The serine protease CORIN promotes progression of gastric cancer by mediating the ERK1/2 MAPK pathway.

The serine protease CORIN catalyzes pro-atrial natriuretic peptide (pro-ANP) into an active ANP and maintains homeostasis of the internal environment. However, it is unclear whether CORIN participates in the regulation of tumor progression. We analyzed the expression profile of CORIN in gastric cancer tissues (GCs) and adjacent nontumoral tissues (NTs). We investigated the prognostic value of CORIN in GC patients. We characterized the in vitro and in vivo activity of CORIN in cultured GC cells with gain-of-function and loss-of-function experiments. The underlying mechanism was explored by using bioinformatics, a signaling antibody array, and confirmative western blot analyses, as well as rescue experiments with highly selective small-molecule inhibitors targeting the ERK1/2 MAPK signaling pathway. CORIN was upregulated in GCs than in NTs. Overexpression of CORIN was correlated with unfavorable prognoses in patients with GC. Ectopic expression of CORIN was promoted, whereas silencing of CORIN suppressed proliferation, colony formation, migration and invasion of GC cells, and tumor growth in vivo. Overexpression of CORIN-induced epithelial-mesenchymal transition (EMT) and activation of the ERK1/2 MAPK signaling pathway, while silencing of CORIN yielded opposite results. The in vitro tumor-promoting potency of CORIN could be antagonized by selective inhibitors targeting the ERK1/2 MAPK pathway. In conclusion, CORIN is a potential prognostic marker and therapeutic target for GC patients, which may promote tumor progression by mediating the ERK1/2 MAPK signaling pathway and EMT in GC cells.

Radiolabelling and preclinical characterisation of [89Zr]Zr-Df-ATG-101 bispecific to PD-L1/4-1BB.

PURPOSE: ATG-101, a bispecific antibody that simultaneously targets the immune checkpoint PD-L1 and the costimulatory receptor 4-1BB, activates exhausted T cells upon PD-L1 crosslinking. Previous studies demonstrated promising anti-tumour efficacy of ATG-101 in preclinical models. Here, we labelled ATG-101 with 89Zr to confirm its tumour targeting effect and tissue biodistribution in a preclinical model. We also evaluated the use of immuno-PET to study tumour uptake of ATG-101 in vivo. METHODS: ATG-101, anti-PD-L1, and an isotype control were conjugated with p-SCN-Deferoxamine (Df). The Df-conjugated antibodies were radiolabelled with 89Zr, and their radiochemical purity, immunoreactivity, and serum stability were assessed. We conducted PET/MRI and biodistribution studies on [89Zr]Zr-Df-ATG-101 in BALB/c nude mice bearing PD-L1-expressing MDA-MB-231 breast cancer xenografts for up to 10 days after intravenous administration of [89Zr]Zr-labelled antibodies. The specificity of [89Zr]Zr-Df-ATG-101 was evaluated through a competition study with unlabelled ATG-101 and anti-PD-L1 antibodies. RESULTS: The Df-conjugation and [89Zr]Zr -radiolabelling did not affect the target binding of ATG-101. Biodistribution and imaging studies demonstrated biological similarity of [89Zr]Zr-Df-ATG-101 and [89Zr]Zr-Df-anti-PD-L1. Tumour uptake of [89Zr]Zr-Df-ATG-101 was clearly visualised using small-animal PET imaging up to 7 days post-injection. Competition studies confirmed the specificity of PD-L1 targeting in vivo. CONCLUSION: [89Zr]Zr-Df-ATG-101 in vivo distribution is dependent on PD-L1 expression in the MDA-MB-231 xenograft model. Immuno-PET with [89Zr]Zr-Df-ATG-101 provides real-time information about ATG-101 distribution and tumour uptake in vivo. Our data support the use of [89Zr]Zr-Df-ATG-101 to assess tumour and tissue uptake of ATG-101.

Tumor targeted alpha particle therapy with an actinium-225 labelled antibody for carbonic anhydrase IX.

