Coagulation abnormalities associated with CAR-T-cell therapy in haematological malignancies: A review.

Chimeric antigen receptor (CAR)-T-cell therapy has demonstrated considerable efficacy and safety in the treatment of patients with relapsed/refractory haematological malignancies. Owing to significant advances, CAR-T-cell therapeutic modality has undergone substantial shifts in its clinical application. Coagulation abnormalities, which are prevalent complications in CAR-T-cell therapy, can range in severity from simple abnormalities in coagulation parameters to serious haemorrhage or disseminated intravascular coagulation associated with life-threatening multiorgan dysfunction. Nonetheless, there is a lack of a comprehensive overview concerning the coagulation abnormalities associated with CAR-T-cell therapy. With an aim to attract heightened clinical focus and to enhance the safety of CAR-T-cell therapy, this review presents the characteristics of the coagulation abnormalities associated with CAR-T-cell therapy, including clinical manifestations, coagulation parameters, pathogenesis, risk factors and their influence on treatment efficacy in patients receiving CAR-T-cell infusion. Due to limited data, these conclusions may undergo changes as more experience accumulates.

Association between temperature and mortality: a multi-city time series study in Sichuan Basin, southwest China.

BACKGROUND: There are few multi-city studies on the association between temperature and mortality in basin climates. This study was based on the Sichuan Basin in southwest China to assess the association of basin temperature with non-accidental mortality in the population and with the temperature-related mortality burden. METHODS: Daily mortality data, meteorological and air pollution data were collected for four cities in the Sichuan Basin of southwest China. We used a two-stage time-series analysis to quantify the association between temperature and non-accidental mortality in each city, and a multivariate meta-analysis was performed to obtain the overall cumulative risk. The attributable fractions (AFs) were calculated to access the mortality burden attributable to non-optimal temperature. Additionally, we performed a stratified analyses by gender, age group, education level, and marital status. RESULTS: A total of 751,930 non-accidental deaths were collected in our study. Overall, 10.16% of non-accidental deaths could be attributed to non-optimal temperatures. A majority of temperature-related non-accidental deaths were caused by low temperature, accounting for 9.10% (95% eCI: 5.50%, 12.19%), and heat effects accounted for only 1.06% (95% eCI: 0.76%, 1.33%). The mortality burden attributable to non-optimal temperatures was higher among those under 65 years old, females, those with a low education level, and those with an alternative marriage status. CONCLUSIONS: Our study suggested that a significant association between non-optimal temperature and non-accidental mortality. Those under 65 years old, females, and those with a low educational level or alternative marriage status had the highest attributable burden.

Prediction nomogram based on 18F-FDG PET/CT and clinical parameters for patients with diffuse large B-cell lymphoma.

The objective of this study was to develop a nomogram including parameters assessed by 18F-FDG PET/CT and clinical parameters for patients with diffuse large B-cell lymphoma (DLBCL) to predict progression-free survival (PFS). A total of 181 patients with pathologically diagnosed DLBCL at Sichuan Cancer Hospital and Institute from March 2015 to December 2020 were enrolled in this retrospective study. The area under the receiver operating characteristic (ROC) curve (AUC) was used to calculate the optimal cutoff values of the semiquantitative parameters (SUVmax, TLG, MTV, and Dmax) for PFS. A nomogram was constructed according to multivariate Cox proportional hazards regression. The predictive and discriminatory capacities of the nomogram were then measured using the concordance index (C-index), calibration plots, and Kaplan-Meier curves. The predictive and discriminatory capacities of the nomogram and the International Prognostic Index of the National Comprehensive Cancer Network (NCCN-IPI) were compared via the C-index and AUC. Multivariate analysis demonstrated that male gender and pretreatment Ann Arbor stage III-IV, non-GCB, elevated lactate dehydrogenase (LDH), number of extranodal organ involvement (Neo)>1, MTV≥152.8 cm3, and Dmax ≥53.9 cm were associated with unfavorable PFS (all p<0.05). The nomogram, including gender, Ann Arbor stage, pathology type, Neo, LDH levels, MTV, and Dmax, showed good prediction accuracy, with a C-index of 0.760 (95% CI: 0.727-0.793), which was higher than that of NCCN-IPI (0.710; 95% CI: 0.669-751). The calibration plots for 2-year demonstrated good consistency between the predicted and observed probabilities for survival time. We established a nomogram including MTV, Dmax, and several clinical parameters to predict the PFS of patients with DLBCL, and the nomogram showed better predictability and higher accuracy than NCCN-IPI.

