Discovery of novel CDK9 inhibitor with tridentate ligand: Design, synthesis and biological evaluation.

Cyclin-dependent kinase 9 (CDK9) plays a role in transcriptional regulation, which had become an attractive target for discovery of antitumor agent. In this work, beyond traditional CDK9 inhibitor with bidentate ligands in ATP binding domain, a series of novel CDK9 inhibitor with tridentate ligand were designed and synthesized. Surprisingly, this unique tridentate ligand structure endows better CDK9 inhibition selectivity compared to other CDK subtypes, and the lead candidate compound Z4-7a showed effective proliferation inhibition in HCT116 cells with acceptable pharmacokinetic properties. Research on the mechanism indicated that Z4-7a could induce apoptosis in the HCT116 cell line by inhibiting phosphorylation of RNA polymerase II at Ser2, which resulted in the inhibition of apoptosis-related genes and proteins expression. In brief, introduction of tridentate ligand might work as a promising strategy for the development of novel selective CDK9 inhibitor.

CD47 and PD-L1 overexpression in proliferating human hepatocytes attenuated immune responses and ameliorated acute liver injury in mice.

Hepatocyte transplantation has the potential to treat acute liver failure and correct liver-based metabolic disorders. Proliferating human hepatocytes (ProliHHs) provide a large-scale source as an alternative to primary human hepatocytes. However, host rejection led to inefficient graft survival and function, which hindered the clinical application of cell therapy. Herein, we employed the lentiviral system to overexpress immunomodulatory factors programmed death-ligand 1 (cluster of differentiation 274) (CD274) and cluster of differentiation 47 (CD47) in ProliHHs. CD47+274 overexpression inhibited macrophage and T cell responses in vitro. After transplantation into mice via the spleen without immunosuppression, CD47+274 ProliHHs accumulation in the liver significantly increased for 48 hours compared with ProliHHs. Consistent with the in vitro results, CD47+274 ProliHHs were less aggregated and infiltrated by macrophages and also recruited fewer T cells in the liver. Seven days after transplantation, the human albumin level of engineered ProliHHs doubled compared with control group. CD47+274 ProliHHs further ameliorated the liver injury induced using concanavalin A. Overall, our results suggested CD47+274 overexpression reduced innate and adaptive immune responses during hepatocyte transplantation, and the survival rate and graft function of transplanted hepatocyte-like cells were all significantly improved.

Genome-Wide Identification of Detoxification Genes in Wild Silkworm Antheraea pernyi and Transcriptional Response to Coumaphos.

For a half-century, the commercial wild silkworm, Antheraea pernyi, has been protected by coumaphos, which is an internal organophosphorus insecticide used to kill the potential parasitic fly larvae inside. Knowledge about the detoxification genes of A. pernyi as well as the detoxification mechanism for this species remains severely limited. In this study, we identified 281 detoxification genes (32 GSTs, 48 ABCs, 104 CYPs, and 97 COEs) in the genome of this insect, which are unevenly distributed over 46 chromosomes. When compared to the domesticated silkworm, Bombyx mori, a lepidopteran model species, A. pernyi has a similar number of ABCs, but a greater number of GSTs, CYPs, and COEs. By transcriptome-based expression analysis, we found that coumaphos at a safe concentration level significantly changed the pathways related to ATPase complex function and the transporter complex in A. pernyi. KEGG functional enrichment analysis indicated that protein processing in the endoplasmic reticulum was the most affected pathway after coumaphos treatment. Finally, we identified four significantly up-regulated detoxification genes (ABCB1, ABCB3, ABCG11, and ae43) and one significantly down-regulated detoxification gene (CYP6AE9) in response to coumaphos treatment, suggesting that these five genes may contribute to detoxification of coumaphos in A. pernyi. Our study provides the first set of detoxification genes for wild silkworms from Saturniidae and highlights the importance of detoxification gene repertoire in insect pesticide tolerance.

Genome-Wide Identification and Transcriptome-Based Expression Profile of Cuticular Protein Genes in Antheraea pernyi.

