scATAC-Ref: a reference of scATAC-seq with known cell labels in multiple species.

Chromatin accessibility profiles at single cell resolution can reveal cell type-specific regulatory programs, help dissect highly specialized cell functions and trace cell origin and evolution. Accurate cell type assignment is critical for effectively gaining biological and pathological insights, but is difficult in scATAC-seq. Hence, by extensively reviewing the literature, we designed scATAC-Ref (https://bio.liclab.net/scATAC-Ref/), a manually curated scATAC-seq database aimed at providing a comprehensive, high-quality source of chromatin accessibility profiles with known cell labels across broad cell types. Currently, scATAC-Ref comprises 1 694 372 cells with known cell labels, across various biological conditions, >400 cell/tissue types and five species. We used uniform system environment and software parameters to perform comprehensive downstream analysis on these chromatin accessibility profiles with known labels, including gene activity score, TF enrichment score, differential chromatin accessibility regions, pathway/GO term enrichment analysis and co-accessibility interactions. The scATAC-Ref also provided a user-friendly interface to query, browse and visualize cell types of interest, thereby providing a valuable resource for exploring epigenetic regulation in different tissues and cell types.

Protein biomarkers and alternatively methylated cell-free DNA detect early stage pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed. DESIGN: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites. RESULTS: Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92). CONCLUSION: A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.

Disease-modifying potential of diphenyl diselenide in an experimental osteoarthritis model.

Oxidative stress is a key factor in the disruption of cartilage homeostasis during the development of osteoarthritis (OA). Organic selenium (Se)-containing compounds such as diselenides have excellent antioxidant activity and may prevent related diseases. We aimed to examine the benefits of the synthetic small molecule diphenyl diselenide (DPDSe) in OA models in vitro and in vivo. Our findings showed that DPDSe could maintain extracellular matrix (ECM) homeostasis and inhibit reactive oxygen species (ROS) production in IL-1ß-treated chondrocytes. In a destabilization of the medial meniscus (DMM)-induced OA mouse model, intra-articular administration of DPDSe alleviated joint degeneration, as evidenced by a decrease in the OARSI score and the restoration of collagen II (COL2) and MMP-13 expression in cartilage tissues. We confirmed that DDS activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in IL-1ß-treated chondrocytes, and its chondroprotective effects were significantly counteracted when Nrf2 signaling was blocked by the inhibitor ML385 or by siRNA-mediated Nrf2 knockdown. The relatively strong performance of DPDSe makes it an ideal candidate for further trials as a disease-modifying OA drug (DMOAD).

M2 Macrophage Membrane-Camouflaged Fe3 O4 -Cy7 Nanoparticles with Reduced Immunogenicity for Targeted NIR/MR Imaging of Atherosclerosis.

Atherosclerosis （AS） is the primary reason behind cardiovascular diseases, leading to approximately one-third of global deaths. Developing a novel multi-model probe to detect AS is urgently required. Macrophages are the primary cells from which AS genesis occurs. Utilizing natural macrophage membranes coated on the surface of nanoparticles is an efficient delivery method to target plaque sites. Herein, Fe3 O4 -Cy7 nanoparticles (Fe3 O4 -Cy7 NPs), functionalized using an M2 macrophage membrane and a liposome extruder for Near-infrared fluorescence and Magnetic resonance imaging, are synthesized. These macrophage membrane-coated nanoparticles (Fe3 O4 @M2 NPs) enhance the recognition and uptake using active macrophages. Moreover, they inhibit uptake using inactive macrophages and human coronary artery endothelial cells. The macrophage membrane-coated nanoparticles (Fe3 O4 @M0 NPs, Fe3 O4 @M1 NPs, Fe3 O4 @M2 NPs) can target specific sites depending on the macrophage membrane type and are related to C-C chemofactor receptor type 2 protein content. Moreover, Fe3 O4 @M2 NPs demonstrate excellent biosafety in vivo after injection, showing a significantly higher Fe concentration in the blood than Fe3 O4 -Cy7 NPs. Therefore, Fe3 O4 @M2 NPs effectively retain the physicochemical properties of nanoparticles and depict reduced immunological response in blood circulation. These NPs mainly reveal enhanced targeting imaging capability for atherosclerotic plaque lesions.