Predictive value of Dmax and %ΔSUVmax of 18F-FDG PET/CT for the prognosis of patients with diffuse large B-cell lymphoma.

PURPOSE: To investigate the prognosis value of a combined model based on 18F-fluoro-deoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) baseline and interim parameters in patients with diffuse large B-cell lymphoma (DLBCL). METHODS: We retrospectively analyzed the PET metabolic parameters and clinical data of 154 DLBCL patients between December 2015 and October 2020. All of these patients underwent 18F-FDG PET/CT scan before treatment and after three or four courses of chemotherapy. The optimal cut-off values for quantitative variables were determined by the receiver operating characteristic (ROC) curve. The baseline and interim PET/CT parameters, which respectively included maximum standardized uptake value (SUVmax0), total metabolic tumor volume (TMTV0), standardized total metabolic tumor volume (STMTV0), and the distance between the two furthest lesions (Dmax) and total tumor lesion glycolysis (TTLG1), SUVmax1, TMTV1, and the rate of change of SUVmax (%ΔSUVmax), and clinical characteristics were analyzed by chi-squared test, Kaplan-Meier survival curve, and Cox regression analysis. RESULTS: Of 154 patients, 35 exhibited disease progression or recurrence. ROC analysis revealed that baseline 18F-FDG PET/CT metabolic parameters, including maximum standardized uptake value (SUVmax0), total metabolic tumor volume (TMTV0), standardized total metabolic tumor volume (STMTV0), and the distance between the two furthest lesions (Dmax), along with interim 18F-FDG PET/CT metabolic parameters such as total tumor lesion glycolysis (TTLG1), SUVmax1, TMTV1, and the rate of change of SUVmax (%ΔSUVmax), were predictive of relapse or progression in DLBCL patients (P < 0.05). The chi-squared test showed that TMTV0, STMTV0, Dmax, SUVmax1, TMTV1, TTLG1, %ΔSUVmax, Deauville score, IPI, Ann Arbor stage, and LDH were associated with patient prognosis (P < 0.05). Multivariate Cox regression analysis showed that Dmax (P = 0.021) and %ΔSUVmax (P = 0.030) were independent predictors of prognosis in DLBCL patients. There were statistically significant differences in PFS among the three groups with high, intermediate, and low risk according to the combination model (P < 0.001). The combination model presented higher predictive efficacy than single indicators. CONCLUSION: The combined model of baseline parameter Dmax and intermediate parameter %ΔSUVmax of 18F-FDG PET/CT improved the predictive efficacy of PFS and contributed to the risk stratification of patients, providing a reference for clinical individualization and precision treatment.

Effects of ambient temperature on mortality among elderly residents of Chengdu city in Southwest China, 2016-2020: a distributed-lag non-linear time series analysis.

