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Background: The third-line treatment for refractory colorectal cancer (CRC) has limited efficacy. This study aimed to evaluate the safety and efficacy of SHR-8068 (an anti-CTLA-4 antibody), combined with adebrelimab (an anti-PD-L1 antibody), and bevacizumab in refractory non-microsatellite instability-high (MSI-H) or proficient mismatch repair (pMMR) CRC. Method: This study is a prospective, open-label, single-center phase Ib/II clinical trial. Patients with pathologically confirmed pMMR/non-MSI-H metastatic colorectal adenocarcinoma who have failed =2 lines prior standard systemic treatments will be enrolled (n=36). The Ib phase will evaluate two dosing regimens of SHR-8068 in combination therapy (n=9 each dosage): SHR-8068 (1 mg per kilogram, every six weeks, intravenously) or SHR-8068 (4 mg per kilogram, every twelve weeks, intravenously) combined with adebrelimab (1200 mg, every three weeks, intravenously) and bevacizumab (7.5 mg per kilogram, every three weeks, intravenously). The efficacy and adverse events (AEs) of these regimens will be assessed to determine the recommended phase II dose (RP2D) of SHR-8068. Those of RP2D group from the phase Ib will be included in the phase II. The study will go to include 18 additional patients according to the onesample log-rank test design in the phase II. The primary endpoint of the Ib phase is safety, with secondary endpoints including the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and quality of life (QOL). The primary endpoint for phase II was PFS, with secondary endpoints including ORR, OS, DCR, safety, and QOL. Identifying biomarkers to predict the efficacy of this regimen is the exploratory study endpoint. Discussion: This proof-of-concept study would provide safety and efficacy signals of this novel combination treatment for the MSS CRCs in the late-line setting. And it may offer new insights on the clinical application of dual immunotherapy combined with anti-angiogenic therapy in the MSS CRC. [ABSTRACT FROM AUTHOR]

Background: Recent studies have yielded conflicting results regarding the relationship between smoking history and the effectiveness of immune checkpoint inhibitors (ICIs) for advanced lung cancer. While some studies have suggested that smoking may enhance the response to immunotherapy in patients with lung cancer, other findings indicate the contrary. Therefore, we conducted a systematic review and meta-analysis to thoroughly examine this association. Methods: We searched the PubMed, Embase, and Scopus databases for clinical trials comparing immunotherapy with conventional chemotherapy as the primary treatment for advanced lung cancer. A random effects model was used to synthesize hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS). We also conducted predefined subgroup analyses to investigate the efficacy disparities between never-smokers and smokers who were administered immunotherapy alone or in combination with chemotherapy, as well as the differences between former and current smokers under similar treatment modalities. Results: Our analysis included data from 17 Phase III clinical trials involving 10,283 patients. The findings indicate that immunotherapy benefits both smokers and never-smokers with lung cancer or non-small cell lung cancer, yielding pooled HRs for OS of 0.74 (95% CI: 0.59-0.92) and 0.73 (95% CI: 0.67-0.80), respectively. A significant interaction effect was not observed (HR: 0.98, 95% CI: 0.77-1.24, pinteraction = 0.14), and the tumor type, immunotherapy combination, and type of immunotherapy did not differ among the groups in the subgroup analyses. Similarly, both former and current smokers experienced a significant survival benefit from immunotherapy, with pooled HRs for OS of 0.79 (95% CI: 0.68-0.91) and 0.71 (95% CI: 0.59-0.87), respectively. However, a significant interaction effect was also not observed (HR: 0.91, 95% CI: 0.74-1.11, pinteraction = 0.14). Conclusion: Our findings suggest that smoking status does not affect the effectiveness of immunotherapy for lung cancer treatment. However, additional high-quality clinical trials are needed to confirm this conclusion. [ABSTRACT FROM AUTHOR]

Background: Older patients with advanced cholangiocarcinoma lack systemic therapy standards. These people have a high risk of chemotherapy, accompanied by adverse reactions and even discontinuation of treatment. Case presentation: We report a 78-year-old female subject with advanced intrahepatic cholangiocarcinoma presenting with unresectable lesions involving the hepatic veins, along with extensive metastatic lymph nodes. After the geriatric assessment, capecitabine was utilized for only one cycle owing to adverse events (AEs). Next, a combination of low-dose lenvatinib and tislelizumab was administrated as a second-line treatment, which resulted in remarkable early tumor shrinkage. The following individual lenvatinib taper enabled a manageable safety profile and durable deep response. A near-complete response was achieved, with the primary tumor significantly reducing from 5.6 cm × 4.7 cm to nearly complete disappearance, accompanied by complete regression of lymph nodes, and both progression-free survival and overall survival exceeding 24 months. Conclusion: The case provides valuable insights that could influence future treatment strategies for older patients with advanced cholangiocarcinoma who are unsuitable for chemotherapy. The dose-individualized chemotherapy-free regime of lenvatinib and tislelizumab might be used in similar cases to improve their outcomes. [ABSTRACT FROM AUTHOR]