Antheraea pernyi is one of the most famous edible and silk-producing wild silkworms of Saturniidae. Structural cuticular proteins (CPs) are the primary component of insect cuticle. In this paper, the CPs in the genome of A. pernyi were identified and compared with those of the lepidopteran model species Bombyx mori, and expression patterns were analyzed based on the transcriptomic data from the larval epidermis/integument (epidermis in the following) and some non-epidermis tissues/organs of two silkworm species. A total of 217 CPs was identified in the A. pernyi genome, a comparable number to B. mori (236 CPs), with CPLCP and CPG families being the main contribution to the number difference between two silkworm species. We found more RR-2 genes expressed in the larval epidermis of fifth instar of A. pernyi than B. mori, but less RR-2 genes expressed in the prothoracic gland of A. pernyi than B. mori, which suggests that the hardness difference in the larval epidermis and prothoracic gland between the two species may be caused by the number of RR-2 genes expressed. We also revealed that, in B. mori, the number of CP genes expressed in the corpus allatum and prothoracic gland of fifth instar was higher than that in the larval epidermis. Our work provided an overall framework for functional research into the CP genes of Saturniidae.

A giant enhancement in the up-conversion luminescence and high temperature sensitivity of Bi3+ doped ZnMoO4:Er3+ up-conversion phosphor.

Luminescence intensity is a critical factor for upconversion (UC) oxides with high phonon energy. Herein, an effective enhancement in UC luminescence is achieved in the ZnMoO4:Er3+ phosphor via Bi3+ doping. UV-vis-NIR diffuse reflectance spectroscopy verifies the fact that the absorption at 980 nm is enhanced by the introduction of Bi3+. The physical mechanism is that Bi3+ doping affects the transition probability between the f-levels of Er3+. Therefore, the green and red emission intensities are increased 82.4 and 37 times, respectively. The dependence of luminescence intensity on the power of Bi3+-doped ZnMoO4:Er3+ combined with density functional theory (DFT) calculations also confirms the proposed energy transfer mechanism. Based on the excellent green emission, the 980 nm excited optical temperature sensing property of the synthesized sample is realized in a wide temperature range by monitoring the intensity of UC luminescence. The theoretically calculated absolute sensitivity of the optical temperature sensor was SA = 3.04% K-1 at 1253 K. This work paves a new way for enhancing UC luminescence and will arouse extensive interest in noncontact temperature-sensing applications.

Association between schizophrenia and prostate cancer risk: Results from a pool of cohort studies and Mendelian randomization analysis.

BACKGROUND: Observational studies analyzing the risk of prostate cancer in schizophrenia patients have generated mixed results. We performed a meta-analysis and a Mendelian randomization (MR) analysis to evaluate the relationship and causality between schizophrenia and the risk of prostate cancer. METHODS: A comprehensive and systematic search of cohort studies was conducted, and a random-effects model meta-analysis was performed to calculate the standardized incidence ratios (SIRs) for prostate cancer incidence among schizophrenia patients versus the general population. To investigate the correlation between genetically-predicted schizophrenia and prostate cancer risk, we used summary statistics from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium (61,106 controls and 79,148 cases), and 75 schizophrenia-associated single nucleotide polymorphisms (SNP) from European descent as the instrumental variable. RESULTS: In the meta-analysis of 13 cohort studies with 218,076 men involved, a decreased risk of prostate cancer was observed among schizophrenia patients [SIR 0.610; 95% confidence interval (CI) 0.500-0.740; p < 0.001] with significant heterogeneity (I2 = 83.3%; p < 0.001). However, MR analysis did not sustain the link between genetically-predicted schizophrenia and prostate cancer [odds ratio (OR) 1.033; 95% CI 0.998-1.069; p = 0.065]. The result was robust against extensive sensitivity analyses. CONCLUSIONS: Our study indicated a decreased risk of prostate cancer in schizophrenia patients through meta-analysis, while MR analysis did not support the connection between schizophrenia and prostate cancer. Due to the interaction of genetic variants between binary exposures, we need to be cautious in interpreting and presenting causal associations. Moreover, further research is needed to investigate underlying factors that might link schizophrenia to the risk of prostate cancer.

The response surface optimization of ß-mannanase produced by Weissella cibaria F1 and its potential in juice clarification.

