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OBJECTIVE: To determine the relationship between CD4 count and other blood indices and to explore the prediction of total lymphocyte count (TLC) for CD4 count in HIV-infected patients. METHODS: Cross-sectional study was performed for the prediction of TLC and other indices for CD4 count, and historical cohort study was performed for the TLC changes as a surrogate for CD4 changes of patients on antiretroviral therapy (ART) to further understanding the utility of TLC changes for AIDS patients' management. RESULTS: In our cross-sectional study, both TLC and white blood corpuscle count positively correlated to CD4 count, but differed in these patients. For patients on ART, the prediction of TLC for CD4 count is better than that of patient without ART. Further investigation of historical cohort study indicated that, among AIDS patients on highly active antiretroviral therapy, their TLC and haemoglobin changes also positively correlated to CD4 change, with a total correlation coefficient of 0.31 (p < 0.01) and 0.19 (p < 0.01) respectively. The prediction of TLC change for CD4 change differed each time point when patients underwent ART. CONCLUSIONS: Total lymphocyte count and its change can be used as alternative in conjunction with other indices to CD4 count and its change in the management of HIV-infected individuals in China. [ABSTRACT FROM AUTHOR]

Background: CMG901 is a novel first-in-class antibody-drug conjugate with a humanised anticlaudin 18.2 antibody linked to microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the antitumour activity and safety of CMG901 in patients with advanced gastric or gastro-oesophageal junction cancer and other solid tumours., Methods: KYM901 is a multicentre, open-label, single-arm, phase 1 trial consisting of dose-escalation and dose-expansion stages. Patients with advanced solid tumours, including gastric or gastro-oesophageal junction and pancreatic cancers, were recruited from 31 hospital sites in China. Eligible patients were aged 18 years or older, were refractory to standard therapy or had no available standard-of-care regimen, and had an Eastern Cooperative Oncology Group performance status score of 0-1, a life expectancy of at least 3 months, and at least one measurable lesion. Patients received intravenous CMG901 every 3 weeks (0·3-3·4 mg/kg in dose escalation and 2·2-3·0 mg/kg in dose expansion) until disease progression, unacceptable toxic effects, initiation of new antitumour therapy, study withdrawal, or death. Primary endpoints were adverse events and dose-limiting toxic effects in the dose-escalation phase, and objective response rate and recommended phase 2 dose in the dose-expansion phase. Confirmed objective response was defined as a partial or complete response that was verified by follow-up imaging at least 4 weeks after the initial assessment. Safety was assessed in all patients who received at least one dose of CMG901 with at least one post-dose safety evaluation. Antitumour activity was assessed in all patients who received at least one dose of CMG901 (full analysis set) and in all CMG901-treated patients with at least one post-dose imaging evaluation and no major protocol deviations (efficacy analysis set). Dose-expansion data for patients with pancreatic cancer will be published separately. Due to small sample sizes, results in patients with other solid tumours (n=2) are not planned for publication. This ongoing trial is registered with ClinicalTrials.gov, NCT04805307., Findings: Between Dec 24, 2020, and Feb 23, 2023, 27 patients were enrolled in the dose-escalation phase (median age 57·0 years [IQR 48·0-63·0]; 14 [52%] male, 13 [48%] female) and 107 patients with gastric or gastro-oesophageal junction cancer in the dose-expansion phase (median age 56·0 years [44·0-64·0]; 57 [53%] male, 50 [47%] female). As of Feb 24, 2024, one dose-limiting toxic effect (grade 3 pancreatitis) occurred at 2·2 mg/kg, and the maximum tolerated dose was not reached in the dose-escalation phase. All 27 patients reported at least one treatment-emergent adverse event, most frequently vomiting (19 [70%]), decreased appetite (16 [59%]), proteinuria (16 [59%]), and anaemia (15 [56%]), and five (19%) had drug-related grade 3 or worse treatment-emergent adverse events. In 107 patients, grade 3 or worse treatment-emergent adverse events occurred in 73 (68%) patients and serious adverse events occurred in 54 (50%) patients in dose expansion. The most common grade 3-4 adverse events were neutrophil count decreased (22 [21%]), anaemia (15 [14%]), and vomiting (11 [10%]). One treatment-related death was reported. At median follow-up of 9·0 months (IQR 4·4-12·9), among 113 patients with gastric or gastro-oesophageal junction cancer in the 2·2-3·0 mg/kg cohort full analysis set across both the dose-escalation and dose-expansion phases, the confirmed objective response rate was 28% (95% CI 20-38; 32 of 113 patients). In the 109 patients included in the efficacy analysis set, the confirmed objective response rate was 29% (95% CI 21-39; 32 of 109 patients). Based on overall safety, activity, and pharmacokinetics of CMG901, 2·2 mg/kg was the proposed recommended phase 2 dose., Interpretation: CMG901 showed a manageable safety profile and had promising antitumour activity in patients with advanced gastric or gastro-oesophageal junction cancer., Funding: KYM Biosciences., Competing Interests: Declaration of interests R-HX reports speaker fees from Bristol Myers Squibb, Roche, MerckSerono, Hutchison, Hengrui, Junshi, Qilu, CPPC, and Henlius and participates on advisory boards for Astellas, MSD, AstraZeneca, Junshi, Hengrui, BeiGene, Innovent, CPPC, and KYM Biosciences. WL and BC are employees of KYM Biosciences. RK is employee of AstraZeneca. All other authors declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: There is an unmet clinical need to enhance the response rate and safety of anti-PD-1/PD-L1-based cancer immunotherapy (IO). Herein, we presented the clinical study of IBI318 (LY3434172), a first-in-class bispecific antibody (bsAb) targeting PD-1 and PD-L1, in patients with advanced tumors., Methods: In this open-label, multicenter Phase Ia/Ib study of IBI318, the Phase Ia involved dose escalation and a safety dose expansion, while the Phase Ib focused on preliminary safety and efficacy evaluation in non-small cell lung cancer (NSCLC) and nasopharyngeal carcinoma (NPC). In Phase Ia, patients with advanced tumors received IBI318 doses ranging from 0.3 to 1200 mg every two weeks (Q2W) to determine the recommended Phase 2 dose (RP2D). In Phase Ib, NSCLC or NPC patients from five cohorts with varying treatment histories received IBI318 at the RP2D. The primary endpoint was safety and the secondary endpoints included efficacy assessed by investigators according to RECIST v1.1, pharmacokinetics, immunogenicity, and pharmacodynamics., Results: From February 11, 2019, to January 25, 2022, a total of 103 eligible patients were enrolled (Phase Ia, n = 55; Phase Ib, n = 48). The median follow-up was 10.1 months (range 0.7-28.6). The RP2D was determined to be 300 mg Q2W. Treatment-related adverse events (TRAEs) of any grades occurred in 88 patients (85.4%), while 10 patients (9.7%) experienced grade ≥ 3 TRAEs. The objective response rate (ORR) was 15.5% and the disease control rate (DCR) was 49.5% in all patients. In Phase Ib, the confirmed ORR was 45.5% in treatment-naïve NSCLC patients and 30.0% in IO-naïve NPC patients who had failed or were intolerant to platinum-based treatments., Conclusions: IBI318 demonstrated a favorable safety profile and preliminary efficacy in treatment-naïve NSCLC and IO-naïve NPC patients. Further clinical studies are needed to assess the full therapeutic potential of PD-1/PD-L1 dual inhibition with bsAbs., Competing Interests: Declarations. Ethics approval and consent to participate: The study protocol and all amendments were approved by the Institutional Review Boards of all participating institutions. All participants provided written informed consent. The study was performed in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: Xiao-Xiao Lu, Yu-Ling Chen, Wen Zhang, Hui Zhou are employees of Innovent Biologics (Suzhou) Co. Ltd. Rui-Hua Xu reports speaker fees from Bristol Myers Squibb, Roche, MerckSerono, Hutchison, Hengrui, Junshi, Qilu, CPPC, Henlius, and participates on advisory board for Astellas, MSD, AstraZeneca, Junshi, Hengrui, BeiGene. Innovent, CPPC, and Keymed., (© 2024. The Author(s).)