BACKGROUND: With complex changes in the global climate, it is critical to understand how ambient temperature affects health, especially in China. We aimed to assess the effects of temperature on daily mortality, including total non-accidental, cardiovascular disease (CVD), respiratory disease, cerebrovascular disease, and ischemic heart disease (IHD) mortality between 2016 and 2020 in Chengdu, China. METHODS: We obtained daily temperature and mortality data for the period 2016-2020. A Poisson regression model combined with a distributed-lag nonlinear model was used to examine the association between temperature and daily mortality. We investigated the effects of individual characteristics by sex, age, education level, and marital status. RESULTS: We found significant non-linear effects of temperature on total non-accidental, CVD, respiratory, cerebrovascular, and IHD mortality. Heat effects were immediate and lasted for 0-3 days, whereas cold effects persisted for 7-10 days. The relative risks associated with extreme high temperatures (99th percentile of temperature, 28 °C) over lags of 0-3 days were 1.22 (95% confidence interval [CI]: 1.17, 1.28) for total non-accidental mortality, 1.40 (95% CI: 1.30, 1.50) for CVD morality, 1.34 (95% CI: 1.24, 1.46) for respiratory morality, 1.33 (95% CI: 1.20, 1.47) for cerebrovascular mortality, and 1.38 (95% CI: 1.20, 1.58) for IHD mortality. The relative risks associated with extreme cold temperature (1st percentile of temperature, 3.0 °C) over lags of 0-14 days were 1.32 (95% CI: 1.19, 1.46) for total mortality, 1.45 (95% CI: 1.24, 1.68) for CVD morality, 1.28 (95% CI: 1.09, 1.50) for respiratory morality, 1.36 (95% CI: 1.09, 1.70) for cerebrovascular mortality, and 1.26 (95% CI: 0.95, 1.68) for IHD morality. We found that hot and cold affects were greater in those over 85 years of age, and that women, individuals with low education levels, and those who were widowed, divorced, or never married, were more vulnerable. CONCLUSIONS: This study showed that exposure to hot and cold temperatures in Chengdu was associated with increased mortality, with people over 85 years old, women, those with low education levels, and unmarried individuals being more affected by hot and cold temperatures.

Polymer-Based Wound Dressings Loaded with Ginsenoside Rg3.

The skin, the largest organ in the human body, mainly plays a protective role. Once damaged, it can lead to acute or chronic wounds. Wound healing involves a series of complex physiological processes that require ideal wound dressings to promote it. The current wound dressings have characteristics such as high porosity and moderate water vapor permeability, but they are limited in antibacterial properties and cannot protect wounds from microbial infections, which can delay wound healing. In addition, several dressings contain antibiotics, which may have bad impacts on patients. Natural active substances have good biocompatibility; for example, ginsenoside Rg3 has anti-inflammatory, antibacterial, antioxidant, and other biological activities, which can effectively promote wound healing. Some researchers have developed various polymer wound dressings loaded with ginsenoside Rg3 that have good biocompatibility and can effectively promote wound healing and reduce scar formation. This article will focus on the application and mechanism of ginsenoside Rg3-loaded dressings in wounds.

A Freshwater Fish-Based Diet Alleviates Liver Steatosis by Modulating Gut Microbiota and Metabolites: A Clinical Randomized Controlled Trial in Chinese Participants With Nonalcoholic Fatty Liver Disease.

INTRODUCTION: We aimed to assess the effects of 2 isoenergetic intervention diets (a freshwater fish-based diet [F group] or freshwater fish-based and red meat-based diets alternately [F/M group]) on liver steatosis and their relationship with intestinal flora in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: In this open-label, 84-day randomized controlled trial, 34 NAFLD patients with hepatic steatosis ≥10% were randomly assigned to the F group or F/M group in a 1:1 ratio using a computer-generated random number allocation by a researcher not involved in the study. Liver fat content and gut microbiota and its metabolites were measured. RESULTS: At the end of intervention, the absolute reduction of hepatic steatosis was significantly greater in the F group than in the F/M group (-4.89% vs -1.83%, P = 0.032). Of the 16 secondary clinical outcomes, the improvement in 7 in the F group was greater compared with the F/M group, including alanine aminotransferase and gamma-glutamyl transferase. Furthermore, dietary freshwater fish and red meat consumption alternately did not exacerbate NAFLD. Moreover, changes in the enrichment of Faecalibacterium, short-chain fatty acids, and unconjugated bile acids and the depletion of Prevotella 9 and conjugated bile acids in the F group were significantly greater compared with the F/M group. DISCUSSION: Higher intake of freshwater fish may be beneficial to NAFLD by regulating gut microbiota and its metabolites, whereas intake of a similar total of animal protein and fat from the alternating freshwater fish and red meat may not be harmful for NAFLD in the dietary management of patients with NAFLD.

Lifestyle as well as metabolic syndrome and non-alcoholic fatty liver disease: an umbrella review of evidence from observational studies and randomized controlled trials.

