First-line camrelizumab (a PD-1 inhibitor) plus apatinib (an VEGFR-2 inhibitor) and chemotherapy for advanced gastric cancer (SPACE): a phase 1 study.

Patients with advanced gastric cancer typically face a grim prognosis. This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma. The primary endpoints included maximum tolerated dose (MTD) in phase 1a and objective response rate (ORR) across phase 1a and 1b. Phase 1a tested three dose regimens of camrelizumab, apatinib, oxaliplatin, and S-1. Dose regimen 1: camrelizumab 200 mg on day 1, apatinib 250 mg every other day, oxaliplatin 100 mg/m² on day 1, and S-1 40 mg twice a day on days 1-14. Dose regimen 2: same as dose regimen 1, but oxaliplatin 130 mg/m². Dose regimen 3: same as dose regimen 2, but apatinib 250 mg daily. Thirty-four patients were included (9 in phase 1a, 25 in phase 1b). No dose-limiting toxicities occurred so no MTD was identified. Dose 3 was set for the recommended phase 2 doses and administered in phase 1b. The confirmed ORR was 76.5% (95% CI 58.8-89.3). The median progression-free survival was 8.4 months (95% CI 5.9-not evaluable [NE]), and the median overall survival (OS) was not mature (11.6-NE). Ten patients underwent surgery after treatment and the multidisciplinary team evaluation. Among 24 patients without surgery, the median OS was 19.6 months (7.8-NE). Eighteen patients (52.9%) developed grade ≥ 3 treatment-emergent adverse events. Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer (ChiCTR2000034109).

Changes in Chemical Composition of Flaxseed Oil during Thermal-Induced Oxidation and Resultant Effect on DSC Thermal Properties.

To investigate the changes in chemical composition of flaxseed oil during thermal-induced oxidation and the resultant effect on thermal properties, samples with different oxidation levels were obtained by being heated at 180 °C for two hours and four hours. The oxidation degree was evaluated using peroxide value (PV), extinction coefficient at 232 nm and 268 nm (K232 and K268), and total polar compounds (TPC). Using chromatography, the fatty acid profile and triacylglycerol (TAG) profile were examined. Differential scanning calorimetry (DSC) was used to determine the crystallization and melting profiles. Thermal-induced oxidation of flaxseed oil led to a significant increase (p < 0.05) in PV, K232, K268, and TPC, but the relative content of linolenic acid (Ln) and LnLnLn reduced dramatically (p < 0.05). TPC derived from lipid degradation affected both crystallization and melting profiles. Statistical correlations showed that the onset temperature (Ton) of the crystallization curve was highly correlated with K232, TPC, and the relative content of LnLnLn (p < 0.05), whereas the offset temperature (Toff) of the melting curve was highly correlated with the relative content of most fatty acids (p < 0.05). This finding provides a new way of rapid evaluation of oxidation level and changes of chemical composition for flaxseed oils using DSC.

Effect of Apatinib Plus Pegylated Liposomal Doxorubicin vs Pegylated Liposomal Doxorubicin Alone on Platinum-Resistant Recurrent Ovarian Cancer: The APPROVE Randomized Clinical Trial.