Small piezoelectric wind-induced vibration energy harvesting systems have been widely studied to provide long-term sustainable green energy for a large number of wireless sensor network nodes. Piezoelectric materials are commonly utilized as transducers because of their ability to produce high output power density and their simple structure, but they are prone to material fracture under large deformation conditions. This paper proposes a magnetic boundary modulated stepped beam wind energy harvesting system. On the one hand, the design incorporates a composite stepped beam with both high- and low-stiffness components, allowing for efficient vibration and electrical energy output at low wind speeds. On the other hand, a magnetic boundary constraint mechanism is constructed to prevent the piezoelectric sheet from breaking due to excessive deformation. Experiments have confirmed that the effective operational wind speed range of the harvester with magnetic boundary constraints is doubled compared to that of the harvester without magnetic boundary constraints. Furthermore, by adjusting the magnetic pole spacing of the boundary, the harvesting system can generate sufficiently high output power under high-wind-speed conditions without damaging the piezoelectric sheet.

Background: Imipenem is a highly effective carbapenem antibiotic, which is widely used in the treatment of many serious bacterial infections. At the same time, it can also cause some adverse reactions, mental abnormalities are the most concerned central nervous system adverse reactions. Different patients respond differently to imipenem, and the effect of imipenem on psychiatric disorders is unclear. Therefore, meta-analysis summarizing the results of multiple previous studies can provide stronger evidence support for clinical guidelines to guide clinical rational use of imipenem to minimize risks., Aim: To systematically review the effects of imipenem on mental-health disorders., Methods: Method in Cochrane Library, Web of science, PubMed, ProQuest, and China's biomedical literature databases Wanfang, Weipu and China HowNet, the related literatures about the controlled trials of imipenem-induced mental disorders from the establishment of the database to May 2024 were searched; the included literatures were analyzed using RevMan 5.4 software; and the heterogeneity among the studies was also discussed., Results: After reviewing the literature published between 2003 and 2017, seven controlled trials with a total of 550 patients were included, with 273 and 277 patients in the control and experimental groups, respectively. The sample size of the study ranged from a minimum of 30 cases to a maximum of 61 cases. Patients in the experimental group were treated with imipenem while the control group was treated with conventional drugs. Meta-analysis showed that the incidence of mental disorders in the experimental group was higher than that in the control group (odds ratio = 3.66, 95% confidence interval: 1.11-12.11, P = 0.030); however, there was no significant difference in the incidence of adverse reactions between the two groups (odds ratio = 0.05, 95% confidence interval: 0.00 to 0.10, P = 0.060). Funnel diagrams showed that the scattered points of each study were symmetrical and distributed in an inverted funnel shape; therefore, there was no publication bias., Conclusion: Imipenem can cause mental disorders in patients. However, the low quality of the included literature may have affected the final results. Therefore, it is necessary to conduct a high-quality randomized controlled study with multiple samples to further confirm the mechanism of imipenem-induced mental disorders and provide effective guidance for clinical treatment., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: APG-1387 is a novel second mitochondrial-derived activator of caspases mimetic, small-molecule inhibitor targeting inhibitor of apoptosis proteins. We report results from two phase I trials evaluating the tolerability, safety, and antitumor activity of APG-1387 monotherapy and APG-1387 plus toripalimab [a programmed cell death 1 (PD-1) inhibitor] for advanced solid tumors., Patients and Methods: Participants aged ≥18 years who had histologically confirmed advanced solid tumors with no appropriate standard of care (or refractory to standard care) were eligible. Patients received escalating intravenous doses of APG-1387 alone or combined with fixed-dose toripalimab (240 mg every 3 weeks) in a '3 + 3' design. Primary endpoints were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) in the monotherapy trial, and recommended phase II dose (RP2D) in the combination therapy trial. Secondary endpoints included the pharmacokinetic and pharmacodynamic profiles and preliminary efficacy in both trials., Results: In the monotherapy trial, 28 subjects were enrolled and received ≥1 treatment cycle. No DLT was reported among the 28 subjects, and the MTD was not reached. One participant (3.6%) had a grade ≥3 treatment-related adverse event (TRAE) of alanine aminotransferase elevation. In efficacy analysis of 23 participants, none achieved an objective response, and the disease control rate was 21.7%. In the combination trial, 22 subjects were enrolled and included in all analyses. There was one DLT of grade 3 lipase elevation. The MTD was not reached. Four grade ≥3 TRAEs occurred in three participants (13.6%), with the most common being lipase elevation (n = 2). The RP2D was 45 mg weekly. The objective response rate was 13.6%, with complete response achieved in one subject, and the disease control rate was 54.5%., Conclusions: APG-1387 45 mg weekly plus toripalimab was well tolerated and is recommended for further study, with preliminary clinical activity observed in study participants with advanced solid tumors., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pancreatic cancer is one of the most lethal cancers with significant radioresistance and tumor repopulation after radiotherapy. As a type of short non-coding RNA that regulate various biological and pathological processes, miRNAs might play vital role in radioresistance. We found by miRNA sequencing that microRNA-26a (miR-26a) was upregulated in pancreatic cancer cells after radiation, and returned to normal state after a certain time. miR-26a was defined as a tumor suppressive miRNA by conventional tumor biology experiments. However, transient upregulation of miR-26a after radiation significantly promoted radioresistance, while stable overexpression inhibited radioresistance, highlighting the importance of molecular dynamic changes after treatment. Mechanically, transient upregulation of miR-26a promoted cell cycle arrest and DNA damage repair to promote radioresistance. Further experiments confirmed HMGA2 as the direct functional target, which is an oncogene but enhances radiosensitivity. Moreover, PTGS2 was also the target of miR-26a, which might potentiate tumor repopulation via delaying the synthesis of PGE2. Overall, this study revealed that transient upregulation of miR-26a after radiation promoted radioresistance and potentiated tumor repopulation, highlighting the importance of dynamic changes of molecules upon radiotherapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Paclitaxel resistance is associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and currently, there is no promising drug for paclitaxel resistance. In this study, we investigated the molecular mechanisms underlying the chemoresistance in human NSCLC-derived cell lines. We constructed paclitaxel-resistant NSCLC cell lines (A549/PR and H460/PR) by long-term exposure to paclitaxel. We found that triptolide, a diterpenoid epoxide isolated from the Chinese medicinal herb Tripterygium wilfordii Hook F, effectively enhanced the sensitivity of paclitaxel-resistant cells to paclitaxel by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we identified the SHH-initiated Hedgehog signaling pathway playing an important role in this process. We demonstrated that triptolide directly bound to HNF1A, one of the transcription factors of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. In NSCLC tumor tissue microarrays and cancer network databases, we found a positive correlation between HNF1A and SHH expression. Our results illuminate a novel molecular mechanism through which triptolide targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This study suggests the potential clinical application of triptolide and provides promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. Schematic diagram showing that triptolide overcomes paclitaxel resistance by mediating inhibition of the HNF1A/SHH/ABCB1 axis., (© 2024. The Author(s).)

