Carbohydrate response element-binding protein (ChREBP) mediates decreased SNAP25 expression in islets from diabetic Goto-Kakizaki (GK) rats.

SNAP25 plays an essential role in the glucose-stimulated insulin secretion (GSIS) of pancreatic ß-cells. Carbohydrate response element-binding protein (ChREBP) is an important transcription factor in ß-cells and, in this study, we aimed to explore whether ChREBP regulates SNAP25 expression in ß-cells. We show that diabetic Goto-Kakizaki (GK) rats exhibited impaired insulin secretion and hyperglycemia, along with decreased SNAP25 expression and ChREBP phosphorylation in islets. SNAP25 knockdown decreased GSIS in ß-cells, while SNAP25 overexpression increased GSIS in ß-cells. Activation or overexpression of ChREBP led to reduced SNAP25 expression and subsequent suppression of GSIS. Conversely, ChREBP knockdown mitigated the reduction in SNAP25 expression caused by high glucose. Mechanistically, the activation of ChREBP by high glucose increased its occupancy and decreased the level of H3K4me3 at the Snap25 promoter. Our findings reveal the novel regulatory mechanisms of SNAP25 expression in ß-cells and suggest that SNAP25 may be involved in the regulation of ß-cell secretory function controlled by ChREBP.

Silyl Radical Generation from Silylboronic Pinacol Esters through Substitution with Aminyl Radicals.

A novel strategy was developed to generate silyl radicals from silylboronic pinacol esters (SPEs) through nucleohomolytic substitution of boron with aminyl radicals. We successfully applied this strategy to obtain diverse organosilicon compounds using SPEs and N-nitrosamines under photoirradiation without any catalyst. The ability to access silyl radicals offers a new perspective for chemists to rapidly construct Si-X bonds.

Ruthenium(II)-Catalyzed Remote C-H Alkylation of Arenes Using Diverse N-Directing Groups through Aziridine Ring Opening.

An efficient approach for the remote C-H alkylation of arenes, employing a variety of N-directing groups is described. This method facilitates the straightforward synthesis of valuable phenylethylamine derivatives by exclusively cleaving the benzylic C-N bond in aziridines. Furthermore, these products can easily remove the protecting groups, resulting in a variety of meta-substituted compounds, such as amines and ketones, which hold significance in synthetic chemistry.

Multi-omics analysis of multiple myeloma patients with differential response to first-line treatment.

The genome backgrounds of multiple myeloma (MM) would affect the efficacy of specific treatment. However, the mutational and transcriptional landscapes in MM patients with differential response to first-line treatment remains unclear. We collected paired whole-exome sequencing (WES) and transcriptomic data of over 200 MM cases from MMRF-COMPASS project. R package, maftools was applied to analyze the somatic mutations and mutational signatures across MM samples. Differential expressed genes (DEG) was calculated using R package, DESeq2. The feature selection of the predictive model was determined by LASSO regression. In silico analysis revealed newly discovered recurrent mutated genes such as TTN, MUC16. TP53 mutation was observed more frequent in nonCR (complete remission) group with poor prognosis. DNA repair-associated mutational signatures were enriched in CR patients. Transcriptomic profiling showed that the activity of NF-kappa B and TGF-ß pathways was suppressed in CR patients. A transcriptome-based response predictive model was constructed and showed promising predictive accuracy in MM patients receiving first-line treatment. Our study delineated distinctive mutational and transcriptional landscapes in MM patients with differential response to first-line treatment. Furthermore, we constructed a 20-gene predictive model which showed promising accuracy in predicting treatment response in newly diagnosed MM patients.

Bortezomib, epirubicin, and dexamethasone (PAD) results in superior free-progression survival compared to bortezomib, cyclophosphamide, and dexamethasone (VCD) treatment in non-transplantation newly diagnosed multiple myeloma patients aged between 50 to 65: a retrospective single-center analysis in non-transplant patients.

Background: To explore the optimum induction therapy for patients with newly diagnosed multiple myeloma (NDMM) who are eligible but have not yet received autologous stem cell transplantation (ASCT) in China. Methods: A total of 140 NDMM patients with cytogenetic background were selected from the Chang Zheng Hospital for this study. The induction therapy consisted of combined bortezomib (1.3 mg/m2, i.v.), cyclophosphamide (200 mg, i.v.), and dexamethasone (20 mg, i.v.) (VCD); or combined bortezomib (1.3 mg/m2, i.v.), epirubicin (50 mg/m2, i.v.), and dexamethasone (20 mg, i.v.) (PAD). All patients received 4-6 cycles of induction therapy until the first remission (defined as reaching at least partial remission), followed by thalidomide (100 mg/every night, p.o.) as the maintenance therapy. Data was analyzed using SPSS18.0 software and Kaplan-Meier and Cox regression analyses. Results: Of the 140 patients enrolled, 56 were treated with VCD and 84 received the PAD regimen. Compared to patients treated with VCD, patients receiving PAD treatment showed better free-progression survival (PFS) (hazard ratio: 0.355; 95% confidence interval: 0.214 to 0.591; P<0.001) and response rates, defined as achieving very good partial response (VGPR) or better (VCD vs. PAD: 47/56 or 83.9% vs. 77/84 or 92.8%; P=0.087). Similarly, the superior efficiency of PAD treatment was observed in different cytogenetic abnormality subgroups, even in patients with 1q21 amplification. Conclusions: This analysis demonstrated that PAD treatment resulted in better PFS compared to VCD in NDMM patients (aged 50-55 years old) who are eligible for but refuse ASCT therapy.

