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Intestinal farnesoid X receptor (FXR) plays a critical role in alcohol-associated liver disease (ALD). We aimed to investigate whether alcohol-induced dysbiosis increased intestinal microRNA194 (miR194) that suppressed Fxr transcription and whether Lactobacillus rhamnosus GG-derived exosome-like nanoparticles (LDNPs) protected against ALD through regulation of intestinal miR194-FXR signaling in mice.Binge-on-chronic alcohol exposure mouse model was utilized. In addition to the decreased ligand-mediated FXR activation, alcohol feeding repressed intestinal Fxr transcription and increased miR194 expression. This transcriptional suppression of Fxr by miR194 was confirmed in intestinal epithelial Caco-2 cells and mouse enteriods. The alcohol feeding-reduced intestinal FXR activation was further demonstrated by the reduced FXR reporter activity in fecal samples and by the decreased fibroblast growth factor 15 (Fgf15) messenger RNA (mRNA) in intestine and protein levels in the serum, which caused an increased hepatic bile acid synthesis and lipogeneses. We further demonstrated that alcohol feeding increased-miR194 expression was mediated by taurine-upregulated gene 1 (Tug1) through gut microbiota regulation of taurine metabolism. Importantly, 3-day oral administration of LDNPs increased bile salt hydrolase (BSH)-harboring bacteria that decreased conjugated bile acids and increased gut taurine concentration, which upregulated Tug1, leading to a suppression of intestinal miR194 expression and recovery of FXR activation. Activated FXR upregulated FGF15 signaling and subsequently reduced hepatic bile acid synthesis and lipogenesis and attenuated ALD. These protective effects of LDNPs were eliminated in intestinal FxrOur results demonstrated that gut microbiota-mediated miR194 regulation contributes to ALD pathogenesis and to the protective effects of LDNPs through modulating intestinal FXR signaling.

BackgroundFor gastric cancer (GC) patients with pylorus outlet obstruction (POO), whether laparoscopic surgery has advantages over open surgery remains unclear. This study aims to investigate the differences between patients with and without POO in open and laparoscopic groups and to determine the differences between laparoscopic distal gastrectomy (LDG) and open distal gastrectomy (ODG) in GC patients with POO.MethodsA total of 241 GC patients with POO who underwent distal gastrectomy at the Department of Gastric Surgery of the First Affiliated Hospital of Nanjing Medical University between 2016 and 2021 were included in this study. A total of 1,121 non-POO patients who underwent laparoscopic surgery and 948 non-POO patients who underwent open surgery from 2016 to 2021 were also enrolled in the study. We compared complication rates and hospital stays between open and laparoscopic groups.ResultsThere was no significant difference for LDG between GC patients with and without POO regarding the overall complication rates (P = 0.063), the Grade III–V complication rate (P = 0.673), and the anastomotic complication rate (P = 0.497) from 2016 to 2021. The patients with POO had longer preoperative hospital stay (P = 0.001) and postoperative hospital stay (P=0.007) compared to patients without POO. No significant difference was observed for open patients between POO and non-POO patients regarding the overall complication rate (P = 0.357), grade III–V complication rate (P = 1.000), and anastomosis-related complication rate (P = 0.766). Compared with open surgery in GC patients with POO (n = 111), the total complication rate of the LDG group was 16.2%, which was significantly lower than that of the open group (26.1%, P = 0.041). No significant differences in the Grade III–V complication rate (P = 0.574) and anastomotic complication rate (P = 0.587) were observed between laparoscopic and open groups. Patients receiving laparoscopic surgery had shorter postoperative hospital stay than open surgery (P = 0.001). More resected lymph nodes (LNs) were also observed in the laparoscopic group (P = 0.0145).ConclusionThe comorbidity of GC with POO does not increase the complication rate after laparoscopic or open distal gastrectomy. In GC patients with POO, laparoscopic surgery shows advantages over open surgery with a lower overall complication rate, shorter postoperative hospital stay, and more harvested lymph nodes. Laparoscopic surgery is a safe, feasible, and effective treatment for GC with POO.

Supplementary table 1 Univariate analysis of influence factors of concordance between ctDNA and tissue DNA detections; Supplementary table 2 Concordance analysis between ctDNA and tissue DNA detections in genetic analysis (Tumor size>10cm, n=23); Supplementary table 3 Concordance analysis between ctDNA and tissue DNA detections in genetic analysis (Ki-67>5%, n=19); Supplementary table 4 Univariate analysis of influence factors of prognosis (Log-rank Test)

Correlation between tumor size, Ki-67 and positive rate of ctDNA mutation.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of digestive tract. In the past, tissue biopsy was the main method for the diagnosis of GISTs. Although, circulating tumor DNA (ctDNA) detection by next-generation sequencing (NGS) may be a feasible and replaceable method for diagnosis of GISTs. We retrospectively analyzed the data for ctDNA and tissue DNA detection from 32 advanced GIST patients. We found that NGS obviously increased the positive rate of ctDNA detection. ctDNA detection identified rare mutations that were not detected in tissue DNA detection. Tumor size and Ki-67 were significant influencing factors of the positive rate of ctDNA detection and concordance between ctDNA and tissue DNA detection. In all patients, the concordance rate between ctDNA and tissue DNA detection was 71.9%, with moderate concordance, but the concordance was strong for patients with tumor size > 10 cm or Ki-67 > 5%. Tumor size, mitotic figure, Ki-67, and ctDNA mutation type were the significant influencing factors of prognosis, but only tumor size and ctDNA mutation type, were the independent prognostic factors for advanced GIST patients. We confirmed that ctDNA detection by NGS is a feasible and promising method for the diagnosis and prognosis of advanced GIST patients. Mol Cancer Ther; 17(1); 290–6. ©2017 AACR.

Imatinib dosages and operation treatment.

Chronic obstructive pulmonary disease (COPD) is a disease with high incidence rate and mortality rates worldwide. It is the third leading cause of death in the world. Nevertheless, little progress has been made in treating and preventing the disease. Under these circumstances, the concept of “early COPD” was proposed. Although this concept is not new, most health-care workers do not fully understand early COPD and tend to confuse it with mild COPD. In this review, we mainly discuss the definition of early COPD and the developmental trajectory of lung function. Although patients with early COPD have no symptoms, their lung function is already lower than that of normal people. A relatively complete definition is needed to identify this group of people. Reduced lung function is the diagnostic criterion for COPD, but lung development is a long-term dynamic process. In addition to smoking and air pollution, we should pay more attention to prenatal and childhood risk factors, for example, parents smoking, birth weight, preterm birth, mode of delivery, childhood respiratory infections and childhood asthma. Health-care workers need to be fully aware of early COPD, to reduce the morbidity of COPD and take effective measures to prevent these risk factors.