ALKBH5 regulates paclitaxel resistance in NSCLC via inhibiting CEMIP-mediated EMT.

N6-methyladenosine (m6A) is the most prevalent mRNA modification, and it is verified to be closely correlated with cancer occurrence and progression. The m6A demethylase ALKBH5 (alkB homolog 5) is dysregulated in various cancers. However, the role and underlying mechanism of ALKBH5 in the pathogenesis and especially the chemo-resistance of non-small cell lung cancer (NSCLC) is poorly elucidated. The current study shows that ALKBH5 expression is reduced in paclitaxel (PTX) resistant NSCLC cells and down-regulation of ALKBH5 usually implies poor prognosis of NSCLC patients. Over-expression of ALKBH5 in PTX-resistant cells can suppress cell proliferation and enhance chemo-sensitivity, while knockdown of ALKBH5 exerts the opposite effect, which further supports the tumor suppressive role of ALKBH5. Over-expression of ALKBH5 can also reverse the epithelial-mesenchymal transition (EMT) process in PTX-resistant cancer cells. Mechanistically, data from RNA-seq, real-time PCR and western blotting indicate that CEMIP (cell migration inducing hyaluronidase 1), also known as KIAA1199, may be the downstream target of ALKBH5. Furthermore, ALKBH5 negatively regulates the CEMIP level by reducing the stability of CEMIP mRNA. Collectively, the current data demonstrate that the ALKBH5/CEMIP axis modulates the EMT process in NSCLC, which in turn regulates the chemo-sensitivity of cancer cells to PTX.

CircHAT1 regulates the proliferation and phenotype switch of vascular smooth muscle cells in lower extremity arteriosclerosis obliterans through targeting SFRS1.

This study aimed to decipher the mechanism of circular ribonucleic acids (circRNAs) in lower extremity arteriosclerosis obliterans (LEASO). First, bioinformatics analysis was performed for screening significantly down-regulated cardiac specific circRNA-circHAT1 in LEASO. The expression of circHAT1 in LEASO clinical samples was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of splicing factor arginine/serine-rich 1 (SFRS1), α-smooth muscle actin (α-SMA), Calponin (CNN1), cyclin D1 (CNND1) and smooth muscle myosin heavy chain 11 (SMHC) in vascular smooth muscle cells (VSMCs) was detected by Western blotting. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) and Transwell assays were used to evaluate cell proliferation and migration, respectively. RNA immunoprecipitation (RNA-IP) and RNA pulldown verified the interaction between SFRS1 and circHAT1. By reanalyzing the dataset GSE77278, circHAT1 related to VSMC phenotype conversion was screened, and circHAT1 was found to be significantly reduced in peripheral blood mononuclear cells (PBMCs) of LEASO patients compared with healthy controls. Knockdown of circHAT1 significantly promoted the proliferation and migration of VSMC cells and decreased the expression levels of contractile markers. However, overexpression of circHAT1 induced the opposite cell phenotype and promoted the transformation of VSMCs from synthetic to contractile. Besides, overexpression of circHAT1 inhibited platelet-derived growth factor-BB (PDGF-BB)-induced phenotype switch of VSMC cells. Mechanistically, SFRS1 is a direct target of circHAT1 to mediate phenotype switch, proliferation and migration of VSMCs. Overall, circHAT1 regulates SFRS1 to inhibit the cell proliferation, migration and phenotype switch of VSMCs, suggesting that it may be a potential therapeutic target for LEASO.

Gastrointestinal cancer precursor risk and mortality in pancreatic intraductal papillary mucinous neoplasms: a nationwide cohort study.