Background: Endometriosis is a common benign gynecological disease that causes dysmenorrhea in women of childbearing age. Malignant tumors derived from endometriosis are rarely reported and are found in only 1% of all patients with endometriosis. Here, we report a well-differentiated squamous cell carcinoma (SCC) caused by squamous metaplasia of endometriosis that co-occurred in the uterus and ovaries., Case Summary: A 57-year-old postmenopausal woman had a 6-month history of irregular uterine bleeding. The uterus and adnexa were examined by computed tomography, and there were two solid cystic masses in the pelvis and right adnexa. Histological findings of surgical specimens showed well-differentiated SCC arising from squamous metaplasia of ectopic endometrial glands in the uterus and ovaries. The patient received chemotherapy after surgery and was followed up for 3 mo without metastasis., Conclusion: The continuity between ectopic endometrial glands and SCC supports that SCC originates from ectopic endometrial glands with metaplasia towards squamous epithelium., Competing Interests: Conflict-of-interest statement: All the authors report o relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Objectives: The relationship between dietary folate intake and non-alcoholic fatty liver disease (NAFLD) is controversial. This study aimed to investigate the relationship between dietary folate equivalent (DFE) intake and NAFLD in U.S. adults., Methods and Study Design: Data from the National Health and Nutrition Examination Survey (NHANES) 2007-2014 were used. NAFLD was defined as a US fatty liver index (FLI) value ≥30. DFE intake was assessed by two 24-hour dietary recall interviews. Multivariable logistic regression models and restricted cubic spline models were used to investigate the association between DFE intake and NAFLD risk., Results: A total of 6,603 adult participants were included in this study. After adjusting for multiple confounding factors, the odds ratios and 95% confidence intervals of NAFLD for the highest quartile versus lowest quartile of DFE intake was 0.77(0.59-0.99). In stratified analyses by sex, age, and body mass index (BMI), there were statistically significant negative associations between DFE intake and NAFLD risk in women and participants with BMI ≥25. Dose-response analysis indicated a negative linear correlation between DFE intake and NAFLD risk., Conclusions: Dietary folate equivalent intake is negatively associated with NAFLD risk in the general U.S. adult population.

The phenolics are the main bioactive substances of Huangshan Gongju, a famous chrysanthemum of China, but their digestive characteristics are still unknown. To explore the digestive properties of Huangshan Gongju phenolics, the flower was extracted and subjected to simulated digestions, and their phenolic profile and activity were analyzed. The results indicated that the total phenolics content and antioxidant activity of the extract varied with the simulated digestion steps, and they generally decreased in the oral and small intestine digestions but increased in the gastric digestion, and high correlations were detected between the total phenolics content and antioxidant activity (0.873 < r < 0.979, p < .01). The change of phenolic profile during the simulated digestions was similar to that of total phenolics content, and six individual phenolics were identified and quantified, and three of them, including chlorogenic acid, apigenin-7-O-rutinoside, and apigenin-7-O-6″-acetylglucoside showed higher recovery (>64.29%), implying they may be the main functional phenolics of Huangshan Gongju. PRACTICAL APPLICATIONS: This study proved that most phenolics in Huangshan Gongju were relatively stable during digestion. The finding may guarantee the application of Huangshan Gongju in the field of functional foods., (© 2022 Wiley Periodicals LLC.)

PIK3CA mutations are highly prevalent in solid tumors. Targeting phosphatidylinositol 3-kinase α is therefore an attractive strategy for treating cancers harboring PIK3CA mutations. Here, we report the results from a phase Ia, open label, dose-escalation and -expansion study (NCT03544905) of CYH33, a highly selective PI3Kα inhibitor, in advanced solid tumors. The primary outcomes were the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of CYH33. The secondary outcomes included evaluation of pharmacokinetics, preliminary efficacy and changes in pharmacodynamic biomarkers in response to CYH33 treatment. The exploratory outcome was the relationship between the efficacy of CYH33 treatment and tumor biomarker status, including PIK3CA mutations. A total of 51 patients (19 in the dose escalation stage and 32 in the dose expansion stage) including 36 (70.6%) patients (4 in the dose escalation stage and 32 in the dose expansion stage) with PIK3CA mutations received CYH33 1-60 mg. The MTD of CYH33 was 40 mg once daily, which was also selected as the RP2D. The most common grade 3/4 treatment-related adverse events were hyperglycemia, rash, platelet count decreased, peripheral edema, and fatigue. Forty-two out of 51 patients were evaluable for response, the confirmed objective response rate was 11.9% (5/42). Among 36 patients harboring PIK3CA mutations, 28 patients were evaluable for response, the confirmed objective response rate was 14.3% (4/28). In conclusion, CYH33 exhibits a manageable safety profile and preliminary anti-tumor efficacy in solid tumors harboring PIK3CA mutations., (© 2022. The Author(s).)

Background: CT053PTSA is a novel tyrosine kinase inhibitor that targets MET, AXL, VEGFR2, FLT3 and MERTK. Here, we present preclinical data about CT053PTSA, and we conducted the first-in-human (FIH) study to evaluate the use of CT053PTSA in adult patients with pretreated advanced solid tumors., Methods: The selectivity and antitumor activity of CT053PTSA were assessed in cell lines in vitro through kinase and cellular screening panels and in cell line-derived tumor xenograft (CDX) and patient-derived xenograft (PDX) models in vivo . The FIH, phase I, single-center, single-arm, dose escalation (3 + 3 design) study was conducted, patients received at least one dose of CT053PTSA (15 mg QD, 30 mg QD, 60 mg QD, 100 mg QD, and 150 mg QD). The primary objectives were to assess safety and tolerability, to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended dose of CT053PTSA for further study. Secondary objectives included pharmacokinetics, antitumor activity., Results: CT053 (free-base form of CT053PTSA) inhibited MET, AXL, VEGFR2, FLT3 and MERTK phosphorylation and suppressed tumor cell angiogenesis by blocking VEGF and HGF, respectively, in vitro . Moreover, cell lines with high MET expression exhibited strong sensitivity to CT053, and CT053 blocked the MET and AXL signaling pathways. In an in vivo study, CT053 significantly inhibited tumor growth in CDX and PDX models. Twenty eligible patients were enrolled in the FIH phase I trial. The most common treatment-related adverse events were transaminase elevation (65%), leukopenia (45%) and neutropenia (35%). DLTs occurred in 3 patients, 1/6 in the 100 mg group and 2/4 in the 150 mg group, so the MTD was set to 100 mg. CT053PTSA was rapidly absorbed after the oral administration of a single dose, and the C max and AUC increased proportionally as the dose increased. A total of 17 patients in this trial underwent tumor imaging evaluation, and 29.4% had stable disease., Conclusions: CT053PTSA has potent antitumor and antiangiogenic activity in preclinical models. In this FIH phase I trial, CT053PTSA was well tolerated and had a satisfactory safety profile. Further trials evaluating the clinical activity of CT053PTSA are ongoing., Competing Interests: Authors NX, NK, YLZ, QZ and YZJ are employed by Sunshine Lake Pharma Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ma, Liu, Zhang, Chen, Chen, Liu, Huang, Yang, Fang, Xi, Kang, Zhuang, Zhang, Jiang, Zhang and Zhao.)

A cascade 6-endo-dig cyclization reaction was developed for the switchable synthesis of halogen and non-halogen-functionalized pyrazolo[3,4- b ]pyridines from 5-aminopyrazoles and alkynyl aldehydes via C≡C bond activation with silver, iodine, or NBS. In addition to its wide substrate scope, the reaction showed good functional group tolerance as well as excellent regional selectivity. This new protocol manipulated three natural products, and the arylation, alkynylation, alkenylation, and selenization of iodine-functionalized products. These reactions demonstrated the potential applications of this new method.

Bipolar disorder (BD) is a complex psychiatric disorder with strong heritability. Identification of new BD risk genes will help determine the mechanism underlying disease pathogenesis. In the present study, we carried out whole genome sequencing for a Chinese BD family with three affected members and three unaffected members, and identified multiple candidate causal variations, including a frameshift mutation in the GOLGB1 gene. Since a GOLGB1 missense mutation was also found in another BD pedigree, we carried out functional studies by downregulating Golgb1 expression in the brain of neonatal mice. Golgb1 deficiency had no effect on anxiety, memory, and social behaviors in young adult mice. However, we found that young adult mice with Golgb1 deficiency exhibited elevated locomotor activity and decreased depressive behaviors in the tail suspension test and the sucrose preference test, but increased depressive behaviors in the forced swim test, resembling the dual character of BD patients with both mania and depression. Moreover, Golgb1 downregulation reduced PSD93 levels and Akt phosphorylation in the brain. Together, our results indicate that GOLGB1 is a strong BD risk gene candidate whose deficiency may result in BD phenotypes possibly through affecting PSD93 and PI3K/Akt signaling., (© 2022. The Author(s).)

