Genomic characterization of peritoneal lavage cytology-positive gastric cancer.

Objective: Positive peritoneal lavege cytology (CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1 and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric cancer. Methods: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31 matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. Whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric cancer. Results: Least absolute shrinkage and selection operator (LASSO) algorithm identified 43 cytology-positive marker genes, while MutSigCV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology (CY0). Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1 and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.

ARHGEF18 can promote BVDV NS5B activation of the host NF-κB signaling pathway by combining with the NS5B-palm domain.

Rho guanine nucleotide exchange factor 18 (ARHGEF18) is a member of the Rho guanine nucleotide exchange factor (RhoGEF) family. RhoGEF plays an important role in the occurrence of tumors and neurological diseases; however, its involvement in host cell resistance against pathogenic microorganisms is mostly unknown. Herein, we report that bovine viral diarrhea virus (BVDV) nonstructural protein 5B (NS5B) can activate the nuclear factor kappa B (NF-κB) signaling pathway to induce an immune response. To clarify the functional domains of NS5B that activate NF-κB signaling, the six structural domains of NS5B were expressed separately: NS5B-core, NS5B-finger, NS5B-palm, NS5B-thumb, NS5B-N and NS5B-c domain. We preliminarily determined that the functional domains of NS5B that activate NF-κB signaling are the finger and palm domains. We used a bovine kidney cell cDNA library and yeast two-hybrid technology to identify that the host protein ARHGEF18 interacts with NS5B. Co-immunoprecipitation assays showed that ARHGEF18 interacts strongly with NS5B-palm. Interestingly ARHGEF18 could promote NF-κB signaling activation by BVDV NS5B. In addition silencing ARHGEF18 significantly inhibited NS5B-palm activation of NF-κB signaling. We concluded that ARHGEF18 can bind to BVDV NS5B through the palm domain to activate the NF-κB pathway. These findings provide direct evidence that BVDV NS5B induces immune responses by activating NF-κB signaling.

Fermentable sugar recovery from durian peel by using ultrasound-assisted chemical pretreatment.

Durian peel, an abundant waste in Malaysia could be a potential substrate for fermentable sugar recovery for value-added biochemical production. Common pretreatment such as acid or alkaline pretreatment resulted in the need for extensive solid washing which generated wastewater. Herein, this study aims to introduce sonication on top of chemical pretreatment to destruct lignin and reduce the chemical usage during the durian peel pretreatment process. In this study, the morphology and the chemical composition of the pretreated durian peels were studied. The sugar yield produced from the chemical pretreatment and the combined ultrasound and chemical pretreatment were compared. The morphology and chemical structure of durian peels were investigated by Scanning Electron Microscope (SEM), Fourier Transform Infrared (FTIR) analysis and X-ray diffraction (XRD). The SEM images showed that the structural change became more significant when sonication was introduced. Second, XRD profile indicated a relatively higher crystallinity index and FTIR spectra displayed a lower intensity of lignin and hemicellulose for ultrasound plus alkaline (UB) pretreatment as compared to acid, alkaline and ultrasound plus acid (UA) pretreatment. UB and UA pretreatment portrayed higher yield (376.60 ± 12.14 and 237.38 ± 3.96 mg reducing sugar/g dry biomass, respectively) than their controls without the application of ultrasound. Therefore, it could be concluded that ultrasound was able to intensify the fermentable sugar recovery from durian peel by inducing physical and chemical effect of cavitation to alter the morphology of durian peel. Fermentation of UB treated durian peel resulted in 2.68 mol hydrogen/mol consumed sugar and 131.56 mL/Lmedium/h of hydrogen productivity. This study is important because it will shed light on a way to handle durian waste disposal problems and generate fermentable sugars for the production of high value-added products.

A simple and sensitive liquid chromatography triple quadrupole mass spectrometry method for the determination of XL092 in monkey plasma and its application to pharmacokinetic study.

