional pressure of 5 kPa. Thanks to the ultra-small pores of the copper foam, the steady-state demulsification efficiency can be still maintained at over 97.5%. During the demulsification process, the accumulation of oil and surfactants within the copper foam can be maintained at low levels, achieving dynamic equilibrium. With the aid of second-stage superhydrophilic copper mesh, the demulsified oil-water mixtures can be rapidly separated. This high-flux, steady-state, and efficient demulsification process shows great potential for industrial applications.

Establishment of a predictive model for blood transfusion after femoral head replacement in elderly patients.

OBJECTIVES: The study aimed to establish a nomogram predictive model for blood transfusion after artificial femoral head replacement surgery in elderly patients with intertrochanteric fractures. PATIENTS AND METHODS: Two hundred five elderly patients (55 males, 150 females; mean age: 82.1±6.6 years; range, 63 to 103 years) with intertrochanteric femoral fractures who underwent artificial femoral head replacement surgery between January 2015 and May 2023 were retrospectively analyzed. The patients were randomly divided into two groups: the training group (n=143) and the validation group (n=62). Within the training group, patients were further categorized into the nontransfused (n=86) and transfused (n=57) groups. Perioperative data were collected for logistic regression analysis to identify risk factors for postoperative blood transfusion. A nomogram model was developed to predict the need for blood transfusion, with assessments including the C-index, receiver operating characteristic curve, decision curve analysis, and clinical impact curve. RESULTS: Logistic regression analysis showed that low preoperative hemoglobin levels, high intraoperative bleeding volume, high drainage volume, the use of wire reinforcement, and history of cerebral infarction were the independent risk factors for transfusion after femoral head replacement. Both decision curve analysis and clinical impact curves indicated that the prediction model could be used as a good prediction tool for blood transfusion after artificial femoral head replacement for intertrochanteric femoral fractures in the elderly. CONCLUSION: A nomogram prediction model that effectively assesses the risk of blood transfusion in elderly patients undergoing femoral head replacement for intertrochanteric femoral fractures was established in this study. This model demonstrated high predictive accuracy and consistency, providing a valuable tool for clinicians to identify high-risk patients and implement early interventions to reduce the need for postoperative blood transfusions.

The HOXC10/NOD1/ERK axis drives osteolytic bone metastasis of pan-KRAS-mutant lung cancer.

While KRAS mutation is the leading cause of low survival rates in lung cancer bone metastasis patients, effective treatments are still lacking. Here, we identified homeobox C10 (HOXC10) as a lynchpin in pan-KRAS-mutant lung cancer bone metastasis. Through RNA-seq approach and patient tissue studies, we demonstrated that HOXC10 expression was dramatically increased. Genetic depletion of HOXC10 preferentially impeded cell proliferation and migration in vitro. The bioluminescence imaging and micro-CT results demonstrated that inhibition of HOXC10 significantly reduced bone metastasis of KRAS-mutant lung cancer in vivo. Mechanistically, the transcription factor HOXC10 activated NOD1/ERK signaling pathway to reprogram epithelial-mesenchymal transition (EMT) and bone microenvironment by activating the NOD1 promoter. Strikingly, inhibition of HOXC10 in combination with STAT3 inhibitor was effective against KRAS-mutant lung cancer bone metastasis by triggering ferroptosis. Taken together, these findings reveal that HOXC10 effectively alleviates pan-KRAS-mutant lung cancer with bone metastasis in the NOD1/ERK axis-dependent manner, and support further development of an effective combinatorial strategy for this kind of disease.

Cardiovascular disease burden in patients with urological cancers: The new discipline of uro-cardio-oncology.