A high efficiency protocol was developed for the synthesis of 2,5-disubstituted oxazoles via iodine-promoted oxidative domino cyclization. These reactions were performed with readily available methyl azaarenes and α-amino ketones under metal-free conditions. This protocol is a simple method with high functional group compatibility, a wide range of substrates, and excellent yield, providing a new way to synthesize azaarene-attached oxazoles.

The cytosolic DNA-sensing cGAS-STING pathway has been proved to be involved in tumor progression and influence the effect of cancer immunotherapy. However, little attentions have been paid to the role of cGAS-STING pathway on cancer stemness. Herein, we found that the cGAS-STING pathway was activated in different tumor cells. cGAS- or STING-knockout impaired the capability of tumor formation in vivo and tumorsphere formation in vitro. In addition, loss of cGAS-STING cascade promoted tumor apoptosis, but inhibited tumor growth and metastasis. We further demonstrated that cGAS-STING pathway potentiated tumor formation by sustaining cancer stemness. Moreover, analysis of RNA-seq showed that cGAS-STING pathway maintained cancer stemness probably by activating STAT3. Our findings highlight the role of intrinsic activation of cGAS-STING pathway in tumorigenesis, and reveal a new mechanism of its regulation of tumor progression via sustaining cancer stemness through STAT3 activation., (Copyright © 2022. Published by Elsevier Inc.)

Background: Nonketotic hyperglycinemia is a metabolic disease with autosomal recessive inheritance due to the glycine cleavage system (GCS) defect leading to the accumulation of glycine that causes severe and fatal neurological symptoms in the neonatal period. Methods: Genomic DNA was extracted from the peripheral blood of the female proband and her family members. The AMT variation was detected in the patient by whole-exome sequencing (WES), and the variant was validated by Sanger sequencing. Results: The WES showed that there were novel compound heterozygous frameshift variations c.977delA (p.Glu326Glyfs*12) and c.982&#95;983insG (p.Ala328Glyfs*22) in exon eight of the AMT gene (NM&#95;000481.4) in the proband. Genetic analysis showed that the former was inherited from the mother, and the latter was inherited from the father. Conclusion: We report the novel compound heterozygous variation of the AMT gene in a Chinese girl with NKH by WES, which has never been reported previously. Our case expanded the AMT gene mutation spectrum, further strengthened the understanding of NKH, and deepened the genetic and clinical heterogeneity of the disease. However, the study of treatment and prognosis is still our future challenge and focus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Hui, Zhang, Chen, Zhang, Zheng, Feng, Wang, Ding, Chen, Ma, Liu and Hao.)

Traditional optical switches relying on the weak, volatile thermo-optic or electro-optic effects of Si or SiN waveguides show a high consumption and large footprint. In this paper, we reported an electric-driven phase change optical switch consisting of a Si waveguide, Ge 2 Sb 2 Te 5 (GST) thin film and graphene heater suitable for large-scale integration and high-speed switching. The reversible transition between the amorphous and crystalline states was achieved by applying two different voltage pulses of 1.4 V (SET) and 4 V (RESET). The optical performance of the proposed switch showed a high extinction ration of 44-46 dB in a wide spectral range (1525-1575 nm), an effective index variation of Δ n eff  = 0.49 and a mode loss variation of Δ α  = 15 dB μ m -1 at the wavelength of 1550 nm. In thermal simulations, thanks to the ultra-high thermal conductivity of graphene, the proposed switch showed that the consumption for the SET process was only 3.528 pJ with a 1.4 V pulse of 5 ns, while a 4 V pulse of 1.5 ns was needed for RESET process with a consumption of 1.05 nJ. Our work is helpful to analyze the thermal-conduction phase transition process of on-chip phase change optical switches, and the design of the low-energy-consumption switch is conducive to the integrated application of photonic chips., (© 2021 IOP Publishing Ltd.)

The effect of anti-programmed cell death 1 (PD-1) antibody in Epstein-Barr virus-associated gastric cancer (EBVaGC) was debatable, and no predictive biomarkers for efficacy have been reported. Public reports on anti-PD-1 antibody monotherapy-treated EBVaGC with available programmed death ligand-1 (PD-L1) expression status were summarized and analyzed. Relevance with clinicopathologic characteristics of PD-L1 expression by immunohistochemistry was analyzed in 159 patients diagnosed with EBVaGC. Relevance with genomic transcriptome and mutation profile of PD-L1 status in EBVaGC was assessed with three datasets, the cancer genome atlas (TCGA), Gene Expression Omnibus (GEO) GSE51575, and GSE62254. Based on the data from 8 reports, patients with positive PD-L1 expression (n = 30) had significantly superior objective response rate (ORR) than patients with negative PD-L1 expression (n = 9) (63.3% vs. 0%, P = .001) in EBVaGC receiving anti-PD-1 antibody monotherapy. PD-L1 positivity was associated with less aggressive clinicopathological characteristics and was an independent predictor for a longer disease-free survival (hazard ratio [ HR ] and 95% CI : 0.45 [0.22-0.92], P = .03) and overall survival ( HR and 95% CI : 0.17 [0.06-0.43], P < .001). Analysis of public EBVaGC transcriptome and mutation datasets revealed enhanced immune-related signal pathways in PD-L1 high EBVaGC and distinct mutation patterns in PD-L1 low EBVaGC. PD-L1 positivity indicates a subtype of EBVaGC with 'hot' immune microenvironment, lower aggressiveness, better prognosis, and higher sensitivity to anti-PD-1 immunotherapy., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: We prepared an anti-p21Ras scFv which could specifically bind with mutant and wild-type p21Ras. However, it cannot penetrate the cell membrane, which prevents it from binding to p21Ras in the cytoplasm. Here, the RGD4C peptide was used to mediate the scFv penetration into tumor cells and produce antitumor effects., Methods: RGD4C-EGFP and RGD4C-p21Ras-scFv recombinant expression plasmids were constructed to express fusion proteins in E. coli, then the fusion proteins were purified with HisPur Ni-NTA. RGD4C-EGFP was used as reporter to test the factors affecting RGD4C penetration into tumor cell. The immunoreactivity of RGD4C-p21Ras-scFv toward p21Ras was identified by ELISA and western blotting. The ability of RGD4C-p21Ras-scFv to penetrate SW480 cells and colocalization with Ras protein was detected by immunocytochemistry and immunofluorescence. The antitumor activity of the RGD4C-p21Ras-scFv was assessed with the MTT, TUNEL, colony formation and cell migration assays. Chloroquine (CQ) was used an endosomal escape enhancing agent to enhance endosomal escape of RGD4C-scFv., Results: RGD4C-p21Ras-scFv fusion protein were successfully expressed and purified. We found that the RGD4C fusion protein could penetrate into tumor cells, but the tumor cell entry of was time and concentration dependent. Endocytosis inhibitors and a low temperature inhibited RGD4C fusion protein endocytosis into cells. The change of the cell membrane potential did not affect penetrability. RGD4C-p21Ras-scFv could penetrate SW480 cells, effectively inhibit the growth, proliferation and migration of SW480 cells and promote this cells apoptosis. In addition, chloroquine (CQ) could increase endosomal escape and improve antitumor activity of RGD4C-scFv in SW480 cells., Conclusion: The RGD4C peptide can mediate anti-p21Ras scFv entry into SW480 cells and produce an inhibitory effect, which indicates that RGD4C-p21Ras-scFv may be a potential therapeutic antibody for the treatment of ras-driven cancers.