Selective antibody targeted delivery of α particle emitting actinium-225 to tumors has significant therapeutic potential. This work highlights the design and synthesis of a new bifunctional macrocyclic diazacrown ether chelator, H2MacropaSqOEt, that can be conjugated to antibodies and forms stable complexes with actinium-225. The macrocyclic diazacrown ether chelator incorporates a linker comprised of a short polyethylene glycol fragment and a squaramide ester that allows selective reaction with lysine residues on antibodies to form stable vinylogous amide linkages. This new H2MacropaSqOEt chelator was used to modify a monoclonal antibody, girentuximab (hG250), that binds to carbonic anhydrase IX, an enzyme that is overexpressed on the surface of cancers such as clear cell renal cell carcinoma. This new antibody conjugate (H2MacropaSq-hG250) had an average chelator to antibody ratio of 4 : 1 and retained high affinity for carbonic anhydrase IX. H2MacropaSq-hG250 was radiolabeled quantitatively with [225Ac]AcIII within one minute at room temperature with micromolar concentrations of antibody and the radioactive complex is stable in human serum for >7 days. Evaluation of [225Ac]Ac(MacropaSq-hG250) in a mouse xenograft model, that overexpresses carbonic anhydrase IX, demonstrated a highly significant therapeutic response. It is likely that H2MacropaSqOEt could be used to modify other antibodies providing a readily adaptable platform for other actinium-225 based therapeutics.

Exploring the induction of endometrial epithelial cell apoptosis in clinical-type endometritis in yaks through the cyt-c/caspase-3 signaling axis.

Endometritis is a significant contributor to reduced productivity in yaks in Tibet, China. The Cyt-c/Caspase-3 signaling axis plays a crucial role in the mitochondrial pathway that triggers cell apoptosis due to endogenous factors. In this study, we examined the endometrial epithelial tissue of yaks with endometritis using pathological examination, immunohistochemical analysis, TUNEL staining, qRT-PCR, and Western blot. The results indicated significant changes in the apoptotic factors of the Cyt-c/Caspase-3 signaling axis. The expression levels of Bak1, Bax, Cyt-c, Apaf-1, Caspase-9, and Caspase-3 were significantly increased (P < 0.05), while the expression level of Bcl-2 was significantly decreased. Immunohistochemistry results revealed significant increase in Bak1, Bax, Cyt-c, Apaf-1, Caspase-9, and Caspase-3 expression in the cytoplasm compared to the healthy group, except for Bcl-2, which showed a significant decrease. Pathological section analysis demonstrated that clinical endometritis in yaks led to structural damage, bleeding, congestion, and inflammatory cell infiltration in the endometrial epithelium. Our study findings indicated that clinical endometritis in yaks can modulate apoptosis of endometrial epithelial cells via the Cyt-c/Caspase-3 signaling pathway, resulting in different levels of damage. This research is pioneering in exploring cell apoptosis induced by clinical endometritis in yaks, offering novel insights and potential strategies for the future prevention and treatment of endometritis in yaks.

Preparation and characterization of a novel triple composite scaffold containing silk fibroin, chitosan, extracellular matrix and the mechanism of Akt/FoxO signaling pathway in colonic cancer cells cultured in 3D.

This work examined the physical and chemical properties and biocompatibility in vivo and in vitro of a unique triple composite scaffold incorporating silk fibroin, chitosan, and extracellular matrix. The materials were blended, cross-linked, and freeze-dried to create a composite scaffold of silk fibroin/chitosan/colon extracellular matrix (SF/CTS/CEM) with varying CEM contents. The SF/CTS/CEM (1:1:1) scaffold demonstrated the preferable shape, outstanding porosity, favorable connectivity, good moisture absorption, and acceptable and controlled swelling and degradation properties. Additionally, HCT-116 cells cultivated with SF/CTS/CEM (1:1:1) showed excellent proliferation capacity, cell malignancy, and delayed apoptosis, according to the in vitro cytocompatibility examination. We also examined the PI3K/PDK1/Akt/FoxO signaling pathway and discovered that cell culture using a SF/CTS/CEM (1:1:1) scaffold may prevent cell death by phosphorylating Akt and suppressing FoxO expression. Our findings demonstrate the potential of the SF/CTS/CEM (1:1:1) scaffold as an experimental model for colonic cancer cell culture and for replicating the three-dimensional in vivo cell growth environment.

Learning from human metabolism for nanomedicine: a convertible bismuth-agent for tumour-selective theranostics.

Tumour-selective theranostic agents have attracted considerable interest over the past decade in oncology owing to their extraordinary anticancer efficacy. However, it still remains a challenge to develop theranostic agents balancing biocompatibility, multidimensional theranostics, tumour-selectivity, and simple components. Inspired by the metabolic pathways of exogenous sodium selenite against selenium-deficient diseases, reported here is the first convertible bismuth-based agent for tumour-selective theranostic functionalities. The specifically overexpressed substances in tumour tissue enable it to act as a natural reactor for the conversion from bismuth selenite to bismuth selenide, activating the theranostic functionalities specifically in tumour tissues. The converted product exhibits excellent multidimensional imaging-guided therapy. This study not only demonstrates a simple agent with both biocompatibility and sophisticated tumour-selective theranostic functionalities, but also pioneers a new approach from emulating nature towards oncological theranostic applications.