When the tunnel boring machine (TBM) construction method is used to build tunnels, if the type of TBM is not appropriate, problems, such as low construction efficiency and increased construction cost, will easily occur. Therefore, it is necessary to build a TBM selection decision-making model to guide TBM selection. In this paper, seven evaluation indexes are selected according to engineering experience and expert suggestions, and the quantitative standards of each index are unified. The modified analytic hierarchy process (MAHP) method is used to determine the weight of each evaluation index. The technique for order preference by similarity to an ideal solution (TOPSIS) method is adopted as the decision-making method of TBM selection. Finally, a TBM selection decision-making model is proposed based on the above methods. In order to verify the reliability of the TBM selection decision-making model proposed in this paper, we selected three projects for case verification and compared them with the previous TBM selection methods. The results show that the decision-making results of the method proposed in this paper are good. Additionally, the method proposed in this paper is more comprehensive and accurate than the previous methods. The model proposed in this paper can provide better suggestions for TBM selection in the project planning stage.

Recognizing and classifying multiple morphological features, such as patterns, sizes, and textures, can provide a comprehensive understanding of their variability and phenotypic evolution. Yet, quantitatively measuring complex morphological characters remains challenging.We provide a machine learning‐based pipeline (SVMorph) to consider and classify complex morphological characters in multiple organisms that have either small or large datasets.Our pipeline integrates two descriptors, histogram of oriented gradient and local binary pattern, to meet various classification needs. We also optimized feature extraction by adding image data augmentation to improve model generalizability.We tested SVMorph on two real‐world examples to demonstrate that it can be used with small training datasets and limited computational resources. Comparing with multiple CNN‐based methods and traditional techniques, we show that SVMorph is reliable and fast in texture‐based individual classification. Thus, SVMorph can be used to efficiently classify multiple morphological characters in distinct nonmodel organisms., Recognizing and classifying multiple morphological features can provide a comprehensive understanding of their variability and phenotypic evolution. We provide a machine learning‐based pipeline (SVMorph) including two descriptors and image data augmentation to consider and classify complex morphological characters. We also tested SVMorph on two real‐world examples to demonstrate that it can be used to efficiently classify multiple morphological characters in distinct nonmodel organisms.

Alcohol‐associated liver disease (ALD) is a major cause of mortality. Gut barrier dysfunction–induced bacterial translocation and endotoxin release contribute to the pathogenesis of ALD. Probiotic Lactobacillus rhamnosus GG (LGG) is known to be beneficial on experimental ALD by reinforcing the intestinal barrier function. In this study, we aim to investigate whether the protective effects of LGG on intestinal barrier function is mediated by exosome‐like nanoparticles (ELNPs) released by LGG. Intestinal epithelial cells and macrophages were treated with LGG‐derived ELNPs (LDNPs) isolated from LGG culture. LDNPs increased tight junction protein expression in epithelial cells and protected from the lipopolysaccharide‐induced inflammatory response in macrophages. Three‐day oral application of LDNPs protected the intestine from alcohol‐induced barrier dysfunction and the liver from steatosis and injury in an animal model of ALD. Co‐administration of an aryl hydrocarbon receptor (AhR) inhibitor abolished the protective effects of LDNPs, indicating that the effects are mediated, at least in part, by intestinal AhR signaling. We further demonstrated that LDNP administration increased intestinal interleukin‐22‐Reg3 and nuclear factor erythroid 2‐related factor 2 (Nrf2)–tight junction signaling pathways, leading to the inhibition of bacterial translocation and endotoxin release in ALD mice. This protective effect was associated with LDNP enrichment of bacterial tryptophan metabolites that are AhR agonists. Conclusions: Our results suggest that the beneficial effects of LGG and their supernatant in ALD are likely mediated by bacterial AhR ligand–enriched LDNPs that increase Reg3 and Nrf2 expression, leading to the improved barrier function. These findings provide a strategy for the treatment of ALD and other gut barrier dysfunction–associated diseases.

Developing favorable charge transfer mode for photocatalytic hydrogen evolution in a photocatalyst is a promising way to enhance photocatalytic activity. In this study, MOF, decorated with different functional groups, was initially used as charge transfer mode convertor coupled with CdS/α-NiS-β-NiS. The NH2-UiO-66/CdS/α-NiS-β-NiS lead to twice and triple higher H2 evolution compared to (OH)2-UiO-66/CdS/α-NiS-β-NiS and UiO-66/CdS/α-NiS-β-NiS respectively under simulated sunlight. The NH2-UiO-66 provides suitable energy band structure to formed Z-scheme with CdS/α-NiS-β-NiS, which plays a synergistic role in the photocatalytic process. The loading of α-NiS-β-NiS significantly improves the visible light absorption ability and provides abundant active sites. As a result, the α-NiS-β-NiS/CdS/NH2-UiO-66 show considerable photocatalytic hydrogen production rate of 17.88 mmol h−1 g−1, which is 7.9 times and 2.5 times as high as-those of pure CdS and 7-α-NiS-β-NiS/CdS, and it also shows a prominent apparent quantum efficiency (AQE) of 14.7% at 420 nm. This work provides a new insight design a metal organic frameworks based heterojunction with highly-efficient photo-induced charge separation and excellent visible-light absorption ability.

Secondary resistance to imatinib (IM) represents a major challenge for therapy of gastrointestinal stromal tumors (GISTs). Aberrations in oncogenic pathways, including autophagy, correlate with IM resistance. Regulation of autophagy-related protein 5 (ATG5) by the ubiquitin-proteasome system is critical for autophagic activity, although the molecular mechanisms that underpin reversible deubiquitination of ATG5 have not been deciphered fully. Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. USP13 preferentially is induced in GIST cells by IM and interacts with ATG5, which leads to stabilization of ATG5 through deubiquitination. Activation of PAK1 promoted phosphorylation of ATG5 thereby enhancing the interaction of ATG5 with USP13. Furthermore, N