Tauopathies are a group of neurodegenerative diseases characterized by hyperphosphorylation of the microtubule-binding protein, tau, and typically feature axon impairment and synaptic dysfunction. Cyclin-dependent kinase5 (Cdk5) is a major tau kinase and its activity requires p35 or p25 regulatory subunits. P35 is subjected to rapid proteasomal degradation in its membrane-bound form and is cleaved by calpain under stress to a stable p25 form, leading to aberrant Cdk5 activation and tau hyperphosphorylation. The type Ib transmembrane protein RPS23RG1 has been implicated in Alzheimer's disease (AD). However, physiological and pathological roles for RPS23RG1 in AD and other tauopathies are largely unclear. Herein, we observed retarded axon outgrowth, elevated p35 and p25 protein levels, and increased tau phosphorylation at major Cdk5 phosphorylation sites in Rps23rg1 knockout (KO) mice. Both downregulation of p35 and the Cdk5 inhibitor roscovitine attenuated tau hyperphosphorylation and axon outgrowth impairment in Rps23rg1 KO neurons. Interestingly, interactions between the RPS23RG1 carboxyl-terminus and p35 amino-terminus promoted p35 membrane distribution and proteasomal degradation. Moreover, P301L tau transgenic (Tg) mice showed increased tau hyperphosphorylation with reduced RPS23RG1 levels and impaired axon outgrowth. Overexpression of RPS23RG1 markedly attenuated tau hyperphosphorylation and axon outgrowth defects in P301L tau Tg neurons. Our results demonstrate the involvement of RPS23RG1 in tauopathy disorders, and implicate a role for RPS23RG1 in inhibiting tau hyperphosphorylation through homeostatic p35 degradation and suppression of Cdk5 activation. Reduced RPS23RG1 levels in tauopathy trigger aberrant Cdk5-p35 activation, consequent tau hyperphosphorylation, and axon outgrowth impairment, suggesting that RPS23RG1 may be a potential therapeutic target in tauopathy disorders.

Objective: CircRNAs are vital factors involved in the pathological processes. This study aims to elucidate the biological functions of hsa&#95;circ&#95;0000337 in affecting the malignant progress of glioma., Patients and Methods: Relative levels of hsa&#95;circ&#95;0000337 in 45 cases of glioma and 24 cases of normal tissues were tested. The correlation between hsa&#95;circ&#95;0000337 and clinical features of glioma was assessed. Proliferative and metastatic abilities of U87 and U251 cells regulated by hsa&#95;circ&#95;0000337 were examined by 5-Ethynyl-2'-deoxyuridine (EdU) and transwell assay, respectively. Potential molecular mechanism of hsa&#95;circ&#95;0000337 on regulating glioma cell functions was clarified by bioinformatic analysis, which was further verified through rescue experiments., Results: Hsa&#95;circ&#95;0000337 was highly expressed in glioma cases. Its level was correlated to poor prognosis of glioma. In vitro experiments obtained the conclusion that hsa&#95;circ&#95;0000337 accelerated proliferative and metastatic abilities of glioma cells. Serving as a ceRNA, hsa&#95;circ&#95;0000337 sponged miRNA-942-5p to upregulate MAT2A, thus inducing the malignant phenotypes of glioma., Conclusions: Hsa&#95;circ&#95;0000337/miRNA-942-5p / MAT2A axis is responsible for the deterioration of glioma. Hsa&#95;circ&#95;0000337 may be a potential therapeutic target for glioma.

On-chip photonics devices relying on the weak, volatile thermo-optic or electro-optic effects of silicon usually suffer from high insertion loss (IL) and a low refractive index coefficient. In this paper, we designed two novel 1 × 1 and 1 × 2 phase-change optical switches based on a signal-mode Si waveguide integrated with a Ge 2 Sb 2 Te 5 (GST) top clad layer, respectively. The three-state switch including amorphous GST (a-GST), face centered cubic crystalline phase (FCC-GST) and hexagonal crystalline phase (HCP-GST) operated by utilizing the dramatic difference in the optical constants between the amorphous and two crystalline phases of GST. In the case of the 1 × 1 optical switch, an extinction ratio (ER) of 8.9 dB and an extremely low IL of 0.8 dB were achieved using an optimum GST length of only 2 μm. While for the 1 × 2 optical switch, low ILs in the range of 0.15 ∼ 0.35 dB for both 'cross' (a-GST) and 'bar' (FCC-GST and HCP-GST) states were also obtained. Additionally, we found that both ILs and mode losses of the switch with HCP-GST were about half lower than those with FCC-GST, which means FCC-GST could be instituted by HCP-GST in the traditional ovonic switch with the consideration of low loss. This research provides the fundamental understanding for the realization of low loss and non-volatile Si-GST hybrid optical switches, with potential for future communication networks.

Transforming growth factor-β1 (TGF-β1) is involved in human cancer development and progression. Nonetheless, the role of TGF-β1 as regards peritoneal metastasis of gastric cancer has not been completely characterized. In the present study, we investigated the exact role of TGF-β1 on peritoneal metastasis of gastric cancer. The results indicated that human peritoneal mesothelial cells (HPMCs) exposed to TGF-β1 or serum-free conditional medium (SF-CM) of SGC7901 that produced a large amount of TGF-β1 became exfoliated, apoptosis and exhibited signs of injury, and the tumor-mesothelial cell adhesion significantly increased. Connective tissue growth factor (CTGF) expression was also increased when HPMCs were exposed to TGF-β1 or SF-CM of SGC7901. However, these effects were significantly decreased when HPMCs were exposed to SF-CM of SGC7901-TGFβS, a TGF-β1 knockdown stable cell line. Animal studies revealed that nude mice injected with SGC7901-TGFβS cells featured a smaller number of peritoneal seeding nodules and lower expression of CTGF in ascites than the control cell lines. These findings suggest that TGF-β1 promotes peritoneal metastasis of gastric cancer and induces CTGF expression. Therefore, blockage of TGF-β1 or TGF-β1 signaling pathway might prevent and treat peritoneal metastasis of gastric cancer., (© 2020 The Author(s).)

The article "Effects of miR-155 on proliferation and apoptosis by regulating FoxO3a/BIM in liver cancer cell line HCCLM3, by W.-W. Liao, C. Zhang, F.-R. Liu, W.-J. Wang, published in Eur Rev Med Pharmacol Sci 2018; 22 (5): 1277-1285. DOI: 10.26355/eurrev&#95;201803&#95;14468. PMID: 29565484." has been withdrawn from the authors. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/14468.

Background: Tumor repopulation is a major cause of radiotherapy failure. Previous investigations highlighted that dying tumor cells played vital roles in tumor repopulation through promoting proliferation of the residual tumor repopulating cells (TRCs). However, TRCs also suffer DNA damage after radiotherapy, and might undergo mitotic catastrophe under the stimulation of proliferative factors released by dying cells. Hence, we intend to find out how these paradoxical biological processes coordinated to potentiate tumor repopulation after radiotherapy., Methods: Tumor repopulation models in vitro and in vivo were used for evaluating the therapy response and dissecting underlying mechanisms. RNA-seq was performed to find out the signaling changes and identify the significantly changed miRNAs. qPCR, western blot, IHC, FACS, colony formation assay, etc. were carried out to analyze the molecules and cells., Results: Exosomes derived from dying tumor cells induced G1/S arrest and promoted DNA damage response to potentiate survival of TRCs through delivering miR-194-5p, which further modulated E2F3 expression. Moreover, exosomal miR-194-5p alleviated the harmful effects of oncogenic HMGA2 under radiotherapy. After a latent time, dying tumor cells further released a large amount of PGE2 to boost proliferation of the recovered TRCs, and orchestrated the repopulation cascades. Of note, low-dose aspirin was found to suppress pancreatic cancer repopulation upon radiation via inhibiting secretion of exosomes and PGE2., Conclusion: Exosomal miR-194-5p enhanced DNA damage response in TRCs to potentiate tumor repopulation. Combined use of aspirin and radiotherapy might benefit pancreatic cancer patients.

