Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

How does the online innovation community climate affect the user's value co-creation behavior: The mediating role of motivation.

Online Innovation Community (OIC) serves as a virtual space for users to exchange products and services, and share knowledge and information. Previous studies have indicated that community climate is an important factor affecting users' value co-creation behavior, however, the influencing process has not been clearly revealed from the perspective of motivation. In this study, we explored the relationship between online innovation community climate (supportive climate and controlling climate), user motivation and value co-creation behavior (user's participation behavior and user's citizenship behavior) based on the SOR model. The study sample included 29,835 pieces of information from 3,315 users in 14 product sections of the OnePlus Community which were analyzed with Mplus8.1. The findings revealed that: (1) The supportive climate had a positive impact on user's citizenship behavior(ß = 0.042), while the controlling climate exerted a significant positive impact on user's citizenship behavior (ß = 0.078) and user's participation behavior(ß = 0.099); (2) The need for achievement played a suppressing effect between community climate and user's participation behavior, the need for power played a suppressing effect between supportive climate and user's value co-creation behavior, and the need for affiliation played a mediating role between supportive climate and user's citizenship behavior (ß = 0.010) and user's participation behavior(ß = 0.006); (3) Community trust positively moderated the relationship between the need for achievement and user's participation behavior(ß = 0.058) as well as between the need for power and user's participation behavior(ß = 0.043).

Methylated ctDNA predicts early recurrence risk in patients undergoing resection of initially unresectable colorectal cancer liver metastases.

Background: Patients with initially unresectable colorectal cancer liver metastases (IU-CRLM) might benefit from using an effective systemic treatment followed by resection of liver metastases but the curative success rate is quite low. Indeed, nearly one-third of patients exhibit early recurrence within the first 6 months after surgery, and these individuals often have poor overall survival. Objectives: This study aims to clarify the application value of serial circulating tumor DNA (ctDNA) analysis in predicting the clinical outcome of IU-CRLM patients following liver metastasectomy. Design: A retrospective study was conducted on a cohort of patients with IU-CRLM between February 2018 and April 2021. Methods: Plasma samples at different time points during CRLM treatment [baseline (BL), preoperation (PRE), postoperation (POST), end-of-treatment (EOT), and progressive disease (PD)] were retrospectively collected from patients with initially unresectable CRLM enrolled at the Sun Yat-sen University Cancer Center. Dynamic changes of SEPTIN 9 (SEPT9) and Neuropeptide Y (NPY) methylated circulating tumor DNA (MetctDNA) levels in serial plasma samples were detected using droplet-digital PCR (ddPCR). Results: SEPT9 and NPY genes were hypermethylated in colon cancer cell lines and tissues while no difference was observed between primary and metastatic tumors. Patients with MetctDNA positive at POST or EOT had significantly lower recurrence-free survival (RFS) compared to patients with MetctDNA negative at these time points [POST: Hazard ratio (HR) 9.44, 95% confidence interval (CI) 5.15-17.30, p < 0.001; EOT: HR 11.48, 95% CI 3.27-40.31, p < 0.001]. Multivariate analysis demonstrated that POST (OR 33.96, 95% CI 4.03-286.10, p = 0.001) and EOT (OR 18.36, 95% CI 1.14-295.71, p = 0.04) MetctDNA was an independent risk factor for early recurrence. Time-dependent receiver operating characteristic curve (T-ROC) analysis revealed that area under the curve (AUC) value was greatest at the relapse time point of 6 months post-intervention, with POST-AUC and EOT-AUC values of 0.74 (95% CI 0.66-0.81) and 0.73 (95% CI 0.53-0.94), respectively. Serial MetctDNA analysis showed that RFS was significantly lower in patients with no MetctDNA clearance compared with those with MetctDNA clearance (HR 26.05, 95% CI 4.92-137.81, p < 0.001). Conclusion: Our study confirmed that serial ctDNA analysis of NPY and SEPT9 gene methylation could effectively predict early recurrence in IU-CRLM patients, especially at POST and EOT.

Effects of Cu (II) on the Growth of Chlorella vulgaris and Its Removal Efficiency of Pollutants in Synthetic Piggery Digestate.