Alcoholic liver disease (ALD) is associated with gut dysbiosis and hepatic inflammasome activation. While it is known that antimicrobial peptides (AMPs) play a critical role in the regulation of bacterial homeostasis in ALD, the functional role of AMPs in the alcohol-induced inflammasome activation is unclear. The aim of this study was to determine the effects of cathelicidin-related antimicrobial peptide (CRAMP) on inflammasome activation in ALD. CRAMP knockout (Camp-/-) and wild-type (WT) mice were subjected to binge-on-chronic alcohol feeding and synthetic CRAMP peptide was administered. Serum/plasma and hepatic tissue samples from human subjects with alcohol use disorder and/or alcoholic hepatitis were analyzed. CRAMP deficiency exacerbated ALD with enhanced inflammasome activation as shown by elevated serum interleukin (IL)-1β levels. Although Camp-/- mice had comparable serum endotoxin levels compared to WT mice after alcohol feeding, hepatic lipopolysaccharide (LPS) binding protein (LBP) and cluster of differentiation (CD) 14 were increased. Serum levels of uric acid (UA), a Signal 2 molecule in inflammasome activation, were positively correlated with serum levels of IL-1β in alcohol use disorder patients with ALD and were increased in Camp-/- mice fed alcohol. In vitro studies showed that CRAMP peptide inhibited LPS binding to macrophages and inflammasome activation stimulated by a combination of LPS and UA. Synthetic CRAMP peptide administration decreased serum UA and IL-1β concentrations and rescued the liver from alcohol-induced damage in both WT and Camp-/- mice. In summary, CRAMP exhibited a protective role against binge-on-chronic alcohol-induced liver damage via regulation of inflammasome activation by decreasing LPS binding and UA production. CRAMP administration may represent a novel strategy for treating ALD. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Microwave-induced fracturing of hard rock can be used to assist mechanical rock breakage and release stress on rock masses in deep underground engineering operations. This is significant to those aiming to improve the construction efficiency and safety of underground tunnelling and ore extraction operations. The research was devoted to exploring the computed tomography (CT) and acoustic emission (AE) characteristics of hard rock subjected to microwave irradiation. For this purpose, microwave irradiation tests at a given power for different irradiation times were conducted on basalt collected from Chifeng, China by utilising a multimode cavity working at a frequency of 2450 MHz. By applying an infrared camera, the temperature distribution on the surface of samples during microwave irradiation was measured. Three-dimensional (3-d) microscopic CT was conducted on samples treated, and not treated, with microwave irradiation to explore the crack propagation regimes in such samples. Based on CT value and P-wave velocities, the damage characteristics of microwave treatment on basalt samples were evaluated. Afterwards, uniaxial compression strength tests were conducted and AE information in the loading process of samples was collected. After conducting microwave irradiation, internal cracks of samples propagated to generate fracture surfaces and surface temperatures of samples were found to have been non-uniformly distributed. The longer the irradiation time, the higher the degree of crack propagation in samples; P-wave velocities both decreased with increasing irradiation duration. With increasing irradiation time, the brittle failure characteristics of basalt shown in the time-dependent change curve of stress on basalt were gradually weakened while ductile failure characteristics were gradually strengthened. The uniaxial compressive strength, corresponding AE energy and cumulative AE energy at peak strength all gradually decreased with increasing irradiation time. The failure stress, the level of stress drop, AE energy, and cumulative AE energy of basalt after different irradiation times reflected consistent fracturing characteristics of basalt, which were interactively validated.

Objective Laparoscopic-assisted total gastrectomy (LATG) is the most common methods of gastrectomy for gastric cancer (GC). However, totally laparoscopic total gastrectomy (TLTG) is uncommon because reconstruction is difficult, especially for the intracorporeal esophagojejunostomy. In this study, we compared short-term oncologic outcomes in TLTG group with linear anastomosis and LATG group. Methods The retrospective cross-sectional study was conducted. The clinic-pathological data of 108 patients underwent TLTG and 153 patients underwent LATG who were admitted to the First Affiliated Hospital of Nanjing Medical University between May 2016 and October 2019 were collected. The clinicopathological characteristics and surgical outcomes before and after propensity score matching (PSM) were compared between the two groups. Furthermore, a systematic review and meta-analysis were conducted. Results Besides the estimated blood loss(P

When a TBM carries out tunnelling in complex strata, there is often low tunnelling efficiency and an increase in tunnelling costs due to the improper selection of tunnelling parameters, the wrong estimation of geological conditions, or adverse geology, so it is necessary to evaluate the tunnelling adaptability of TBM construction. In this paper, based on hydraulic engineering in Xinjiang, 11 evaluation indexes of TBM tunnelling adaptability are determined by comprehensively considering the influence of tunnelling parameters, geological conditions, and adverse geological factors on TBM tunnelling adaptability. After that, the membership function of each evaluation index is determined by referring to the existing research results and fuzzy mathematics method, and the weight of each evaluation index is determined and adjusted by the analytic hierarchy process (AHP)–entropy weight (EW) method. Finally, the adaptability evaluation method and evaluation model of TBM tunnelling are put forward. The TBM tunnelling adaptability evaluation model proposed in this paper is verified by relying on the actual situation of three interval tunnels in the project, and good effects are obtained. This study can provide a reference for the evaluation of TBM tunnelling adaptability in similar strata.

Fibroblast growth factor 21 (FGF21) is a glucose and lipid metabolic regulator. Recent research revealed that FGF21 was also induced by inflammatory stimuli. Its role in inflammatory bowel disease (IBD) has not been investigated. In this study, an experimental IBD model was established in FGF21 knockout (KO) and wild-type (WT) mice by adding 2.5% (wt/vol) dextran sodium sulfate (DSS) to their drinking water for 7 days. The severity of the colitis and the inflammation of the mouse colon tissues were analyzed. In WT mice, acute DSS treatment induced an elevation in plasma FGF21 and a significant loss of body weight in a time-dependent manner. Surprisingly, the loss of body weight and the severity of the colitis induced by DSS treatment in WT mice were significantly attenuated in FGF21 KO mice. Colon and circulating pro-inflammatory factors were significantly lower in the FGF21 KO mice compared to the WT mice. As shown by BrdU staining, the FGF21 KO mice demonstrated increased colonic epithelial cell proliferation. DSS treatment reduced intestinal Paneth cell and goblet cell numbers in the WT mice, and this effect was attenuated in the FGF21 KO mice. Mechanistically, FGF21 deficiency significantly increased the signal transducer and activator of transcription (STAT)-3 activation in intestinal epithelial cells and increased the expression of IL-22. Further study showed that the expression of suppressor of cytokine signaling-2/3 (SOCS 2/3), a known feedback inhibitor of STAT3, was significantly inhibited in the DSS-treated FGF2 KO mice compared to the WT mice. We conclude that FGF21 deficiency attenuated the severity of DSS-induced acute colitis, which is likely mediated by enhancing the activation of the IL-22-STAT3 signaling pathway in intestinal epithelial cells.

Background Chemotherapy can significantly improve the disease‐free survival and overall survival of patients with advanced gastric cancer (GC). 5‐fluorouracil (5‐FU) is frequently applied in the clinic, acting as a first‐line chemotherapy drug of advanced GC, which could be used alone or combining platinum drugs. However, its efficacy is significantly attenuated by chemoresistance, which is associated with patients’ poor survival. Recently, there is evidence suggesting that dysregulation of autophagy may contribute to drug resistance in cancer, and circular RNAs (circRNAs) also take part in chemoresistance. However, whether circRNAs participate in 5‐FU chemoresistance through autophagy remains largely unknown. Methods RNA sequencing technologies and bioinformatics analysis were performed in GC. Sanger sequencing, Actinomycin D assay and RNase R assay confirmed the circular structure of circular CPM (circCPM). Various cell line models and animal models were used to explore related functions in vitro and in vivo. Quantitative Real‐time PCR (qRT‐PCR), fluorescence in situ hybridization, ribonucleic acid; (RNA) pulldown assays, RNA binding protein immunoprecipitation assays and Luciferase reporter assays were applied to explore involved pathways. Results circCPM was up‐regulated in 5‐FU resistant GC cell lines and tissue. Moreover, high circCPM expression is positively associated with poor survival. Silencing circCPM greatly improved chemosensitivity in vitro and in vivo. Mechanistically, it directly binds to miR‐21‐3p in the cytoplasm and therefore increases the expression of PRKAA2, contributing to the activation of autophagy and chemoresistance. Conclusion Our results reveal that circCPM has a crucial role in regulating GC autophagy and 5‐FU resistance by targeting PRKAA2. It may function as a new theory basis for assessing the curative effect of GC and reversing 5‐FU chemoresistance., CircCPM is up‐regulated in 5‐FU resistant gastric cancer cells and tissues. CircCPM modulates autophagy by working as a sponge of miR‐21‐3p, thereby up‐regulating PRKAA2 expression. CircCPM regulates gastric cancer 5‐FU chemoresistance through the miR‐21‐3p/ PRKAA2 axis.