Cancer remains a major cause of mortality worldwide, and urological cancers are the most common cancers among men. Several therapeutic agents have been used to treat urological cancer, leading to improved survival for patients. However, this has been accompanied by an increase in the frequency of survivors with cardiovascular complications caused by anticancer medications. Here, we propose the novel discipline of uro-cardio-oncology, an evolving subspecialty focused on the complex interactions between cardiovascular disease and urological cancer. In this comprehensive review, we discuss the various cardiovascular toxicities induced by different classes of antineoplastic agents used to treat urological cancers, including androgen deprivation therapy, vascular endothelial growth factor receptor tyrosine kinase inhibitors, immune checkpoint inhibitors, and chemotherapeutics. In addition, we discuss possible mechanisms underlying the cardiovascular toxicity associated with anticancer therapy and outline strategies for the surveillance, diagnosis, and effective management of cardiovascular complications. Finally, we provide an analysis of future perspectives in this emerging specialty, identifying areas in need of further research.

Identifying cell type-specific transcription factor-mediated activity immune modules reveal implications for immunotherapy and molecular classification of pan-cancer.

Systematic investigation of tumor-infiltrating immune (TII) cells is important to the development of immunotherapies, and the clinical response prediction in cancers. There exists complex transcriptional regulation within TII cells, and different immune cell types display specific regulation patterns. To dissect transcriptional regulation in TII cells, we first integrated the gene expression profiles from single-cell datasets, and proposed a computational pipeline to identify TII cell type-specific transcription factor (TF) mediated activity immune modules (TF-AIMs). Our analysis revealed key TFs, such as BACH2 and NFKB1 play important roles in B and NK cells, respectively. We also found some of these TF-AIMs may contribute to tumor pathogenesis. Based on TII cell type-specific TF-AIMs, we identified eight CD8+ T cell subtypes. In particular, we found the PD1 + CD8+ T cell subset and its specific TF-AIMs associated with immunotherapy response. Furthermore, the TII cell type-specific TF-AIMs displayed the potential to be used as predictive markers for immunotherapy response of cancer patients. At the pan-cancer level, we also identified and characterized six molecular subtypes across 9680 samples based on the activation status of TII cell type-specific TF-AIMs. Finally, we constructed a user-friendly web interface CellTF-AIMs (http://bio-bigdata.hrbmu.edu.cn/CellTF-AIMs/) for exploring transcriptional regulatory pattern in various TII cell types. Our study provides valuable implications and a rich resource for understanding the mechanisms involved in cancer microenvironment and immunotherapy.

Nanoparticles-encapsulated doxorubicin alleviates drug resistance of osteosarcoma via inducing ferroptosis.

To determine the effects of polymeric nanoparticle for doxorubicin (Dox) delivery and treatment of drug-resistant Osteosarcoma (OS) cells. Methoxy-polyethylene glycol amino (mPEG-NH2) and platinum bio-mimetic polycaprolactone-cysteine (PtBMLC) were crosslinked to obtain glutathione (GSH)-responsive mPEG-NH2-PtBMLC polymer to encapsulate Dox (named as Nano-Dox). The particle size and zeta potential of the nanoparticles were measured, and internalization of Dox by OS cells was observed. After treatment with Nano-Dox, cell proliferation was determined by cell counting kit 8 (CCK-8) and colony formation assay. Cell migration and invasion were determined by Transwell assay. Cell cycle arrest was assessed by flow cytometry. The induction of ferroptosis was analyzed by abnormal accumulation of total iron, Fe2+. Nano-Dox exhibited a stronger localization in OS cells (p < 0.01). Nano-Dox induced more significant suppression of drug-resistant OS cell growth (p < 0.01), migration (p < 0.01), and invasion (p < 0.01), compared with the single Dox treatment group, along with decreased expression of N-cadherin, Snail, and Vimentin, suggesting impaired cancer migration and invasion. The treatment with Nano-Dox induced notable cell cycle arrest at G0/G1 phase (p < 0.01) and accumulation of iron, Fe2+, and MDA (p < 0.01), as well as suppressed the protein levels of glutathione peroxidase 4 (GPX4) and SLC7A11. Administration of ferroptosis inhibitor (Fer-1) reversed the anti-proliferation effects of Nano-Dox (p < 0.01). The Dox delivered by the polymeric nanoparticle system notably enhanced its effects on suppressing the growth, migration, and invasion of drug-resistant OS cells via inducing ferroptosis. The application of environment response polymer enhanced the delivery of Dox and the therapeutic effects on OS.