Studies have shown that the crystallization phase state of Ge 2 Sb 2 Te 5 (GST) can be reversibly modulated by femtosecond (fs) laser multiple pulses, which have excellent applications in reconfigurable multi-level operation fields. In this study, the temporal-spatial crystalline evolution dynamics of amorphous GST film is investigated during two fs laser pulses excitation through a pump-probe shadowgraph imaging technique. A quasi-amorphous phase state, which is different from that in the initial as-deposited amorphous GST, is emerged through the first fs laser pulse excitation with a pulse energy lower than crystallization threshold. The experimental results reveal that a crystallization enhancement effect can be induced through the second pulse excitation based on this quasi-amorphous surface structure. The stimulative cluster generated in the quasi-amorphous reduces the amorphous-to-crystalline phase transition threshold for the second fs laser pulse irradiation. The spatially-resolved phase-transition threshold extension effect in a horizontal direction is proposed with the increasing pulse number to summarize the mechanism of the crystallization enhancement effect. The specific-grain-appearance (coarse grains and fine grains representing different phase transition approach) distributed area induced by single and double fs laser pulses irradiation are experimentally demonstrated corresponding to threshold extension theory.

Background: Depression is associated with inflammation and Alzheimer's disease (AD). However, detailed molecular mechanisms linking mood, neuroinflammation and AD remain unclear. Although changes in peripheral inflammatory factors such as Interleukin 18 (IL18), and AD-associated amyloid-β (Aβ) peptides have been linked to depression, a solid relationship between these factors in depressive disorder has yet to be established. This study aims to further determine whether plasma IL18, Aβ40, Aβ42, and the AD-associated tangle component Tau, as well as IL18 single nucleotide polymorphisms (SNPs) may be biomarkers for depression., Methods: We measured plasma IL18, Aβ40, Aβ42, and Tau in 64 depressive patients and 75 healthy controls, and characterized genotypes of three IL18 SNPs (rs187238, rs1946518 and rs1946519) in these subjects. Comparisons between depressive patients and controls were carried out in males, in females or in combination. Regression analyses were conducted to examine the correlation between these parameters., Results: We found that none of the plasma levels of IL18, Aβ40, Aβ42, and Tau, the ratio of Aβ42/Aβ40, and the genotypes of IL18 SNPs were significantly different between combined depressive patients and combined healthy controls, or between male depressive patients and male controls. However, IL18 levels were less in females than in males in healthy people and were significantly increased in female depressive patients compared to female controls. Moreover, IL18 and standardized IL18 were correlated with standardized Aβ42/Aβ40 ratio and standardized Tau in depressive patients., Conclusions: Plasma IL18 may be a potential biomarker for depression in women., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

A novel spatial-resolved electrochemiluminescent (ECL) ratiometry for cardiac troponin I (cTnI) analysis was developed using resonance energy transfer (RET) and a coreactant consumption strategy for signal amplification. Specifically, the spatial-resolved dual-disk glassy carbon electrodes were modified with CdS nanowires (CdS NWs) and luminol-gold nanoparticles (L-Au NPs) as potential-resolved ECL emitters, respectively. After stepwise immobilization of anti-cTnI and bovine serum albumin on the dual-disk electrodes, the CdS NWs-based electrode, with varied concentrations of cTnI, was used to provide a working signal, whereas the L-Au NPs-based electrode, with a fixed amount of cTnI, was employed to provide the reference signal. To efficiently amplify the working signal on the CdS NWs-based electrode, an anti-cTnI-reduced graphene oxide-gold nanoparticles-catalase probe (anti-cTnI-rGO-Au NPs-CAT) was loaded onto the electrode to form a sandwich immunocomplex. The RET from CdS NWs to Au NPs and the coreactant (i.e. H2O2) consumption by the CAT generate a significant ECL decrease on the CdS NWs-based electrode in the presence of cTnI. This novel and sensitive ratiometric detection mode for cTnI was achieved using the ratio values of the working signal of the CdS NWs-based electrode and the reference signal of the L-Au NPs-based electrode. The integration of RET and coreactant consumption strategy in the designed spatial-resolved ratiometric platform endows the immunosensor with a wide linear range of 5.0 × 10-13 - 1.0 × 10-7 g mL-1 and a low detection limit of 0.10 pg mL-1 for cTnI. Furthermore, the method exhibits high accuracy and sensitivity for cTnI determination in human serum samples.

Background: This study will assess the effectiveness and safety of acupuncture for the treatment of patients with diabetic peripheral neuropathy (DPN)., Methods: We will comprehensively search electronic databases of MEDLINE, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, and China National Knowledge Infrastructure from their inception to July 1, 2019. We will also search grey literature to avoid missing any potential studies. Randomized controlled trials related to acupuncture for the treatment of DPN will be included. All record literatures are searched without language limitation. Two researchers will independently carry out research selection, data extraction, and research quality evaluation. We will perform RevMan 5.3 software for statistical analysis., Results: Primary outcomes consist of severity of neuropathy and pain intensity. Secondary outcomes include diabetes mellitus duration, body mass index, HbA1c level, blood glucose levels, and adverse events., Conclusion: The findings of this study will summarize recent evidence for the effectiveness and safety of acupuncture for the treatment of patients with DPN., Ethics and Dissemination: We will not analyze individual data, thus no ethic approval is needed. The results of this study are expected to be published at a peer-reviewed journal., Prospero Registration Number: PROSPERO CRD42019139635.

Background: Although synaptic impairment is a prerequisite to cognitive deficiencies in Alzheimer's disease (AD), mechanisms underlying the dysregulation of essential synaptic scaffolding components and their integrity remain elusive. RPS23RG1 is a newly identified protein implicated in AD. However, the physiological function of RPS23RG1 has yet to be determined., Methods: We investigated the role of RPS23RG1 in maintaining synaptic structure and function in cell cultures and in Rps23rg1 knockout mice and determined whether targeting RPS23RG1-mediated pathways has therapeutic potential in APP/PS1 AD model mice., Results: Deletion of the Rps23rg1 gene resulted in severe memory deficits and impairment of postsynaptic structure and function, with marked reductions in postsynaptic densities-93 and -95 (PSD-93 and PSD-95) levels. RPS23RG1 interacted with PSD-93/PSD-95 through its intracellular domain, consequently sequestering PSD-93/PSD-95 from murine double minute 2-mediated ubiquitination and degradation, thereby maintaining synaptic function. Restoration of PSD-93/PS-D95 levels reversed synaptic and memory deficits in Rps23rg1 knockout mice. We further observed attenuated RPS23RG1 expression in human AD, which positively correlated with PSD-93/PSD-95 levels. Importantly, an RPS23RG1-derived peptide comprising a unique PSD-93/PSD-95 interaction motif rescued synaptic and cognitive defects in Rps23rg1 knockout and AD mouse models., Conclusions: Our results reveal a role for RPS23RG1 in maintaining synaptic integrity and function and provide a new mechanism for synaptic dysfunction in AD pathogenesis. This demonstrates that RPS23RG1-mediated pathways show good therapeutic potential in AD intervention., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Pseudomonas aeruginosa biofilm lifestyle exhibits multidrug resistance in chronic bacterial infections. Alternative antimicrobial compounds or combination drug therapies must be urgently developed. In this work, the antibiofilm effect of Ag nanoparticle (AgNP) combined with the quorum sensing inhibitor (QSI) 4-nitropyridine N-oxide (4NPO) on P. aeruginosa biofilms was investigated. The biofilm biomass of P. aeruginosa was considerably reduced by 1.56-50 mg/L AgNP. However, 4NPO enhanced the ability of AgNP to inhibit P. aeruginosa biofilm formation (P < 0.05). The combination of AgNP with 4NPO could continuously inhibit biofilm development after 12 h, and 50 mg/L AgNP combined with 6.25 mg/L 4NPO thoroughly suppressed biofilm growth. The expression levels of QS genes and exopolysaccharide genes of biofilm treated with the combination of AgNP with 4NPO (AgNP-4NPO combination) were lower than those treated with AgNP alone (P < 0.05). Additional extracellular proteins and polysaccharides were determined in the samples treated with AgNP-4NPO combination. Based on proteomic analysis, this result was attributed to cell rupture caused by antimicrobial agents and intracellular materials released. The combination of the two antimicrobial agents could weaken the swimming ability of bacterial cells by damaging bacterial flagella and blocking rhlA gene expression. Thus, AgNP combined with QSI showed stronger antibiofilm ability than AgNP alone. These results may contribute to the development of antimicrobial agents.