XL092 is a potent ATP-competitive inhibitor of multiple receptor tyrosine kinases that is undergoing clinical development for the treatment of lung cancer. In this study, an LC triple quadrupole mass spectrometry method was established to measure XL092 in monkey plasma. A Waters ACQUITY UPLC BEH C18 column was used for chromatographic separation. The mobile phase consisted of water containing 0.1% formic acid and acetonitrile with a gradient elution at the flow rate of 0.4 mL/min. Multiple reaction monitoring mode was used for quantitative analysis of XL092 in positive electrospray ionization. In the concentration range of 0.5-1000 ng/mL, XL092 showed excellent linearity in monkey plasma with a correlation coefficient greater than 0.995 (r > 0.995). The lowest limit of quantification was 0.5 ng/mL. The intra- and inter-day relative standard deviations were <9.99%, while the relative error ranged from -12.50% to 8.10%. The mean recovery was over 82.51%. XL092 was stable in monkey plasma after storage under certain conditions. The validated method was demonstrated to be selective, sensitive, and reliable, and has been successfully applied to the pharmacokinetic study of XL092 in monkey plasma. XL092 showed moderate short half-life (~3.81 h) and good oral bioavailability (80%).

Evidence for cytochrome P450 3A4-mediated metabolic activation of SCO-267.

SCO-267 is a potent G-protein-coupled receptor 40 agonist that is undergoing clinical development for the treatment of type 2 diabetes mellitus. The current work was undertaken to investigate the bioactivation potential of SCO-267 in vitro and in vivo. Three SCO-267-derived glutathione (GSH) conjugates (M1-M3) were found both in rat and human liver microsomal incubations supplemented with GSH and nicotinamide adenine dinucleotide phosphate. Two GSH conjugates (M1-M2) together with two N-acetyl-cysteine conjugates (M4-M5) were detected in the bile of rats receiving SCO-267 at 10 mg/kg. The identified conjugates suggested the generation of quinone-imine and ortho-quinone intermediates. CYP3A4 was demonstrated to primarily catalyze the bioactivation of SCO-267. In addition, SCO-267 concentration-, time-, and NADPH-dependently inactivated CYP3A in human liver microsomes using testosterone as a probe substrate, along with KI and kinact values of 4.91 µM and 0.036 min-1 , respectively. Ketoconazole (a competitive inhibitor of CYP3A) displayed no significant protective effect on SCO-267-induced CYP3A inactivation. However, inclusion of GSH showed significant protection. These findings revealed that SCO-267 undergoes a facile CYP3A4-catalyzed bioactivation with the generation of quinone-imine and ortho-quinone intermediates, which were assumed to be involved in SCO-267 induced CYP3A inactivation. These findings provide further insight into the bioactivation pathways involved in the generation of reactive, potentially toxic metabolites of SCO-267. Further studies are needed to evaluate the influence of SCO-267 metabolism on the safety of this drug in vivo.

Impact of obese patients in ovarian cancer surgery on postoperative wound complications: A meta-analysis.

The effect of obesity on wound-related outcomes in post-ovarian cancer patients is not clear. A number of studies on the association of fat with post-operation injury in ovarian carcinoma have produced contradictory findings. This study aims to conduct a study of the available data to assess the association of obese individuals with significant surgery results in ovarian cancer. We looked up Cochrane Library, Embase, and PubMed for qualifying research on ovarian cancer operations to determine the primary evidence for evaluating the association of obesity with post-surgical wound injury in ovarian cancer. The odds ratio (OR) was analysed with a fixed effect model if the variability of the study was small; otherwise, the analysis of the data was done with a random effect model. Out of 1259 related trials which were reviewed for eligibility, 6 publications were chosen from 2009 to 2019, 3076 patients who had had an operation for ovarian cancer. Obesity has been linked to an increased rate of wound-related complications in ovarian cancer operations compared to those without obesity (OR, 0.50; 95% CI, 0.37, 0.69 p < 0.0001). Non-obesity was significantly less likely to occur with respect to operation time compared to those with obesity (MD, -48.00; 95% CI, -55.33, -40.68 p < 0.00001). There were no statistically significant differences in the rate of haemorrhage after the operation (OR, 0.26; 95% CI, 0.04, 1.57, p = 0.14). Because of the limited number of trials in this meta-analysis, caution should be exercised in their treatment. More high-quality research with a large sample is required in order to confirm the findings.