Background: Older patients with advanced cholangiocarcinoma lack systemic therapy standards. These people have a high risk of chemotherapy, accompanied by adverse reactions and even discontinuation of treatment. Case presentation: We report a 78-year-old female subject with advanced intrahepatic cholangiocarcinoma presenting with unresectable lesions involving the hepatic veins, along with extensive metastatic lymph nodes. After the geriatric assessment, capecitabine was utilized for only one cycle owing to adverse events (AEs). Next, a combination of low-dose lenvatinib and tislelizumab was administrated as a second-line treatment, which resulted in remarkable early tumor shrinkage. The following individual lenvatinib taper enabled a manageable safety profile and durable deep response. A near-complete response was achieved, with the primary tumor significantly reducing from 5.6 cm × 4.7 cm to nearly complete disappearance, accompanied by complete regression of lymph nodes, and both progression-free survival and overall survival exceeding 24 months. Conclusion: The case provides valuable insights that could influence future treatment strategies for older patients with advanced cholangiocarcinoma who are unsuitable for chemotherapy. The dose-individualized chemotherapy-free regime of lenvatinib and tislelizumab might be used in similar cases to improve their outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Fengxiangxing Huairang Daqu (FHD) is one of the major types of Daqu in China. However, the relationship between the microbial community structure at different stages, the changes in the sensory characteristics, fermentation characteristics, volatiles, the most critical process point, and the quality formation of FHD is not clear. Methods: Based on microscopic characterization, PacBio SMRT sequencing, and HS-SPME-GC-MS volatile metabolite analysis revealed the relationship between FHD quality formation and the dynamics of Qupi. Results: The results showed that the 12th day of the culture was the most critical process point, highlighting the most significant differences in microbial community structure, sensory characteristics, fermentation characteristics, and flavor substances. Bacillus licheniformis (43.25%), Saccharopolyspora rectivirgula (35.05%), Thermoascus aurantiacus (76.51%), Aspergillus amstelodami (10.81%), and Saccharomycopsis fibuligera (8.88%) were the dominant species in FHD. S. fibuligera, A. amstelodami, and T. aurantiacus were associated with the snow-white color of the FHD epidermis, the yellow color of the interior, and the gray-white color, respectively. The abundance of T. aurantiacus, A. amstelodami, B. licheniformis, and S. rectivirgula was positively associated with the esterifying power and liquefying power of FHD. The abundance of T. aurantiacus and A. amstelodami was positively correlated with the saccharifying power of FHD. The abundance of S. fibuligera was positively related to the fermenting power of FHD. A total of 248 volatiles were detected in Qupi, mainly including alcohols, esters, aldehydes, and ketones. Of them, eleven volatiles had a significant effect on the flavor of Qupi, such as 1-butanol-3-methyl-, hydrazinecarboxamide, ethanol, phenylethyl alcohol, ethyl acetate, 2-octanone, 1-octen-3-ol, formic acid-hexyl ester, (E)-2-octen-1-ol, ethyl hexanoate, and 2(3H)-furanone-dihydro-5-pentyl-. The abundance of B. licheniformis, S. rectivirgula, T. aurantiacus, and S. fibuligera was positively correlated with the alcohols, aromatic compounds, and phenols in FHD. The abundance of S. fibuligera was positively correlated with the acids, esters, and hydrocarbons in FHD. Discussion: These results indicate important theoretical basis and technical support for controllable adjustment of FHD microbial community structure, stable control of FHD quality, and precise, effective, and large-scale guidance of FHD production. [ABSTRACT FROM AUTHOR]

Objectives: We evaluated the long-term effects of air pollution controls on health and health inequity among Chinese >45 years of age. Methods: Data were derived from the China Health Aging and Retirement Longitudinal Survey and the China National Environmental Monitoring Centre. Decreases in PM2.5 and PM10 were scaled to measure air quality controls. We used a quasi-experimental design to estimate the impact of air quality controls on self-reported health and health inequity. Health disparities were estimated using the concentration index and the horizontal index. Results: Air pollution controls significantly improved self-reported health by 20% (OR 1.20, 95% CI, 1.02-1.42). The poorest group had a 40% (OR 1.41, 95% CI, 0.96-2.08) higher probability of having excellent self-reported health after air pollution controls. A pro-rich health inequity was observed, and the horizontal index decreased after air pollution controls. Conclusion: Air pollution controls have a long-term positive effect on health and health equity. The poorest population are the main beneficiaries of air pollution controls, which suggests policymakers should make efforts to reduce health inequity in air pollution controls. [ABSTRACT FROM AUTHOR]