Dissecting microenvironment in cystadenomas and hepatic cysts based on single nucleus RNA-sequencing data.

Hepatic cystadenoma is a rare disease, accounting for about 5% of all cystic lesions, with a high tendency of malignant transformation. The preoperative diagnosis of cystadenoma is difficult, and some cystadenomas are easily misdiagnosed as hepatic cysts at first. Hepatic cyst is a relatively common liver disease, most of which are benign, but large hepatic cysts can lead to pressure on the bile duct, resulting in abnormal liver function. To better understand the difference between the microenvironment of cystadenomas and hepatic cysts, we performed single-nuclei RNA-sequencing on cystadenoma and hepatic cysts samples. In addition, we performed spatial transcriptome sequencing of hepatic cysts. Based on nucleus RNA-sequencing data, a total of seven major cell types were identified. Here we described the tumor microenvironment of cystadenomas and hepatic cysts, particularly the transcriptome signatures and regulators of immune cells and stromal cells. By inferring copy number variation, it was found that the malignant degree of hepatic stellate cells in cystadenoma was higher. Pseudotime trajectory analysis demonstrated dynamic transformation of hepatocytes in hepatic cysts and cystadenomas. Cystadenomas had higher immune infiltration than hepatic cysts, and T cells had a more complex regulatory mechanism in cystadenomas than hepatic cysts. Immunohistochemistry confirms a cystadenoma-specific T-cell immunoregulatory mechanism. These results provided a single-cell atlas of cystadenomas and hepatic cyst, revealed a more complex microenvironment in cystadenomas than in hepatic cysts, and provided new perspective for the molecular mechanisms of cystadenomas and hepatic cyst.

Efficacy and safety of intravenous tranexamic acid in microscopic modified radical mastoidectomy: a study protocol for a prospective, randomised, double-blind controlled trial.

INTRODUCTION: Radical mastoidectomy is a common procedure for chronic suppurative otitis media, typically performed under a microscope. The smooth operation is closely related to the clarity of the operative field. Our trial is designed to investigate whether the intravenous administration of tranexamic acid (TXA) can improve the clarity of the operative field, reduce the operative time, and increase surgeon satisfaction. METHODS AND ANALYSIS: This study is a prospective, randomised, double-blinded, controlled trial that aims to investigate the effects of TXA on patients with otitis media. The trial will include patients between the ages of 18 and 65 who will be randomly assigned to either the TXA group or the control group. In the TXA group, patients will receive 1 g of TXA diluted to 20 mL of normal saline before anaesthesia induction while the control group will receive 20 mL of normal saline. The primary outcome measure will be the Modena Bleeding Score, which will assess the clarity of the surgical field. Secondary outcomes will include the surgeon's satisfaction with surgical conditions, operation time, laboratory measurements (prothrombin time, activated partial thromboplastin time, fibrin degradation products, D-dimer) and levels of inflammatory factors (such as IL-6) at 24 hours postoperatively. In addition, the incidence of general adverse reactions such as postoperative nausea, vomiting and dizziness; serious adverse events such as arterial and venous thromboembolism, myocardial infarction and epilepsy within 90 days will be compared between the two groups. ETHICS AND DISSEMINATION: The protocol was approved by the Ethics Committee of Peking University People's Hospital (2021PHB173-001), on 19 July 2021. The trial results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ChiCTR2100049183.

Wnt5a deficiency in osteocalcin-expressing cells could not alleviate the osteoarthritic phenotype in a mouse model of post-traumatic osteoarthritis.