A ß-mannanase-producing lactic acid bacteria (LAB) was identified as Weissella cibaria F1 according to physiological and biochemical properties, morphological observations, partial sequence of 16S rRNA gene and API 50 CHL test. In order to improve the yield of ß-mannanase, the response surface methodology (RSM) was originally used to optimize the fermentation conditions. The optimization results showed that when the konjac powder, glucose, and initial pH were 9.46 g/L, 14.47 g/L and 5.67, respectively, the ß-mannanase activity increased to 38.81 ± 0.33 U/mL, which was 1.33 times compared to initial yield (29.28 ± 0.26 U/mL). This result was also supported by larger clearance on the konjac powder-MRS agar plate through Congo Red dyeing. The W. cibaria F1 ß-mannanase could improve the clarity of five fruits juice, i.e., apple, orange, peach, persimmon and blue honeysuckle. Among these, peach juice was the most obvious, clarity increasing by 12.8%. These results collectively indicated that W. cibaria F1 ß-mannanase had an applicable potential in food-level fields.

Sucrose Transporter AtSUC9 Mediated by a Low Sucrose Level is Involved in Arabidopsis Abiotic Stress Resistance by Regulating Sucrose Distribution and ABA Accumulation.

Sucrose (Suc) transporters (SUCs or SUTs) are important regulators in plant growth and stress tolerance. However, the mechanism of SUCs in plant abiotic stress resistance remains to be dietermined. Here, we found that AtSUC9 expression was induced by abiotic stress, including salt, osmotic and cold stress conditions. Disruption of AtSUC9 led to sensitive responses to abiotic stress during seed germination and seedling growth. Further analyses indicated that the sensitivity phenotype of Atsuc9 mutants resulted from higher Suc content in shoots and lower Suc content in roots, as compared with that in wild-type (WT) plants. In addition, we found that the expression of AtSUC9 is induced in particular by low levels of exogenous and endogenous Suc, and deletion of AtSUC9 affected the expression of the low Suc level-responsive genes. AtSUC9 also showed an obvious response to treatments with low concentrations of exogenous Suc during seed germination, seedling growth and Suc distribution, and Atsuc9 mutants hardly grew in abiotic stress treatments without exogenous Suc. Moreover, our results illustrated not only that deletion of AtSUC9 blocks abiotic stress-inducible ABA accumulation but also that Atsuc9 mutants had a lower content of endogenous ABA in stress conditions than in normal conditions. Deletion of AtSUC9 also inhibited the expression of many ABA-inducible genes (SnRk2.2/3/6, ABF2/3/4, ABI1/3/4, RD29A, KIN1 and KIN2). These results indicate that AtSUC9 is induced in particular by low Suc levels then mediates the balance of Suc distribution and promotes ABA accumulation to enhance Arabidopsis abiotic stress resistance.

Structures, physical properties and antibacterial activity of silver nanoparticles of Lactiplantibacillus plantarum exopolysaccharide.

Lactic acid bacteria (LAB) exopolysaccharide (EPS) has good water absorption, high viscosity, good stability, so it was widely used in probiotics fields. In this study, EPS-producing LAB strain Lactiplantibacillus plantarum HDL-03 was isolated and identified. Moreover, the HDL-03 EPS was used as a stabilizer and mixed with AgNO3 to synthesize a novel nanoparticle AgNPs whose structure and properties were explored. The monosaccharide composition and molecular weight indicated that HDL-03 EPS was a heteropolysaccharide composed of mannose and glucose. Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR) spectroscopy analysis and methylation results jointly proved it was a heteropolysaccharide containing 1,3-Manp and 1,6-Glcp. The X-Ray diffraction (XRD) results showed that this EPS has an amorphous structure, while the synthesized AgNPs have crystalline properties. The scanning electron microscopy (SEM) and transmission electron microscopy (TEM) results indicated EPS had a smooth and dense sheet structure, while the surface of AgNPs became rougher and large holes appeared after synthesis. Zeta particle size analysis suggested that the particle size of AgNPs increased by 36.63 nm compared to HDL-03 EPS. FT-IR analysis exhibited that the position of the characteristic peaks of AgNPs changed. The OH moving from a wavelength of 3388.49 cm-1 to a wavelength of 3316.79 cm-1 and telescopic vibration peak changed from 1356.07 cm-1 to 1344.22 cm-1. A plate inhibition test revealed the effect of different concentrations of EPS and AgNO3 synthesized AgNPs on the diameter of inhibition circle produced by the indicator bacteria Escherichia coli and Staphylococcus aureus. Furthermore, AgNPs were applied to the indicator bacteria, which the minimum inhibitory concentration (MIC), time-inhibitory curve, and changes in extracellular conductivity, nucleic acids, proteins, ATP, and lactate dehydrogenase (LDH) levels were determined. The AgNPs inhibited the growth of E. coli and S. aureus and exhibited outstanding antimicrobial properties. With the increase of treatment time, the degree of cell membrane damage increased, the permeability enhanced, and the intracellular substances leaked. These results indicate that HDL-03 EPS has good potential for applications in the production of food packaging, antimicrobials, catheters, textiles and coatings.