BACKGROUND AND AIMS: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a precursor of pancreatic cancer. While earlier research has shown a high prevalence of synchronous/metachronous extrapancreatic tumors in IPMN patients, these studies have often been small with retrospective data collection. The aim of the study was to examine absolute and relative risks of non-pancreatic gastrointestinal (GI) cancer precursors and mortality in histologically confirmed IPMN. METHODS: Through the nationwide ESPRESSO histopathology cohort, we retrieved data on IPMN between 1965 and 2016. Each index case was matched to ≤5 general population controls. Through Cox regression, we estimated hazard ratios (HRs) for future GI cancer precursors and death. RESULTS: A total of 117 patients with IPMN and 539 age- and sex-matched controls were included. Over a median of 2.1 years of follow up, we confirmed two (1.7%) incident GI cancer precursors in IPMN vs. four (0.7%) in controls, corresponding to an HR of 1.89 (95%CI = 0.34-10.55). By contrast, IPMN patients were at increased risk of death (HR 3.61 (95%CI = 1.79-7.27)). The most common cause of death in IPMN was pancreatic cancer (n = 14; 45.2% of all deaths). CONCLUSIONS: We found no association between IPMN and other GI cancer precursors. This argues against comprehensive routine surveillance for other GI cancer precursors in IPMN patients. Mortality was increased in IPMN with pancreatic cancer being the most common cause of death, indicating the need for lifelong follow up in all resected and non-resected patients with IPMN. However, results should be confirmed in larger cohorts.

The effect of exercise training intervention for patients with abdominal aortic aneurysm on cardiovascular and cardiorespiratory variables: an updated meta-analysis of randomized controlled trials.

OBJECTIVE: The purpose of this meta-analysis was to evaluate the effect of exercise training intervention in patients with abdominal aortic aneurysm (AAA). METHODS: Eight randomized controlled trials (RCTs) that recruited 588 AAA patients were extracted using 4 databases (PubMed, Embase, Wanfang Data, and Cochrane Library). Physiological and biochemistry parameters that included in this study are high-sensitivity C-reactive protein (hs-CRP), respiratory peak oxygen uptake rate (VO2peak), triglyceride (TG), total cholesterol (TC), anaerobic threshold (AT), the diameter of AAA, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), and matrix metalloproteinase-9 (MMP-9). Standard mean difference (SMD) was used to assess the between group effect. RESULTS: This meta-analysis was synthesized with findings from RCTs and found that hs-CRP (SMD, - 0.56 mg/dL; 95% CI: - 0.90 to 0.22; P = 0.001), VO2peak (SMD, 0.4 mL/kg/min; 95% CI, 0.21 to 0.60; P < 0.001), TG (SMD, - 0.39 mg/dL; 95% CI: - 0.02 to 0.77; P = 0.04), and AT (SMD, 0.75 mL/kg/min; 95% CI, 0.54 to 0.96; P < 0.001) were significantly improved in the exercise groups, while the size of AAA (SMD, - 0.15; 95% CI: - 0.36 to 0.06; P = 0.15), TC (SMD, 0.16 mg/dL; 95% CI: - 0.10 to 0.42; P = 0.23), HDL/LDL ratio (SMD, - 0.06; 95% CI: - 0.32 to 0.20; P = 0.64), HDL (SMD, - 0.09; 95% CI: - 0.39 to 0.20; P = 0.54), LDL (SMD, 0.08; 95% CI: - 0.21 to 0.38; P = 0.59), and MMP-9 (SMD, - 0.23 mg/dL; 95% CI: - 0.53 to 0.06; P = 0.12) did not differ in the exercise groups compared with the controls. CONCLUSION: Exercise intervention improved some of the CVD risk factors but not all, hs-CRP, VO2peak and AT were significantly improved after exercise intervention, while, changes of MMP-9, the size of AAA, and the overall lipids profile were not. Exercise intervention provides an additional solution for improving cardiorespiratory capacity and health status among AAA patients, and might lead to a delay of AAA progression.

Cancer Diagnoses After Recent Weight Loss.