Endoscopic balloon dilatation in the management of paediatric-acquired subglottic stenosis in children.

OBJECTIVE: To summarise our experience and the outcomes of endoscopic balloon dilatation (EBD) in the management of paediatric-acquired subglottic stenosis (SGS), and to further explore the influencing factors of successful EBD. METHOD: A retrospective case series study was conducted involving 33 paediatric patients diagnosed with acquired SGS who underwent EBD as the primary treatment from January 2012 to December 2021. The collected information included patient demographics, aetiology, time from extubation to operation, initial grade of SGS, descriptions of stenosis tissues, presence of tracheotomy, number of dilatation procedures and co-morbidity. The follow-up results were collected and analysed. RESULT: Thirty-three paediatric patients with an average age of 31.0 months who underwent EBD were included in the study. According to the Myers-Cotton classification, four (12.1%) patients had Grade I stenosis, nine (27.3%) had Grade II, 20 (60.6%) had Grade III and none had Grade IV. Of these, 15 (45.5%) exhibited acute lesions and 18 (54.5%) exhibited chronic lesions. The mean number of dilatation procedures per patient was 1.88 ± 1.05, and 19 (57.6%) patients received dilatations more than once. The overall success rate was 72.7%, with 100% for Grade I, 88.9% for Grade II and 60.0% for Grade III. There was a significant difference between the distribution of the stenosis grades in the successful and failed cases (p < 0.05). The mean number of dilatation procedures was 1.47 ± 0.64 and 2.22 ± 1.22 per patient in those with acute lesions and chronic lesions, respectively. The patients with chronic lesions had a significantly higher number of dilatations than those with acute lesions (p < 0.05). The success rate was 86.7% for acute lesions and 61.1% for chronic lesions. The correlation between the type of subglottic lesions and procedural success was not statistically significant (p > 0.05). CONCLUSION: Acquired SGS in paediatric patients can be successfully managed using EBD. The dilatation procedures should be performed in a timely manner, early treatment could prevent the need for multiple procedures and smaller stenosis grades could improve the success rate of the surgery.

Modified Hongyu Decoction promotes wound healing by activating the VEGF/PI3K/Akt signaling pathway.

Wound healing is a considerable problem for clinicians. Ever greater attention has been paid to the role of Chinese herbal monomers and compounds on wound healing. This study aims to elucidate the wound healing mechanism of Modified Hongyu Decoction (MHD) in vivo and in vitro. MHD wound healing activity in vivo was evaluated using an excision rat model. H and E staining, Masson's staining and immunofluorescence of wound tissue on days 7 and 14 were performed to evaluate the efficacy of MHD on wound healing. Subsequently, human umbilical vein endothelial cells (HUVECs) were used to evaluate wound healing characteristics in vitro. Cell Counting Kit-8 (CCK-8) and scratch assays were conducted to assess the effects of MHD on the proliferation and migration of HUVECs. The involvement of the VEGF/PI3K/Akt signaling pathway was assessed by western blotting. The rats in the MHD group displayed more neovascularization and collagen fibers. Western blotting of wound tissue showed that VEGF, PI3K, p-Akt and p-eNOS expression were significantly increased (p<0.05) in the MHD group. Cell Counting Kit-8 and scratch assays demonstrated that MHD promoted HUVECs proliferation and migration. MHD treatment significantly increased VEGF, PI3K, p-Akt and p-eNOS expression in HUVECs (p<0.05), which was inhibited by LY294002. Both in vivo and in vitro data indicated that MHD promotes wound healing by regulating the VEGF/PI3K/Akt signaling pathway.

Atractylone in the Atractylodes macrocephala Rhizoma Essential Oil and Its Anti-Inflammatory Activity.