Structure and Properties of Exopolysaccharide Produced by Gluconobacter frateurii and Its Potential Applications.

An exopolysaccharide (EPS)-producing bacterium was isolated from apricot fermentation broth and identified as Gluconobacter frateurii HDC-08 (accession number: OK036475.1). HDC-08 EPS is a linear homopolysaccharide mainly composed of glucose linked by α-(1,6) glucoside bonds. It contains C, H, N and S elements, with a molecular weight of 4.774 × 106 Da. Microscopically, it has a smooth, glossy and compact sheet structure. It is an amorphous noncrystalline substance with irregular coils. Moreover, the EPS showed surface hydrophobicity and high thermal stability with a degradation temperature of 250.76 °C. In addition, it had strong antioxidant properties against DPPH radicals, ABPS radicals, hydroxyl radicals and H2O2. The EPS exhibited high metal-chelating activity and strong emulsifying ability for soybean oil, petroleum ether and diesel oil. The milk solidification test indicated that the EPS had good potential in fermented dairy products. In general, all the results demonstrate that HDC-08 EPS has promise for commercial applications as a food additive and antioxidant.

Investigation of the causal relationship between inflammatory bowel disease and type 2 diabetes mellitus: a Mendelian randomization study.

Background: Type 2 diabetes mellitus (T2DM) and inflammatory bowel disease (IBD) have been associated, according to various epidemiological research. This study uses Mendelian randomization (MR) to investigate the causal link between T2DM and IBD. Methods: To investigate the causal relationship between IBD and T2DM risk using European population data from the genome-wide association study (GWAS) summary datasets, we constructed a two-sample MR study to evaluate the genetically predicted impacts of liability towards IBD outcomes on T2DM risk. As instrumental variables (IVs), we chose 26 single nucleotide polymorphisms (SNPs) associated with IBD exposure data. The European T2DM GWAS data was obtained from the IEU OpenGWAS Project database, which contains 298,957 cases as the outcome data. The causal relationship between T2DM and IBD using a reverse MR analysis was also performed. Results: The two-sample MR analysis, with the Bonferroni adjustment for multiple testing, revealed that T2DM risk in Europeans is unaffected by their IBD liability (odds ratio (OR): 0.950-1.066, 95% confidence interval (CI): 0.885-1.019, p = 0.152-0.926). The effects of liability to T2DM on IBD were not supported by the reverse MR analysis either (OR: 0.739-1.131, 95% confidence interval (CI): 0.651-1.100, p = 0.058-0.832). MR analysis of IBS on T2DM also have no significant causal relationship (OR: 0.003-1.007, 95% confidence interval (CI): 1.013-5.791, p = 0.069-0.790). FUMA precisely mapped 22 protein-coding genes utilizing significant SNPs of T2DM acquired from GWAS. Conclusion: The MR study showed that the existing evidence did not support the significant causal effect of IBD on T2DM, nor did it support the causal impact of T2DM on IBD.

lncRNA Gm20257 alleviates pathological cardiac hypertrophy by modulating the PGC-1α-mitochondrial complex IV axis.

Pathological cardiac hypertrophy, a major contributor to heart failure, is closely linked to mitochondrial function. The roles of long noncoding RNAs (lncRNAs), which regulate mitochondrial function, remain largely unexplored in this context. Herein, a previously unknown lncRNA, Gm20257, was identified. It markedly increased under hypertrophic stress in vivo and in vitro. The suppression of Gm20257 by using small interfering RNAs significantly induced cardiomyocyte hypertrophy. Conversely, the overexpression of Gm20257 through plasmid transfection or adeno-associated viral vector-9 mitigated angiotensin II-induced hypertrophic phenotypes in neonatal mouse ventricular cells or alleviated cardiac hypertrophy in a mouse TAC model respectively, thus restoring cardiac function. Importantly, Gm20257 restored mitochondrial complex IV level and enhanced mitochondrial function. Bioinformatics prediction showed that Gm20257 had a high binding score with peroxisome proliferator-activated receptor coactivator-1 (PGC-1α), which could increase mitochondrial complex IV. Subsequently, Western blot analysis results revealed that Gm20257 substantially affected the expression of PGC-1α. Further analyses through RNA immunoprecipitation and immunoblotting following RNA pull-down indicated that PGC-1α was a direct downstream target of Gm20257. This interaction was demonstrated to rescue the reduction of mitochondrial complex IV induced by hypertrophic stress and promote the generation of mitochondrial ATP. These findings suggest that Gm20257 improves mitochondrial function through the PGC-1α-mitochondrial complex IV axis, offering a novel approach for attenuating pathological cardiac hypertrophy.

