Leakage current simulations of Low Gain Avalanche Diode with improved Radiation Damage Modeling

We report precise TCAD simulations of IHEP-IME-v1 Low Gain Avalanche Diode (LGAD) calibrated by secondary ion mass spectroscopy (SIMS). Our setup allows us to evaluate the leakage current, capacitance, and breakdown voltage of LGAD, which agree with measurements' results before irradiation. And we propose an improved LGAD Radiation Damage Model (LRDM) which combines local acceptor removal with global deep energy levels. The LRDM is applied to the IHEP-IME-v1 LGAD and able to predict the leakage current well at -30 $^{\circ}$C after an irradiation fluence of $\Phi_{eq}=2.5 \times 10^{15} ~n_{eq}/cm^{2}$. The charge collection efficiency (CCE) is under development

Bayesian Data Augmentation Dose Finding with Continual Reassessment Method and Delayed Toxicities

A major practical impediment when implementing adaptive dose-finding designs is that the toxicity outcome used by the decision rules may not be observed shortly after the initiation of the treatment. To address this issue, we propose the data augmentation continual reassessment method (DA-CRM) for dose finding. By naturally treating the unobserved toxicities as missing data, we show that such missing data are nonignorable in the sense that the missingness depends on the unobserved outcomes. The Bayesian data augmentation approach is used to sample both the missing data and model parameters from their posterior full conditional distributions. We evaluate the performance of the DA-CRM through extensive simulation studies, and also compare it with other existing methods. The results show that the proposed design satisfactorily resolves the issues related to late-onset toxicities and possesses desirable operating characteristics: treating patients more safely, and also selecting the maximum tolerated dose with a higher probability. The new DA-CRM is illustrated with two phase I cancer clinical trials. KEY WORDS: Bayesian adaptive design; late-onset toxicity; nonignorable missing data; maximum tolerated dose; phase I trial. 1

Intrapartum and early postpartum glycemic profiles in women with gestational diabetes mellitus: an observational study

Abstract. Background:. Data on the glycemic profile of pregnant women with gestational diabetes mellitus (GDM) during the perinatal period are sparse. This study described the intrapartum and early postpartum glucose profiles among pregnant women with GDM, and analyzed factors potentially affecting glycemic parameters during the period. Methods:. This was a prospective observational study conducted from March 2020 to November 2021. Pregnant women with GDM receiving lifestyle interventions alone during pregnancy and matched women with non-diabetic pregnancies (NDPs) were enrolled from among patients admitted to the obstetrics department for childbirth. Glucose monitoring was performed via a flash glucose monitoring (FGM) system on admission, and glucose readings during labor and early postpartum were analyzed. The clinical characteristics and FGM-based parameters of participants in the two groups were compared. Results:. A total of 124 participants (mean age: 29.5 ± 3.5 years, 92 [74.2%] primipara) were included in the final analysis. A total of 17,571 glucose readings were retrieved. There were no significant differences in clinical characteristics between the GDM (n = 60) and NDP (n = 64) groups. The average glucose level was 92.2 mg/dL, and the level was higher in the GDM group (95.5 ± 12.1 mg/dL vs. 89.1 ± 13.4 mg/dL, P = 0.008) during the intrapartum and early postpartum periods. The data were split into the intrapartum period (from the start of labor to delivery of the placenta) and the early postpartum period (within 24 h after placental delivery) for analysis. During intrapartum, women with GDM exhibited glycemic profiles and fluctuations similar to those in the NDP group. However, women with GDM had higher postpartum glucose levels (97.7 ± 13.4 mg/dL vs. 90.8 ± 15.3 mg/dL, P = 0.009), a longer time spent >140 mg/dL (8.7 ± 9.3% vs. 5.9 ± 10.3%, P = 0.011), and greater glycemic fluctuations than those with NDP. Postpartum hyperglycemia in GDM might be associated with high parity and postprandial glucose abnormalities in GDM screening tests. Conclusion:. Compared to those with normoglycemia, pregnant women with GDM receiving lifestyle interventions alone had similar intrapartum glucose profiles but higher early postpartum glucose levels and greater glucose variability, providing evidence for modification of the current perinatal glucose monitoring strategy for GDM. Trial Registration:. ChiCTR.org.cn, ChiCTR200003097

Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization

The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer (NSCLC). Constitutively active EGFR mutations, including in-frame deletion in exon 19 and L858R point mutation in exon 21, contribute about 90% of all EGFR-activating mutations in NSCLC. Although oral EGFR-tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show dramatic clinical efficacy with significantly prolonged progression-free survival in patients harboring these EGFR-activating mutations, most of these patients will eventually develop acquired resistance. Researchers have recently named genomic instability as one of the hallmarks of cancer. Genomic instability usually involves a transient phase of polyploidization, in particular tetraploidization. Tetraploid cells can undergo asymmetric cell division or chromosome loss, leading to tumor heterogeneity and multidrug resistance. Therefore, identification of signaling pathways involved in tetraploidization is crucial in overcoming drug resistance. In our present study, we found that gefitinib could activate YAP-MKK3/6-p38 MAPK-STAT3 signaling and induce tetraploidization in gefitinib-resistance cells. Using p38 MAPK inhibitors, SB203580 and losmapimod, we could eliminate gefitinib-induced tetraploidization and overcome gefitinib-resistance. In addition, shRNA approach to knockdown p38α MAPK could prevent tetraploidy formation and showed significant inhibition of cancer cell growth. Finally, in an in vivo study, losmapimod could successfully overcome gefitinib resistance using an in-house established patient-derived xenograft (PDX) mouse model. Overall, these findings suggest that losmapimod could be a potential clinical agent to overcome gefitinib resistance in NSCLC

The application of extracellular vesicles in colorectal cancer metastasis and drug resistance: recent advances and trends

Abstract Colorectal cancer (CRC) has high incidence and mortality rates and is one of the most common cancers of the digestive tract worldwide. Metastasis and drug resistance are the main causes of cancer treatment failure. Studies have recently suggested extracellular vesicles (EVs) as a novel mechanism for intercellular communication. They are vesicular particles, which are secreted and released into biological fluids, such as blood, urine, milk, etc., by a variety of cells and carry numerous biologically active molecules, including proteins, nucleic acids, lipids, metabolites, etc. EVs play a crucial part in the metastasis and drug resistance of CRC by delivering cargo to recipient cells and modulating their behavior. An in-depth exploration of EVs might facilitate a comprehensive understanding of the biological behavior of CRC metastasis and drug resistance, which might provide a basis for developing therapeutic strategies. Therefore, considering the specific biological properties of EVs, researchers have attempted to explore their potential as next-generation delivery systems. On the other hand, EVs have also been demonstrated as biomarkers for the prediction, diagnosis, and presumed prognosis of CRC. This review focuses on the role of EVs in regulating the metastasis and chemoresistance of CRC. Moreover, the clinical applications of EVs are also discussed. Graphical Abstrac

The therapeutic value of bifidobacteria in cardiovascular disease

Abstract There has been an increase in cardiovascular morbidity and mortality over the past few decades, making cardiovascular disease (CVD) the leading cause of death worldwide. However, the pathogenesis of CVD is multi-factorial, complex, and not fully understood. The gut microbiome has long been recognized to play a critical role in maintaining the physiological and metabolic health of the host. Recent scientific advances have provided evidence that alterations in the gut microbiome and its metabolites have a profound influence on the development and progression of CVD. Among the trillions of microorganisms in the gut, bifidobacteria, which, interestingly, were found through the literature to play a key role not only in regulating gut microbiota function and metabolism, but also in reducing classical risk factors for CVD (e.g., obesity, hyperlipidemia, diabetes) by suppressing oxidative stress, improving immunomodulation, and correcting lipid, glucose, and cholesterol metabolism. This review explores the direct and indirect effects of bifidobacteria on the development of CVD and highlights its potential therapeutic value in hypertension, atherosclerosis, myocardial infarction, and heart failure. By describing the key role of Bifidobacterium in the link between gut microbiology and CVD, we aim to provide a theoretical basis for improving the subsequent clinical applications of Bifidobacterium and for the development of Bifidobacterium nutritional products

Genomic basis of evolutionary adaptation in a warm-blooded fish

PUBLIC SUMMARY: Endothermy has evolved multiple times not only in mammals and birds but also in fishes (teleosts and chondrichthyans) A chromosome-level genome sequence of the whole-body endothermic opah was generated, explaining genetic changes in heat production, sensory, and adaptive immune system Convergent evolution in endothermic vertebrate lineages was investigated, and genes essential for heart function and metabolic heat production were screened Analyses of the unique pectoral muscle of opah revealed that numerous proteins were co-opted from dorsal swimming muscles for thermogenesis and oxidative phosphorylation ABSTRACT: Few fishes have evolved elevated body temperatures compared to ambient temperatures and only in opah (Lampris spp) is the entire body affected. To understand the molecular basis of endothermy, we analyzed the opah genome and identified 23 genes with convergent amino acid substitutions across fish, birds, and mammals, including slc8b1, which encodes the mitochondrial Na+/Ca2+ exchanger and is essential for heart function and metabolic heat production. Among endothermic fishes, 44 convergent genes with suggestive metabolic functions were identified, such as glrx3, encoding a crucial protein for hemoglobin maturation. Numerous genes involved in the production and retention of metabolic heat were also found to be under positive selection. Analyses of opah’s unique inner heat-producing pectoral muscle layer, an evolutionary key-innovation, revealed that many proteins were co-opted from dorsal swimming muscles for thermogenesis and oxidative phosphorylation. Thus, the opah genome provides valuable resources and opportunities to uncover the genetic basis of thermal adaptations in fish