The aim of this study was to conduct a screening of potential therapeutic compounds found in the Atractylodes macrocephala rhizoma essential oil (AO) and explore its mechanism of action in the treatment of ulcerative colitis (UC). An inflammation cell model was employed in conjunction with phospho-antibody array technology to explore potential therapeutic compounds of AO and their anti-inflammatory and antioxidant effects. Furthermore, we assessed their efficacy and mechanisms of action in treating dextran sulfate sodium (DSS)-induced colitis in mice. Via the screening process, we identified atractylone (ATR) as the primary active compound in AO. It has been demonstrated that ATR can both decrease the levels of tumor necrosis factor (TNF)-α and reactive oxygen species (ROS) and increase the expression of adhesion proteins such as claudin, ZO-1, and occludin in vitro. Moreover, ATR has been shown to improve UC symptoms in vivo. Via a non-targeted metabolomics analysis of colon tissue, we identified 57 distinct metabolites that responded to ATR treatment. Subsequent analysis of the metabolic pathways revealed that the action of ATR was primarily focused on the amino acid metabolism pathway. In summary, ATR may alleviate the symptoms of UC by regulating multiple signaling pathways. Additionally, ATR has a comprehensive function in anti-inflammation, antioxidative stress, and intestinal injury reduction.

Subchronic feeding study of glyphosate-tolerant maize GG2 with the gr79-epsps and gat genes in Wistar Han RCC rats.

The genetically modified (GM) maize GG2 contains gr79-epsps and gat genes, conferring glyphosate tolerance. The present study aimed to investigate potential effects of maize GG2 in a 90-day subchronic feeding study on Wistar Han RCC rats. Maize grains from GG2 or non-GM maize were incorporated into diets at concentrations of 25% and 50% and administered to Wistar Han RCC rats (n = 10/sex/group) for 90 days. The basal-diet group of rats (n = 10/sex/group) were fed with common commercialized rodent diet. Compared with rats fed with the corresponding non-GM maize and the basal-diet, no biologically relevant differences were observed in rats fed with the maize GG2, according to the results of body weight/gain, feed consumption/utilization, clinical signs, mortality, ophthalmology, clinical pathology (hematology, prothrombin time, urinalysis, serum chemistry), organ weights, and gross and microscopic pathology. Under the conditions of this study, these results indicated that maize GG2 is as safe as the non-GM maize in this 90-day feeding study.

CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer.

BACKGROUND: Bladder cancer (BCa) is the fourth most common malignant tumor with a poor prognosis worldwide. Further exploration and research are needed to unmask the underlying roles and molecular mechanisms of circular RNAs. In the current study, our findings showed that circXRN2 suppresses tumor progression driven by histone lactylation by activating the Hippo pathway in human bladder cancer. METHODS: RNA immunoprecipitation (RIP) followed by circRNA sequencing confirmed circXRN2 as the research object. Overexpression of circXRN2 and knockdown of TAZ/YAP further verified the biological functions in T24 and TCCSUP cells. RIP, immunoprecipitation and coimmunoprecipitation were used to elucidate the interaction between circXRN2 and LATS1. A Seahorse metabolic analyzer was used to determine the glycolytic rate. Cleavage under targets and Tagmentation (CUT&Tag) and chromatin immunoprecipitation (ChIP) were employed to ensure the regulatory roles of H3K18 lactylation in the transcriptional activity of LCN2. RESULTS: CircXRN2 is aberrantly downregulated in bladder cancer tissues and cell lines. CircXRN2 inhibits the proliferation and migration of tumor cells both in vitro and in vivo. In addition, circXRN2 serves as a negative regulator of glycolysis and lactate production. Mechanistically, circXRN2 prevents LATS1 from SPOP-mediated degradation by binding to the SPOP degron and then activates the Hippo signaling pathway to exert various biological functions. The circXRN2-Hippo pathway regulatory axis further modulates tumor progression by inhibiting H3K18 lactylation and LCN2 expression in human bladder cancer. CONCLUSIONS: CircXRN2 suppresses tumor progression driven by H3K18 lactylation by activating the Hippo signaling pathway in human bladder cancer. Our results indicated novel therapeutic targets and provided promising strategies for clinical intervention in human bladder cancer.

A 90-day feeding study of genetically modified maize LP007-1 in wistar han RCC rats.