365 Background: The dose escalation phase was presented early, and confirmed that the recommended phase II dose (RP2D) was camrelizumab (200 mg, d1) plus apatinib (250 mg, qd), S-1(40 mg, bid, d1-14) and oxaliplatin (130 mg/m2, d1) every 3 weeks followed by camrelizumab (200 mg, d1) plus apatinib (250 mg, qd) every 3 weeks. Methods: Patients (pts) aged 18-75 years, with unresectable or potentially resectable G/GEJ adenocarcinoma, HER2-negative or unknown HER2 status and no previous systemic therapy, were enrolled to receive combination therapy. Primary endpoint was Objective response rate (ORR) by RECIST 1.1, secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), surgical resection rate and safety. Results: From Jun, 2020 to July 2022, 35 pts were enrolled (9 pts in dose escalation phase, 26 pts in dose expansion phase), with a median follow-up of 8.0 months (95% CL, 6.7-12.2). Median age (range) was 59(19-68), 94.3% (33/35) were male, 20% (7/35) were diagnosed with GEJ adenocarcinoma, 60% (21/35) had liver metastases. At data cutoff, 33 pts were included in the efficacy analysis. The ORR was 90.9%, with 30 (90.9%) PR. SD were 1 (3.0%) with a DCR of 93.9%. In addition, 9 pts showed an unconfirmed PR with a confirmed ORR of 80.8%. Median PFS was 10.2 months (95% CI, 5.5-22.3), with the median OS not reached yet. Conversion to resectable G/GEJ adenocarcinoma was identified in 9 (25.7%) pts. Of them, 2 pts were observed complete pathology response. 94.3% pts experienced treatment related adverse event (TRAE), with 45.7% being grade ≥3. The most frequent grade ≥3 TRAE were GGT increased (31.4%, 11/35), rash (11.4%, 4/35), alkaline phosphatase increased (11.4%, 4/35)、neutrophil count decreased (8.6%, 3/35). No new safety signal was identified. Conclusions: Camrelizumab plus apatinib and SOX followed by camrelizumab plus apatinib demonstrated encouraging antitumor activity and manageable toxicity as first line therapy for patients with G/GEJ adenocarcinoma. Clinical trial information: ChiCTR2000034109 .

Few data are available regarding comprehensive or quantitative assessment of fish feed considering both the environmental and feeding impacts. Aiming to fill the gap, an experimental study to investigate the effects of three fish feeds on concentrations of nutrients and crucian carp (Carassius carassius) growth was conducted in laboratory aquariums in the presence and absence of prometryn. Results showed that weight gain rates of crucian carp treated with Tong Wei (TW) feed were 106.3% and 2.0% higher than that of Zhong Shan (ZS) and Zhong Liang (ZL) feeds, a possible explanation was that the quality of protein in TW feed was highest as evidenced by the protein efficiency ratios. Meanwhile, TW feed posed relatively lighter effects on water qualities (between ZL and ZS). Prometryn significantly inhibited the growth of crucian carp and thus affected concentrations of nutrients in water indirectly. The relationships between weight gain rates of fish and concentrations of nutrients in water (R2 = 0.929–0.990) were developed. In sum, this study suggested that it is realizable to obtain better fish growth performance with lesser degrading effects on water qualities by producing and selecting appropriate feed regardless of prometryn existence, and the developed equations could be used as a basis for future studies.

Alcohol consumption and obesity are known risk factors of steatohepatitis. Here, we report that the deficiency of CRAMP (cathelicidin-related antimicrobial peptide—gene name: Camp) is protective against a high-fat diet (HFD) plus acute alcohol (HFDE)-induced liver injury. HFDE markedly induced liver injury and steatosis in WT mice, which were attenuated in Camp–/– mice. Neutrophil infiltration was lessened in the liver of Camp–/– mice. HFDE feeding dramatically increased epididymal white adipose tissue (eWAT) mass and induced adipocyte hypertrophy in WT mice, whereas these effects were attenuated by the deletion of Camp. Furthermore, Camp–/– mice had significantly increased eWAT lipolysis, evidenced by up-regulated expression of lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). The depletion of Camp also increased uncoupling protein 1 (UCP1)-dependent thermogenesis in the brown adipose tissue (BAT) of mice. HFDE fed Camp–/– mice had elevated protein levels of fibroblast growth factor 21 (FGF21) in the eWAT, with an increased adiponectin production, which had been shown to alleviate hepatic fat deposition and inflammation. Collectively, we have demonstrated that Camp–/– mice are protected against HFD plus alcohol-induced liver injury and steatosis through FGF21/adiponectin regulation. Targeting CRAMP could be an effective approach for prevention/treatment of high-fat diet plus alcohol consumption-induced steatohepatitis.

The rapid separation and transport of photogenerated carriers are pivotal toward enhancing the photocatalytic performance. Herein, CdS nanoparticles are grown in situ on oxygen deficiency-rich WO3−x nanosheets, successfully providing a direct Z-scheme CdS/WO3−x heterojunction to enhance photocatalytic hydrogen production. We demonstrate an effective electron collection in the Z-scheme CdS/WO3−x heterojunction by regulating the relative content of WO3−x. The optimized CdS/20 wt% WO3−x (CW20) affords a high photocatalytic hydrogen production rate of 6545.3 μmol g−1 h−1 in lactic acid aqueous solution under visible light (400–800 nm), which is about 54.1 times that of pure CdS (121.0 μmol g−1 h−1). In addition, CW20 also provides a considerable external quantum efficiency (EQE) of 10.03% at λ = 420 nm. The best-performing CW20 sample is explored by cyclic stability experiment and XRD characterization after hydrogen production, which reveals the robust stability of CW20. The excellent photocatalytic activity can be attributed to the formation of a Z-scheme CdS/WO3−x heterojunction, resulting in an efficient spatial separation of photogenerated carriers. Electron and hole catalytic centers are maintained in two separate components to minimize the adverse products of photocatalytic hydrogen production. This study uncovers the role of oxygen deficiency based on the Z-scheme heterojunction in affecting electron transfer and reaction sites, opening new opportunities for achieving efficient hydrogen production.