Objectives: Wnt5a, which regulates the activities of osteoblasts and osteoclasts, is reportedly overexpressed in osteoarthritis (OA) tissues. The purpose of this study was to elucidate its role in the development of OA by deleting Wnt5a in osteocalcin (OCN)-expressing cells. Materials and Methods: Knee OA was induced by anterior cruciate ligament transection (ACLT) in OCN-Cre;Wnt5afl/fl knockout (Wnt5a-cKO) mice and control littermates. Eight weeks after surgery, histological changes, cell apoptosis, and matrix metabolism of cartilage were evaluated by toluidine blue, TUNEL staining, and im-immunohistochemistry analyses, respectively. In addition, the subchondral bone microarchitecture of mice was examined by micro-computed tomography (micro-CT). Results: Histological scores show substantial cartilage degeneration occurred in ACLT knees, coupled with decreased collagen type II expression and enhanced matrix metalloproteinase 13 expression, as well as higher proportions of apoptotic cells. Micro-CT results show that ACLT resulted in decreased bone mineral density, bone volume/trabecular volume, trabecular number, and structure model index of subchondral bones in both Wnt5a-cKO and control littermates; although Wnt5a-cKO mice display lower BMD and BV/TV values, no significant difference was observed between Wnt5a-cKO and control mice for any of these values. Conclusion: Our findings indicate that Wnt5a deficiency in OCN-expressing cells could not prevent an osteoarthritic phenotype in a mouse model of post-traumatic OA.

Intravenous tranexamic acid significantly improved visualization and shortened the operation time in microscopic middle ear surgery: a randomized controlled trial.

BACKGROUND: The microscopic middle ear surgery involves a limited operating space and numerous important anatomical structures in which good visualization is crucial, as even a small amount of bleeding can greatly affect the clarity of surgical field. This study aims to investigate whether intravenous 1 g of tranexamic acid can improve surgical visualization and further shorten the operation time in microscopic middle ear surgery. METHODS: This study is a prospective, randomized, double-blind, controlled trial conducted from December 2021 to December 2022, enrolling patients who were scheduled for microscopic modified radical mastoidectomy due to chronic otitis media. In addition to standard techniques to optimize the surgical field, participants were randomized into the TXA (tranexamic acid) group (1 g diluted to 20 ml normal saline) and the control group (20 ml normal saline). The primary outcome was assessed based on the clarity of the surgical field using the Modena Bleeding Score. Secondary outcomes included operation time, the surgeon satisfaction with the visual clarity, postoperative 24 h coagulation parameters, and the incidence of adverse events. Student's t -test, χ2 test, and ANOVA of repeated measures were used for statistical analyses. RESULTS: A total of 28 patients were enrolled in each group using a 1:1 randomized allocation with similar demographic characteristics, including 24 male and 32 female individuals, and the mean age is 45.6±11.9 years. The surgical visualization in the TXA group was significantly better than that of the control group (2.29±0.46 vs. 2.89±0.31, P <0.001) as assessed by the Modena Bleeding Score. Furthermore, the TXA group demonstrated a shorter operation time compared to the control group (88.61±10.9 vs. 105.2±15.9, P <0.001) and higher surgeon satisfaction with surgical field (7.82±0.55 vs. 6.50±0.64, P <0.001). No statistically significant differences were found in postoperative coagulation parameters in the two groups. No TXA-related adverse events or complications occurred during the 12-month follow-up. CONCLUSION: Intravenous 1 g of TXA can further significantly improve the visual clarity in the microscopic middle ear surgery and shorten the operation time based on other standard measures implemented.

Optimizing drug combination and mechanism analysis based on risk pathway crosstalk in pan cancer.