LP007-1 is a variety of insect-resistant and herbicide-tolerant maize containing the modified cry1Ab, cry2Ab, vip3Aa and cp4-epsps genes. The food safety assessment of the maize LP007-1 was conducted in Wistar Han RCC rats by a 90-days feeding study. Maize grains from both LP007-1 or its corresponding non-genetically modified control maize AX808 were incorporated into rodent diets at 25% and 50% concentrations by mass and administered to rats (n = 10/sex/group) for 90 days. A commercialized rodent diet was fed to an additional group as the basal-diet group. The diets of all groups were nutritionally balanced. No biologically relevant differences were observed in rats fed with maize LP007-1 compared to rats fed with AX808 and the basal-diet with respect to body weight/gain, food consumption/utilization, clinical signs, mortality, ophthalmology, clinical pathology (hematology, prothrombin time, activation of partial thrombin time, serum chemistry, urinalysis), organ weights, and gross and microscopic pathology. Considering the circumstances of this study, the results provided evidence that LP007-1 maize did not exhibit toxicity in the 90-day feeding study.

Nocaviogua A and B: two lipolanthines from root-nodule-associated Nocardia sp.

Nocaviogua A (1) and B (2), two lipolanthines featuring a non-canonical avionin (Avi)-containing macrocycle and a long acyl chain, were identified from the mutualistic actinomycete Nocardia sp. XZ19_369, which was isolated from the nodules of sea buckthorn collected in Tibet. Their planar structures were elucidated via extensive analyses of 1D and 2D NMR, as well as HRMS data. The absolute configurations were fully elucidated by advanced Marfey's analysis and GIAO NMR calculations, representing the first time that the configurations of this family of lipolanthines have been determined. Nocaviogua A (1) exhibited weak cytotoxicity against human chronic uveal melanoma cells (UM92-1), non-small cell lung cancer (NCI-H2170), and breast cancer (MDA-MB-231). Our work provides valuable information on this burgeoning class of lipolanthines for further investigations.

Individual surveillance by competing risk model for patients with hepatocellular carcinoma occurrence in all-cause cirrhosis.

PURPOSE: It was of great significance to identify someone with a high risk of hepatocellular carcinoma (HCC) occurrence and make a diagnosis as early as possible. Therefore, we aimed to develop and validate a new, objective, and accurate prediction model, and convert it into a nomogram to make a personalized prediction of cancer occurrence in cirrhotic patients with different etiologies. METHODS: The present study included 938 patients with cirrhosis from January 1, 2011, to December 31, 2012. Patients were prospectively followed-up until January 1, 2018. We used a competing risk model and the Fine-Gray test to develop and validate the prediction model and to plot a nomogram based on the model established. RESULTS: At the end of follow-up, 202 (21.5%) patients developed HCC, with a 5-year incidence of 19.0% (corrected for competing risk model). Based on the competing risk regression method, we built a prediction model including age, gender, etiology, lymphocyte, and A/G ratio. Three groups with different risks were generated on account of tertiles of the 5-year risk predicted by the model. The cumulative 1-, 3-, and 5-year incidences of HCC were 2.0%, 20.8%, and 42.3% in high-risk group, 0.9%, 10.1%, and 17.7% in medium-risk group, and 0%, 2.0%, 8.5% in low-risk group (P < 0.001). The model showed excellent discrimination and calibration in predicting the risk of HCC occurrence in patients with all-cause cirrhosis. CONCLUSION: The model could make an individual prediction of cancer occurrence and stratify patients based on predicted risk, regardless of the causes of cirrhosis.

Diagnostic value of contrast-enhanced ultrasound combined with MRI for cervical hyperplastic, tuberculosis-infected, and metastatic lymph nodes.