Developing well-designed architectures plays a decisive role in accelerating photo-generated carrier transport in composite photocatalysts. Herein, a microporous sulfur-doped (S-doped) NH2-UiO-66 bridged ZnIn2S4/MoS2 sheet heterostructure photocatalyst is synthesized through thermolysis of sulfur rich precursors to functionalize the organic ligands of NH2-UiO-66 to boost photocatalytic efficiency. XPS spectra confirm the existence of S-doped NH2-UiO-66, and Raman spectra show transition metal-assisted sulfuration instead of carbonization. FT-IR spectra further confirm the formation of Zn–O–C covalent bonds at the interface between NH2-UiO-66 and ZnIn2S4. In particular, the Zn–O–C bonds preserve the energy of photo-generated electrons and inhibit the energy relaxation of electrons at the interface of the heterostructure. In addition, NH2-UiO-66 with a high photocatalytic response greatly facilitates the transport of photo-generated electrons not only as an electron transport bridge but also as an electron donor. Profiting from the unique design of the ternary composite, the sample exhibits excellent PHE performance. The obtained ZnIn2S4/NH2-UiO-66/5%-MoS2 (5.69 mmol h−1 g−1) exhibits the highest H2 evolution rate, which is 15 and 1.9 times higher than those of ZnIn2S4 (0.369 mmol h−1 g−1) and 5%-MoS2/ZnIn2S4 (2.93 mmol h−1 g−1), respectively. In addition, the apparent quantum efficiency of the ZnIn2S4/NH2-UiO-66/5%-MoS2 composite (7.95%) is higher than that of the 5%-MoS2/ZnIn2S4 composite (3.12%) at 420 nm. This work provides new insight into designing novel and highly efficient photocatalysts for photocatalytic hydrogen evolution.

Microbiome dysbiosis is strongly associated with alcoholic liver disease (ALD). Recent studies on comprehensive analyses of microbiome compositional and functional changes have begun to uncover the mechanistic relation between microbiome and the pathogenesis of ALD. Importantly, targeting the microbiome has become a potential strategy for the prevention and treatment of ALD. In this review, we summarize the clinical evidence of microbiome dysbiosis in ALD patients, and experimental advances in microbiome and metabolomic functional changes in animals with different species and genetic backgrounds in ALD. We also summarize the studies in humanized intestinal microbiome and fecal microbiota transplantation in mice. We introduce new developments in the studies on the role of the circulating bacterial microbiome, oral bacterial microbiome and fungal microbiome in the development of ALD. We highlight the potential mechanisms by which microbiome dysbiosis contributes to ALD, including short chain fatty acid changes, bile acid metabolism, intestinal barrier function, release of bacterial and fungal products, and inflammation. In addition, we summarize the recent developments targeting the microbiome in prevention and treatment of ALD, including dietary nutrient interference, herbal medicine, antibiotics, anti-fungal agents, probiotics, engineered bacterial therapy, fecal transplantation and oral hygiene. Although recent preclinical studies have advanced our understanding of the microbiome and ALD, clinical studies, especially prospective studies with large samples, are needed to better understand the cause-effect of microbiome dysbiosis in ALD. Identifying new precision-based strategies targeting the microbiome are expected to be developed as more effective therapies in ALD. Keywords: Microbiome, Dysbiosis, Alcoholic liver disease (ALD)

Objectives High fructose feeding changes fibroblast growth factor 21 (FGF21) regulation. Lactobacillus rhamnosus GG (LGG) supplementation reduces fructose-induced non-alcoholic fatty liver disease (NAFLD). The aim of this study was to determine the role of FGF21 and underlying mechanisms in the protective effects of LGG. Methods FGF21 knockout (KO) mice and C57BL/6 wild type (WT) mice were fed 30% fructose for 12 weeks. LGG was administered to the mice in the last 4 weeks during fructose feeding. FGF21-adiponectin (ADPN)-mediated hepatic lipogenesis and inflammation were investigated. Results FGF21 expression was robustly increased after 5-weeks of feeding and significantly decreased after 12-weeks of feeding in fructose-induced NAFLD mice. LGG administration reversed the depressed FGF21 expression, increased adipose production of ADPN, and reduced hepatic fat accumulation and inflammation in the WT mice but not in the KO mice. Hepatic nuclear carbohydrate responsive-element binding protein (ChREBP) was increased by fructose and reduced by LGG, resulting in a reduction in the expression of lipogenic genes. The methylated form of protein phosphatase 2A (PP2A) C, which dephosphorylates and activates ChREBP, was upregulated by fructose and normalized by LGG. Leucine carboxyl methyltransferase-1, which methylates PP2AC, was also increased by fructose and decreased by LGG. However, those beneficial effects of LGG were blunted in the KO mice. Hepatic dihydrosphingosine-1-phosphate, which inhibits PP2A, was markedly increased by LGG in the WT mice but attenuated in the KO mice. LGG decreased adipose hypertrophy and increased serum levels of ADPN, which regulates sphingosine metabolism. This beneficial effect was decreased in the KO mice. Conclusion LGG administration increases hepatic FGF21 expression and serum ADPN concentration, resulting in a reduced ChREBP activation through dihydrosphingosine-1-phosphate-mediated PP2A deactivation, and subsequently reversed fructose-induced NAFLD. Thus, our data suggest that FGF21 is required for the beneficial effects of LGG in reversal of fructose-induced NAFLD., Highlights • Lactobacillus rhamnosus GG (LGG) attenuates fructose-induced NAFLD. • LGG increases FGF21 and adiponectin expression. • LGG inhibits fructose-activated ChREBP and reduces hepatic lipogenesis. • FGF21 is required for the therapeutic effects of LGG against fructose-induced NAFLD.

Four new species are described in two psilodercid genera, Qiongocera Li & Li, 2017 and Relictocera Li & Li, 2017: Qiongoceraluoxuan Li & Li, sp. nov. (♂♀) from China, Relictocerawugen Li & Li, sp. nov. (♂♀) and R.sigen Li & Li, sp. nov. (♂) from Vietnam, and R.qianzi Li & Li, sp. nov. (♂♀) from Thailand. These genera were previously thought to be monotypic. In addition, one species of the genus Merizocera Fage, 1912 is transferred to Relictocera: Relictoceramus (Deeleman-Reinhold, 1995), comb. nov. (♂♀). The types of the new species are deposited in the Institute of Zoology, Chinese Academy of Sciences (IZCAS) in Beijing.

