Changes in three tumor markers in patients with advanced lung adenocarcinoma after combination therapy with pemetrexed and platinum: Short-term treatment efficacy

Purpose: To study changes in three tumor markers before and after combination treatment with pemetrexed and platinum, and evaluate the short-term therapeutic effectiveness of the treatment in advanced lung adenocarcinoma (ALA) subjects. Method: Patients with ALA (n =120) admitted to JinHua Municipal Central Hospital from January 2017 to May 2018 were selected as the research subjects. According to the results of chemotherapy, they were divided into two groups: significantly-reduced tumor volume group (90 cases), and nonsignificantly-reduced tumor volume group (21 cases). The two groups were treated with chemotherapy using a combination of pemetrexed and cisplatin. The levels of CEA, CA125 and CYFRA21-1 before and after chemotherapy were assayed to determine their relationship with short-term therapy effectiveness. Result: Overall analysis of tumor markers in the 120 patients with ALA showed statistically significant reduction in overall tumor marker levels before and after chemotherapy (p < 0.05). At the end of chemotherapy, the tumor markers were markedly reduced in subjects with significant tumor volume, and there was statistical difference between the two groups before chemotherapy (p < 0.05). Changes in CEA, CA125 and CYFRA21-1 were positively correlated with the chemotherapeutic effects on patients with ALA. Conclusion: In ALA patients treated with pemetrexed and platinum, changes in serum CEA, CA125 and CYFRA21-1 profiles before and after treatment depend on the effect of chemotherapy, and they are reliable for prediction of short-term therapeutic efficacy

Bayesian modelling of high-throughput sequencing assays with malacoda.

NGS studies have uncovered an ever-growing catalog of human variation while leaving an enormous gap between observed variation and experimental characterization of variant function. High-throughput screens powered by NGS have greatly increased the rate of variant functionalization, but the development of comprehensive statistical methods to analyze screen data has lagged. In the massively parallel reporter assay (MPRA), short barcodes are counted by sequencing DNA libraries transfected into cells and the cell\u27s output RNA in order to simultaneously measure the shifts in transcription induced by thousands of genetic variants. These counts present many statistical challenges, including overdispersion, depth dependence, and uncertain DNA concentrations. So far, the statistical methods used have been rudimentary, employing transformations on count level data and disregarding experimental and technical structure while failing to quantify uncertainty in the statistical model. We have developed an extensive framework for the analysis of NGS functionalization screens available as an R package called malacoda (available from github.com/andrewGhazi/malacoda). Our software implements a probabilistic, fully Bayesian model of screen data. The model uses the negative binomial distribution with gamma priors to model sequencing counts while accounting for effects from input library preparation and sequencing depth. The method leverages the high-throughput nature of the assay to estimate the priors empirically. External annotations such as ENCODE data or DeepSea predictions can also be incorporated to obtain more informative priors-a transformative capability for data integration. The package also includes quality control and utility functions, including automated barcode counting and visualization methods. To validate our method, we analyzed several datasets using malacoda and alternative MPRA analysis methods. These data include experiments from the literature, simulated assays, and primary MPRA data. We also used luciferase assays to experimentally validate several hits from our primary data, as well as variants for which the various methods disagree and variants detectable only with the aid of external annotations

Decreased adiponectin and increased inflammation expression in epicardial adipose tissue in coronary artery disease

<p>Abstract</p> <p>Background</p> <p>Disorders of endocrine substances in epicardial adipose tissue are known causes of coronary artery disease (CAD). Adiponectin is associated with cardiovascular disease. However, expression of adiponectin in epicardial adipose tissue and its function in CAD pathogenesis is unclear. This study investigates adiponectin expression in epicardial adipose tissue in CAD patients.</p> <p>Methods</p> <p>Vessels or adipose tissue samples collected from CAD patients and non-CAD controls were examined after immunochemical staining. Adiponectin, cytokines of interleukin-6 (IL-6) and necrosis factor-α (TNF-α) and toll-like receptor 4 (TLR4) expression level in adipose tissue were measured using real-time quantitative RT-PCR. Adiponectin concentrations in peripheral and coronary sinus vein plasma were measured with enzyme-linked immunosorbent assay. Peripheral vein plasma biochemistries were performed with routine laboratory techniques. Monocytes were collected from blood using lymphocyte separation medium. Expression level of cytokines and transcription factor NF-κB were measured to learn the effect of adiponectin on stearic acid-stimulated monocytes. Percentage of TLR4 positive monocytes was analyzed using flow cytometry.</p> <p>Results</p> <p>Histological examination revealed increased macrophage infiltration into epicardial adipose tissue of CAD patients. Decreased adiponectin displayed by real-time quantitative RT-PCR was associated with enhanced cytokines of IL-6 and TNF-α or TLR4 expression level in epicardial adipose tissue, suggesting decreased circulating adiponectin may be useful as a more sensitive predictor for coronary atherosclerosis than routine laboratory examinations. Adiponectin suppressed secretion of IL-6 and TNF-α in stimulated monocytes and TLR4 was expressed on cell surfaces.</p> <p>Conclusions</p> <p>Endocrine disorders in epicardial adipose tissue are strongly linked to CAD, and adiponectin has a protective effect by inhibiting macrophage-mediated inflammation.</p