The neutrophil-lymphocyte ratio and immunosuppressive acidic protein may be useful parameters for predicting depression among middle-aged patients with diffuse large B cell lymphoma.

BACKGROUND: Patients with diffuse large B cell lymphoma (DLBCL) may experience depression. Growing evidence shows that depression interacts with immunity. However, the relationship between depression and immunity among DLBCL patients has not been investigated, despite reports indicating that patients with DLBCL often suffer from depression. METHODS: To accurately investigate the relationship between depression and immunity, 82 primarily diagnosed middle-aged patients with DLBCL who received standard chemotherapy were enrolled. The patients were divided into depressed and nondepressed groups according to Zung Self-rating Depression Scale (SDS) scores. Prozac was used to treat patients with depression until their symptoms were alleviated. The concentration of immunosuppressive acidic protein (IAP); percentages of cluster of differentiation (CD)3+, CD4+, and CD8+ T lymphocytes and CD56+ natural killer (NK) cells; absolute lymphocyte count (ALC); and neutrophil--lymphocyte ratio (NLR) were calculated at enrollment and after treatment. RESULTS: A higher score on the depression test was positively associated with serum IAP levels and NLR, and negatively associated with ALC. The levels of NLR and serum IAP in the depressed patients were significantly higher compared to those in the nondepressed patients. CONCLUSIONS: Our results suggest for the first time that IAP and the NLR are closely correlated with depression and may be parameters for predicting depression.

Integrated Transcriptomic Analysis Reveals a Distinctive Role of YAP1 in Extramedullary Invasion and Therapeutic Sensitivity of Multiple Myeloma.

Multiple myeloma (MM) is the second most common hematologic malignancy. There are no standard therapeutic guidelines for extramedullary invasion (EM). We performed a retrospective integrated transcriptomic analysis based on GEO, TCGA, and Oncomine datasets with a total of over 2,500 cases enrolled. GSVA analysis was performed on GSE24080. The external validation cohorts include GSE9782, GSE2658, MMRF-COMPASS, and Oncomine. The data of MGUS to relapsed MM were acquired from GSE6477, GSE5900, and Oncomine. The data of EM were acquired from GSE39683 and GSE66291. Single-cell level transcriptome data of MM and EM were acquired from GSE106218. GSVA analysis revealed that 559 cases could be divided into 2 groups based on the expression of oncogenic pathways with prognostic significances. Group 1 with a specific phenotype of YAP1-MYC+ exhibited an unpromising prognosis. The univariate analysis revealed YAP1 as a tumor suppressor in MM. The activity of DNA repair, glycolysis, and oxidative phosphorylation was significantly higher in YAP1-MYC+ MM, which is in concordance with EM myeloma cells based on single-cell analysis. Furthermore, we discovered that YAP1-MYC+ MM patients exhibited an improved response for IMiD treatment. Collectively, YAP1-MYC+MM patients might suffer a worse prognosis and stronger propensity for EM progression.

Rapid BMI Increases and Persistent Obesity in Small-for-Gestational-Age Infants.

Purpose: In order to compensate for the early intrauterine growth restriction, small-for-gestational age (SGA) infants have "catch-up growth" after birth. Increased caloric intake has been suggested for SGA infants conventionally. It is important to determine if the early growth rate of body mass index (BMI) is associated with risk of persistent obesity later in life. In this longitudinal cohort study, we assessed the BMI of a large cohort of children who were SGA at birth to determine their risk of persistent obesity at school age (6-7 years) due to excessive weight gain in the first 3 years of life. Methods: We collected the height and weight data of 23,871 SGA babies. A polynomial function was used to fit the BMI-for-age z-score (BAZ) values of 0-6 years old SGA children and interpolate their growth trajectory. In addition, we screened out 6,959 children from 23,871 children to further evaluate the dynamic changes of early childhood BMI. We divided the school-age children into groups as non-obese (BAZ < 2) and obese (BAZ > 2), and determined the association between changes in BMI and school-age obesity. Results: From the perspective of BMI distribution, the interpolated growth trajectory indicated that SGA children reaching overweight status or developing obesity by 3 years of age, continued to have obesity until school age (R2, 0.65; R2, 0.21). The retrospective analysis showed that children who were overweight and had obesity during school age had a high BMI from early age. By analyzing the changes in early BMI, we found that the fastest growth of SGA children occurred in the early infancy before 6 months and they continued to grow rapidly for a period of time. Interestingly, former SGA children who maintained a near overweight (1 < BAZ < 2) status before the age of 2 maintained an appropriate growth rate and usually did not develop obesity. Conclusions: A rapid increase in BMI during early infancy in former SGA newborns leads to a persistent risk of obesity. The energy intake of SGA infants should appropriately meet the infants' growth needs and early BMI changes should be closely monitored for an optimal integrated management.