Regulation of charged reverse micelles on particle charging in nonpolar media.

By considering the mechanism of preferential adsorption, we systemically investigated the charging behavior of spherical particles in nonpolar media by the regulation of charged inverse micelles. Using the nonlinear Poisson-Boltzmann equation, we simulated the effects of micelle concentrations, particle concentrations, and particle sizes on the surface potential of spheres at the thermodynamic equilibrium of the system. As a result, we found two different micelle concentration-dependent regions for the surface potential of spheres which can be explained in terms of the mechanism of preferential adsorption and the electrostatic properties of charged reverse micelles between the particle surface and the double layer. Additionally, similar results were observed in an experiment for studying zeta potential of colloidal particles dispersed in AOT (sodium di-2-ethylhexyl sulfosuccinate)-dodecane solution.

Fasting Plasma Glucose and Glycated Hemoglobin Levels as Risk Factors for the Development of Hypertension: A Retrospective Cohort Study.

Introduction: Hypertension (HTN) is a significant risk factor for cardiovascular disease. Identifying new risk factors for hypertension is crucial. This study aims to determine the predictive value of fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) in the development of hypertension. Methods: In this study, we examined 16,026 individuals without diabetes and other cardiovascular risk factors who were underwent annual screening at the People's Hospital of Yuxi, Yunnan, China from 2013 to 2016. The participants were divided into two groups: normoglycemic and prediabetic. Normoglycemia was defined as having an HbA1c level of less than 5.7% and an FPG level of less than 5.6 mmol/ L. Prediabetes was defined according to the ADA criteria, which includes having an HbA1c level between 5.7% and 6.5%, or an impaired fasting glucose level between 5.6 mmol/L and 7.0 mmol/L. The participants were further divided into four subgroups based on their FPG and HbA1c levels: normoglycemia, impaired HbA1c only, FPG only, and both parameters impaired. Results: The cohort study was conducted on 16,026 participants from Yunnan, China, consisting of 60.6% males and 39.4% females, with a mean age of 44.6 ± 12.5 years. The study revealed that prediabetes was independently associated with an increased risk for HTN (OR 1.53, 95% CI 1.41~1.67, P < 0.001). The analysis of different subgroups of HbA1c and FPG showed that FPG was a better predictor of HTN than HbA1c, regardless of the group. Conclusion: FPG and HbA1c were significantly associated with the future development of HTN in individuals with prediabetes.

Association Between Visceral Fat Area and Glycated Hemoglobin in Type 2 Diabetics: A Retrospective Study.

Introduction: Obesity is a risk factor for the development of type 2 diabetes (T2DM) as well as its associated metabolic complications. Central obesity, characterized by an increased visceral fat area (VFA), is contributed to the development of T2DM. However, the relationship between VFA and HbA1c is not particularly clear. Methods: A total of 3173 patients with T2DM participated in the study at the Metabolic Management Center (MMC), with anthropometric and biochemical measurements recorded. To examine the association between HbA1c and VFA, fitting curves were plotted, facilitating a comprehensive observation of their relationship. Results: HbA1c was inversely associated with VFA (ß -1.79, 95% CI -2.34~-1.24, P < 0.001). The fitted curve shows that VFA increased with the increase of HbA1c when it was less than 8.62%. When it was greater than 8.62%, VFA decreased as HbA1c increased. Using linear inflection point analysis, we found that its inflection point interval falls within 8.36%~8.88%. Conclusion: VFA was positively associated with HbA1c in individuals with T2DM. Furthermore, the relationship between the two variables was an inverted U-shaped association.

Genome-Wide Association Study Identified Novel SNPs Associated with Chlorophyll Content in Maize.