Importance: Weight loss is common in primary care. Among individuals with recent weight loss, the rates of cancer during the subsequent 12 months are unclear compared with those without recent weight loss. Objective: To determine the rates of subsequent cancer diagnoses over 12 months among health professionals with weight loss during the prior 2 years compared with those without recent weight loss. Design, Setting, and Participants: Prospective cohort analysis of females aged 40 years or older from the Nurses' Health Study who were followed up from June 1978 until June 30, 2016, and males aged 40 years or older from the Health Professionals Follow-Up Study who were followed up from January 1988 until January 31, 2016. Exposure: Recent weight change was calculated from the participant weights that were reported biennially. The intentionality of weight loss was categorized as high if both physical activity and diet quality increased, medium if only 1 increased, and low if neither increased. Main Outcome and Measures: Rates of cancer diagnosis during the 12 months after weight loss. Results: Among 157 474 participants (median age, 62 years [IQR, 54-70 years]; 111 912 were female [71.1%]; there were 2631 participants [1.7%] who self-identified as Asian, Native American, or Native Hawaiian; 2678 Black participants [1.7%]; and 149 903 White participants [95.2%]) and during 1.64 million person-years of follow-up, 15 809 incident cancer cases were identified (incident rate, 964 cases/100 000 person-years). During the 12 months after reported weight change, there were 1362 cancer cases/100 000 person-years among all participants with recent weight loss of greater than 10.0% of body weight compared with 869 cancer cases/100 000 person-years among those without recent weight loss (between-group difference, 493 cases/100 000 person-years [95% CI, 391-594 cases/100 000 person-years]; P < .001). Among participants categorized with low intentionality for weight loss, there were 2687 cancer cases/100 000 person-years for those with weight loss of greater than 10.0% of body weight compared with 1220 cancer cases/100 000 person-years for those without recent weight loss (between-group difference, 1467 cases/100 000 person-years [95% CI, 799-2135 cases/100 000 person-years]; P < .001). Cancer of the upper gastrointestinal tract (cancer of the esophagus, stomach, liver, biliary tract, or pancreas) was particularly common among participants with recent weight loss; there were 173 cancer cases/100 000 person-years for those with weight loss of greater than 10.0% of body weight compared with 36 cancer cases/100 000 person-years for those without recent weight loss (between-group difference, 137 cases/100 000 person-years [95% CI, 101-172 cases/100 000 person-years]; P < .001). Conclusions and Relevance: Health professionals with weight loss within the prior 2 years had a significantly higher risk of cancer during the subsequent 12 months compared with those without recent weight loss. Cancer of the upper gastrointestinal tract was particularly common among participants with recent weight loss compared with those without recent weight loss.

The recovery potential and utilization pathway of chemical energy from wastewater pollutants during wastewater treatment in China.

Research on the potential for chemical energy recovery and the optimization of recovery pathways in different regions of China is still lacking. This study aimed to address this gap by evaluating the potential and optimize the utilization pathways for chemical energy recovery in various regions of China for achieving sustainable wastewater treatment. The results showed that the eastern and northeastern regions of China exhibited higher chemical energy levels under the existing operating conditions. Key factors affecting chemical energy recovery included chemical oxygen demand removal (ΔCOD), treatment scale, and specific energy consumption (µ) of wastewater treatment plants (WWTPs). Furthermore, the average improvement in the chemical energy recovery rate with an optimized utilization pathway was approximately 40% in the WWTPs. The use of the net-zero energy consumption (NZE) model proved effective in improving the chemical energy recovery potential, with an average reduction of greenhouse gas (GHG) emissions reaching next to 95% in the investigated WWTPs.

Precision Engineering of the Co-immobilization of Enzymes for Cascade Biocatalysis.

The design and orderly layered co-immobilization of multiple enzymes on resin particles remain challenging. In this study, the SpyTag/SpyCatcher binding pair was fused to the N-terminus of an alcohol dehydrogenase (ADH) and an aldo-keto reductase (AKR), respectively. A non-canonical amino acid (ncAA), p-azido-L-phenylalanine (p-AzF), as the anchor for covalent bonding enzymes, was genetically inserted into preselected sites in the AKR and ADH. Employing the two bioorthogonal counterparts of SpyTag/SpyCatcher and azide-alkyne cycloaddition for the immobilization of AKR and ADH enabled sequential dual-enzyme coating on porous microspheres. The ordered dual-enzyme reactor was subsequently used to synthesize (S)-1-(2-chlorophenyl)ethanol asymmetrically from the corresponding prochiral ketone, enabling the in situ regeneration of NADPH. The reactor exhibited a high catalytic conversion of 74 % and good reproducibility, retaining 80 % of its initial activity after six cycles. The product had 99.9 % ee, which that was maintained in each cycle. Additionally, the double-layer immobilization method significantly increased the enzyme loading capacity, which was approximately 1.7 times greater than that of traditional single-layer immobilization. More importantly, it simultaneously enabled both the purification and immobilization of multiple enzymes on carriers, thus providing a convenient approach to facilitate cascade biocatalysis.