Combination therapy can greatly improve the efficacy of cancer treatment, so identifying the most effective drug combination and interaction can accelerate the development of combination therapy. Here we developed a computational network biological approach to identify the effective drug which inhibition risk pathway crosstalk of cancer, and then filtrated and optimized the drug combination for cancer treatment. We integrated high-throughput data concerning pan-cancer and drugs to construct miRNA-mediated crosstalk networks among cancer pathways and further construct networks for therapeutic drug. Screening by drug combination method, we obtained 687 optimized drug combinations of 83 first-line anticancer drugs in pan-cancer. Next, we analyzed drug combination mechanism, and confirmed that the targets of cancer-specific crosstalk network in drug combination were closely related to cancer prognosis by survival analysis. Finally, we save all the results to a webpage for query ( http://bio-bigdata.hrbmu.edu.cn/oDrugCP/ ). In conclusion, our study provided an effective method for screening precise drug combinations for various cancer treatments, which may have important scientific significance and clinical application value for tumor treatment.

The CSF1-CSF1R pathway in the trigeminal ganglion mediates trigeminal neuralgia via inflammatory responses in mice.

BACKGROUND: Trigeminal neuralgia (TN) is the most severe type of neuropathic pain. The trigeminal ganglion (TG) is a crucial target for the pathogenesis and treatment of TN. The colony-stimulating factor 1 (CSF1) - colony-stimulating factor 1 receptor (CSF1R) pathway regulates lower limb pain development. However, the effect and mechanism of the CSF1-CSF1R pathway in TG on TN are unclear. METHODS: Partial transection of the infraorbital nerve (pT-ION) model was used to generate a mouse TN model. Mechanical and cold allodynia were used to measure pain behaviors. Pro-inflammatory factors (IL-6, TNF-a) were used to measure inflammatory responses in TG. PLX3397, an inhibitor of CSF1R, was applied to inhibit the CSF1-CSF1R pathway in TG. This pathway was activated in naïve mice by stereotactic injection of CSF1 into the TG. RESULTS: The TN model activated the CSF1-CSF1R pathway in the TG, leading to exacerbated mechanical and cold allodynia. TN activated inflammatory responses in the TG manifested as a significant increase in IL-6 and TNF-a levels. After using PLX3397 to inhibit CSF1R, CSF1R expression in the TG declined significantly. Inhibiting the CSF1-CSF1R pathway in the TG downregulated the expression of IL-6 and TNF-α to reduce allodynia-related behaviors. Finally, mechanical allodynia behaviors were exacerbated in naïve mice after activating the CSF1-CSF1R pathway in the TG. CONCLUSIONS: The CSF1-CSF1R pathway in the TG modulates TN by regulating neuroimmune responses. Our findings provide a theoretical basis for the development of treatments for TN in the TG.

Resveratrol activation of SIRT1/MFN2 can improve mitochondria function, alleviating doxorubicin-induced myocardial injury.

Background: Doxorubicin is a widely used cytotoxic chemotherapy agent for treating different malignancies. However, its use is associated with dose-dependent cardiotoxicity, causing irreversible myocardial damage and significantly reducing the patient's quality of life and survival. In this study, an animal model of doxorubicin-induced cardiomyopathy was used to investigate the pathogenesis of doxorubicin-induced myocardial injury. This study also investigated a possible treatment strategy for alleviating myocardial injury through resveratrol therapy in vitro. Methods: Adult male C57BL/6J mice were randomly divided into a control group and a doxorubicin group. Body weight, echocardiography, surface electrocardiogram, and myocardial histomorphology were measured. The mechanisms of doxorubicin cardiotoxicity in H9c2 cell lines were explored by comparing three groups (phosphate-buffered saline, doxorubicin, and doxorubicin with resveratrol). Results: Compared to the control group, the doxorubicin group showed a lower body weight and higher systolic arterial pressure, associated with reduced left ventricular ejection fraction and left ventricular fractional shortening, prolonged PR interval, and QT interval. These abnormalities were associated with vacuolation and increased disorder in the mitochondria of cardiomyocytes, increased protein expression levels of α-smooth muscle actin and caspase 3, and reduced protein expression levels of Mitofusin2 (MFN2) and Sirtuin1 (SIRT1). Compared to the doxorubicin group, doxorubicin + resveratrol treatment reduced caspase 3 and manganese superoxide dismutase, and increased MFN2 and SIRT1 expression levels. Conclusion: Doxorubicin toxicity leads to abnormal mitochondrial morphology and dysfunction in cardiomyocytes and induces apoptosis by interfering with mitochondrial fusion. Resveratrol ameliorates doxorubicin-induced cardiotoxicity by activating SIRT1/MFN2 to improve mitochondria function.