Importance: There are substantial unmet therapeutic needs in patients with platinum-resistant recurrent ovarian cancer (PROC), and novel therapeutic strategies should be explored. Objective: To evaluate the efficacy and safety of treatment with apatinib (a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor) plus pegylated liposomal doxorubicin (PLD) for PROC. Design, Setting, and Participants: The APPROVE trial was performed as an open-label, randomized clinical trial at 11 hospitals in China between March 22, 2018, and November 16, 2020. Patients with histologically confirmed ovarian cancer who had experienced disease progression during or within 6 months of discontinuing any prior line of treatment with platinum-based chemotherapy were eligible. This primary analysis was based on data that were current as of January 28, 2021. Interventions: Patients received PLD alone (40 mg/m2, intravenously, every 4 weeks, for up to 6 cycles) or PLD plus apatinib (250 mg, orally, daily). Main Outcomes and Measures: The primary end point was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, in the intent-to-treat population. Results: In total, 152 female patients were randomized, with 78 (51.3%) in the apatinib plus PLD group (median age, 54 years; range, 22-76 years) and 74 (48.7%) in the PLD group (median age, 56 years; range, 33-72 years). The median follow-up duration was 8.7 months (IQR, 4.7-14.1 months). The median PFS was 5.8 months (95% CI, 3.8-8.8) for treatment with apatinib plus PLD vs 3.3 months (95% CI, 2.1-3.8) for PLD (hazard ratio, 0.44; 95% CI, 0.28-0.71; P < .001). The median overall survival was 23.0 months (95% CI, 18.9 to not reached) with treatment with apatinib plus PLD vs 14.4 months (95% CI, 12.1-23.4) with PLD (hazard ratio, 0.66; 95% CI, 0.40-1.09). The most frequent grade 3 or higher treatment-emergent adverse events were decreased neutrophil counts (11 [14.9%] in the apatinib plus PLD group vs 6 [8.3%] in the PLD group), hypertension (6 [8.1%] vs none), and decreased white blood cell count (5 [6.8%] vs 3 [4.2%]). Two patients receiving treatment with apatinib plus PLD experienced grade 2 fistulas. Conclusions and Relevance: This randomized clinical trial found that treatment with apatinib plus PLD showed promising efficacy and manageable toxic effects in patients with PROC and may be a new alternative treatment option in this setting. Trial Registration: Clinicaltrials.gov Identifier: NCT04348032.

A Phase III Multicenter Randomized Clinical Trial of 60 Gy versus 50 Gy Radiation Dose in Concurrent Chemoradiotherapy for Inoperable Esophageal Squamous Cell Carcinoma.

PURPOSE: In this multicenter phase 3 trial, the efficacy and safety of 60 Gy and 50 Gy doses delivered with modern radiotherapy technology for definitive concurrent chemoradiotherapy (CCRT) in patients with inoperable esophageal squamous cell carcinoma (ESCC) were evaluated. PATIENTS AND METHODS: Patients with pathologically confirmed stage IIA‒IVA ESCC were randomized 1:1 to receive conventional fractionated 60 Gy or 50 Gy to the tumor and regional lymph nodes. Concurrent weekly chemotherapy (docetaxel 25 mg/m2; cisplatin 25 mg/m2) and two cycles of consolidation chemotherapy (docetaxel 70 mg/m2; cisplatin 25 mg/m2 days 1‒3) were administered. RESULTS: A total of 319 patients were analyzed for survival, and the median follow-up was 34.0 months. The 1- and 3-year locoregional progression-free survival (PFS) rates for the 60 Gy group were 75.6% and 49.5% versus 72.1% and 48.4%, respectively, for the 50 Gy group [HR, 1.00; 95% confidence interval (CI), 0.75‒1.35; P = 0.98]. The overall survival rates were 83.7% and 53.1% versus 84.8% and 52.7%, respectively (HR, 0.99; 95% CI, 0.73‒1.35; P = 0.96), whereas the PFS rates were 71.2% and 46.4% versus 65.2% and 46.1%, respectively (HR, 0.97; 95% CI, 0.73‒1.30; P = 0.86). The incidence of grade 3+ radiotherapy pneumonitis was higher in the 60 Gy group (nominal P = 0.03) than in the 50 Gy group. CONCLUSIONS: The 60 Gy arm had similar survival endpoints but a higher severe pneumonitis rate compared with the 50 Gy arm. Fifty Gy should be considered as the recommended dose in CCRT for ESCC.

Deletion of the MBP1 Gene, Involved in the Cell Cycle, Affects Respiration and Pseudohyphal Differentiation in Saccharomyces cerevisiae.