C. vulgaris has a positive effect on the removal of nutrients from pig farm biogas slurry. However, swine wastewater often contains heavy metal ions, such as Cu (II), which may have impacts on the nutrient removal performance of C. vulgaris. Additionally, the heavy metal ions in wastewater can be adsorbed by microalgae. In this study, the stress effect of Cu (II) on the growth of Chlorella vulgaris, the Cu (II) removal by microalgae, and the effect of different concentrations of Cu (II) on the nutrient removal efficiency of C. vulgaris in biogas slurries were explored. The results showed that the microalgae biomass of microalgae on the sixth day of the experiment was the highest in the treatment with a Cu (II) concentration of 0.5 mg/L, which was 30.1% higher than that of the 2.5 mg/L group. C. vulgaris had higher removal efficiencies of Cu (II) at a Cu (II) concentration of 0.1~1.5 mg/L. The-OH, C=O, -COOH, and C-O groups on the surface of the algal cells play a significant role in the removal of Cu (II). The removal rates of COD, NH3-N, TN, and TP by C. vulgaris at a Cu (II) concentration of 0.5 mg/L were the highest, which were 89.0%, 53.7%, 69.6%, and 47.3%, respectively.

A 3-Year Survival Update from a Phase 2 Study of Paclitaxel Plus Cisplatin and 5-Fuorouracil Induction Chemotherapy for Locally Advanced Borderline-Resectable Esophageal Squamous Cell Carcinoma: The NEOCRTEC-1601 Clinical Trial.

BACKGROUND: This study updated 3-year analyses to further characterize the impact of docetaxel, cisplatin, and fluorouracil (TPF) chemotherapy followed by surgery. METHODS: This study was a single-center phase 2 clinical trial. Patients with a diagnosis of borderline resectable esophageal squamous cell carcinoma (BR-ESCC) because of the primary tumor or bulky lymph node that potentially invaded adjacent organs were eligible. The treatment started with TPF chemotherapy followed by surgery if the cancer was resectable, or by concurrent chemoradiation if it was unresectable. This updated report presents the 3-year overall survival (OS) and progression-free survival (PFS) rates. RESULTS: Surgery was performed for 27 patients (57.4%), and R0 resection was confirmed in 25 patients (53.2%). Pathologic complete response was confirmed in four patients (8.5%). The median follow-up time for the surviving patients was 44.8 months (range, 3.4-74.6 months). The median OS for all the patients was 41.9 months (95% confidence interval [CI], 18.6-65.3 months), with a median PFS of 38.7 months (95% CI, 23.5-53.9 months). The 3-year survival rate for all the patients was 54.4%. The 3-year survival rate for the R0 patients was 65.4%. CONCLUSION: Long-term follow-up evaluation confirmed that TPF followed by surgery is feasible and promising in terms of survival for BR-ESCC patients. Trial Registration ClinicalTrials.gov identifer: NCT02976909.

Comparative effectiveness and safety for the treatments despite optimized renin-angiotensin system blockade among IgA nephropathy patients at high-risk of disease progression: A network meta-analysis of randomized controlled trials.

OBJECTIVE: Approximately 20-40% of IgA nephropathy patients would develop end-stage renal disease, for whom safety concerns remained a major setback when using conventional pharmaceutical treatments. Evidence is lacking for optimal selection of effective and safe pharmaceuticals to slow the disease progression. To compare the effectiveness and safety profile of different treatments despite optimized RAS blockade for IgA nephropathy patients at high-risk of disease progression. STUDY DESIGN: PubMed, ScienceDirect and Web of science databases published from 1990 to March 18th, 2023 without language restriction. Immunosuppressant and cortico-steroid treatments were considered as two independent regimens. RESULTS: Fifteen trials with 1,983 participants were evaluated for the occurrence of five outcomes. For ESRD, dapagliflozin was superior to placebo (RR: 0.30; 95% CI 0.11, 0.80), immunosuppressant (RR:0.14; 95% CI 0.02,0.81) and RAS (RR:0.10; 95% CI 0.01,0.69). Glucocorticoid was superior to placebo (RR: 0.71; 95%CI 0.52,0.99). For clinical remission, immunosuppressant was superior to placebo (RR: 2.71; 95%CI 1.16, 6.31) and RAS monotherapy (RR: 2.87; 95%CI 1.60, 5.17). For 50% reduction in 24 h proteinuria or UPCR, immunosuppressant was superior to placebo (RR: 2.71; 95%CI 1.16, 6.31) and RAS monotherapy (RR: 2.40; 95%CI 1.04, 5.55). For SAE, dapagliflozin was superior to glucocorticoid (RR: 0.22; 95%CI 0.09, 0.54), whereas glucocorticoid was inferior to placebo (RR: 2.91; 95%CI 1.39, 6.07). Cluster ranking showed dapagliflozin appeared to have the lowest SAE risk and the best comparative therapeutic efficacy in preventing ESRD. CONCLUSIONS: The current findings highlighted dapagliflozin was a promising pharmaceutical treatment alternative to achieve optimal outcomes for IgA nephropathy patients at high risk of disease progression. REGISTRATION: PROSPERO CRD42022374418.