BACKGROUND & AIMS: Recent epidemiological studies have indicated that NAFLD is pathologically associated with a sedentary lifestyle, unhealthy dietary habits and metabolic syndrome. An umbrella review of meta-analyses was performed to summarize the quality of evidence regarding the epidemiologic associations between lifestyle, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD) in regards to risk and treatment. METHODS: We searched PubMed, Web of Science and Embase Database from inception until June 1, 2021. Meta-analyses of observational studies and randomized controlled trials (RCTs) examining the associations of lifestyle as well as metabolic syndrome with NAFLD risk or treatment were screened. We assessed meta-analyses of observational studies based on random-effect summary effect sizes and their P values, 95% prediction intervals, heterogeneity, and small-study effects. For meta-analyses of RCTs, outcomes with a random-effect P < 0.005 and a high-GRADE assessment were classified as strong evidence. RESULTS: A total of 37 publications were included in this review: twenty-two publications reporting 41 meta-analyses of observational studies (37 unique outcomes) and 15 publications reporting 81 meta-analyses of RCTs (63 unique outcomes) met the inclusion criteria. Methodological quality was high for 97% of the included meta-analyses. Quality of evidence was rated high only for the association of sugar-sweetened soda consumption with increased NAFLD risk in meta-analyses of observational studies. Only 3 therapeutic interventions (green tea improving ALT, TG, TC and LDL, omega-3 PUFAs improving HOMR-IR and plasma glucose, and exercise improving RT and ALT) from meta -analyses of RCTs with suggestive (change to high/low/etc) levels of evidence were identified. CONCLUSION: Despite many meta-analyses exploring the associations of lifestyle as well as metabolic syndrome with the risk or treatment of NAFLD, robust clinical RCTs are needed to further investigate the associations between lifestyle modifications and incidence of NAFLD or therapeutic effects on disease progression.

Insulin-Like Growth Factor 1 Receptor Drives Hepatocellular Carcinoma Growth and Invasion by Activating Stat3-Midkine-Stat3 Loop.

BACKGROUND: Activation of the insulin-like growth factor 1 receptor (IGF-1R)-mediated Janus kinase (JAK)1/2-Stat3 pathway contributes to hepatocarcinogenesis. Specifically, a previous study showed that IGF-1R inhibition downregulated Midkine expression in hepatocellular carcinoma (HCC). AIMS: The present study investigated the role of IGF-1R-JAK1/2-Stat3 and Midkine signaling in HCC, in addition to the molecular link between the IGF-1R-Stat3 pathway and Midkine. METHODS: The expression levels of IGF-1R, Stat3, and Midkine were measured using reverse transcription-quantitative PCR, following which the association of IGF-1R with Stat3 and Midkine expression was evaluated in HCC. The molecular link between the IGF-1R-Stat3 pathway and Midkine was then investigated in vitro before the effect of IGF-1R-Stat3 and Midkine signaling on HCC growth and invasion was studied in vitro and in vivo. RESULTS: IGF-1R, Stat3, and Midkine mRNA overexpressions were all found in HCC, where the levels of Stat3 and Midkine mRNA correlated positively with those of IGF-1R. In addition, Midkine mRNA level also correlated positively with Stat3 mRNA expression in HCC tissues. IGF-1R promoted Stat3 activation, which in turn led to the upregulation of Midkine expression in Huh7 cells. Similarly, Midkine also promoted Stat3 activation through potentiating JAK1/2 phosphorylation. Persistent activation of this Stat3-Midkine-Stat3 positive feedback signal loop promoted HCC growth and invasion, the inhibition of which resulted in significant antitumor activities both in vitro and in vivo. CONCLUSIONS: Constitutive activation of the IGF-1R-mediated Stat3-Midkine-Stat3 positive feedback loop is present in HCC, the inhibition of which can serve as a potential therapeutic intervention strategy for HCC.

Long noncoding RNA 91H overexpression contributes to the growth and metastasis of HCC by epigenetically positively regulating IGF2 expression.