The energy transfer efficiency, strongly depending on the distance of donor-acceptor pair, is always a crucial factor for the construction of elegant electrochemiluminescence resonance energy transfer (ECL-RET)-based biosensors. In this paper, a novel and efficient ECL-RET in 2D/2D heterostructured g-C 3 N 4 /MnO 2 was developed using g-C 3 N 4 nanosheets (g-C 3 N 4 NSs) as energy donor and MnO 2 nanosheets (MnO 2 NSs) as energy acceptor. In this system, MnO 2 NSs in-situ grew on g-C 3 N 4 NSs to form the 2D/2D heterostructure, greatly shortening the distance of the donor-acceptor pair (g-C 3 N 4 -MnO 2 ) and thus greatly enhancing the RET efficiency. To demonstrate the performance of the system, a signal "off-on" ECL sensor was designed for glutathione (GSH) analysis. In the absence of GSH, MnO 2 significantly quenched the ECL intensity of g-C 3 N 4 owing to ECL-RET in this 2D/2D g-C 3 N 4 /MnO 2 heterostructure (ECL signal "off"). Upon the addition of GSH, MnO 2 was reduced to Mn 2+ by GSH and g-C 3 N 4 was released from the heterostructured g-C 3 N 4 /MnO 2 , generating a recovery of ECL intensity (ECL signal "on"). Under the optimal conditions, the designed ECL-RET signal "off-on" sensor realized the sensitive detection of GSH ranged from 0.2-100 μM with the detection limit of 0.05 μM. Furthermore, the as-prepared ECL-RET sensor exhibits good performance in the determination of GSH in human serum samples. The ECL-RET in 2D/2D heterostructure provides an ingenious way for the exploitation of novel ECL biosensing systems., (Copyright © 2019. Published by Elsevier B.V.)

A novel electrochemiluminescence resonance energy transfer (ECL-RET) system using versatile gold nanorods as energy acceptors was introduced into the ECL biochemical analysis. A spatial- and potential-resolved platform coupled with the ECL-RET strategy was developed for simultaneous determination of two acute myocardial infarction markers.

The structures of pestalrones A-B were revised via reinterpretation of the NMR data and a brief chemical transformation from the co-occurring polyketides, in our investigation on the secondary metabolites of Pestalotiopsis zonata, which also afforded a new α-pyrone derivative, pestazonatic acid, and four known analogs.

We investigated cfr -positive and -negative MRSA strains isolated from animals and humans in different geographical areas of China, from 2011 to 2016. Twenty cfr -positive strains (15.6%) were identified from 128 MRSA strains including 17 from food animals and three from humans. The resistance rates and prevalence of the tested antibiotic resistance genes (ARGs) in the cfr -positive MRSA isolates were higher than that in the cfr -negative MRSA isolates. All cfr -positive MRSA isolates were co-carrying fexA and ermC , and had significantly higher optrA incidence rate vs. the cfr -negative isolates ( P < 0.05). In addition, multilocus sequence typing (MLST) assays showed that ST9 and spa -type t899 were the most prevalent ST and spa types in the study strains. However, all of the 20 cfr -positive and 10 randomly selected cfr -negative MRSA isolates were clonally unrelated as determined by pulsed-field gel electrophoresis (PFGE) analyses. Importantly, the cfr gene was successfully transferred to a recipient Staphylococcus aureus strain RN4220 from 13 of the 20 cfr -positive MRSA isolates by electroporation. Among these 13 cfr -positive MRSA isolates, two different genetic contexts surrounding cfr were determined and each was associated with one type of cfr -carrying plasmids. Of note, the predominant genetic context of cfr was found to be a Tn 558 variant and locate on large plasmids (∼50 kb) co-harboring fexA in 11 of the 13 MRSA isolates. Furthermore, the cfr gene was also identified on small plasmids (∼ 7.1 kb) that co-carried ermC in two of the 13 MRSA isolates. Our results demonstrated a high occurrence of multi-drug resistance in cfr -positive MRSA isolates, and the spread of cfr might be attributed to horizontal dissemination of similar cfr -carrying transposons and plasmids.

Background: Colorectal cancer (CRC) is the most common type of gastrointestinal cancer. CRC gene therapy mediated by adenovirus holds great promise for the treatment of malignancies. However, intravenous delivery of adenovirus exhibits limited anti-tumor activity in vivo when used alone., Methods: In this study, the antitumor activity of the recombinant adenovirus KGHV500 was assessed with the MTT, TUNEL, Matrigel invasion and cell migration assays. To enhance the intravenous delivery of KGHV500 in vivo, cytokine-induced killer (CIK) cells were used as a second vector to carry KGHV500. We explored whether CIK cells could carry the recombinant adenovirus KGHV500 containing the anti-p21Ras single chain fragment variable antibody (scFv) gene into tumors and enhance antitumor potency., Results: Our results showed that KGHV500 exhibited significant antitumor activity in vitro. In the nude mouse SW480 tumor xenograft model, the combination of CIK cells with KGHV500 could induce higher antitumor activity against colorectal cancer in vivo than that induced by either CIK or KGHV500 alone. After seven days of treatment, adenovirus and scFv were detected in tumor tissue but were not detected in normal tissues by immunohistochemistry. Therefore, KGHV500 replicates in tumors and successfully expresses anti-p21Ras scFv in a colorectal cancer xenograft model., Conclusions: Our study provides a novel strategy for the treatment of colorectal cancer by combining CIK cells with the recombinant adenovirus KGHV500 which carried anti-p21 Ras scFv.

It is valuable to develop a sensing platform for not only detecting a tumor marker in body fluids but also measuring its expression at single cells. In the present study, a simple closed bipolar electrodes-based electrochemiluminescence (BPEs-ECL) imaging strategy was developed for visual immunoassay of prostate specific antigen (PSA) at single cells using functional nanoprobes of heterogeneous Ru(bpy) 3 2+ @SiO 2 /Au nanoparticles. Multiple-assisted ECL signal amplification strategy was introduced into the detection system on the basis of the synergetic amplifying effect of the anodic and cathodic amplification. On the basis of the synergetic amplifying effect, the detection limits of PSA by using photomultiplier tube and charge-coupled device (CCD) imaging are 3.0 and 31 pg/mL, respectively. The obtained immunosensor was employed to evaluate PSA levels in serum samples with a satisfying result. Moreover, the obtained functional nanoprobes were used to visually profile the PSA expression on the surface of single LNCaP cells (a kind of prostate cancer cells) based on a bare BPE. The results show that the functional nanoprobes-based ECL imaging immunoassay provides a promising visual platform for detecting tumor markers (proteins and cancer cells) and thus shows a high potential in cancer diagnosis.

The cathodic electrochemiluminescence (ECL) behaviour of nontoxic MoS2 quantum dots (QDs) was studied for the first time using potassium peroxydisulfate as the co-reactant. Ag-PAMAM NCs, serving as difunctional tags for quenching and enhancing ECL of MoS2-reduced graphene oxide composites, were introduced into the ECL detection system for signal amplification. By modulating the interparticle distance between MoS2 QDs and Ag-PAMAM NCs, the ECL quenching from resonance energy transfer and the ECL enhancement from surface plasma resonance were realized. Coupling the good ECL performance of MoS2 QDs with the excellent ECL quenching and enhancement effects of Ag-PAMAM NCs, a novel MoS2 QDs-based ECL biosensing platform for sensitive detection of microRNA-21 was achieved with a detection limit of 0.20 fmol L-1 (S/N = 3). This method was successfully applied to the determination of microRNA-21 in human serum samples with recoveries of 90.0-110.0%, suggesting great potential for its applications in biological and chemical analysis.