Full-length 16S rRNA gene sequencing and machine learning reveal the bacterial composition of inhalable particles from two different breeding stages in a piggery.

Bacterial loading aggravates the harm of particulate matter (PM) to public health and ecological systems, especially in operations of concentrated animal production. This study aimed to explore the characteristics and influencing factors of bacterial components of inhalable particles at a piggery. The morphology and elemental composition of coarse particles (PM10, aerodynamic diameter ≤ 10 µm) and fine particles (PM2.5, aerodynamic diameter ≤ 2.5 µm) were analyzed. Full-length 16 S rRNA sequencing technology was used to identify bacterial components according to breeding stage, particle size, and diurnal rhythm. Machine learning (ML) algorithms were used to further explore the relationship between bacteria and the environment. The results showed that the morphology of particles in the piggery differed, and the morphologies of the suspected bacterial components were elliptical deposited particles. Full-length 16 S rRNA indicated that most of the airborne bacteria in the fattening and gestation houses were bacilli. The analysis of beta diversity and difference between samples showed that the relative abundance of some bacteria in PM2.5 was significantly higher than that in PM10 at the same pig house (P < 0.01). There were significant differences in the bacterial composition of inhalable particles between the fattening and gestation houses (P < 0.01). The aggregated boosted tree (ABT) model showed that PM2.5 had a great influence on airborne bacteria among air pollutants. Fast expectation-maximization microbial source tracking (FEAST) showed that feces was a major potential source of airborne bacteria in pig houses (contribution 52.64-80.58 %). These results will provide a scientific basis for exploring the potential risks of airborne bacteria in a piggery to human and animal health.

Rapid Start-Up Characteristics of Anammox under Different Inoculation Conditions.

The long multiplication time and extremely demanding enrichment environment requirements of Anammox bacteria (AAOB) have led to difficult reactor start-ups and hindered its practical dissemination. Few feasibility studies have been reported on the recovery of AAOB activity initiation after inlet substrate disconnection caused by an unfavorable condition, and few factors, such as indicators of the recovery process, have been explored. Therefore, in this experiment, two modified expanded granular sludge bed reactors (EGSB) were inoculated with 1.5 L anaerobic granular sludge (AGS) + 1 L Anammox sludge (AMS) (R1) and 2.5 L anaerobic granular sludge (AGS) (R2), respectively. After a long-term (140 days) starvation shock at a high temperature (38 °C), the bacteria population activity recovery experiments were conducted. After 160 days, both reactors were successfully started up, and the total nitrogen removal rates exceeded 87%. Due to the experimental period, the total nitrogen removal rate of R2 was slightly higher than that of R1 in the final stage. However, it is undeniable that R2 had a relatively long activity delay during startup, while R1 had no significant activity delay during startup. The sludge obtained from R1 had a higher specific anammox activity (SAA). Analysis of the extracellular polymer substances (EPS) results showed that the extracellular polymer content in R1 was higher than that in R2 throughout the recovery process, indicating that R1 had higher sludge stability and denitrification performance. Scanning electron microscopy (SEM) analysis showed that more extracellular filamentous bacteria could be seen in the R1 reactor with better morphology of Anammox bacteria. In contrast, the R2 reactor had fewer extracellular hyphae and micropores as a percentage and higher filamentous bacteria content. The results of microbial 16SrDNA analysis showed that R1 used AAOB as inoculum to initiate Anammox, and the reactor was enriched with Anammox bacteria earlier and in much greater abundance than R2. The experimental results indicated that inoculating mixed anaerobic granular sludge and Anammox sludge to initiate an anammox reactor was more effective.