Objective: To explore the diagnostic value of contrast-enhanced ultrasound (CEUS) combined with magnetic resonance imaging (MRI) for cervical abnormal lymph nodes. Methods: We retrospectively reviewed the clinical records of 150 patients undergoing lymph node examinations at Hangzhou Chest Hospital from January 2017 to December 2019. According to the characteristics of lymph nodes, the patients were divided into three groups: 45 patients had hyperplastic lymph nodes (HLNs; Group-A), 55 had lymph node tuberculosis (LNTB; Group-B), 50 had metastatic lymph nodes (MLN; Group-C). We compared the ultrasonic examination and MRI results between the groups, and compared the diagnostic value of CEUS alone and CEUS plus MRI. Results: Lower resistance indexes (RI) for Groups-A and B than Group-C(P<0.05). Mixed blood flow type was predominant in Group-A, while the lymphohilum type was predominant in Group-B, and the marginal type was predominant in Group-C(P<0.05). The proportion of non-uniform types in Group-B was significantly higher than that in Groups-A and C(P<0.05). After enhancement, the proportions of non-uniform types in Groups-A and B were higher than Group-C(P<0.05). The results of MRI examination showed that positive reinforcement integral (PEI) and maximum slope of increase (MSI) values increased sequentially from Group-B to Group-A, and then to Group-C(P<0.05); while time to peak (TTP) values increased sequentially from Group-C to Group-A, and then to Group-B(P<0.05). The diagnosis accuracy of CEUS combined with MRI was significantly higher than that of CEUS alone(P<0.05). RI-PEI, RI-MSI, and RI-TTP showed high specificity and sensitivity in the diagnosis and differentiation of HLNs, LNTB, and MLNs(P<0.05). Conclusion: CEUS combined with MRI can significantly facilitate the differential diagnosis between HLNs, LNTB, and MLNs. The two diagnosis methods combined improve the diagnosis accuracy of cervical lymph node diseases.

Effects of Polyunsaturated Fatty Acids on Colorectal Cancer Patients: A Meta-Analysis of Randomized Controlled Trials.

This study aimed to investigate the effects of polyunsaturated fatty acids (PUFAs) on patients with colorectal cancer (CRC). Electronic databases such as PubMed and Web of Science were searched. Studies on the application of PUFAs in patients with CRC, published up to January 2022, were conducted. Twelve studies involving 702 CRC patients were included. For patients undergoing surgery, subgroup analyses indicated that preoperative supplementation with PUFAs improved total postoperative infectious complications (RR: 0.37, p = 0.02). Furthermore, the supplementation of PUFAs in preoperative (WMD: -2.27, p < 0.001) and postoperative (WMD: -2.66, p = 0.01) groups was effective in shortening the postoperative hospital stay for patients with CRC. Tumor necrosis factor-α (TNF-α) (SMD: -0.56, p = 0.007) and interleukin-6 (IL-6) (SMD: -0.54, p = 0.004) levels were lower in all CRC patients receiving PUFAs intervention than in the control group. Moreover, supplementation with PUFAs in chemotherapy patients significantly increased albumin (WMD: 0.48, p = 0.03) and decreased C-reactive protein (CRP) (WMD: -6.12, p = 0.02) compared to the control group. This study demonstrated that PUFAs intervention could diminish the total postoperative infection complications of CRC patients, shorten the postoperative hospital stay, and reduce inflammation.

Exosome is involved in liver graft protection after remote ischemia reperfusion conditioning.

BACKGROUND: Remote ischemic perconditioning (RIPerC) has been demonstrated to protect grafts from hepatic ischemia-reperfusion injury (IRI). This study investigated the role of exosomes in RIPerC of liver grafts in rats. METHODS: Twenty-five rats (including 10 donors) were randomly divided into five groups (n = 5 each group): five rats were used as sham-operated controls (Sham), ten rats were for orthotopic liver transplantation (OLT, 5 donors and 5 recipients) and ten rats were for OLT + RIPerC (5 donors and 5 recipients). Liver architecture and function were evaluated. RESULTS: Compared to the OLT group, the OLT + RIPerC group exhibited significantly improved liver graft histopathology and liver function (P < 0.05). Furthermore, the number of exosomes and the level of P-Akt were increased in the OLT + RIPerC group. CONCLUSIONS: RIPerC effectively improves graft architecture and function, and this protective effect may be related to the increased number of exosomes. The upregulation of P-Akt may be involved in underlying mechanisms.

Single-cell RNA sequencing analysis reveals the relationship of bone marrow and osteopenia in STZ-induced type 1 diabetic mice.