The identification of tumor markers is of great importance for clinical diagnosis but accurate detection with high sensitivity is still a great challenge. In present work, a spatial-resolved dual-signal-output electrochemiluminescent (ECL) ratiometric assay platform was constructed for sensitive detection of prostate specific antigen (PSA) on a dual-disk glassy carbon electrode. To fabricate the platform, flower-like CdS three-dimensional (3D) assemblies and Ru(bpy) 3 2+ -conjugated silica nanoparticles (Ru(bpy) 3 2+ @RuSi NPs), were immobilized onto the two disks as cathodic and anodic ECL emitters, respectively. After the stepwise modification of the gold nanoparticles, antibody for PSA, and bovine serum albumin onto the two disks respectively, the Ru(bpy) 3 2+ @RuSi NPs-based disk were incubated with varied concentration of PSA as working electrode, whereas the flower-like CdS 3D assemblies-based disk with fixed concentration of PSA were taken as internal reference electrode. The label free assay of PSA was realized by the ratio of anodic ECL signal from working electrode to the cathodic ECL signal from the internal reference electrode (ECL anode /ECL cathode ). On the basis of the spatial-resolved dual-signal-output ratiometric ECL sensor, the PSA can be detected accurately with a linear range of 0.001 - 50ng/mL at a concentration as low as 0.34pg/mL. Furthermore, the proposed method was applied for PSA determination in human serum samples with satisfying results. Thanks to the same modified process of the two disks, this universal design well avoids environmental errors including the interference caused in the biological recognition process, which effectively reduces the false positive or negative errors, exhibiting a greatly improved accuracy, reliability and sensitivity., (Copyright © 2017. Published by Elsevier B.V.)

Objective: MiR-155 has been shown to be up-regulated in hepatocellular carcinoma (HCC) patients. B-cell lymphoma-2 (Bcl-2) interacting mediator of cell death (BIM) regulates cell proliferation and apoptosis, as its down-regulation is involved in HCC onset. Transcriptional factor FoxO3a mediates BIM expression and is related to HCC pathogenesis. Bioinformatics analysis showed targeted regulation of FoxO3a by miR-155. This study aims to investigate whether miR-155 plays a role in mediating FoxO3a/BIM signal pathway and HCC occurrence., Patients and Methods: HCC patients were collected for tumor and adjacent tissues, in which microRNA-155 (miR-155) and FoxO3a expressions were examined. In vitro cultured HCCLM3, HepG2 and L-02 cells were tested for basal apoptotic rate by flow cytometry and were compared for miR-155 and FoxO3a expression. Dual-luciferase reporter gene assay demonstrated the targeted relationship between miR-155 and FoxO3a. HCCLM3 cells were treated with miR-155 inhibitor and/or FoxO3a-pMD18-T. Cell apoptosis and proliferation were examined by using flow cytometry and MTT assays, respectively. Western blot and spectrometry assay were employed to quantify the FoxO3a, BIM expressions, and caspase activity., Results: Compared to adjacent tissues, HCC tissues had significantly higher miR-155 and significantly lower FoxO3a expression (p<0.05). HCCLM3 and HepG2 cells had significantly lower FoxO3a expression and basal apoptotic rate compared to L02 cells, whilst miR-155 level was significantly higher (p<0.05). MiR-155 targeted and inhibited 3'-UTR of FoxO3a, increasing BIM expression, caspase-3, and caspase-9 activities, and enhancing cell apoptosis and weakening proliferation., Conclusions: HCC tissues elevated the miR-155 and suppressed the FoxO3a expressions. MiR-155 targeted and inhibited FoxO3a expression to suppress the BIM, depress caspase-3 and caspase-9 activities, therefore inhibiting the HCC cell apoptosis and facilitating proliferation.

An ascorbic acid oxidase (AAO)-ascorbic acid bioevent-based electron donor consumption mode was introduced into the PEC bioassay for the first time. Ternary hybrid bismuth sulfide/silver sulfide/TiO 2 nanotube arrays as the photoelectrode coupled with AAO attached to SiO 2 as a dual signal quenching strategy were employed for sensitivity enhancement.

The complete mitochondrial genome sequence of Microhyla fissipes from Yi-Lan, Taiwan was determined through Sanger sequencing. The total length was 16,729 nucleotide base pairs. The genome included distinctive 37 genes, one light-strand replication origin and one control region. Regardless indels the non-coding genes were more conserved than the coding genes within Microhyla , as well as in Kaloula . The abnormal high differences in ND5 (0.2316) and ND6 (0.2406) between Taiwan and China samples is interesting for further studies., Competing Interests: The authors report no conflicts of interest., (© 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

A novel niosomal delivery system was designed and investigated for the targeted delivery of daunorubicin (DNR) against acute myeloid leukemia (AML). Anti-CD123 antibodies conjugated to Mal-PEG 2000 -DSPE were incorporated into normal niosomes (NS) via a post insertion method to afford antibody-modified niosomes (CD123-NS). Next, NS was modified with varying densities of antibody (0.5 or 2%, antibody/Span 80, molar ratio), thus providing L-CD123-NS and H-CD123-NS. We studied the effect of antibody density on the uptake efficiency of niosomes in NB4 and THP-1 cells, on which CD123 express differently. Our results demonstrate CD123-NS showed significantly higher uptake efficiency than NS in AML cells, and the uptake efficiency of CD123-NS has been ligand density-dependent. Also, AML cells preincubated with anti-CD123 antibody showed significantly reduced cellular uptake of CD123-NS compared to control. Further study on the uptake mechanism confirmed a receptor-mediated endocytic process. Daunorubicin (DNR)-loaded H-CD123-NS demonstrated a 2.45- and 3.22-fold higher cytotoxicity, compared to DNR-loaded NS in NB4 and THP-1 cells, respectively. Prolonged survival time were observed in leukemic mice treated with DNR-H-CD123-NS. Collectively, these findings support that the CD123-NS represent a promising delivery system for the treatment of AML.

Background: Pancreatic cancer is a highly lethal disease with a poor prognosis while metformin has been associated with a decreased risk of pancreatic cancer. Although the benefit of metformin was observed for pancreatic cancer prevention, it is not clear whether it can also affect the survival of pancreatic cancer patients with type 2 diabetes mellitus. A systematic review and meta-analysis was conducted to assess the effect of metformin on the survival of pancreatic cancer patients with type 2 diabetes mellitus., Methods: Two independent authors searched PubMed and Web of science up to 08/07/2016. We assessed studies for eligibility, extracted data, and examined their quality, with the primary outcome as overall survival. We used published hazard ratio (HR) available or estimated based on other survival data. We pooled the data and used a random-effect model to combine direct comparisons from included articles. We also investigated treatment effects by different countries, quality and the time of metformin initiation., Results: We found that there was a relative survival benefit associated with metformin treatment compared with non-metformin treatment in both overall survival (OS) ([HR] 0.84; 95% confidence interval [CI]: 0.73 - 0.96). These associations were also observed in subgroups of Asian countries and high quality articles., Conclusions: Our results support the notion that metformin maybe the best anti-diabetic medicine of choice in patients with pancreatic cancer and concurrent type 2 diabetes mellitus. The perspectives of enhancing survival of pancreatic cancer patients with diabetes mellitus by the use of metformin deserve more attention in future research and clinical practice.

Metastasis is an important hallmark of malignant tumors. In this study, we developed a microfluidic system to screen highly metastatic sublines via differential resolution of cell invasiveness. The system was composed of a PDMS-glass device connected with a syringe pump and a Petri dish. To facilitate the selection process, a long-term cell invasion driving force based on a chemotactic factor gradient was created using the Petri dish-based liquid supply pattern, and the invasive cells were collected for round-by-round selection via an open region in the chip. Using the system, we established an SGC-7901/B2 subline from the human gastric cancer SGC-7901 cell line by only two rounds of selection. In vitro assays showed that the SGC-7901/B2 cells were superior to the parental cells in proliferation and invasiveness. Furthermore, an in vivo tumorigenicity assay demonstrated that compared with the parental cells, the subline had stronger spontaneous metastatic and proliferative capability, which led to a shorter survival duration. Additionally, the protein expression differences including E-cadherin and Smad3 between the subline and parental cells were revealed. In conclusion, this microfluidic system is a highly effective tool for selecting highly metastatic sublines, and SGC-7901/B2 cells could serve as a potential model for tumor metastasis research.