Conflict or Collaboration-The Impact of Knowledge Endowment Heterogeneity on Remix in Open Collaborative Communities.

With the emergence of online open platforms and communities, remix has drawn much attention as an essential source of innovation whereby the knowledge endowment of online community users plays a crucial role. This study constructs a structural equation model to explore the impact of user knowledge endowment heterogeneity on remix through the mediating effect of their collaborative psychology. In this empirical study, we collected 25,032 pieces of data from Thingiverse (a 3D printing community) users and their published designs. The findings are as follows. Explicit knowledge endowment heterogeneity has a positive impact on the quantity of remix but a negative impact on its quality. Likewise, the implicit knowledge endowment heterogeneity positively affects the quantity of remix but has no significant effect on its quality. Users' conflicting psychology plays a mediating role between knowledge endowment heterogeneity and remix, while their collaborative psychology negatively mediates merely between explicit knowledge endowment heterogeneity and remix quality. By unraveling the relationship between user knowledge endowment heterogeneity, collaborative psychology, and remix, this study is significant in understanding users' remix process in open collaborative communities and illuminating their psychological mechanism in this process.

Removal of microorganisms and antibiotic resistance genes from swine wastewater: a comparison between polyaluminum chloride (PAC), polyaluminum sulfate (LST), and aluminum hydroxide iron (LT).

The presence of antibiotic-resistant bacteria (ARB) and antibiotic-resistance genes (ARGs) in swine wastewater may present a threat to the environment and public health. Conventional swine wastewater treatment processes generally fail to effectively reduce the content of ARGs. Therefore, it is necessary to develop a highly efficient and low-cost treatment method to solve this environmental problem. In doing so, we evaluated the application of three common coagulants in the treatment of swine wastewater. Using metagenomics, we evaluated the removal efficiency of ARG loads, as well as the effect of coagulation on the structure and diversity of swine wastewater, and on the bacterial community. The results showed that the three coagulants could effectively reduce the physicochemical pollution indexes of swine wastewater (e.g., TP, NTU, COD). After treatment, the loads of a variety of antibiotics in the swine wastewater were significantly reduced, with the exception of NFX and SMD, which were all close to 100%. At the same time, in evaluating the total number of microbial colonies and the total number of fecal Escherichia coli bacteria under the three conditions, Polyaluminum Chloride (PAC) ranked first among the three coagulants with 89.18%, 93.07%, 89.92%, 98.76%, 99.60%, and 98.68%. Metagenomic analysis revealed that the abundance of cfcC, tetX, mphE, msrE, tet36, and other ARGs in the water sample after the LST treatment was significantly lower than that of the original swine wastewater sample. These findings demonstrate the feasibility of using coagulants to treat swine wastewater, which is of great significance for improving water quality and reducing the potential impacts of ARGs.

CERS6-AS1 contributes to the malignant phenotypes of colorectal cancer cells by interacting with miR-15b-5p to regulate SPTBN2.