Pancreatoblastoma (PB), a neoplasm derived from pancreatic follicular cells, primarily affects the pediatric population. Although infrequent in adults, it is associated with a considerably worse prognosis. Approximately one-third of patients are diagnosed with metastatic disease, with liver metastases being the most prevalent. Diagnosis relies on histopathological alterations including squamous vesicles, positive staining for CK8/CK18/CK19, and nuclear displacement of ß-catenin. Additionally, liver metastases demonstrate substantial enhancement during the arterial phase of a contrast-enhanced computed tomography (CT) scan. Surgical resection serves as the principal therapeutic approach for addressing primary lesions and liver metastatic PB. In instances where surgical intervention is not viable, patients may derive benefits from systemic therapy and radiotherapy. This particular case report presents the clinical details of a 27-year-old female patient diagnosed with PB, who subsequently developed multiple liver metastases following a pancreaticoduodenectomy. Genomic examinations revealed the presence of ERBB2 amplification, RAD54L deletion, low TMB-L, and MSS in the patient. Despite the patient undergoing chemotherapy and Her-2 targeted therapy in conjunction with immunotherapy, no reduction in lesion size was observed until the administration of surufatinib. Subsequently, a notable outcome ensued, where the metastatic lesions were effectively excised via surgical intervention. Surufatinib has demonstrated a progression-free survival (PFS) of no less than 14 months, and the patient's survival has endured for a duration of 33 months. This indicates the potential efficacy of surufatinib as a viable therapeutic alternative for adult patients afflicted with PB. [ABSTRACT FROM AUTHOR]

Background: The prognostic value of an effective biomarker, pan-immuneinflammation value (PIV), for head and neck squamous cell carcinoma (HNSCC) patients after radical surgery or chemoradiotherapy has not been well explored. This study aimed to construct and validate nomograms based on PIV to predict survival outcomes of HNSCC patients. Methods: A total of 161 HNSCC patients who underwent radical surgery were enrolled retrospectively for development cohort. The cutoff of PIV was determined using the maximally selected rank statistics method. Multivariable Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed to develop two nomograms (Model A and Model B) that predict disease-free survival (DFS). The concordance index, receiver operating characteristic curves, calibration curves, and decision curve analysis were used to evaluate the nomograms. A cohort composed of 50 patients who received radiotherapy or chemoradiotherapy (RT/CRT) alone was applied for generality testing of PIV and nomograms. Results: Patients with higher PIV (=123.3) experienced a worse DFS (HR, 5.01; 95% CI, 3.25-7.72; p<0.0001) and overall survival (OS) (HR, 5.23; 95% CI, 3.34-8.18; p<0.0001) compared to patients with lower PIV (<123.3) in the development cohort. Predictors of Model A included age, TNM stage, neutrophil-tolymphocyte ratio (NLR), and PIV, and that of Model B included TNM stage, lymphocyte-to-monocyte ratio (LMR), and PIV. In comparison with TNM stage alone, the two nomograms demonstrated good calibration and discrimination and showed satisfactory clinical utility in internal validation. The generality testing results showed that higher PIV was also associated with worse survival outcomes in the RT/CRT cohort and the possibility that the two nomograms may have a universal applicability for patients with different treatments. Conclusions: The nomograms based on PIV, a simple but useful indicator, can provide prognosis prediction of individual HNSCC patients after radical surgery and may be broadly applicated for patients after RT/CRT alone. [ABSTRACT FROM AUTHOR]

Fecal DNA test has emerged as a non-invasive alternative for colorectal cancer (CRC) screening in average-risk population. However, there is currently insufficient evidence in China to demonstrate the effectiveness of populationbased CRC screening using fecal DNA based test. Here, a large-scale real-world study for CRC screening was implemented in Wuhan, Hubei province, China. A total of 98,683 subjects aged between 45 and 60 years were screened by a fecal DNA test (ColoTect®) which detected methylation status of SDC2, ADHFE1, and PPP2R5C. Participants who tested positive were advised to receive diagnostic colonoscopy. 4449 (4.5%) subjects tested positive for fecal DNA test, and 3200 (71.9%) underwent colonoscopy. Among these, 2347 (73.3%) had abnormal colonoscopy findings, of which 1330 (56.7%) subjects received pathological diagnosis. Detection rates for CRC and advanced precancerous lesions were 1.3% and 2.3%, respectively. Detection rates for nonadvanced adenomas and polyps were 14.0% and 21.6%, respectively. 28.0% of all colonoscopies showed colorectal neoplasm but lack pathological diagnosis. 6.1% showed other abnormalities such as enteritis. In conclusion, preliminary real-world evidence suggested that fecal DNA tests had promising diagnostic yield in populationbased CRC screening. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced stage, presenting limited therapeutic options and a grim prognosis due to its aggressive nature. Despite ongoing exploration of various combination therapies, a standardized treatment approach after the first-line treatment progress remains elusive. This report details the cases of two patients with unresectable advanced PDAC who underwent distinct conversion treatment regimens involving immune checkpoint inhibitors (ICIs). Remarkably, both patients became eligible for surgery following different anti-PD-1 antibody-based conversion therapies, ultimately achieving R0 resection. In essence, our findings highlight the efficacy of the anti-PD-1 antibody combined with a tyrosine kinase inhibitor (TKI) regimen and chemotherapy alongside anti-PD-1 antibody as viable conversion therapies for preoperative advanced PDAC. Tumor immune microenvironment (TIME) analysis underscores the intratumoral and intertumoral heterogeneity observed in the postoperative immune landscape of surgical specimens. This insight contributes to a deeper understanding of the potential benefits of these conversion therapies in addressing the challenging landscape of advanced PDAC. [ABSTRACT FROM AUTHOR]