Mbp1p is a component of MBF (MluI cell cycle box binding factor, Mbp1p-Swi6p) and is well known to regulate the G1-S transition of the cell cycle. However, few studies have provided clues regarding its role in fermentation. This work aimed to recognize the function of the MBP1 gene in ethanol fermentation in a wild-type industrial Saccharomyces cerevisiae strain. MBP1 deletion caused an obvious decrease in the final ethanol concentration under oxygen-limited (without agitation), but not under aerobic, conditions (130 rpm). Furthermore, the mbp1Δ strain showed 84% and 35% decreases in respiration intensity under aerobic and oxygen-limited conditions, respectively. These findings indicate that MBP1 plays an important role in responding to variations in oxygen content and is involved in the regulation of respiration and fermentation. Unexpectedly, mbp1Δ also showed pseudohyphal growth, in which cells elongated and remained connected in a multicellular arrangement on yeast extract-peptone-dextrose (YPD) plates. In addition, mbp1Δ showed an increase in cell volume, associated with a decrease in the fraction of budded cells. These results provide more detailed information about the function of MBP1 and suggest some clues to efficiently improve ethanol production by industrially engineered yeast strains. IMPORTANCE Saccharomyces cerevisiae is an especially favorable organism used for ethanol production. However, inhibitors and high osmolarity conferred by fermentation broth, and high concentrations of ethanol as fermentation runs to completion, affect cell growth and ethanol production. Therefore, yeast strains with high performance, such as rapid growth, high tolerance, and high ethanol productivity, are highly desirable. Great efforts have been made to improve their performance by evolutionary engineering, and industrial strains may be a better start than laboratory ones for industrial-scale ethanol production. The significance of our research is uncovering the function of MBP1 in ethanol fermentation in a wild-type industrial S. cerevisiae strain, which may provide clues to engineer better-performance yeast in producing ethanol. Furthermore, the results that lacking MBP1 caused pseudohyphal growth on YPD plates could shed light on the development of xylose-fermenting S. cerevisiae, as using xylose as the sole carbon source also caused pseudohyphal growth.

Risk assessment approaches for evaluating cumulative exposures to multiple pesticide residues in agro-products using seasonal vegetable monitoring data from Hainan, China: a case study.

Risks from combined exposure to multiple chemicals in food have prompted a growing concern for their effect on human health. Risk management of chemical mixtures should be based on developing and harmonizing methodologies to scientifically evaluate their cumulative adverse effects. In this study, a simplified tiered approach of cumulative exposure assessment is described along with a case study of vegetables in China's Hainan province during 2012-2014. This case study could be a reference for the Chinese National Risk Assessment Programs for vegetable and fruit products. In the proposed assessment approach, Tier 1 acts as a screening tier to categorize and evaluate chemicals under a conservative scenario, and it prioritizes the pesticides of most concern. Tier 2 refines the grouping of substances from Tier 1 and normalizes the toxic potency of the chemicals to sum the exposure of chemical mixtures in a given assessment group. Tier 3 applies the refined exposure model and the input parameter distribution to create probabilistic models using Monte Carlo simulation. This approach will be helpful in the cumulative exposure assessment where data on pesticide residues are sufficient, but the individual dietary consumption is inadequate.

Enhanced ethanol production from sugarcane molasses by industrially engineered Saccharomyces cerevisiae via replacement of the PHO4 gene.

Replacement of a novel candidate ethanol fermentation-associated regulatory gene, PHO4, from a fast-growing strain MC15, as determined through comparative genomics analysis among three yeast strains with significant differences in ethanol yield, is hypothesised to shorten the fermentation time and enhance ethanol production from sugarcane molasses. This study sought to test this hypothesis through a novel strategy involving the transfer of the PHO4 gene from a low ethanol-producing, yet fast-growing strain MC15 to a high ethanol-producing industrial strain MF01 through homologous recombination. The results indicated that PHO4 in the industrially engineered strain MF01-PHO4 displayed genomic stability with a mean maximum ethanol yield that rose to 114.71 g L-1, accounting for a 5.30% increase in ethanol yield and 12.5% decrease in fermentation time in comparison with that in the original strain MF01, which was the current highest ethanol-producing strain in SCM fermentation in the reported literature. These results serve to advance our current understanding of the association between improving ethanol yield and replacement of PHO4, while providing a feasible strategy for industrially engineered yeast strains to improve ethanol production efficiently.

Lack of associations between the FTO polymorphisms and gestational diabetes: A meta-analysis and trial sequential analysis.