INTRODUCTION: Type 1 diabetes (T1D) is a multifactorial autoimmune disease. Broad knowledge about the genetics, epidemiology and clinical management of T1D has been achieved, but understandings about the cell varieties in the bone marrow during T1D remain limited. OBJECTIVES: We aimed to present a profile of the bone marrow cells and reveal the relationship of bone marrow and osteopenia in streptozotocin (STZ)-induced T1D mice. METHODS: The whole bone marrow cells from the femurs and tibias of healthy (group C) and STZ-induced T1D mice (group D) were collected for single-cell RNA sequencing analysis. Single-cell flow cytometry and immunohistochemistry were performed to confirm the proportional changes among bone marrow neutrophils (BM-neutrophils) (Cxcr2+, Ly6g+) and B lymphocytes (Cd19+). X-ray and micro-CT were performed to detect bone mineral density. The correlation between the ratio of BM-neutrophils/B lymphocytes and osteopenia in STZ-induced T1D mice was analyzed by nonparametric Spearman correlation analysis. RESULTS: The bone marrow cells in groups C and D were divided into 12 clusters, and 249 differentially expressed genes were found. The diversity of CD45+ immune cells between groups C and D were greatly affected: the proportion of BM-neutrophils showed a significant increase while the proportion of B lymphocytes in group D showed a significant decrease. X-ray and micro-CT analyses confirmed that osteopenia occurred in group D mice. In addition, the results of single-cell flow cytometry and correlation analysis showed that the ratio of BM-neutrophils/B lymphocytes negatively correlated with osteopenia in STZ-induced T1D mice. CONCLUSION: A single-cell RNA sequencing analysis revealed the profile and heterogeneity of bone marrow immune cells in STZ-induced T1D mice for the first time. The ratio of BM-neutrophils/B lymphocytes negatively correlated with osteopenia in STZ-induced T1D mice, which may enhance understanding for treating T1D and preventing T1D-induced osteopenia.

Efficacy of PD-1/PD-L1 inhibitors in patients with advanced gastroesophageal cancer: An updated meta-analysis based on randomized controlled trials.

Background: This study aimed to investigate the clinical efficacy of programmed death-1 receptor and ligand-1 (PD-1/PD-L1) inhibitors in gastroesophageal cancer patients and the relationship between their clinicopathological features and curative treatment effects. Methods: A systematic search was conducted for articles published before April 2022 from online databases (PubMed, EMBASE, Web of Science and the Cochrane Library). The main outcome was overall survival (OS). Results: This meta-analysis comprised 16 studies involving 9,304 participants. The results indicated that compared with chemotherapy, patients treated with PD-1/PD-L1 inhibitors had significantly improved OS (HR = 0.80; p < 0.001) but no significant improvement in progression-free survival (PFS) (p = 0.185). Subgroup analyses demonstrated that PD-1/PD-L1 inhibitors combined with chemotherapy, esophageal squamous cell carcinoma, male, Asian patients and combined positive score (CPS) ≥1 were significantly associated with better survival outcomes. Further, subgroup analysis of gender revealed that the OS of all subgroups containing male patients was significantly improved compared with chemotherapy, unlike that of female patients. In addition, the line of therapy, Lauren classification, age and eastern cooperative oncology group (ECOG) performance status were not associated with PD-1/PD-L1 inhibitors efficacy. Conclusion: The results indicated that PD-1/PD-L1 inhibitors could prolong the OS of advanced gastroesophageal cancer patients. Clinicopathological features such as therapeutic schedules, tumor types, histological type, gender, geographical region and PD-L1 expression status (CPS) seemed to be associated with survival outcomes.

Effect of Tool Coatings on Machining Properties of Compacted Graphite Iron.

Compacted graphite iron (CGI) has become the most ideal material for automotive engine manufacturing owing to its excellent mechanical properties. However, tools are severely worn during processing, considerably shortening their lifespan. In this study, we prepared a series of cemented carbide-coated tools and evaluated their coating properties in cutting tests. Among all tested coatings, PVD coating made of AlCrN (AC) presented with the best surface integrity and mechanical properties, achieving the best comprehensive performance in the coating test. The AC-coated tool also exhibited the best cutting performance at a low speed of 120 m/min, corresponding to a 60% longer cutting life and the lowest workpiece surface roughness relative to other coated tools. In the cutting test at a high speed of 350 m/min, the CVD double-layer coated tool (MT) with a TiCN inner layer of and an Al2O3 outer layer had a 70% longer cutting life and the lowest workpiece surface roughness relative to other coated tools.