Single-cell landscape and clinical outcomes of infiltrating B cells in colorectal cancer.

B cells constitute a major component of infiltrating immune cells in colorectal cancer (CRC). However, the characteristics of B cells and their clinical significance remain unclear. In this study, using single-cell RNA sequencing and multicolour immunofluorescence staining experiments, we identified five distinct subtypes of B cells with their marker genes, distribution patterns and functional properties in the CRC tumour microenvironment. Meanwhile, we found a higher proportion of IgG plasma cells in tumour sites than that in adjacent normal mucosal tissues. In addition, the CXCL13-producing CD8+ T cells in the tumour tissues could promote the formation of tertiary lymphoid structure (TLS) B cells, and the CCL28-CCR10 axis is pivotal for IgG plasma cell migration from the periphery of TLSs to the tumour stroma. Finally, we identified four distinct colon immune classes (CICs: A-D) and found that CD20+ B cells within TLSs were enriched in one immune-inflamed or hot tumour group (CIC D). This B cell-rich group, which was characterized by strong antigen presentation, IgG plasma cells accumulation, microsatellite instability-high (MSI-H) and high tumour mutation burden (TMB-H), as well as immunosuppressive property in particular, might become a potential predictive biomarker for future immunotherapy. Additionally, in an immunotherapy cohort, patients with the enrichment of B cells and TLSs were demonstrated to obtain significant therapeutic advantages. Together, our findings provide the detailed landscape of infiltrating B cells and their potential clinical significance in CRC.

Identification of Potential Biomarkers for Cancer Cachexia and Anti-Fn14 Therapy.

BACKGROUND: Developing therapies for cancer cachexia has not been successful to date, in part due to the challenges of achieving robust quantitative measures as a readout of patient treatment. Hence, identifying biomarkers to assess the outcomes of treatments for cancer cachexia is of great interest and important for accelerating future clinical trials. METHODS: We established a novel xenograft model for cancer cachexia with a cachectic human PC3* cell line, which was responsive to anti-Fn14 mAb treatment. Using RNA-seq and secretomic analysis, genes differentially expressed in cachectic and non-cachectic tumors were identified and validated by digital droplet PCR (ddPCR). Correlation analysis was performed to investigate their impact on survival in cancer patients. RESULTS: A total of 46 genes were highly expressed in cachectic PC3* tumors, which were downregulated by anti-Fn14 mAb treatment. High expression of the top 10 candidates was correlated with low survival and high cachexia risk in different cancer types. Elevated levels of LCN2 were observed in serum samples from cachectic patients compared with non-cachectic cancer patients. CONCLUSION: The top 10 candidates identified in this study are candidates as potential biomarkers for cancer cachexia. The diagnostic value of LCN2 in detecting cancer cachexia is confirmed in patient samples.

Patient-Derived Organoid Model in the Prediction of Chemotherapeutic Drug Response in Colorectal Cancer.

As an emerging technology in precision medicine, the patient-derived organoid (PDO) technology has been indicated to provide novel modalities to judge the sensitivity of individual tumors to cancer drugs. In this work, an in vitro model of colorectal cancer (CRC) was established using the PDO culture, and it is demonstrated that the PDO samples preserved, to a great extent, the histologic features and marker expression of the original tumor tissues. Subsequently, cancer drugs 5-FU, oxaliplatin, and irinotecan were selected and screened on five CRC PDO samples, while the patient-derived organoid xenograft (PDOX) model was applied for comparison. The receiver operating characteristic (ROC) curve was drawn according to the IC50 data from the PDO model and the relative tumor proliferation rate (T/C%) from PDOX. Interestingly, the area under the ROC curve was 0.84 (95% CI, 0.64-1.04, P value = 0.028), which suggested that the IC50 of cancer drugs from the PDO model was strongly correlated with PDOX responses. In addition, the optimal sensitivity cutoff value for drug screening in CRC PDOs was identified at 10.35 µM, which could act as a reference value for efficacy evaluation of 5-FU, oxaliplatin, and irinotecan in the colorectal cancer drug screening. Since there are no unified criteria to judge the sensitivity of drugs in vitro, our work provides a method for establishing in vitro evaluation criteria via PDO and PDOX model using the patient tissues received from local hospitals, exhibiting potential in clinical cancer therapy and precision medicine.