Chlorophyll is an essential component that captures light energy to drive photosynthesis. Chlorophyll content can affect photosynthetic activity and thus yield. Therefore, mining candidate genes of chlorophyll content will help increase maize production. Here, we performed a genome-wide association study (GWAS) on chlorophyll content and its dynamic changes in 378 maize inbred lines with extensive natural variation. Our phenotypic assessment showed that chlorophyll content and its dynamic changes were natural variations with a moderate genetic level of 0.66/0.67. A total of 19 single-nucleotide polymorphisms (SNPs) were found associated with 76 candidate genes, of which one SNP, 2376873-7-G, co-localized in chlorophyll content and area under the chlorophyll content curve (AUCCC). Zm00001d026568 and Zm00001d026569 were highly associated with SNP 2376873-7-G and encoded pentatricopeptide repeat-containing protein and chloroplastic palmitoyl-acyl carrier protein thioesterase, respectively. As expected, higher expression levels of these two genes are associated with higher chlorophyll contents. These results provide a certain experimental basis for discovering the candidate genes of chlorophyll content and finally provide new insights for cultivating high-yield and excellent maize suitable for planting environment.

Human-Induced Hepatocytes-Derived Extracellular Vesicles Ameliorated Liver Fibrosis in Mice Via Suppression of TGF-ß1/Smad Signaling and Activation of Nrf2/HO-1 Signaling.

Liver fibrosis is a wound-healing response caused by persistent liver injury and often occurs in chronic liver diseases. Effective treatments for liver fibrosis are still pending. Recent studies have revealed that extracellular vesicles (EVs) derived from primary hepatocytes (Hep-EVs) have therapeutic potential for multiple liver diseases. However, Hep-EVs are difficult to manufacture in bulk because of the limited sources of primary hepatocytes. Human-induced hepatocytes (hiHep) are hepatocyte-like cells that can expand in vitro, and their cell culture supernatant is thus an almost unlimited resource for EVs. This study aimed to investigate the potential therapeutic effects of EVs derived from hiHeps. hiHep-EVs inhibited the expression of inflammatory genes and the secretion of inflammation-related cytokines, and suppressed the activation of hepatic stellate cells by inhibiting the transforming growth factor (TGF)-ß1/Smad signaling pathway. The anti-inflammatory and antifibrotic effects of hiHep-EVs were similar to those of mesenchymal stem cell-EVs. Furthermore, the administration of hiHep-EVs ameliorated oxidative stress, inflammation, and fibrosis in a CCl4-induced liver fibrosis mouse model. The expression of α smooth muscle actin, collagen I, and collagen III was reduced, which may be attributed to the regulation of matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 by hiHep-EVs, and the protein expression of Nrf2, HO-1, and NQO1 was increased. Taken together, our results suggested that hiHep-EVs alleviated liver fibrosis by activating the Nrf2/HO-1 signaling pathway and inhibiting the TGF-ß1/Smad signaling pathway. This study revealed the hepatoprotective effect of hiHep-EVs, and provided a new approach to treating liver fibrosis.

Glycemic dispersion: a new index for screening high glycemic variability.

OBJECTIVE: For patients with diabetes, high-frequency and -amplitude glycemic variability may be more harmful than continuous hyperglycemia; however, there is still a lack of screening indicators that can quickly and easily assess the level of glycemic variability. The aim of this study was to investigate whether the glycemic dispersion index is effective for screening high glycemic variability. METHODS: A total of 170 diabetes patients hospitalized in the Sixth Affiliated Hospital of Kunming Medical University were included in this study. After admission, the fasting plasma glucose, 2-hour postprandial plasma glucose, and glycosylated hemoglobin A1c were measured. The peripheral capillary blood glucose was measured seven times in 24 h, before and after each of three meals and before bedtime. The standard deviation of the seven peripheral blood glucose values was calculated, and a standard deviation of > 2.0 was used as the threshold of high glycemic variability. The glycemic dispersion index was calculated and its diagnostic efficacy for high glycemic variability was determined by the Mann-Whitney U test, receiver operating characteristic (ROC) curve and, Pearson correlation analysis. RESULTS: The glycemic dispersion index of patients with high glycemic variability was significantly higher than that of those with low glycemic variability (p < 0.01). The best cutoff value of the glycemic dispersion index for screening high glycemic variability was 4.21. The area under the curve (AUC) was 0.901 (95% CI: 0.856-0.945) and had a sensitivity of 0.781 and specificity of 0.905. It was correlated with the standard deviation of blood glucose values (r = 0.813, p < 0.01). CONCLUSIONS: The glycemic dispersion index had good sensitivity and specificity for screening high glycemic variability. It was significantly associated with the standard deviation of blood glucose concentration and is simple and easy to calculate. It was an effective screening indicator of high glycemic variability.