Accumulating evidence indicates that long noncoding RNAs (lncRNAs) act as tumor promoters or suppressors in various types of cancer. Previous investigations suggest that ceramide synthase 6 (CERS6) antisense RNA 1 (CERS6-AS1) acts as an oncogene in breast cancer; however, its role in colorectal cancer is unknown. This study aimed to explore the molecular mechanism of CERS6-AS1 in colorectal cancer. Gene expression in colorectal cancer was examined using reverse transcription-quantitative polymerase chain reaction and western blot analyses. The viability and proliferation of colorectal cancer cells were measured by Cell Counting Kit-8 assays and colony formation assays. The migratory and invasive capacities of the colorectal cancer cells were assessed by Transwell assay. Cell stemness was examined by sphere-formation assay. Mechanistically, RNA pull-down assays, RNA immunoprecipitation assays, and luciferase reporter assays were performed to explore the relationship among CERS6-AS1, miR-15b-5p and spectrin beta, non-erythrocytic 2 (SPTBN2). Moreover, a xenograft tumor model was established to investigate the role of CERS6-AS1 in vivo. We found that CERS6-AS1 and SPTBN2 were highly expressed in colorectal cancer tissues and cells. CERS6-AS1 depletion inhibited cell viability, proliferation, migration, and invasion; the epithelial-mesenchymal transition process and stemness. It suppressed xenograft tumor growth in colorectal cancer. Moreover, SPTBN2 levels were positively regulated by CERS6-AS1 and negatively regulated by miR-15b-5p in colorectal cancer cells. Rescue assays revealed that SPTBN2 reversed the inhibitory effect of CERS6-AS1 deficiency on the malignant behaviors of colorectal cancer cells. Overall, the lncRNA CERS6-AS1 facilitates malignant phenotypes of colorectal cancer cells by targeting miR-15b-5p to upregulate SPTBN2.

Effects of interlayer spacing and oxidation degree of graphene oxide nanosheets on water permeation: a molecular dynamics study.

Graphene oxide (GO) membranes have shown great potential in the applications of water filtration and desalination. The flow behavior and structural properties of water molecules through GO nanochannels are still under debate. In this work, molecular dynamics simulations were performed to explore the effects of interlayer spacing and oxidation degree of GO nanochannels on water transport. The results show that GO nanosheets have strong adsorption capacity. The adsorbed layer of water molecules on GO surface is thermodynamically stable and not easy to flow. When the interlayer spacing falls into the range of 0.6 ~ 1.0 nm, water molecules form into single or double adsorbed layers between two GO nanosheets. When the interlayer spacing is bigger than 1.2 nm, the other water layers in the middle of nanochannel become disordered. Taking the separation performance based on size exclusion into consideration, the most suitable interlayer spacing for water nanofiltration is approximate 1.2 nm, which has one flowing layer of water molecules. Oxygen-containing groups are unfavorable for water permeation, as more and more hydrogen bonds prevent water flowing on GO surface with the increasing oxidation degree. Our simulation results may help to improve the design of GO nanofiltration membranes for water treatment.

Paclitaxel plus cisplatin and 5-fluorouracil induction chemotherapy for locally advanced borderline-resectable esophageal squamous cell carcinoma: a phase II clinical trial.

PURPOSE: This phase II trial aimed to assess the safety and efficacy of paclitaxel in combination with cisplatin and 5-fluorouracil (TPF) induction chemotherapy followed by surgery for locally advanced borderline-resectable esophageal squamous cell carcinoma (BR-ESCC). METHODS: Patients with primary tumor or bulky lymph nodes that might invade nearby organs were eligible. Treatment started with 2-3 cycles of TPF induction chemotherapy, followed by surgery if the tumor was assessed resectable, or by radical concurrent chemoradiotherapy if unresectable. The primary endpoint was pathologically proven complete resection (R0) rate. RESULTS: From July 2014 to February 2019, a total of 47 patients were enrolled. After TPF chemotherapy, 27 patients (57.4%) received surgery and 11 patients (23.4%) received radical concurrent chemoradiotherapy. R0 resection was confirmed in 25 patients (53.2%, 95% confidence interval (CI) 38.9-67.5%). Pathologic complete response was confirmed in four patients (8.5%). The median overall survival (OS) and progression-free survival (PFS) for all patients were 33.3 months and 20.3 months, respectively. The median OS was significantly more favorable in surgery group than in chemoradiotherapy and chemotherapy alone group [33.3 months vs 14.1 months, hazard ratio 0.32 (95% CI 0.12-0.88), p = 0.027]. During induction chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (29.8%), leucopenia (21.3%) and stomatitis (4.3%). No serious postoperative complications were observed in patients undergoing surgery. CONCLUSIONS: The treatment strategy of induction chemotherapy followed by surgery is promising for patients with locally advanced BR-ESCC. To further improve the R0 resection rate, more effective induction chemotherapy regimens need to be explored. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02976909.

Effect of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Women: A Randomized Clinical Trial.