Meta-analysis on the prevalence of bovine hydatid disease in China from 2000 to 2021.

Cystic Echinococcosis (hydatidosis) is caused by the larval stage of Echinococcus spp. It is an animal-borne zoonotic parasitic disease with local epidemic and natural foci, which is very common in northwest China. In recent years, a considerable attention has been paid to the epidemic investigation of hydatid disease in humans and sheep, but there are few large-scale epidemic investigation and data analysis of bovine hydatid disease. We systematically reviewed and analyzed the prevalence of bovine hydatid disease (2000-2021) in China for the first time. Several databases including CNKI, Wanfang, VIP Chinese periodical database, Baidu Library, PubMed and ScienceDirect were used to search 57 articles and 72 sets of valid data about bovine hydatid disease in China from 2000 to 2021. We used the random effect model in META package of R software, and PAS for rate conversion. The subgroup analysis and univariate meta regression analysis were used to reveal the factors leading to the heterogeneity of the study. The total prevalence rate of bovine hydatid disease in China from 2000 to 2021 is estimated to be 17.27% (10898/63113). According to the analysis of sampling years, the lowest positive rate since 2016 is 7.54% (1503/19929). The highest prevalence rate of bovine hydatid disease is 53.93% (4340/8048). The infection rate of bovine liver accounted for the highest proportion of the total infections, 45.2% (2040/4507). We also assessed the effects of different geographical and climatic factors on the prevalence of bovine hydatid disease. The results showed that the prevalence rate of hydatid disease was higher in cold and humid areas. Although the infection rate of bovine hydatid disease has declined in recent years, it is still necessary to carry out long-term surveillance and control of hydatid disease, cut off the infection route and reduce the risk of infection in high-risk areas.

White matter microstructure differences in individuals with dependence on cocaine, methamphetamine, and nicotine: Findings from the ENIGMA-Addiction working group.

BACKGROUND: Nicotine and illicit stimulants are very addictive substances. Although associations between grey matter and dependence on stimulants have been frequently reported, white matter correlates have received less attention. METHODS: Eleven international sites ascribed to the ENIGMA-Addiction consortium contributed data from individuals with dependence on cocaine (n = 147), methamphetamine (n = 132) and nicotine (n = 189), as well as non-dependent controls (n = 333). We compared the fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) of 20 bilateral tracts. Also, we compared the performance of various machine learning algorithms in deriving brain-based classifications on stimulant dependence. RESULTS: The cocaine and methamphetamine groups had lower regional FA and higher RD in several association, commissural, and projection white matter tracts. The methamphetamine dependent group additionally showed lower regional AD. The nicotine group had lower FA and higher RD limited to the anterior limb of the internal capsule. The best performing machine learning algorithm was the support vector machine (SVM). The SVM successfully classified individuals with dependence on cocaine (AUC = 0.70, p < 0.001) and methamphetamine (AUC = 0.71, p < 0.001) relative to non-dependent controls. Classifications related to nicotine dependence proved modest (AUC = 0.62, p = 0.014). CONCLUSIONS: Stimulant dependence was related to FA disturbances within tracts consistent with a role in addiction. The multivariate pattern of white matter differences proved sufficient to identify individuals with stimulant dependence, particularly for cocaine and methamphetamine.

Diagnostic Value of sST2 in Cardiovascular Diseases: A Systematic Review and Meta-Analysis.

Biomarkers such as B-type natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), cardiac troponin (cTn), and CK-MB contribute significantly to the diagnosis of cardiovascular disease (CVD). Recent studies have demonstrated that suppression of tumorigenicity 2 (ST2) is associated with CVD, but a meta-analysis of ST2 levels in different CVDs has yet to be conducted. Therefore, the present study aimed to investigate soluble ST2 (sST2) levels in patients with ischemic heart disease (IHD), myocardial infarction (MI), and heart failure (HF). A total of 1,425 studies were searched across four databases, of which 16 studies were included in the meta-analysis. The Newcastle-Ottawa Quality Assessment Scale (NOS) values of all 16 studies were ≥7. The meta-analysis results indicated that the sST2 level was not correlated with IHD (standard mean difference [SMD] = 0.58, 95% confidence interval [95% CI] = 0.00 to 1.16, p = 0.05) or MI (weighted mean difference [WMD] = 0.17, 95% CI = -0.22 to 0.55, p = 0.40) but was significantly associated with HF (WMD = 0.21, 95% CI = 0.04 to 0.38, p = 0.02; I 2 = 99%, p < 0.00001). sST2 levels did not differ significantly between patients with IHD or MI and healthy individuals; however, we believe that ST2 could be used as an auxiliary diagnostic biomarker of HF.