BACKGROUND: Molecular epidemiological studies have sought associations between Fat mass and obesity associated (FTO) gene polymorphisms and gestational diabetes mellitus (GDM) risk, but findings are inconsistent. Hence, we performed a meta-analysis to clarify this problem. METHODS: Case-control studies reporting the relationship of three FTO polymorphisms (rs9939609, rs8050136, and rs1421085) and GDM published before June 2018 were searched in 6 electronic databases such as PubMed and Embase. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Trial sequential analysis (TSA) was performed to evaluate the type 1 and type 2 errors. RESULTS: A total of 5 studies involving 703 GDM cases and 2700 controls for rs9939609, 3 studies involving 1144 GDM cases and 909 controls for rs8050136, and 2 studies involving 207 GDM cases and 205 controls for rs1421085, were included in the meta-analysis. No association was observed between the three polymorphisms with the GDM risk under all genetic models. For example, the ORs and its 95% CIs under dominant genetic model were 0.88 (0.59, 1.33) for rs9939609, 1.11 (0.91, 1.35) for rs8050136, and 0.91 (0.58, 1.41) for rs1421085, respectively. Under TSA, there are insufficient levels of evidence for all of these three polymorphisms. CONCLUSION: The present meta-analysis provides statistical evidence indicating a lack of association between FTO polymorphismsand GDM risk. More studies with larger sample size are needed to confirm these null associations.

Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation-Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF).

BACKGROUND: Obstructive sleep apnea (OSA) is common in patients with atrial fibrillation (AF). Little is known about the impact of OSA on AF treatment and long-term outcomes. We studied whether patients with OSA have a greater likelihood of progressing to more persistent forms of AF or require more hospitalizations and/or worse outcomes compared with patients without OSA. METHODS: A total of 10,132 patients were enrolled between June 2010 and August 2011 in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) and followed for up to 2 years. The prevalence of OSA and continuous positive airway pressure (CPAP) treatment was captured at baseline. The association between OSA and major cardiovascular outcomes was analyzed using multivariable hierarchical logistic regression modeling and Cox frailty regression model. RESULTS: Of the 10,132 patients with AF, 1,841 had OSA. Patients with OSA were more symptomatic (22% vs 16% severe/disabling symptoms; P < .0001) and more often on rhythm control therapy (35% vs 31%; P = .0037). In adjusted analyses, patients with OSA had higher risk of hospitalization (hazard ratio [HR], 1.12; 95% CI, 1.03-1.22; P = .0078), but no difference in the risks of death (HR, 0.94; 95% CI, 0.77-1.15; P = .54); the composite of CV death, myocardial infarction, and stroke/transient ischemic attack (HR, 1.07; 95% CI, 0.85-1.34; P = .57); major bleeding (HR, 1.18; 95% CI, 0.96-1.46; P = .11); or AF progression (HR, 1.06; 95% CI, 0.89-1.28; P = .51). Patients with OSA on CPAP treatment were less likely to progress to more permanent forms of AF compared with patients without CPAP (HR, 0.66; 95% CI, 0.46-0.94; P = .021). CONCLUSION: Compared with those without, AF patients with OSA have worse symptoms and higher risks of hospitalization, but similar mortality, major adverse cardiovascular outcome, and AF progression rates. CLINICAL TRIAL REGISTRATION: NCT01165710 (http://www.clinicaltrials.gov).

Label-free monitoring of T cell activation by the impedance-based xCELLigence system.

T cells play a critical role in maintaining the normal function of the adaptive immune response, with their dysfunction resulting in a variety of autoimmune and immunodeficiency diseases. Efficient and accurate detection of T cell function is therefore crucial to clinical diagnosis and development of immunomodulators. A variety of in vitro cellular systems are currently employed for analyzing T cell activation, yet all suffer from some combination of low throughput, unnatural conditions and long assay times. Label-free technologies are capable of detecting phenotypic responses to treatments under physiological conditions, thereby potentially accelerating drug discovery by facilitating the use of disease-relevant cell models for functional assessment and clinical diagnosis. The xCELLigence system is an impedance based label-free platform that allows for dynamic monitoring of subtle morphological and adhesive changes in cells, such as those induced during T cell activation. Here we describe the development and validation of a T cell activation assay based upon electrical impedance. Co-activation of Jurkat cells with anti-CD28 and anti-CD3 functional antibodies led to impedance changes that were rapidly and sensitively recorded (within 30 minutes). This phenomenon was also observed in human peripheral blood mononuclear cells. These changes reflect morphological and adhesive alterations correlated with cytoskeletal reorganization as verified by microscopy. They were functionally dependent on canonical T cell signaling pathways, including calcium-mediated signals and Src family kinases because relevant inhibitors impaired T cell activation. Our results provide a convenient approach to measure T cell activation in real-time and to elucidate the underlying mechanisms of action through probing with small molecules.

Dynamic monitoring of ß-cell injury with impedance and rescue by glucagon-like peptide-1.