Alterations in gut bacterial homeostasis result in changes in intestinal metabolites. To investigate the effects of alcohol on fecal metabolites and the role of cathelicidin-related antimicrobial peptide (CRAMP) in alcoholic liver disease (ALD), CRAMP knockout (KO) and their control wild type (WT) mice were fed a Lieber-DeCarli liquid diet with or without alcohol. Polar metabolites in mouse feces were analyzed by GC × GC-MS and 2DLC-MS, and the concentrations of short chain fatty acids (SCFAs) were measured by GC-MS. A total of 95 and 190 metabolites were detected by GC × GC-MS and 2DLC-MS, respectively. Among the significantly changed metabolites, taurine and nicotinic acid were decreased in WT mice fed alcohol, which were also down-regulated in KO mice fed without alcohol. Interestingly, these two metabolites were increased in KO mice fed alcohol compared to them in WT controls. Additionally, SCFAs were significantly decreased in WT mice fed alcohol and in KO mice fed without alcohol, whereas two branched-chain SCFAs were increased by alcohol treatment in KO mice. In summary, the analytical platforms employed in this study successfully dissected the alterations of polar metabolites and SCFAs in fecal samples, which helped understand the effects of alcohol consumption and CRAMP in intestinal metabolism and alcohol-induced liver injury.

Contraposing the problem of cutter wear and other issues in TBM boring in erosive and hard strata, this paper analyzes the boring parameters and cutter wear amount in the trial 2 km of TBM section in Qinling Tunnel of Han River to Wei River Water Diversion Project. Then several pieces of advice are proposed and analysis results suggest that the inadequate amount of cutters around No. 43 cutter causes their relatively high wear. Experiments of disc cutter breaking hard rock are conducted, showing that the specific energy of TBM used for breaking rock is relatively low while the efficiency high when the S/p (the ratio of cutter space to penetration) is between 25 and 30. Relevant scaled experiments indicate a critical penetration value beyond which the mass wear rate of disc cutter surges. The experiment also proves that round-blade disc cutter could effectively reduce the wear. The research could provide reference for the cutter-head design and parameter control of TBM in similar geologies.

Background: Abnormal glycosylation of proteins has been identified in almost all types of cancers and is closely related to the cancer progression, metastasis, and survival of cancer patients. This study was to explore the values of serum tumor abnormal protein (TAP), an abnormal glycochain protein, in the diagnosis and prognosis of gastric cancer (GC). Methods: A total of 335 GC patients were included as the study group, and another 335 subjects served as the control group. Tumor abnormal protein expression was compared between the 2 groups. Correlation analysis was used to assess the correlations of TAP with clinicopathological factors. Gastric cancer patients were divided into training set and test set at a ratio of 2:1. Univariate and multivariate Cox regression analyses in training set were used to evaluate the prognostic significance of TAP in GC patients and explore the independent risk factors for overall survival (OS) and disease-free survival (DFS) to establish a prognostic model, followed by testing of the model. According to the median of TAP, 335 GC patients were divided into 2 groups to plot the survival curves of OS and DFS. Results: Tumor abnormal protein expression in the study group was significantly higher than in the control group. Taking the best cut-off value of TAP (110.128 μm2) as the diagnostic criteria for GC, the sensitivity and specificity of TAP were 83.58% and 97.61%, respectively, and the area under the receiver operating characteristics (ROC) curve was 0.935, which was not inferior to computed tomography (CT). Tumor abnormal protein expression was an independent risk factor for OS and DFS. The prognostic predictive value of TAP was better than that of pathological stage in GC patients. The model with TAP was effective in predicting prognosis. Conclusion: Tumor abnormal protein is an effective indicator for early screening and prognostic evaluation of GC and can also assist the clinical diagnosis and treatment of GC.

Background Systemic inflammation relates to the initiation and progression of acute respiratory distress syndrome (ARDS). Neutrophil-to-lymphocyte ratio (NLR) and red blood cell distribution width (RDW)/albumin ratio have been reported to be predictive prognostic biomarkers in ARDS patients. However, the role of monocyte-to-lymphocyte ratio (MLR) as a prognostic inflammatory biomarker in a variety of diseases is rarely mentioned in ARDS. In this study, we explored the relationship between MLR and disease severity in ARDS patients and compared it with other indicators associated with 28-day mortality in patients with ARDS. Methods We retrospectively included 268 patients who fulfilled the Berlin definition of ARDS and were admitted to a single institute from 2016 to 2020. Clinical characteristics and experimental test data were collected from medical records within 24 h after the ARDS diagnosis. MLR, NLR, and RDW/albumin ratio levels were calculated. The primary clinical outcome was 28-day mortality. Logistic regression analysis was used to illustrate the relationship between indicators and 28-day mortality. Receiver operating characteristic (ROC) curve was used to evaluate the area under the curve (AUC), and propensity score matching (PSM) was employed to validate our findings. Results The median MLR values were higher for non-survivors than for survivors before and after matching (PP=0.001, respectively). MLR values were significantly associated with 28-day mortality (OR 2.956; 95% CI 1.873–4.665; PP Conclusions Higher MLR values were associated with 28-day mortality in patients with ARDS. Further investigation is required to verify this relationship with prospectively collected data.

Pancreatic mixed serous neuroendocrine neoplasm (PMSNN) is an extremely rare disease. Only a few cases on the surgical treatment of PMSNN have been reported in the literature, and it is unclear whether there is invasion of important peripancreatic vessels.We report the case of a 39-year-old female patient with PMSNN accompanied by invasion of important peripancreatic vessels. She underwent surgery and achieved satisfactory recovery.Abdominal enhanced CT images showed an enhanced mass with a nonenhanced cyst involving the head and body of the pancreas, which invaded important peripancreatic vessels. The lesion had been misdiagnosed and mistreated as a metastatic carcinoma before admission.CT 3-dimensional (3D) visualization reconstruction images showed intact peripancreatic vessels. Radical pancreatoduodenectomy was successfully performed and confirmed that the main blood vessels around the pancreas were only compressed or even wrapped by the mass, but not penetrated.The patient recovered well and was discharged on the 19th day after surgery. Pathological examination reported the diagnosis of PMSNN with the collision type combination and the well-differentiated grade 2 pancreatic neuroendocrine tumor. She was followed up for 18 months without any abnormalities.This case demonstrates that surgical treatment of PMSNN with invasion of peripancreatic vessels can be successful. Preoperative abdominal CT 3D visualization reconstruction is helpful in determining the degree of invasion of important peripancreatic vessels, and plays a key role in formulating an accurate surgical plan and improving patient outcome.