Tumor biology, immune infiltration and liver function define seven hepatocellular carcinoma subtypes linked to distinct drivers, survival and drug response.

BACKGROUND & AIMS: Tumor heterogeneity is jointly determined by the components of the tumor ecosystem (TES) including tumor cells, immune cells, stromal cells, and non-cellular components. We aimed to identify subtypes using TES-related genes and determine subtype specific drivers and treatments for hepatocellular carcinoma (HCC). METHODS: We collected 68 genesets depicting tumor biology, immune infiltration, and liver function, totaling 2831 genes, and collected mRNA profiles and clinical data for over 6000 tumors from 65 datasets in the GEO, TCGA, ICGC, and several other databases. We designed a three-step clustering pipeline to identify subtypes. The microenvironment, genomic alteration, and drug response differences were systematically compared among subtypes. RESULTS: Seven subtypes (TES-1/2/3/4/5/6/7) were revealed in 159 tumors from the CHCC-HBV cohort. We constructed a single sample classifier using paired genes (sscpgsTES). TES subtypes were significantly associated with multiple clinical variables including etiology, and survival in 14 of 17 cohorts and the meta-cohort. TES-1 had the poorest prognosis and highest proliferation level. Both TES-2 and TES-7 were immune-enriched, however, TES-2 had a significantly worse prognosis, and hypoxic and immunosuppressive microenvironment. TES-4 had activated Wnt pathway, driven by CTNNB1 mutation. Good prognosis TES-6 exhibited the best differentiation. TES-5 and TES-3 were considered as novel subclasses by comparing with ten previous subtyping systems. TES-5 tumors had high AFP but good overall survival, and ∼45% of them harbored AXIN1 mutation. TES-3 was immune and stromal desert, may be driven by high copy number alteration burden, and had the poorest response to immune checkpoint inhibitor. TES-1 and TES-2 had significantly lower response to transarterial chemoembolization, but they showed significantly higher sensitivity to compound YM-155. CONCLUSIONS: Tumor ecosystem subtypes expand existing HCC subtyping systems, have distinct drivers, prognosis, and treatment vulnerabilities.

Reconstructing the immunosenescence core pathway reveals global characteristics in pan-cancer.

Immunosenescence has been demonstrated to play an important role in tumor progression. However, there is lacking comprehensive analyses of immunosenescence-related pathways. Meanwhile, the sex disparities of immunosenescence in cancer are still poorly understood. In this study, we analyzed the multi-omics data of 12,836 tumor samples, including genomics, transcriptomics, epigenomics, proteomics, and metabolomics. We systematically identified immunosenescence pathways that were disordered across cancer types. The mutations and copy number variations of immunosenescence pathways were found to be more active in pan-cancer. We reconstructed the immunosenescence core pathways (ISC-pathways) to improve the ability of prognostic stratification in 33 cancer types. We also found the head and neck squamous carcinoma (HNSC) contained abundant sex-specific immunosenescence features and showed sex differences in survival. We found that OSI-027 was a potential sex-specific drug in HNSC tumors, which tended to be more effective in male HNSC by targeting the MTOR gene in the PI3K-Akt signaling pathway. In conclusion, our study provided a systematic understanding of immunosenescence pathways and revealed the global characteristics of immunosenescence in pan-cancer. We highlighted MTOR gene could be a powerful immunosenescence biomarker of HNSC that helps to develop sex-specific immunosenescence drugs.