[Safety of modified T-piece resuscitator versus nasal cannula oxygen in electronic bronchoscopy for infants: a prospective randomized controlled study]. / 改良Tç»„åˆå¤è‹å™¨ä¸Žé¼»å¯¼ç®¡å¸æ°§ç”¨äºŽå©´å„¿ç”µå­æ”¯æ°”ç®¡é•œæ£€æŸ¥çš„å®‰å ¨æ€§æ¯”è¾ƒï¼šä¸€é¡¹å‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To optimize the oxygen therapy regimens for infants with pulmonary diseases during bronchoscopy. METHODS: A prospective randomized, controlled, and single-center clinical trial was conducted on 42 infants who underwent electronic bronchoscopy from July 2019 to July 2021. These infants were divided into a nasal cannula (NC) group and a modified T-piece resuscitator (TPR) group using a random number table. The lowest intraoperative blood oxygen saturation was recorded as the primary outcome, and intraoperative heart rate and respiratory results were recorded as the secondary outcomes. RESULTS: Compared with the NC group, the modified TPR group had a significantly higher level of minimum oxygen saturation during surgery and a significantly lower incidence rate of hypoxemia (P<0.05). In the modified TPR group, there were 6 infants with mild hypoxemia, 2 with moderate hypoxemia, and 1 with severe hypoxemia, while in the NC group, there were 3 infants with mild hypoxemia, 5 with moderate hypoxemia, and 9 with severe hypoxemia (P<0.05). The modified TPR group had a significantly lower incidence rate of intraoperative respiratory rhythm abnormalities than the NC group (P<0.05), but there was no significant difference in the incidence rate of arrhythmias between the two groups (P>0.05). CONCLUSIONS: Modified TPR can significantly reduce the risk of hypoxemia in infants with pulmonary diseases during electronic bronchoscopy, and TPR significantly decreases the severity of hypoxemia and the incidence of respiratory rhythm abnormalities compared with traditional NC.

Being Breastfed in Infancy and Risk of Colorectal Cancer and Precursor Lesions.

BACKGROUND & AIMS: Emerging evidence implicates the importance of perinatal and early-life exposures in colorectal cancer (CRC) development. However, it remains unclear whether being breastfed in infancy is associated with CRC risk in adult life, particularly early adulthood. METHODS: We prospectively investigated the association between history of being breastfed and risk of CRC and its precursor lesions among 66,634 women 46-93 years of age from the Nurses' Health Study and 92,062 women 27-68 years of age from the Nurses' Health Study II. Cox regression and logistic regression for clustered data were used to estimate hazard ratios for CRC and odds ratios for CRC precursors, respectively. RESULTS: During 3.5 million person-years of follow-up, we identified 1490 incident cases of CRC in 2 cohorts. Having been breastfed was associated with a 23% (95% confidence interval [CI], 10% to 38%) increased risk of CRC. The risk of CRC increased with duration of being breastfed (Ptrend < .001). These findings were validated using breastfeeding information from the mothers of a subset of participants. Among younger participants from the Nurses' Health Study II, a significant association was observed between being breastfed and increased risk of high-risk adenomas under 50 years of age (odds ratio, 1.46; 95% CI, 1.16 to 1.83). Consistently, having been breastfed was associated with increased risk of CRC among participants ≤55 years of age (hazard ratio, 1.38; 95% CI, 1.06 to 1.80). CONCLUSIONS: Being breastfed in infancy was associated with increased risk of CRC in adulthood, including among younger adults. However, further research is needed to understand the underlying biological mechanisms, as this association does not establish causation.

Mst1 attenuates myocardial ischemia/reperfusion injury following heterotopic heart transplantation in mice through regulating Keap1/Nrf2 axis.