BACKGROUND & AIMS: Long noncoding RNA 91H is transcribed from the H19/IGF2 locus and contributes to the development of breast and oesophagus cancers by regulating the expression of IGF2, but the regulation mechanism remains poorly characterized. Here, we explored the role of 91H in hepatocellular carcinoma (HCC) and the mechanism of IGF2 expression regulation by 91H. METHODS: Firstly, the expression of 91H was analysed in HCC by quantitative RT-PCR, the association of 91H with survival was evaluated by the Kaplan-Meier method and the effect of 91H on the growth and invasion of HCC was investigated by the in vitro and in vivo studies. Then, the association of 91H with the expression of IGF2 was evaluated in HCC tissues, and the effect of 91H on the expression of IGF2 was investigated by 91H knockdown. Finally, the binding of RBBP5 to 91H and the binding of RBBP5, activating H3K4me3 mark and repressive H3K27me3 mark to the P3 and P4 promoters of IGF2 gene were studied by RIP and ChIP respectively. RESULTS: The overexpression of 91H was found in HCC and in association with the growth, metastasis and shorter survival time of HCC. The knockdown of 91H down-regulated the IGF2 expression in HCC, and the mechanism was correlated with the decreased enrichment of RBBP5 and H3K4me3 and increased enrichment of H3K27me3 at the bivalent P3 and P4 promoters. CONCLUSIONS: The overexpression of 91H promotes tumour growth and metastasis, and is associated with a poor prognosis of HCC at least partially by positively regulating the expression of IGF2 through bivalent histone modification changes characterized by H3K4me3 and H3K27me3 at the P3 and P4 promoters.

Grain consumption and risk of gastric cancer: a meta-analysis.

This study evaluated the relationship between grain consumption and the risk of gastric cancer. A total of 19 studies met the inclusion criteria. For whole grain consumption, there was a 13% reduction in the risk of gastric cancer (p = .003), and a subgroup analysis showed that a large amount of whole grain consumption reduced the risk of gastric cancer by 44% (p < .001). For refined grain consumption, there was a 36% increase in the risk of gastric cancer (p < .001); a subgroup analysis showed that a large and a moderate amount of refined grain consumption increased the risk of gastric cancer by 63% (p < .001) and 28% (p < .001), respectively. A large intake of whole grains might be protective against gastric cancer, whereas the ingestion of refined cereals may be a risk factor for gastric cancer. Moreover, the risk of cancer increases with the increase of refined grain intake.

Mean peak systolic velocity of superior thyroid artery for the differential diagnosis of thyrotoxicosis: a diagnostic meta-analysis.

BACKGROUND: Thyrotoxicosis is often caused by destructive thyroiditis (DT) or Graves' disease (GD), and a prompt and accurate differential diagnosis for thyrotoxicosis is needed as management strategy differs. A meta-analysis of published literature was performed to evaluate the diagnostic accuracy for differentiating GD from DT patients by the measurement of mean peak systolic velocity of superior thyroid artery (STA-PSV) using ultrasonography. METHODS: The databases of Embase, Pubmed, Cochrane, Web of Science, Wanfang, and CNKI were retrieved without time limit to identify eligible studies. The statistical information and scientific quality were assessed and classified. The data were analyzed using Stata12.0 software. RESULTS: A total of 11 studies with 1052 cases only from Asia were included. Meta-analysis results showed the pooled sensitivity and pooled specificity of STA-PSV by ultrasonography were 0.86 (95% CI, 0.80-0.90) and 0.93 (95% CI, 0.86-0.97) in distinguishing GD from DT, respectively, with the AUC of 0.94 (95% CI, 0.92-0.96) . CONCLUSION: STA-PSV by ultrasonography is a useful diagnostic method in differentiating GD from DT. More studies from other countries are needed to further evaluate the accuracy of STA-PSV for the differential diagnosis of thyrotoxicosis.

Significantly decreased and more variable expression of major CYPs and UGTs in liver microsomes prepared from HBV-positive human hepatocellular carcinoma and matched pericarcinomatous tissues determined using an isotope label-free UPLC-MS/MS method.