Biomarkers for Cancer Cachexia: A Mini Review.

Cancer cachexia is a common condition in many cancer patients, particularly those with advanced disease. Cancer cachexia patients are generally less tolerant to chemotherapies and radiotherapies, largely limiting their treatment options. While the search for treatments of this condition are ongoing, standards for the efficacy of treatments have yet to be developed. Current diagnostic criteria for cancer cachexia are primarily based on loss of body mass and muscle function. However, these criteria are rather limiting, and in time, when weight loss is noticeable, it may be too late for treatment. Consequently, biomarkers for cancer cachexia would be valuable adjuncts to current diagnostic criteria, and for assessing potential treatments. Using high throughput methods such as "omics approaches", a plethora of potential biomarkers have been identified. This article reviews and summarizes current studies of biomarkers for cancer cachexia.

H2O2-Driven Anticancer Activity of Mn Porphyrins and the Underlying Molecular Pathways.

Mn(III) ortho-N-alkyl- and N-alkoxyalkyl porphyrins (MnPs) were initially developed as superoxide dismutase (SOD) mimics. These compounds were later shown to react with numerous reactive species (such as ONOO-, H2O2, H2S, CO3 •-, ascorbate, and GSH). Moreover, the ability of MnPs to oxidatively modify activities of numerous proteins has emerged as their major mechanism of action both in normal and in cancer cells. Among those proteins are transcription factors (NF-κB and Nrf2), mitogen-activated protein kinases, MAPKs, antiapoptotic bcl-2, and endogenous antioxidative defenses. The lead Mn porphyrins, namely, MnTE-2-PyP5+ (BMX-010, AEOL10113), MnTnBuOE-2-PyP5+ (BMX-001), and MnTnHex-2-PyP5+, were tested in numerous injuries of normal tissue and cellular and animal cancer models. The wealth of the data led to the progression of MnTnBuOE-2-PyP5+ into four Phase II clinical trials on glioma, head and neck cancer, anal cancer, and multiple brain metastases, while MnTE-2-PyP5+ is in Phase II clinical trial on atopic dermatitis and itch.

Mapping cortical and subcortical asymmetries in substance dependence: Findings from the ENIGMA Addiction Working Group.

Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence.

Analgesic effect of perioperative ketamine for total hip arthroplasties and total knee arthroplasties: A PRISMA-compliant meta-analysis.

BACKGROUND: Total hip arthroplasties (THA) and total knee arthroplasties (TKA) are always associated with a frequent incidence of postoperative pain. Effective pain management after surgery is quite essential for surgeons and patients. The purpose of the present meta-analysis is to evaluate the analgesic effect of perioperative ketamine after THA and TKA. METHODS: Seven online databases, Embase, Cochrane Library, Pubmed, Web of Science, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database (CBM), and Wanfang Data were searched for the related randomized controlled trials (RCT) by August 15, 2019. The qualities of the included studies were assessed based on the Cochrane Handbook for Systematic Reviews of Interventions 5.0. The visual analog scale (VAS), morphine equivalent consumption, and the side effects were used to evaluate the postoperative analgesic effect of ketamine by meta-analysis, which was performed by Review Manager version 5.3 software. RESULTS: The VAS scores at 6 hours, 12 hours, 24 hours, and 48 hours after surgery were statistically lower in the ketamine group. The morphine equivalent consumptions in 24 hours and 48 hours after surgery were also significantly lower in the ketamine group. For the side effects, no statistical differences in odds ratio (OR) of sedation, dizziness, hallucination, sweating, pruritus, urinary retention, constipation, version trouble, nightmares, and delirium were observed between the ketamine group and the control group. But postoperative nausea and vomiting (PONV) showed lower OR in the ketamine group. CONCLUSION: The present meta-analysis demonstrated perioperative ketamine could be used as a safe and effective analgesic agent for THA and TKA.

Generation of reporter cell lines for factors inducing muscle wasting in cancer cachexia.