Ischemia reperfusion (I/R) injury remains a frequent adverse event that accompanies heart transplantation. Oxidative stress and aberrant production of free radicals were regarded as the culprit of cell death and tissue damage in post-transplant IR injury. Mst1 has been identified as a mediator of oxidative stress and Nrf2 regulates anti-oxidative enzymes, however, the interaction between Mst1 and Nrf2 anti-oxidative stress pathway remains to be clarified in the event of cardiac IR injury. Herein, the model of ischemia-reperfusion injury in heterotopic heart transplantation mice was firstly established.. We observed that cardiac IR induced upregulation of Mst1 and activation of Nrf2/HO-1pathway in mice receiving heterotopic heart transplantation. Further Cobalt dichloride-induced oxidative stress model of RAW264.7 macrophage cells were then established to mimic cardiac I/R injury, results showed that exposure to CoCl2 induced the upregulation of Mst1 and activation of Keap1/Nrf2 pathway, and genetic ablation of Mst-1 and inhibition of Keap1/Nrf2 pathway aggravated oxidative damage in those cells. Additional in vivo study showed that transfection of Mst1 shRNA spurred ROS generation and worsened cardiac damage in IR mice. Meanwhile, Mst1-KD mice receiving heart transplantation showed markedly downregulation of Nrf2, HO-1 yet upregulation of Keap1, indicating diminished protective effect against tissue damage caused by IR probably owing to the frustration of Keap1/Nrf2 pathway. Taken together, our findings demonstrated the protective effect of Mst1 from cardiac IR injury via triggering Keap1/Nrf2 axis and suppressing ROS generation, which shed light on the promising role of Mst1 in transitional management of IR injury resulted from cardiac transplantation.

Tanshinone IIA ameliorates Aß transendothelial transportation through SIRT1-mediated endoplasmic reticulum stress.

BACKGROUND: The disruption of blood-brain barrier (BBB), predominantly made up by brain microvascular endothelial cells (BMECs), is one of the characteristics of Alzheimer's disease (AD). Thus, improving BMEC function may be beneficial for AD treatment. Tanshinone IIA (Tan IIA) has been proved to ameliorate the cognitive dysfunction of AD. Herein, we explored how Tan IIA affected the function of BMECs in AD. METHODS: Aß1-42-treated brain-derived endothelium cells.3 (bEnd.3 cells) was employed for in vitro experiments. And we performed molecular docking and qPCR to determine the targeting molecule of Tan IIA on Sirtuins family. The APPswe/PSdE9 (APP/PS1) mice were applied to perform the in vivo experiments. Following the behavioral tests, protein expression was determined through western blot and immunofluorescence. The activities of oxidative stress-related enzymes were analyzed by biochemically kits. Nissl staining and thioflavin T staining were conducted to reflect the neurodegeneration and Aß deposition respectively. RESULTS: Molecular docking and qPCR results showed that Tan IIA mainly acted on Sirtuin1 (SIRT1) in Sirtuins family. The inhibitor of SIRT1 (EX527) was employed to further substantiate that Tan IIA could attenuate SIRT1-mediated endoplasmic reticulum stress (ER stress) in BMECs. Behavioral tests suggested that Tan IIA could improve the cognitive deficits in APP/PS1 mice. Tan IIA administration increased SIRT1 expression and alleviated ER stress in APP/PS1 mice. In addition, LRP1 expression was increased and RAGE expression was decreased after Tan IIA administration in both animals and cells. CONCLUSION: Tan IIA could promote Aß transportation by alleviating SIRT1-mediated ER stress in BMECs, which ameliorated cognitive deficits in APP/PS1 mice.

A two-stage genome-wide association study identifies novel germline genetic variations in CACNA2D3 associated with radiotherapy response in nasopharyngeal carcinoma.