Tumor regression grade combined with post-therapy lymph node status: A novel independent prognostic factor for patients treated with neoadjuvant therapy followed by surgery in locally advanced gastroesophageal junction and gastric carcinoma.

BACKGROUND: Tumor regression grade (TRG) is a measure of histopathological response to neoadjuvant therapy (NAT). Post-therapy lymph node (ypN) metastasis was reported as a prognostic factor. However, the evaluation of the treatment effectiveness of NAT has not been well studied. Here, we explored whether TRG combined with ypN status could be a prognostic factor for gastroesophageal junction (GEJ) and gastric cancer (GC). Besides, we aimed at making clear the association of different neoadjuvant regimens with different TRG and ypN status. METHODS: 376 patients with GEJ or GC accepting NAT in Peking University Cancer Hospital were retrospectively collected from January 1, 2003 to June 30, 2021. According to TRG and ypN status, patients were innovatively categorized into four groups: TRG0N0, TRG1-3N0, TRG0-1N+, and TRG2-3N+. We applied Kaplan-Meier method and log-rank test to testify the differences in disease free survival (DFS) and overall survival (OS) among four groups. Univariate and multivariate analyses were performed to examine the relationships between TRG combined with ypN status and prognosis. RESULTS: We observed significant survival differences among the four groups (p < 0.001, respectively). Median DFS and OS of patients with TRG0N0, TRG1-3N0, and TRG0-1N+ were not reached, whereas these of patients with TRG2-3N+ were 17.37 months (95% CI, 14.14-20.60 months) and 39.97 months (95% CI, 27.05-52.89 months). TRG combined with ypN status was still an independent predictor for both DFS (p < 0.001) and OS (p < 0.001) in multivariate analysis. Chi-squared test showed TRG combined with ypN status was significantly associated with different preoperative treatments (p < 0.001). Patients receiving immunotherapy achieved the highest TRG0N0 rate (31.9%). CONCLUSION: Our results demonstrate that TRG combined with ypN status is a novel independent predictor of both DFS and OS in resectable, locally advanced GEJ and GC. Neoadjuvant immunotherapy achieved the highest TRG0N0 rate.

Comparative study of type 2 diabetes mellitus-associated gut microbiota between the Dai and Han populations.

BACKGROUND: The global prevalence of type 2 diabetes mellitus (T2DM) is increasing. T2DM is associated with alterations of the gut microbiota, which can be affected by age, illness, and genetics. Previous studies revealed that there are discriminating microbiota compositions between the Dai and the Han populations. However, the specific gut microbiota differences between the two populations have not been elucidated. AIM: To compare the gut microbiota differences in subjects with and without T2DM in the Dai and Han populations. METHODS: A total of 35 subjects of the Han population (including 15 healthy children, 8 adult healthy controls, and 12 adult T2DM patients) and 32 subjects of the Dai population (including 10 healthy children, 10 adult healthy controls, and 12 adult T2DM patients) were enrolled in this study. Fasting venous blood samples were collected from all the subjects for biochemical analysis. Fecal samples were collected from all the subjects for DNA extraction and 16S rRNA sequencing, which was followed by analyses of the gut microbiota composition. RESULTS: No significant difference in alpha diversity was observed between healthy children and adults. The diversity of gut microbiota was decreased in T2DM patients compared to the healthy adults in both the Dai and Han populations. There was a significant difference in gut microbiota between healthy children and healthy adults in the Han population with an increased abundance of Bacteroidetes and decreased Firmicutes in children. However, this difference was less in the Dai population. Significant increases in Bacteroidetes in the Han population and Proteobacteria in the Dai population and decreases in Firmicutes in both the Han and Dai population were observed in T2DM patients compared to healthy adults. Linear discriminant analysis Effect Size analysis also showed that the gut microbiota was different between the Han and Dai populations in heathy children, adults, and T2DM patients. Four bacteria were consistently increased and two consistently decreased in the Han population compared to the Dai population. CONCLUSION: Differences in gut microbiota were found between the Han and Dai populations. A significant increase in Bacteroidetes was related to the occurrence of T2DM in the Han population, while a significant increase in Proteobacteria was related to the occurrence of T2DM in the Dai population.