Importance: The prevention of chemotherapy-induced nausea and vomiting has an important role in the overall management of cancer treatment. Objective: To evaluate whether adding aprepitant to palonosetron and dexamethasone can further prevent the incidence and severity of nausea and vomiting caused by FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) chemotherapy regimens among women with gastrointestinal cancer at higher risk. Design, Setting, and Participants: This phase 3, double-blind, placebo-controlled randomized clinical trial recruited young women (age ≤50 years) who drank little or no alcohol and had gastrointestinal cancer for which they received FOLFOX or FOLFIRI chemotherapy. A total of 248 women were enrolled and assigned in the ratio 1:1 to intervention and control groups from August 4, 2015, to March 31, 2020. Intention-to-treat analysis was used to evaluate patient baseline characteristics and efficacy. The analysis was conducted on October 30, 2020. Interventions: Patients were randomly assigned to the aprepitant group (aprepitant, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 6 mg, orally 30 minutes before chemotherapy initiation on day 1) or the placebo group (placebo, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally on each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 12 mg, orally 30 minutes before chemotherapy initiation on day 1). Main Outcomes and Measures: The primary end point was the complete response (CR) rate, defined as the proportion of patients without emesis episodes or rescue medication use during the overall phase of the first cycle. Other efficacy indicators, such as no vomiting and no nausea, were measured as the secondary and exploratory end points. Results: A total of 248 women from 4 clinical centers in China entered this study, and 243 patients (aprepitant regimen, 125 patients [51.4%]; placebo regimen, 118 patients [48.5%]) were evaluable for efficacy and safety; mean (SD) age of the total population was 40.1 (7.3) years. The CR rate was significantly higher in the aprepitant group vs the control group overall (107 [87.0%] vs 80 [66.7%]; P < .001) and in the acute (114 [92.7%] vs 91 [75.8%]; P = .001) and delayed (109 [88.6%] vs 84 [70.0%]; P = .001) phases of the trial. The incidence of adverse events was similar between the 2 groups (100 [80.0%] vs 96 [81.3%]; P = .79), and no grade 3 or 4 aprepitant treatment-related adverse events were observed. Multivariable analysis revealed that aprepitant use was the only independent factor associated with CR during the overall phase. Conclusions and Relevance: The combination of aprepitant with palonosetron and dexamethasone provided increased antiemetic efficacy in the FOLFOX or FOLFIRI chemotherapy regimen and was well tolerated by younger women with gastrointestinal cancer who have a history of little or no alcohol consumption. Trial Registration: ClinicalTrials.gov Identifier: NCT03674294.

Bioequivalence Analysis of 2 Dapoxetine Hydrochloride Formulations in Healthy Chinese Male Volunteers Under Fed and Fasting Conditions: A Randomized, Open-Label, 2-Sequence, 2-Period, 2-Way Crossover Study.

This study assessed whether the reference and test formulations of dapoxetine hydrochloride were bioequivalent under fed and fasting conditions postadministration of a single dose as well as evaluated the safety profile of these 2 formulations. This study was a randomized, single-center, 2-period, open-label, 2-way crossover design study with a washout period of 7 days between each period. The study included 80 subjects, 40 under fed and 40 under fasting conditions. During each study period, the subjects were administered a single oral dose of either the reference or the test formulation, followed by collection of plasma samples 70 hours postdose. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was performed to determine the concentrations of dapoxetine in plasma samples along with the calculation of Cmax , AUC0-t, and AUC0-inf . In addition, adverse events were monitored to determine the safety of these formulations. The geometric mean ratio (90%CI) for the reference and test formulations was 86% to 100%, 89% to 103%, and 89% to 103% under fasting conditions and 92% to 107%, 91% to 100%, and 92% to 101% under fed conditions for Cmax , AUC0-t , and AUC0-inf , respectively. The 90%CIs for the test/reference ratio for AUC and Cmax were within the acceptable limits of bioequivalence, thus demonstrating bioequivalence for these 2 dapoxetine hydrochloride formulations.

Metabolic engineering of Zymomonas moblis for ethylene production from straw hydrolysate.