BACKGROUND: Radiotherapy (RT) is the standard treatment for nasopharyngeal carcinoma (NPC). However, due to individual differences in radiosensitivity, biomarkers are needed to tailored radiotherapy to cancer patients. However, comprehensive genome-wide radiogenomic studies on them are still lacking. The aim of this study was to identify genetic variants associated with radiotherapy response in patients with NPC. METHODS: This was a large­scale genome-wide association analysis (GWAS) including a total of 981 patients. 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant loci were further genotyped using MassARRAY system and TaqMan SNP assays in the validation stages of 847 patients. This study used logistic regression analysis and multiple bioinformatics tools such as PLINK, LocusZoom, LDBlockShow, GTEx, Pancan-meQTL and FUMA to examine genetic variants associated with radiotherapy efficacy in NPC. RESULTS: After genome-wide level analysis, 19 SNPs entered the validation stage (P < 1 × 10- 6), and rs11130424 ultimately showed statistical significance among these SNPs. The efficacy was better in minor allele carriers of rs11130424 than in major allele carriers. Further stratified analysis showed that the association existed in patients in the EBV-positive, smoking, and late-stage (III and IV) subgroups and in patients who underwent both concurrent chemoradiotherapy and induction/adjuvant chemotherapy. CONCLUSION: Our study showed that rs11130424 in the CACNA2D3 gene was associated with sensitivity to radiotherapy in NPC patients. TRIAL REGISTRATION NUMBER: Effect of genetic polymorphism on nasopharyngeal carcinoma chemoradiotherapy reaction, ChiCTR-OPC-14005257, Registered 18 September 2014, http://www.chictr.org.cn/showproj.aspx?proj=9546 .

Magnetic Resonance Deep Learning Radiomic Model Based on Distinct Metastatic Vascular Patterns for Evaluating Recurrence-Free Survival in Hepatocellular Carcinoma.

BACKGROUND: The metastatic vascular patterns of hepatocellular carcinoma (HCC) are mainly microvascular invasion (MVI) and vessels encapsulating tumor clusters (VETC). However, most existing VETC-related radiological studies still focus on the prediction of VETC status. PURPOSE: This study aimed to build and compare VETC-MVI related models (clinical, radiomics, and deep learning) associated with recurrence-free survival of HCC patients. STUDY TYPE: Retrospective. POPULATION: 398 HCC patients (349 male, 49 female; median age 51.7 years, and age range: 22-80 years) who underwent resection from five hospitals in China. The patients were randomly divided into training cohort (n = 358) and test cohort (n = 40). FIELD STRENGTH/SEQUENCE: 3-T, pre-contrast T1-weighted imaging spoiled gradient recalled echo (T1WI SPGR), T2-weighted imaging fast spin echo (T2WI FSE), and contrast enhanced arterial phase (AP), delay phase (DP). ASSESSMENT: Two radiologists performed the segmentation of HCC on T1WI, T2WI, AP, and DP images, from which radiomic features were extracted. The RFS related clinical characteristics (VETC, MVI, Barcelona stage, tumor maximum diameter, and alpha fetoprotein) and radiomic features were used to build the clinical model, clinical-radiomic (CR) nomogram, deep learning model. The follow-up process was done 1 month after resection, and every 3 months subsequently. The RFS was defined as the date of resection to the date of recurrence confirmed by radiology or the last follow-up. Patients were followed up until December 31, 2022. STATISTICAL TESTS: Univariate COX regression, least absolute shrinkage and selection operator (LASSO), Kaplan-Meier curves, log-rank test, C-index, and area under the curve (AUC). P < 0.05 was considered statistically significant. RESULTS: The C-index of deep learning model achieved 0.830 in test cohort compared with CR nomogram (0.731), radiomic signature (0.707), and clinical model (0.702). The average RFS of the overall patients was 26.77 months (range 1-80 months). DATA CONCLUSION: MR deep learning model based on VETC and MVI provides a potential tool for survival assessment. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Can vitamin B6 alleviate the adverse reactions of quadruple anti-Helicobacter pylori regimen? : randomized controlled trial.