PURPOSE: To determine the liver expression of cytochrome P450 (CYPs) and uridine 5'-diphosphate-glucuronosyltransferases (UGTs), the major phase I and II metabolism enzymes responsible for clearance and detoxification of drugs, xenobiotic and endogenous substances. METHODS: A validated isotope label-free method was established for absolute and simultaneous quantification of 9 CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D, 2E1 and 3A4) and 5 UGTs (1A1, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes using LC-MS/MS. RESULTS: The LC-MS/MS method displayed excellent dynamic range (at least 250-fold) and high sensitivity for each of the signature peptides with acceptable recovery, accuracy and precision. The protein expression profile of CYP and UGT isoforms were then determined in match microsomes samples prepared from patients with HBV-positive human hepatocellular carcinoma (HCC). In the tumor microsomes, the average absolute amounts of 8 major CYP isoforms (except CYP2C19) and 3 UGT isoforms (UGT1A1, UGT1A4 and UGT2B7) were decreased significantly (p < 0.05), whereas UGT1A6 and UGT1A9 levels were unchanged (p > 0.05). In addition, among isoforms with altered expression, 6 of 8 CYP isoforms and all three UGT isoforms were much more variable in tumor microsomes. Lastly, the importance of CYP3A4 was greatly diminished whereas the importance of UGT1A6 was enhanced in tumor microsomes. CONCLUSION: The use of an isotope label-free absolute quantification method for the simultaneous determination of 9 CYPs and 5 UGTs in human liver microsomes reveals that expression levels of CYPs and UGTs in human liver are severely impact by HCC, which could impact drug metabolism, disposition and pharmacotherapy.

Breast cancer resistance protein-mediated efflux of luteolin glucuronides in HeLa cells overexpressing UDP-glucuronosyltransferase 1A9.

PURPOSE: UDP-glucuronosyltransferases (UGTs) are responsible for the formation of glucuronides of polyphenolic flavonoids. This study investigated the UGT1A9-mediated glucuronidation of luteolin and the kinetics of luteolin glucuronide efflux. METHOD: HeLa cells overexpressing UGT1A9 (HeLa-UGT1A9) were used to determine the kinetics of breast cancer resistance protein (BCRP)-mediated transport of luteolin glucuronides. Human UGT isoforms were used to determine glucuronidation rates. RESULTS: UGT1A9 was found to catalyze the production of four luteolin glucuronides, including three known monoglucuronides and a novel 3', 4'-diglucuronide. Ko143, a potent specific inhibitor of BCRP, significantly inhibited efflux of luteolin monoglucuronides from HeLa1A9 cells and increased their intracellular levels in a dose-dependent manner. The formation of luteolin diglucuronide was observed when intracellular concentration of total monoglucuronides went above 0.07 nM. CONCLUSIONS: Intracellular accumulation of diglucuronide was detected at high monoglucuronide concentrations (>0.07 nM). Diglucuronide production is speculated to be a compensatory pathway for luteolin disposition.

Rg3-loaded P407/CS/HA hydrogel inhibits UVB-induced oxidative stress, inflammation and apoptosis in HaCaT cells.

UVB radiation can damage human skin, whereas Ginsenoside Rg3, the active ingredient in red ginseng that is processed from ginseng (Panax ginseng C.A. Meyer), could inhibit UVB induced cell damage through anti-oxidation. Meanwhile, P407/CS/HA hydrogel has significant biomedical applications as carriers of drugs. However, the beneficial effects of Rg3-loaded hydrogel (Rg3-Gel) on human HaCaT keratinocytes induced by UVB have rarely been reported. In our study, Rg3 was loaded into hydrogel and the effect of Rg3-Gel against UVB­induced Hacat cells damages was determined by measuring its ability to alleviate UVB­induced elevation of oxidative stress, pro-inflammatory and apoptotic response. We found that the treatment with Rg3-Gel inhibited the generation of intracellular ROS and MDA and upregulated the expression of antioxidant enzymes SOD and GSH-Px which were inhibited by UVB exposure. Increased levels of pro-inflammatory cytokines TNF­α, COX­2, iNOS and IL­1ß following UVB irradiation were suppressed by the introduction of Rg3-Gel. Additionally, the level of Bcl-2 was decreased and the expression of Bax and Caspase3 were enhanced by Rg3-Gel treatment. In conclusion, Rg3-Gel equipped with the synergistic effect of Rg3 and hydrogel has an effective inhibitory effect on UVB-induced oxidative stress, inflammatory and apoptosis.