ß-Cell injury plays an important role in the development of type 1 and type 2 diabetes. Most of the ß-cell bioassays depend on labeling or endpoint assessments that might not capture the true physiology or pathology of the injury process. In the current study, we dynamically detected a broad range of pathological and pharmacological responses to four toxicants (cytokine mixture, free fatty acid mixture, streptozotocin, and hydrogen peroxide) in living ß-cells (INS-1E and MIN6) by a label-free, cell-based assay system named xCELLigence, codeveloped by ACEA Biosciences and Roche Diagnostics. Our results suggest that the impedance readout is highly sensitive and provides more information than some of the conventional endpoint cytotoxicity assays for ß-cell injury such as the Cell Counting Kit-8 (CCK-8) and morphology measurements. Furthermore, this system was used to evaluate the anti-injury effects of glucagon-like peptide-1 (GLP-1) and its nonpeptidic mimetic Boc5 by monitoring responses to four toxicants in two ß-cell lines. This study confirms that the protective property of Boc5 on ß-cells is similar to that of GLP-1.

A continued saga of Boc5, the first non-peptidic glucagon-like peptide-1 receptor agonist with in vivo activities.

Glucagon-like peptide-1 (GLP-1)-based therapy presents a promising option for treating type 2 diabetes. However, there are several limitations relative to the peptidic GLP-1 mimetics currently on the market or under development. This concern has led to a continued interest in the search for non-peptidic agonists for GLP-1 receptor (GLP-1R). Here, we briefly review the discovery, characterization and current status of a novel class of cyclobutane-derivative-based non-peptidic agonists for GLP-1R, including Boc5 and its newly discovered analogue WB4-24. Although the oral bioavailability of such compounds still poses great challenges, the progress made so far encourages us to identify a truly 'druggable' small molecule agonist for GLP-1R.

Initial analysis of the hemocyanin subunit type 1 (Hc1 gene) from Locusta migratoria manilensis.

Hemocyanins are copper-containing (Cu(+)) proteins that transport oxygen in many arthropods hemolymph. We characterized Hc1 gene from the grasshopper species Locusta migratoria manilensis. In particular, we cloned and sequenced the corresponding cDNAs and studied their expression at different developmental stages. The cDNA of Hc1 gene (GenBank accession no.:HQ213937) is 2271 bp in length and the open reading frame is 2016 bp, which encodes a 672 amino acids protein with a calculated molecular mass of 77.9 kD and the isoelectric point of 6.06. Sequence alignment analysis result showed that this gene shares 94.7% identity with Schistocerca americana EHP. In addition, analysis of quantitative RT-PCR indicated that, LmiHc1 was expressed in the embyro (24, 39, 62, 86, 144, and 193 h after hatch), nymphs (1st instar, 2nd instar, 3rd instar, 4th instar and 5th instar) and in adult. These results showed that Hc1 plays an important role in grasshopper, which may be related to an enhanced oxygen supply. Phylogenetic analysis of insecta based on Hc1 are basically consistent with the morphology.

Effects of a maternal diet supplemented with chocolate and fructose beverage during gestation and lactation on rat dams and their offspring.

1. Consumption of a high-fat and high-energy diet during pregnancy leads to a risk of long-term consequences on fetal development, as well as on the postnatal health of offspring. To investigate the effects of such a diet on fetal programming, we established a high-energy intake pregnant rat model using chocolate and fructose beverage as supplements to a normal chow diet. 2. Pregnant Sprague-Dawley rats were assigned to either chow (control) or a diet supplemented with chocolate and fructose beverage throughout gestation and lactation. The male F(1) pups received normal chow diet after weaning. Physiological or pathological changes in dams and pups (e.g. glucose and lipid metabolism) were evaluated. 3. The results showed that dams offered the high-fat (mainly from chocolate) and high-calorie diet during gestation consumed more energy and gained more weight than chow-fed dams. Over-consumption of chocolate reduced chow intake in dams, leading to low maternal protein supply. As a result, pups from these dams exhibited reduced birth weight that lasted until adulthood. The high-energy diet during lactation led to increased total body fat, as well as impaired liver function, in offspring; thus, the lactational diet is suggested to be a stronger determinant of offspring fat metabolism than gestational diet. 4. The results of the study suggest that over-supply of carbohydrates, such as chocolate and fructose, either during gestation or lactation has a negative impact on the well-being of offspring.