Introduction Emerging infectious diseases, especially the coronavirus disease identified in 2019 (COVID-19), can be complicated by a severe exacerbation in the Th17 cell-mediated IL-17 proinflammatory immune storm. This enhanced immune response plays a major role in mortality and morbidity, including neurological symptoms. We hypothesized that countering the cytokine storm with thiamine may have therapeutic efficacy in lowering the Th17 cell proinflammatory response. We used an in vitro study and corroborated those results in disease controls (DC). We developed an effective dose range and model for key pharmacokinetic measures with the potential of targeting the cytokine storm and neurological symptoms of COVID-19. Study Participants and Methods We investigated the effect of a three-week 200 mg dose of thiamine in lowering the Th17 response in sixteen DC (proinflammatory origin due to heavy alcohol drinking) patients; and eight healthy control/volunteers (HV) as a pilot clinical-translational investigation. To further investigate, we performed an in vitro study evaluating the effectiveness of thiamine treatment in lowering the Th17 proinflammatory response in a mouse macrophage cell line (RAW264.7) treated with ethanol. In this in vitro study, 100 mg/day equivalent (0.01 ug/ml) thiamine was used. Based on recent publications, we compared the results of the IL-17 response from our clinical and in vitro study to those found in other proinflammatory disease conditions (metabolic conditions, septic shock, viral infections and COVID-19), including symptoms, and dose ranges of effective and safe administration of thiamine. We developed a dose range and pharmacokinetic profile for thiamine as a novel intervention strategy in COVID-19 to alleviate the effects of the cytokine storm and neurological symptoms. Results The DC group showed significantly elevated proinflammatory cytokines compared to HV. Three-week of 200 mg daily thiamine treatment significantly lowered the baseline IL-17 levels while increased IL-22 levels (anti-inflammatory response). This was validated by an in vitro macrophage response using a lower thiamine dose equivalent (100 mg), which resulted in attenuation of IL-17 and elevation of IL-22 at the mRNA level compared to the ethanol-only treated group. In humans, a range of 79-474 mg daily of thiamine was estimated to be effective and safe as an intervention for the COVID-19 cytokine storm. A literature review showed that several neurological symptoms of COVID-19 (which exist in 45.5% of the severe cases) occur in other viral infections and neuroinflammatory states that may also respond to thiamine treatment. Discussion The Th17 mediated IL-17 proinflammatory response can potentially be attenuated by thiamine. Thiamine, a very safe drug even at very high doses, could be repurposed for treating the cytokine/immune storm of COVID-19 and the subsequent neurological symptoms observed in COVID-19 patients. Further studies using thiamine as an interventional/prevention strategy in severe COVID-19 patients could identify its precise anti-inflammatory role.

The prediction of cutterhead torque of earth pressure balance (EPB) shield machine is mainly studied. First, the idea of shield tunneling stage division is proposed. The process of shield tunneling from start to stop (or pause) is divided into start-up and stationary driving stages. Using the change point detection method based on linear regression, the separation points between start-up stage and stationary driving stage are identified from the original construction data, and the datasets of the two stages are extracted, respectively. Then, for the start-up stage, the linear regression method is suggested for the cutterhead torque prediction, since there is a strong linear correlation between the key parameters such as the cutterhead torque and the thrust force. Meanwhile, for the stationary driving stage, considering the fact that the key parameters vary smoothly and show obvious inertia, the long short-term memory (LSTM) network method can be used to establish the relationship model between cutterhead torque and other key parameters, such as the thrust force. Through the test experiments of construction data in Zhengzhou, Luoyang, and Dalian shield projects, the results show that the proposed segmented modeling method possesses good adaptability and the cutterhead torque prediction model has high prediction accuracy.

An important strategy to improve the performance of catalysts is loading nanoparticle co-catalysts of better dispersion and conductivity. In this work, the ZIF-67-derived CoP quantum dot (QD) anchored graphitized carbon skeleton as a co-catalyst is loaded on CdS nanorods (NRs), while the CoP QDs derived from ZIF-67 are anchored to the carbon skeleton under phosphation and carbonization simultaneously. The porous, graphitized carbon skeleton can not only disperse CoP QDs, increasing active sites for the hydrogen reduction reaction, but also provide electron transfer channels, promoting electron transfer and increasing conductivity. In addition, the metallicity of CoP QDs makes it possible to form Schottky junctions, which is beneficial to the electron transfer at the interface. The results show that the composite photocatalyst can extensively improve the photocatalytic activity and stability, the H2 production rate is 104 947 μmol h−1 g−1 under visible light irradiation (λ ≥ 400 nm), up to 55.2 times that of bare CdS NRs, the apparent quantum yield (AQY) reaches a high value of 32.16% at 420 nm, and the structure of the photocatalyst did not change after the reaction. This work provides an innovative method for the preparation of highly efficient noble metal-free photocatalysts for the conversion of solar energy into hydrogen energy, which has bright prospects in industrial application.

IntroductionEmerging infectious diseases, especially the coronavirus disease identified in 2019 (COVID-19), can be complicated by a severe exacerbation in the Th17 cell-mediated IL-17 proinflammatory immune storm. This enhanced immune response plays a major role in mortality and morbidity, including neurological symptoms. We hypothesized that countering the cytokine storm with thiamine may have therapeutic efficacy in lowering the Th17 cell proinflammatory response. We used anin vitrostudy and corroborated those results in disease controls (DC). We developed an effective dose range and model for key pharmacokinetic measures with the potential of targeting the cytokine storm and neurological symptoms of COVID-19.Study Participants and MethodsWe investigated the effect of a three-week 200 mg dose of thiamine in lowering the Th17 response in sixteen DC (proinflammatory origin due to heavy alcohol drinking) patients; and eight healthy control/volunteers (HV) as a pilot clinical-translational investigation. To further investigate, we performed anin vitrostudy evaluating the effectiveness of thiamine treatment in lowering the Th17 proinflammatory response in a mouse macrophage cell line (RAW264.7) treated with ethanol. In thisin vitrostudy, 100 mg/day equivalent (0.01 µg/ml) thiamine was used. Based on recent publications, we compared the results of the IL-17 response from our clinical andin vitrostudy to those found in other proinflammatory disease conditions (metabolic conditions, septic shock, viral infections and COVID-19), including symptoms, and dose ranges of effective and safe administration of thiamine. We developed a dose range and pharmacokinetic profile for thiamine as a novel intervention strategy in COVID-19 to alleviate the effects of the cytokine storm and neurological symptoms.ResultsThe DC group showed significantly elevated proinflammatory cytokines compared to HV. Three-week of 200 mg daily thiamine treatment significantly lowered the baseline IL-17 levels while increased IL-22 levels (anti-inflammatory response). This was validated by anin vitromacrophage response using a lower thiamine dose equivalent (100 mg), which resulted in attenuation of IL-17 and elevation of IL-22 at the mRNA level compared to the ethanol-only treated group. In humans, a range of 79-474 mg daily of thiamine was estimated to be effective and safe as an intervention for the COVID-19 cytokine storm. A literature review showed that several neurological symptoms of COVID-19 (which exist in 45.5% of the severe cases) occur in other viral infections and neuroinflammatory states that may also respond to thiamine treatment.DiscussionThe Th17 mediated IL-17 proinflammatory response can potentially be attenuated by thiamine. Thiamine, a very safe drug even at very high doses, could be repurposed for treating the cytokine/immune storm of COVID-19 and the subsequent neurological symptoms observed in COVID-19 patients. Further studies using thiamine as an interventional/prevention strategy in severe COVID-19 patients could identify its precise anti-inflammatory role.