Cyclocarya paliurus leaves extracts alleviate metabolic phenotypes in Chinese T2DM patients by modulating gut microbiota and metabolites: a clinical randomized controlled trial.

Objective: We aimed to investigate the effect of Cyclocarya paliurus leaves extracts (CP) on glucose and blood lipid metabolism and its relationship with intestinal flora in type 2 diabetes mellitus (T2DM) patients. Methods: In this open-label, 84-day randomized controlled trial, a total of 38 T2DM patients were randomly assigned to the CP group or the Glipizide group (G group) in a 2:1 ratio. T2DM-associated metabolic phenotypes, gut microbiota and metabolites including short-chain fatty acids (SCFAs) and bile acids (BAs) were detected. Results: At the end of intervention, CP, like Glipizide, significantly improved HbA1c level and other glucose metabolism parameters (fasting plasma glucose (FBG), 2-hour post-meal blood glucose (2hPBG), the area under curve of oral glucose tolerance test glucose (OGTT glucose AUC)). Moreover, CP also resulted in the significant improvement in the levels of blood lipid and blood pressure. Notably, the improvement in blood lipid(triglycerides (TG) and high-density lipoprotein cholesterol (HDL-c)) and blood pressure (diastolic blood pressure (DBP)) was significantly greater in the CP group compared with the G group. Furthermore, the liver and kidney function parameters did not significantly change in both CP group and the G group over the 84-day period. Additionally, the enrichment of potentially beneficial bacteria (Faecalibacterium and Akkermansia), SCFAs and unconjugated BAs and the depletion of potential pathogenic bacteria (Prevotella_9) and conjugated BAs were observed in the CP group, while the abundances of the gut microbial were kept stable in the G group after intervention. Conclusion: CP displays a more beneficial effect in the alleviation of T2DM-associated metabolic phenotypes than glipizide by regulating gut microbiota and metabolites in T2DM patients, with no significant effects on liver and kidney function.

Donor CD7 Chimeric Antigen Receptor T Cell Bridging to Allogeneic Hematopoietic Stem Cell Transplantation for T Cell Hematologic Malignancy.

It is crucial to quickly bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematopoietic reconstitution. Here we report on the efficacy and safety of donor CD7 chimeric antigen receptor (CAR) T cell therapy (CAR-T) bridging to allo-HSCT in treating 12 patients with relapsed/refractory (r/r) T-ALL or T-cell lymphoblastic lymphoma (T-LBL). The median time from CAR-T infusion to allo-HSCT was 33.5 days (range, 30 to 55 days). With reduced-intensity conditioning, all patients except 1 successfully engrafted. With a mean follow-up of 301 days (range, 238 to 351 days), the remaining 11 patients were alive and disease-free at their last follow-up. Acute graft-versus-host disease (GVHD) was observed in 3 patients, and chronic GVHD developed in 3 patients, all with a limited pattern. Under the current protocol, infection was the main complication post-transplantation, and all infections were well controlled except in 1 patient, who died of multiple organ failure caused by an infection-induced inflammatory cytokine storm at days 14 post-transplantation. One patient relapsed (CD7+), and 3 patients became minimal residual disease (MRD) positive (CD7+ in 1, CD7- in 1, fusion gene positive only in 1). Subsequently, all 3 of these patients achieved an MRD-negative complete remission with either CD7 CAR-T reinfusion or immunosuppressive agent withdrawal. Our study shows for the first time that a novel strategy of donor CD7 CAR-T bridging to allo-HSCT can be highly effective and feasible in improving disease-free survival for patients with r/r T-ALL or T-LBL.

The Ecological Status and Change in High-Latitude Coral Assemblages at the Xuwen Coral Reef, Northern South China Sea: Insight into the Status and Causes in 2020.