Superhydrophobic flow channel surface and its impact on PEM fuel cell performance

Water management is a critical issue in polymer electrolyte membrane fuel cells (PEMFCs), and it is normally achieved through the modification of surface wettability condition for the cell components. In this study, superhydrophobic surface-coating materials were developed and the gas flow channel surfaces were modified for superhydrophobic surface property with small sliding angles (SAs). The coated surface characteristics were measured, including static contact angle (CA), SA and CA hysteresis as well as surface geometrical properties. The flow characteristics through such surface-coated channels were measured, and comparison was made with hydrophilic channels and channels coated with poly(tetrafluoroethylene), a commonly used surface-coating agent in PEMFCs. It was found that the presently modified superhydrophobic flow channels yield the lowest resistance to the two-phase flow; and both the mechanical and thermal stabilities of the attained superhydrophobicity for the coated surfaces were also investigated. It was demonstrated experimentally that such coated flow channels result in improved PEMFC performance due to improved water management.Natural Sciences and Engineering Research Council of Canada through a Strategic Projects Grant Supplemental Competition (Grant No.: STPSC 357087–07) Auto21 Networks of Centres of Excellence is gratefully acknowledge

Functionalization of CD36 Cardiovascular Disease and Expression Associated Variants by Interdisciplinary High Throughput Analysis.

CD36 is a platelet membrane glycoprotein whose engagement with oxidized low-density lipoprotein (oxLDL) results in platelet activation. The CD36 gene has been associated with platelet count, platelet volume, as well as lipid levels and CVD risk by genome-wide association studies. Platelet CD36 expression levels have been shown to be associated with both the platelet oxLDL response and an elevated risk of thrombo-embolism. Several genomic variants have been identified as associated with platelet CD36 levels, however none have been conclusively demonstrated to be causative. We screened 81 expression quantitative trait loci (eQTL) single nucleotide polymorphisms (SNPs) associated with platelet CD36 expression by a Massively Parallel Reporter Assay (MPRA) and analyzed the results with a novel Bayesian statistical method. Ten eQTLs located 13kb to 55kb upstream of the CD36 transcriptional start site of transcript ENST00000309881 and 49kb to 92kb upstream of transcript ENST00000447544, demonstrated significant transcription shifts between their minor and major allele in the MPRA assay. Of these, rs2366739 and rs1194196, separated by only 20bp, were confirmed by luciferase assay to alter transcriptional regulation. In addition, electromobility shift assays demonstrated differential DNA:protein complex formation between the two alleles of this locus. Furthermore, deletion of the genomic locus by CRISPR/Cas9 in K562 and Meg-01 cells results in upregulation of CD36 transcription. These data indicate that we have identified a variant that regulates expression of CD36, which in turn affects platelet function. To assess the clinical relevance of our findings we used the PhenoScanner tool, which aggregates large scale GWAS findings; the results reinforce the clinical relevance of our variants and the utility of the MPRA assay. The study demonstrates a generalizable paradigm for functional testing of genetic variants to inform mechanistic studies, support patient management and develop precision therapies

Racial Difference in Human Platelet PAR4 Reactivity Reflects Expression of PCTP and miR-376c

Racial differences in the pathophysiology of atherothrombosis are poorly understood. We explored the function and transcriptome of platelets in healthy black (n = 70) and white (n = 84) subjects. PAR4 thrombin receptor induced platelet aggregation and calcium mobilization were significantly greater in black subjects. Numerous differentially expressed (DE) RNAs were associated with both race and PAR4 reactivity, including phosphatidylcholine transfer protein (PCTP), and platelets from blacks expressed higher levels of PC-TP protein. PC-TP inhibition or depletion blocked activation of platelets or megakaryocytic cell lines through PAR4 but not PAR1. MiR-376c levels were DE by race and PAR4 reactivity, and were inversely correlated with PCTP mRNA levels, PC-TP protein levels and PAR4 reactivity. MiR-376c regulated expression of PC-TP in human megakaryocytes. A disproportionately high number of miRNAs DE by race and PAR4 reactivity, including miR-376c, are encoded in the DLK1-DIO3 locus, and were lower in platelets from blacks. These results support PC-TP as a regulator of the racial difference in PAR4-mediated platelet activation, indicate a genomic contribution to platelet function that differs by race, and emphasize a need to consider race effects when developing anti-thrombotic drugs