Background: This study aimed to compare patient outcomes after laparoscopic distal gastrectomy with uncut Roux-en-Y reconstruction for gastric cancer between a group who underwent a duodenal stump reinforcement procedure and those who did not.Methods: Data from 233 patients with gastric cancer (GC) undergoing distal gastrectomy under laparoscope combined with uncut Roux-en-Y reconstruction were retrospectively investigated. Patients were divided into two groups. The non-reinforcement group (NR) underwent surgery from June 2014 to March 2015 with no reinforcement of the duodenal stump (n=54) and the reinforcement group (R) underwent surgery from April 2015 to June 2018 with reinforcement of the duodenal stump (n=179). In group R, the duodenum was divided using an endoscope-assisted linear stapler, which was reinforced by a purse-string suture along the duodenal staple line. Results: Duodenal stump leakage was observed in 2 patients from group NR (3.7%), while no duodenal stump leakage or fistula was detected in group R. In addition, no significant difference was observed in the patient characteristics between group NR and R.Conclusions: The incidence of duodenal stump leakage can be reduced by reinforcement with a purse-string suture.

Tunnel Boring Machine (TBM) is an effective machine for building hard-rock tunnel. However, the interaction between the cutter of TBM and rock is the key factor before engineering construction, which will cause a lot of unnecessary losses and trouble in the construction process. The reason is that the disc cutter, the core tool of TBM broken easily during the construction process. Engineering practice shows that TBM cutters’ overhaul (including inspection, replacement and repairment) in high abrasive stratum takes almost one-third time of tunnelling as well as the cost of digging construction. To address the problems mentioned above, it is necessary to study the cutter wear prediction of the high abrasive stratum. In this paper, based on the working principle of TBM, the experimental disc cutters were scaled to 1/10 of the actual cutter, and a composite wear test device model of the cutter had been manufactured. Furthermore, the engineering data was collected from the Yin Han Ji Wei project as an example to establish a TBM cutter wear prediction method. The results show that the model can be used to make wear experiments of small size cutters and the cutter life prediction of TBM.

We aimed to investigate the role of intracellular imatinib concentration in drug resistance and the expression of candidate drug transporters in gastrointestinal stromal tumor (GIST) cell lines.The imatinib concentrations were measured by the liquid chromatography-tandem mass spectrometry (LC-MS/MS). The expression of candida te drug transporters was detected by qRT-PCR.The tissue imatinib concentrations in imatinib resistant patients were significantly lower than that of sensitive patients (p .05). Compared with parental cell lines, the intracellular imatinib concentration was notably lower in imatinib resistant GIST cell lines. For candidate transporters, MRP1 and BCRP were overexpressed in resistant GIST cell lines.The intracellular imatinib concentration may play a crucial role in imatinib resistance and the intracellular differences of imatinib concentration may be induced by the upregulation of efflux transporters. Our study highlights the importance of intracellular imatinib concentration and the potential of using imatinib transporters as therapeutic targets for patients with GIST.

An oxygen deficiency modified Z-scheme CdS/WO3-x nanohybrid with MoS2 as the cocatalyst was synthesized by a microwave hydrothermal method and was used for photocatalytic hydrogen production under visible light irradiation. Loadings of WO3-x and MoS2 as well as the synthesis time of the microwave-assisted hydrothermal process were optimized, and the physicochemical and optical properties of the as-prepared photocatalysts were characterized by various techniques. Results showed that the material with 30 wt% of WO3-x, 0.1 wt% of MoS2 and a preparation time of 120 minutes exhibited the most desirable morphology and structure for hydrogen production. The maximum hydrogen production of 2852.5 μmol g-1 h-1 was achieved, which was 5.5 times that of pure CdS (519.1 μmol g-1 h-1) and 1.5 times that of CdS/30 wt% WO3-x (1879.0 μmol g-1 h-1), and the external quantum efficiency (EQE) reached 10.0% at 420 nm. The improvement of photocatalytic performance could be attributed to the Z-scheme formed between CdS and WO3-x and MoS2 as an electron trap. It is worth mentioning that the size of the composite had a negative correlation with the H2 production rate.

e16053 Background: The combination of camrelizumab, an anti-PD-1 monoclonal antibody, and apatinib, a selective VEGFR-2 inhibitor, has shown synergistic antitumor effects in G/GEJ adenocarcinoma patients. We aimed to evaluate the safety and efficacy of camrelizumab combined with low-dose apatinib and SOX in the first-line treatment of advanced G/GEJ adenocarcinoma. Methods: In this study (ChiCTR2000034109), eligible patients were diagnosed as unresectable or potentially resectable G/GEJ adenocarcinoma, HER2-negative or unknown HER2 status, and treatment-naive with inhibitors of VEGFR or PD-1/PD-L1. In dose escalation phase, 9 patients (3 in each group) were given with camrelizumab (200 mg, d1), apatinib (250 mg, qod/qd), and SOX regimen (oxaliplatin, 100/130 mg/m2, d1; S-1, 40 mg, bid, d1-14) every 3 weeks. Afterwards, the optimal combination integrated with safety and efficacy would be applied in dose expansion phase for another 33 patients. After up to 6-8 cycles of quadruple therapy, patients with complete response (CR)/partial response (PR)/stable disease (SD) would continue camrelizumab plus apatinib therapy until disease progression, intolerable toxicities, physician/patient withdrawal, or up to 2 years of camrelizumab therapy. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. The primary endpoints were maximum tolerated dose and objective response rate (ORR). Results: From Jun 12, 2020 to Jul 26, 2021, no patient reported any dose-limiting toxicity in the dose escalation phase, thus another 11 eligible patients had been enrolled to receive quadruple therapy with apatinib (250 mg, qd) and oxaliplatin (130 mg/m2, d1). The patients were characterized with a median age of 59 years (range, 46-57), 30% GEJ adenocarcinoma, 100% lymph node metastasis, and 45% liver metastases. As of Nov 30, 2021, with a median follow-up of 10.9 months (range, 4.2-17.6), safety and efficacy were assessed in 19 evaluable patients, with overall response of 18 PR and 1 SD. Confirmed ORR and DCR were 94.7% (95% CI, 71.9%-99.7%) and 100% (95% CI, 79.1%-100%), respectively. The median PFS, median DOR and estimated 1-year OS rate were 8.3 months (95% CI, 6.1-10.5), 6.7 months (95% CI, 5.9-7.5) and 59.0%, respectively, with the median OS not reached yet. Conversion surgery had been conducted in 2/19 (10.5%) patients, with one case of pathological CR and one clinical CR. Grade 3-4 treatment-related adverse events occurred in 45% of patients, with rash ranking the most frequent. No new safety signal was identified. Conclusions: Camrelizumab combined with low-dose apatinib and SOX showed high level of safety and efficacy in the first-line treatment of advanced G/GEJ adenocarcinoma. Clinical trial information: ChiCTR2000034109.