Taking the coral communities of the Xuwen coral reef in 2020 as the research object, we analyzed the species composition, diversity, and interspecific Spearman correlation of the scleractinian coral communities, investigated the features and spatial distribution of the scleractinian coral community, and discussed the correlation between the community composition and environmental factors to identify the affecting factors and their sources. These results showed that (1) compared with the survey in 2004, the coverage of corals in 2020 had significantly decreased, while the dominant genera were still Goniopora and Porites. The coral morphology was massive, and the diversity of the coral community (Shannon-Wiener index, H') was 2.87. The distribution of coral was uneven. The competition among some dominant species of coral was intense. (2) The mass coral bleaching event in the NSCS in August 2020 did not cause severe coral death in the short term on the Xuwen coral reef. (3) The growth of the coral community in 2020 might be greatly affected by high suspended solids and nutrient levels, which were related to the current, mariculture, and coastal erosion. (4) Anthropogenic activities such as coastal aquaculture and fishing were the major factors leading to the reduction in coral coverage on Xuwen coral reef in the past 10 years.

Fish consumption in multiple health outcomes: an umbrella review of meta-analyses of observational and clinical studies.

Background: Omega-3 polyunsaturated fatty acids are known to be associated with numbers of health benefits, and which can be uptake from fish. The aim of this study was to evaluate the current evidence of associations between consumption of fish and diverse health outcomes. Here, we performed an umbrella review to summarize the breadth, strength, and validity of the evidence derived from meta-analyses and systematic reviews of fish consumption on all health outcomes. Methods: The methodological quality of the included meta-analyses and the quality of the evidence were assessed by the Assessment of Multiple Systematic Reviews (AMSTAR) and the grading of recommendations, assessment, development, and evaluation (GRADE) tools, respectively. The umbrella review identified 91 meta-analyses with 66 unique health outcomes, of which 32 outcomes were beneficial, 34 showed nonsignificant associations and only one was harmful (myeloid leukemia). Results: A total of 17 beneficial associations [all-cause mortality, prostate cancer mortality, cardiovascular disease (CVD) mortality, esophageal squamous cell carcinoma (ESCC), glioma, non-Hodgkin lymphoma (NHL), oral cancer, acute coronary syndrome (ACS), cerebrovascular disease, metabolic syndrome, age-related macular degeneration (AMD), inflammatory bowel disease (IBD), Crohn's disease (CD), triglycerides, vitamin D, high-density lipoprotein (HDL)-cholesterol, and multiple sclerosis (MS)], and eight nonsignificant associations [colorectal cancer (CRC) mortality, esophageal adenocarcinoma (EAC), prostate cancer, renal cancer, ovarian cancer, hypertension, ulcerative colitis (UC), and rheumatoid arthritis (RA)] were evaluated as moderate/high quality of evidence. According to dose-response analyses, consumption of fish, especially fatty types, seems generally safe at one-two servings per week and could exert protective effects. Conclusions: Fish consumption is often associated with a variety of health outcomes, both beneficial and harmless, but only about 34% of the associations were graded as based on a moderate/high quality of evidence, and additional multicenter high quality randomized controlled trials (RCTs) with a large sample size are needed to verify these findings in the future.

A new novel mutation in FBN1 causes autosomal dominant Marfan syndrome in a Chinese family.

PURPOSE: Screening of mutations in the fibrillin-1 (FBN1) gene in a Chinese family with autosomal dominant Marfan syndrome (MFS). METHODS: It has been reported that FBN1 mutations account for approximately 90% of Autosomal Dominant MFS. FBN1 mutations were analyzed in a Chinese family of 36 members including 13 MFS patients. The genomic DNAs from blood leukocytes of the patients and their relatives were isolated and the entire coding region of FBN1 was amplified by PCR. The sequence of FBN1 was dertermined with an ABI 3100 Genetic Analyzer. RESULTS: A previously unreported the missense mutation G214S (caused by a 640 A→G heterozygous change) in FBN1 was identified in the Chinese family. The mutation was associated with the disease phenotype in patients, but not detected in their relatives or in the 100 normal controls. CONCLUSIONS: This is the first report of molecular characterization of FBN1 in the MFS family of Chinese origin. Our results expand the spectrum of FBN1 mutations causing MFS and further confirm the role of FBN1 in the pathogenesis of MFS. Direct sequencing of the mutation in FBN1 may be used for diagnosis of MFS.