Biological ethylene production is a promising sustainable alternative approach for fossil-based ethylene production. The high glucose utilization of Z. mobilis makes it as a promising bioethylene producer. In this study, Zymomonas mobilis has been engineered to produce ethylene through the introduction of the synthetic ethylene-forming enzyme (EFE). We also investigated the effect of systematically knocking out the competitive metabolic pathway of pyruvate in an effort to improve the availability of pyruvate for ethylene production in Z. mobilis expressing EFE. Guided by these results, we tested a number of conjectures that could improve the α-ketoglutarate supply. Optimization of these pathways and different substrate supplies resulted in a greater production of ethylene (from 1.36 to 12.83 nmol/OD600/mL), which may guide future engineering work on ethylene production using other organisms. Meanwhile, we achieved an ethylene production of 5.8 nmol/OD600/mL in the ZM532-efe strain using enzymatic straw hydrolysate of corn straw as the sole carbon source. As a preferred host in biorefinery technologies using lignocellulosic biomass as feedstock, heterologous expression of EFE in Z. mobilis converts the non-ethylene producing strain into an ethylene-producing one using a metabolic engineering approach, which is of great significance for the utilization of cellulosic biomass in the future. KEY POINTS: • Heterologous expression of EFE in Z. mobilis successfully converted the non-ethylene producing strain into an ethylene producer (1.36 nmol/OD600/mL). Targeted modifications of the central carbon metabolism can effectively improve ethylene production (peak production: 8.3 nmol/OD600/mL). • The addition of nutrients to the medium can further increase the production of ethylene (peak production: 12.8 nmol/OD600/mL). • The ZM532-efe strain achieved an ethylene production of 5.8 nmol/OD600/mL when enzymatic hydrolysate of corn straw was used as the sole carbon source.

Recombinant human endostatin plus paclitaxel/nedaplatin for recurrent or metastatic advanced esophageal squamous cell carcinoma: a prospective, single-arm, open-label, phase II study.

Background The prognosis of esophageal squamous cell carcinoma (ESCC) are still poor. Nedaplatin/paclitaxel regimen has shown activity with lower toxicity in metastatic ESCC. Recombinant human endostatin (Rh-endostatin), an inhibitor of angiogenesis, has shown inhibitory effects on ESCC xenograft. We assessed the activity and safety of Rh-endostatin plus paclitaxel/nedaplatin in patients with recurrent or metastatic advanced ESCC. Methods In this single-center, open-label, single-arm, phase II study, patients with recurrent/metastatic or unresectable advanced ESCC were recruited. Eligible patients received the multidrug combination therapy with Rh-endostatin (30 mg/day on days 1-14), paclitaxel (150 mg/m2 on day 4) and nedaplatin (80 mg/m2 on day 4) every 3 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, disease control rate, overall survival. Results Between Jan 29, 2015 and Dec 31, 2019, 53 patients were enrolled and received at least one dose of Rh-endostatin. Median progression-free survival was 5.1 months (95% CI: 3.7-6.6), with a 6 month progression-free survival of 41% (95% CI: 25-56). Median overall survival was 13.2 months (95% CI: 8.0-18.4), with a 1-year overall survival of 51% (95% CI: 36-67). 21 (42%, 95% CI: 28-56) of 50 patients had an objective response and 35 (70.00%, 95% CI: 57-83) had a disease control. Treatment-related adverse events of grade 3 or worse were reported in 13 (24.5%) patients. The most common grade 3 or 4 treatment-related adverse events were neutropenia (9 patients [17%]) and anaemia (2 [3.8%]). No treatment-related death occurred. Conclusions Rh-endostatin plus paclitaxel/nedaplatin has anti-tumour activity with acceptable tolerability in patients with recurrent or metastatic advanced ESCC. Randomized controlled trial is needed to confirm the efficacy of this regimen.

Discovery of First-In-Class Potent and Selective Tropomyosin Receptor Kinase Degraders.