BACKGROUND: Vitamin B6 is an essential water-soluble vitamin for humans. It is often used to prevent a variety of neuropathies, relieve vomiting, and relieve symptoms such as hand and foot neuritis. AIM: To evaluate whether vitamin B6 can alleviate the adverse reactions caused by the quadruple anti-Helicobacter pylori treatment regimen containing minocycline and metronidazole. METHODS: In this randomized controlled trial, 280 patients with H. pylori infection were randomly placed into one of two treatment groups-the conventional treatment group and the vitamin B6 supplement treatment group-for 2 weeks. The primary endpoint was the total incidence of adverse reactions up to 2 weeks after treatment initiation. The study was designed according to CONSORT Medicinal Interventions. And it was registered with Chinese Clinical Trial Registry under the number ChiCTR2100053833. RESULTS: In terms of efficacy, vitamin B6 does not affect the efficacy of conventional regimen. In the vitamin B6 supplement treatment group, the incidence of adverse reactions was 56.92%, which was significantly lower than the 74.62% observed in the conventional treatment group. In addition, the severity of adverse reactions was also significantly reduced. The proportion of moderate to severe central nervous system symptoms decreased from 58.7 to 14.63%. And, the proportion of moderate to severe gastrointestinal reactions decreased from 33.33 to 0%. We speculate that the mechanism of vitamin B6 of reducing adverse reaction may be related to the production of GABA in the brain. CONCLUSIONS: Vitamin B6 can alleviate adverse reactions of the quadruple anti-H. pylori regimen containing minocycline and metronidazole.

Characterization of Duodenal Microbiota in Patients with Acute Pancreatitis and Healthy Controls.

OBJECTIVE: The small intestinal bacterial overgrowth (SIBO) in acute pancreatitis correlates with the severity of the disease. However, corresponding studies on the microbial composition of the duodenal mucosa of patients are uncommon. METHODS: Duodenal mucosal biopsies were collected by gastroscopy from 16 patients with mild acute pancreatitis (the Ap group) and 16 healthy individuals (the control group) and subjected to histological studies as well as bacterial 16S rRNA gene sequencing. Caerulein and L-arginine were used to induce mild acute pancreatitis (MAP) and severe acute pancreatitis (SAP) in mice, respectively, and their pancreas and duodenum were collected for histological studies. RESULTS: H&E analysis displayed no significant pathological damage in the descending duodenum of patients with acute pancreatitis compared with that of the controls. Immunofluorescence and Real-time PCR revealed that the expressions of tight junction proteins (TJPs) in duodenal mucosa were decreased in acute pancreatitis. The results of the alpha diversity analysis revealed no significant difference between the two groups, while LEfSe and the random forest revealed a few differences, indicating that the descending duodenum mucosal microbiota changed slightly in patients with mild acute pancreatitis. We observed the pathological changes and the expression of TJPs in the duodenum in the three groups of mice and found that SAP mice had more severe pathological damage in the duodenum. Furthermore, the expression of TJPs in the duodenum was lower in the MAP and SAP groups of mice compared to control mice, but it was similar in both groups. CONCLUSION: Patients with mild acute pancreatitis had mild duodenal barrier dysfunction and slight changes in duodenal mucosal microbiota.

Evaluation of the star family doctors training program: an observational cohort study of a novel continuing medical education program for general practitioners within a compact medical consortium: a quantitative analysis.

INTRODUCTION: To determine the effectiveness of the Star Family Doctors Training Program, a comprehensive Continuing professional development (CPD) program for general practitioners (GPs) in a compact medical consortium. PATIENTS AND METHODS: Observational cohort study with a quantitative analyses in primary health care institutions in Sichuan Province. The interventions were as following: (1) The Star Family Doctors Training Program is a full-time, local government allocation program certified by the Health Department of Sichuan Province, emphasizing small group learning and practice, and using standard patients and medical patient simulators; 30 participants were selected by their institutions. (2) The control group underwent a self-financed after-work CPD program using conventional lectures; 50 participants were self-selected. Short-term effectiveness assessed using immediate post-training tests and self-evaluations; long-term (1 year) effectiveness evaluated using self-reported surveys. RESULTS: The study involved 80 GPs (28.75% men; mean age: 38.2 ± 9.2 years). The average post-training total score was higher in the STAR group than in the control group (72.83 ± 5.73 vs. 68.18 ± 7.64; p = 0.005). Compared to the controls, STAR participants reported seeing more patients (all p < 0.05), and had more patients who signed family-doctor contracts (p = 0.001) as well as increased patient satisfaction (p = 0.03), respectively. STAR-group trainees appraised the program higher and were more willing to recommend it to colleagues (90% vs. 64%, p = 0.011). CONCLUSION: The Star Family Doctors Training Program achieved good responses and provides a reference for future CPD programs.