Rapidly identifying cachexia-inducing factors that directly induce muscle wasting is an existing challenge. We developed two reporter cell lines that allow swift detection of such factors in blood from patients. C2C12 myoblasts were used for the establishment of reporter cells. A luciferase reporter gene, driven by promoters of wasting genes, Muscle RING-finger protein-1 (MuRF1) and Muscle Atrophy F-Box Protein (MAFbx/Atrogin-1) were used for the construction of reporter constructs. Increased expression of these genes in muscle tissue under wasting conditions was shown in vivo and in vitro. We found these reporter cell lines could detect factors associated with cancer cachexia, such as myostatin (Mstn), activin A, and TNF-α. We further investigated the capacity to directly detect a cachectic state using plasma samples from cachectic mice and cancer patients. Activation of the reporter cell lines was observed by the addition of plasma from mice with cancer cachexia and serum samples from patients with pancreatic or colorectal cancer. These results indicate that the reporter cell lines are competent as a tool for screening cachexia-inducing factors and potentially distinguishing a cachectic state induced by cancer.

Bcl-2 family proteins, beyond the veil.

Apoptosis is an important part of both health and disease and is often regulated by the BCL-2 family of proteins. These proteins are either pro- or anti-apoptotic, existing in a delicate balance during homeostasis. They are best known for their role in regulating the activation of caspases and the execution of a cell in response to a variety of stimuli. However, it is often forgotten that these BCL-2 family proteins also have important roles to play in cell maintenance that are not associated with apoptosis. These include roles in regulating processes such as cell cycle progression, mitochondrial function, autophagy, intracellular calcium concentration, glucose and lipid metabolism, and the unfolded protein response. In addition to these established alternate functions, further discoveries are being made that have potential therapeutic benefits in diseases such as cancer. BOK, a BCL-2 family protein thought comparable to multidomain pro-apoptotic proteins BAX and BAK, has recently been identified as a key player in metabolism of and resistance to the commonly used chemotherapeutic 5-FU. As a result of such findings, which could see the potential use of BOK as a biomarker for 5-FU sensitivity or mimetic molecules as a resensitization strategy, new targets and mechanisms of pathology may arise from further investigation into the realm of alternate functions of BCL-2 family proteins.

The exploration of new therapeutic targets for HPV-negative head and neck squamous cell cancer through the construction of a ceRNA network and immune microenvironment analysis.

Previous studies have shown that human papillomavirus (HPV)-negative patients with head and neck squamous cell cancer (HNSCC) suffer from an unsatisfactory prognosis. Long noncoding RNAs (lncRNAs) have been verified to participate in many biological processes, including regulating gene expression as competing endogenous RNAs (ceRNAs), while few studies focused the ceRNA network regulation mechanism in patients with HPV-negative HNSCC tumor. Meanwhile, the immune microenvironment may be critical in the development and prognosis of HPV-negative tumors. Our study aimed to further investigate the pathogenesis and potential biomarkers for the diagnosis, therapy and prognosis of HPV-negative HNSCC through a ceRNA network. Comprehensively analyzing the sequencing data of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) in The Cancer Genome Atlas HNSCC dataset, we constructed a differentially expressed ceRNA network containing 131 lncRNAs, 35 miRNAs and 162 mRNAs. Then, survival analysis in the network was cited to explore the prognostic biomarkers. Eight mRNAs, nine lncRNAs, and one miRNA were identified to be associated with prognosis. Neuropilin (NRP) binding function, retinoid X receptor (RXR) binding, and the vascular endothelial growth factor (VEGF) signaling pathway were associated with the enrichment analysis, and they also related to the immune microenvironment. Combined with the analysis of the immune microenvironment differences, we obtained new targeted therapies using an RXR agonist, or a combination of the VEGF monoclonal antibody and an NRP antagonist, which may provide a promising future for HPV-negative HNSCC patients.

BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals.

BCL-2 family proteins regulate the mitochondrial apoptotic pathway. BOK, a multidomain BCL-2 family protein, is generally believed to be an adaptor protein similar to BAK and BAX, regulating the mitochondrial permeability transition during apoptosis. Here we report that BOK is a positive regulator of a key enzyme involved in uridine biosynthesis; namely, uridine monophosphate synthetase (UMPS). Our data suggest that BOK expression enhances UMPS activity, cell proliferation, and chemosensitivity. Genetic deletion of Bok results in chemoresistance to 5-fluorouracil (5-FU) in different cell lines and in mice. Conversely, cancer cells and primary tissues that acquire resistance to 5-FU down-regulate BOK expression. Furthermore, we also provide evidence for a role for BOK in nucleotide metabolism and cell cycle regulation. Our results have implications in developing BOK as a biomarker for 5-FU resistance and have the potential for the development of BOK-mimetics for sensitizing 5-FU-resistant cancers.