RJUA-QA: A Comprehensive QA Dataset for Urology

We introduce RJUA-QA, a novel medical dataset for question answering (QA) and reasoning with clinical evidence, contributing to bridge the gap between general large language models (LLMs) and medical-specific LLM applications. RJUA-QA is derived from realistic clinical scenarios and aims to facilitate LLMs in generating reliable diagnostic and advice. The dataset contains 2,132 curated Question-Context-Answer pairs, corresponding about 25,000 diagnostic records and clinical cases. The dataset covers 67 common urological disease categories, where the disease coverage exceeds 97.6\% of the population seeking medical services in urology. Each data instance in RJUA-QA comprises: (1) a question mirroring real patient to inquiry about clinical symptoms and medical conditions, (2) a context including comprehensive expert knowledge, serving as a reference for medical examination and diagnosis, (3) a doctor response offering the diagnostic conclusion and suggested examination guidance, (4) a diagnosed clinical disease as the recommended diagnostic outcome, and (5) clinical advice providing recommendations for medical examination. RJUA-QA is the first medical QA dataset for clinical reasoning over the patient inquiries, where expert-level knowledge and experience are required for yielding diagnostic conclusions and medical examination advice. A comprehensive evaluation is conducted to evaluate the performance of both medical-specific and general LLMs on the RJUA-QA dataset. Our data is are publicly available at \url{https://github.com/alipay/RJU_Ant_QA}.Comment: An initial versio

Spatial and temporal variation of net primary productivity of herbaceous marshes and its climatic drivers in China

Herbaceous marshes are widely distributed in China and are vital to regional ecological security and sustainable development. Vegetation net primary productivity (NPP) is a vital indicator of vegetation growth. Climatic change can significantly affect NPP, but variations in NPP of herbaceous marsh and their responses to climate change in China remain unclear. Using meteorological data and MODIS NPP data during 2000-2020, this study analyzed the spatial and temporal variations of NPP and their responses to climate change in Chinese herbaceous marshes. We found that the annual NPP of herbaceous marshes in China increased significantly at a rate of 3.34 g C/m2/a from 2000 to 2020, with an average value of 336.60 g C/m2. The increased annual total precipitation enhanced the national average NPP, whereas annual mean temperature had no significant effect on the national average NPP. Regionally, precipitation had a significant positive effect on the NPP in temperate semi-arid and arid and temperate semi-humid and humid marsh regions. For the first time, we discovered asymmetry effects of daytime and nighttime temperatures on NPP in herbaceous marshes of China. In temperate humid and semi-humid marsh regions, increased summer daytime temperature decreased the NPP while increased summer nighttime temperature increased the NPP. In the Tibetan Plateau, increased autumn daytime temperature, as well as summer daytime and nighttime temperatures could increase the NPP of herbaceous marshes. This study highlights the different influences of seasonal climate change on the NPP of herbaceous marshes in China and indicates that the differential effects of daytime and nighttime temperatures should be considering in simulating the NPP of herbaceous marshes in terrestrial ecosystem models, especially under the background of global asymmetric diurnal warming

Cold-induced modulation and functional analyses of the DRE-binding transcription factor gene, GmDREB3, in soybean (Glycine max L.)

DREB (dehydration-responsive element-binding protein) transcription factors have important roles in the stress-related regulation network in plants. A DREB orthologue, GmDREB3, belonging to the A-5 subgroup of the DREB subfamily, was isolated from soybean using the RACE (rapid amplification of cDNA ends) method. Northern blot analysis showed that expression of GmDREB3 in soybean seedlings was induced following cold stress treatment for 0.5 h and was not detected after 3 h. However, it was not induced by drought and high salt stresses or by abscisic acid (ABA) treatment. This response was similar to those of members in the A-1 subgroup and different from those of other members in the A-5 subgroup, suggesting that the GmDREB3 gene was involved in an ABA-independent cold stress-responsive signal pathway. Furthermore, analysis of the GmDREB3 promoter elucidated its cold-induced modulation. A promoter fragment containing bases −1058 to −664 was involved in response to cold stress, and its effect was detected for 1 h after treatment, but a transcriptional repressor appeared to impair this response by binding to a cis-element in the region −1403 to −1058 at 24 h after the beginning of cold stress. Moreover, the GmDREB3 protein could specifically bind to the DRE element in vitro, and activated expression of downstream reporter genes in yeast cells. In addition, overexpression of GmDREB3 enhanced tolerance to cold, drought, and high salt stresses in transgenic Arabidopsis. Physiological analyses indicated that the fresh weight and osmolality of GmDREB3 transgenic Arabidopsis under cold stress were higher than those of wild-type controls. GmDREB3 transgenic tobacco accumulated higher levels of free proline under drought stress and retained higher leaf chlorophyll levels under high salt stress than wild-type tobacco. In addition, constitutive expression of GmDREB3 in transgenic Arabidopsis caused growth retardation, whereas its expression under control of the stress-inducible Rd29A promoter minimized negative effects on plant growth under normal growth conditions, indicating that a combination of the Rd29A promoter and GmDREB3 might be useful for improving tolerance to environmental stresses in crop plants