Associations between modifiable risk factors and frailty: a Mendelian randomisation study.

BACKGROUND: Early identification of modifiable risk factors is essential for the prevention of frailty. This study aimed to explore the causal relationships between a spectrum of genetically predicted risk factors and frailty. METHODS: Univariable and multivariable Mendelian randomisation (MR) analyses were performed to explore the relationships between 22 potential risk factors and frailty, using summary genome-wide association statistics. Frailty was accessed by the frailty index. RESULTS: Genetic liability to coronary artery disease (CAD), type 2 diabetes mellitus (T2DM), ischaemic stroke, atrial fibrillation and regular smoking history, as well as genetically predicted 1-SD increase in body mass index, systolic blood pressure, diastolic blood pressure, low-density lipoprotein cholesterol, triglycerides, alcohol intake frequency and sleeplessness were significantly associated with increased risk of frailty (all p<0.001). In addition, there was a significant inverse association between genetically predicted college or university degree with risk of frailty (beta -0.474; 95% CI (-0.561 to -0.388); p<0.001), and a suggestive inverse association between high-density lipoprotein cholesterol level with risk of frailty (beta -0.032; 95% CI (-0.055 to -0.010); p=0.004). However, no significant causal associations were observed between coffee consumption, tea consumption, serum level of total testosterone, oestradiol, 25-hydroxyvitamin D, C reactive protein or moderate to vigorous physical activity level with frailty (all p>0.05). Results of the reverse directional MR suggested bidirectional causal associations between T2DM and CAD with frailty. CONCLUSIONS: This study provided genetic evidence for the causal associations between several modifiable risk factors with lifetime frailty risk. A multidimensional approach targeting these factors may hold a promising prospect for prevention frailty.

Nitrogen Fixation by Benzene into Pyridine and Aniline in Water/Nitrogen Plasma.

We demonstrated direct conversion of benzene into pyridine and aniline, assisted through exact mass measurements (m/z 80.0494, 93.0574, and 94.0651, respectively), through the interaction of benzene with water/nitrogen vapor plasma produced by corona discharge. Systematic analysis using a series of isotopic standards indicated that formation of pyridine and aniline occurred through the reaction between neutral benzene and reactive N+(OH2)2 in water/nitrogen plasma; exact mass measurements of products and intermediates supported this hypothesis. As the proportion of water vapor in plasma increased over time, the reaction proceeded from exclusive formation of protonated pyridine to formation of protonated aniline as the main product; theoretical simulations indicated that the presence of water vapor promoted proton migration to elicit formation of protonated aniline. The reactions we discovered suggest a new mechanism for direct nitrogen fixation.

Systematical analyses of large-scale transcriptome reveal viral infection-related genes and disease comorbidities.

Perturbation of transcriptome in viral infection patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent transcriptome and identification of robust biomarkers is not complete. In this study, we manually collected 23 datasets related to 6,197 blood transcriptomes across 16 types of respiratory virus infections. We applied a comprehensive systems biology approach starting with whole-blood transcriptomes combined with multilevel bioinformatics analyses to characterize the expression, functional pathways, and protein-protein interaction (PPI) networks to identify robust biomarkers and disease comorbidities. Robust gene markers of infection with different viruses were identified, which can accurately classify the normal and infected patients in train and validation cohorts. The biological processes (BP) of different viruses showed great similarity and enriched in infection and immune response pathways. Network-based analyses revealed that a variety of viral infections were associated with nervous system diseases, neoplasms and metabolic diseases, and significantly correlated with brain tissues. In summary, our manually collected transcriptomes and comprehensive analyses reveal key molecular markers and disease comorbidities in the process of viral infection, which could provide a valuable theoretical basis for the prevention of subsequent public health events for respiratory virus infections.