We report compounds 5 (CG416) and 6 (CG428) as two first-in-class tropomyosin receptor kinase (TRK) degraders that target the intracellular kinase domain of TRK. Degraders 5 and 6 reduced levels of the tropomyosin 3 (TPM3)-TRKA fusion protein in KM12 colorectal carcinoma cells and inhibited downstream PLCγ1 signaling at sub-nanomolar concentrations. Both degraders also degraded human wild-type TRKA with similar potency. Interestingly, both degraders, especially 6, showed selectivity for the degradation of endogenous TPM3-TRKA over ectopically expressed ATP/GTP binding protein-like 4 (AGBL4)-TRKB or ETS variant transcription factor 6 (ETV6)-TRKC fusion proteins in KM12 cells. Global proteomic profiling assays demonstrated that 5 is highly selective for the intended target. TPM3-TRKA protein degradation induced by 5 and 6 was further confirmed to be mediated through cereblon and the ubiquitin-proteasome system. Compared with the parental TRK kinase inhibitor, both degraders exhibited higher potency for inhibiting growth of KM12 cells. Moreover, both 5 and 6 showed good plasma exposure levels in mice. Therefore, 5 and 6 are valuable chemical tool compounds for investigating the in vivo function of TRK fusion during tumorigenesis. Our study also paves the way for pharmacological degradation of TRK.

Replacing water and nutrients for ethanol production by ARTP derived biogas slurry tolerant Zymomonas mobilis strain.

BACKGROUND: Reducing fresh water consumption and nutrient addition will be an effective way to reduce the whole cost of bioethanol production. On the other hand, treatment of biogas slurry derived from anaerobic digestion (AD), in which a great amount of nutrients is still left, costs too much to remove these pollutants. It would be beneficial for both digestate valorization and ethanol production if biogas slurry is used for producing bioethanol. However, both hyperosmosis and potential biotoxic components of the biogas slurry can severely inhibit fermentation. RESULTS: In this study, two rounds of atmospheric and room temperature plasma (ARTP) mutagenesis combined with adaptive laboratory evolution (ALE) were applied to improve the adaptability and genetic stability of Zymomonas mobilis in biogas slurry. Mutants D95 and S912 were identified. Growth of the mutants was remarkably improved in biogas slurry. The highest ethanol productivity reached 0.63 g/L/h which was 61.7% higher than ZM4 (0.39 g/L/h). Genomic re-sequencing results also revealed that single nucleic variations (SNVs) and Indels occurred in the mutants, which are likely related to inhibitor in biogas slurry and low pH tolerance. CONCLUSIONS: Our study demonstrated that these mutant strains have great potential to produce ethanol using biogas slurry to replace fresh water and nutrients.

Measurement of Blood Thiamine Metabolites for Alzheimer's Disease Diagnosis.

BACKGROUND: Brain glucose hypometabolism is an invariant feature and has significant diagnostic value for Alzheimer's disease. Thiamine diphosphate (TDP) is a critical coenzyme for glucose metabolism and significantly reduced in brain and blood samples of patients with Alzheimer's disease (AD). AIMS: To explore the diagnostic value of the measurement of blood thiamine metabolites for AD. METHODS: Blood TDP, thiamine monophosphate, and thiamine levels were detected using high performance liquid chromatography (HPLC). The study included the exploration and validation phases. In the exploration phase, the samples of 338 control subjects and 43 AD patients were utilized to establish the models for AD diagnosis assayed by receiver operating characteristic (ROC) curve, including the variable γ that represents the best combination of thiamine metabolites and age to predict the possibility of AD. In the validation phase, the values of models were further tested for AD diagnosis using samples of 861 control subjects, 81 AD patients, 70 vascular dementia patients, and 13 frontotemporal dementia patients. RESULTS: TDP and the γ exhibited significant and consistent values for AD diagnosis in both exploration and validation phases. TDP had 0.843 and 0.837 of the areas under ROC curve (AUCs), 77.4% and 81.5% of sensitivities, and 78.1% and 77.2% of specificities respectively in the exploration and validation phases. The γ had 0.938 and 0.910 of AUCs, 81.4% and 80.2% of sensitivities, and 90.5% and 87.2% of specificities respectively in the exploration and validation phases. TDP and the γ can effectively distinguish AD from vascular dementia (64.3% for TDP, 67.1% for γ) and frontotemporal dementia (84.6% for TDP, 100.0% for γ). Interpretation. The measurement of blood thiamine metabolites by HPLC is an ideal diagnostic test for AD with inexpensive, easy to perform, noninvasive merits.