Working memory (WM) maintenance relies on multiple brain regions and inter-regional communications. The hippocampus and entorhinal cortex (EC) are thought to support this operation. Besides, EC is the main gateway for information between the hippocampus and neocortex. However, the circuit-level mechanism of this interaction during WM maintenance remains unclear in humans. To address these questions, we recorded the intracranial electroencephalography from the hippocampus and EC while patients (N = 13, six females) performed WM tasks. We found that WM maintenance was accompanied by enhanced theta/alpha band (2-12 Hz) phase synchronization between the hippocampus to the EC. The Granger causality and phase slope index analyses consistently showed that WM maintenance was associated with theta/alpha band-coordinated unidirectional influence from the hippocampus to the EC. Besides, this unidirectional inter-regional communication increased with WM load and predicted WM load during memory maintenance. These findings demonstrate that WM maintenance in humans engages the hippocampal--entorhinal circuit, with the hippocampus influencing the EC in a load-dependent manner. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate the performance of a new double-antigen sandwich test that is based on the light-initiated chemiluminescent assay (LiCA®) for detecting anti-hepatitis C virus antibodies (anti-HCV) in comparison to Architect®. Methods: Analytical characteristics and diagnostic performance were tested using seroconversion panels and large pools of clinical samples. Positive results were validated by the strip immunoblot assay (RIBA) and HCV RNA. Results: Repeatability and within-lab imprecision of LiCA® anti-HCV were 1.31%-3.27%. The C5-C95 interval was -5.44%-5.03% away from C50. LiCA® detected seroconversion in an average of 28.9 days and showed a mean of 3.7 (p = 0.0056) days earlier than Architect®. In a pool of 239 samples with known HCV genotypes 1 to 6, both assays correctly detected all subjects. In 16,305 clinical patient sera, LiCA® detected 4 false-negative (0.25‰) and 14 false-positive (0.86‰) anti-HCV cases, while Architect® recorded 6 false-negative (0.37‰) and 138 false-positive (8.46‰) subjects, respectively. Compared to Architect®, LiCA® presented a significantly better performance in specificity (99.91% vs. 99.14%, n = 16,018, p < 0.0001), positive predictive value (95.29% vs. 67.06%, n = 419, p < 0.0001), and overall accuracy (99.89% vs. 99.12%, n = 16,305, p < 0.0001), while no significant difference in sensitivity (98.61% vs. 97.91%, n = 287, p = 0.5217) and negative predictive value (99.98% vs. 99.96%, n = 15,886, p = 0.3021) was seen. An S/Co value of 3.28 was predicted to be the threshold with a positivity =95% for the LiCA® anti-HCV assay. Conclusion: LiCA® anti-HCV is a precise and fully automatic chemiluminescent assay with superior sensitivity and specificity. The assay can be used as a valuable tool to supplement the diagnosis of HCV infection. [ABSTRACT FROM AUTHOR]

Objectives To explore the possible role of peripheral lesions (PLs) detected by ultrawide field (UWF) imaging system on central neurovascular structure and retinal function. Methods Ninety-seven diabetic patients were included in this cross-sectional study using UWF pseudocolour colour imaging with Optos Daytona (Optos, PLC). UWF images were graded as with predominantly peripheral lesions (PPLs) and without PPL. Macular neurovascular alterations and retinal function were measured by optical coherence tomography angiography (OCTA) and RETeval device, respectively. Central microcirculation and retinal function were compared between eyes with and without PPL. Results The study evaluated 186 eyes (97 patients; 43 females (44.3%)), including 92 eyes without PPL and 94 eyes with PPL. Central retinal vessel density was comparable between eyes with and without PPL. Delayed implicit time and decreased pupil area ratio were found in the PPL group compared with eyes without PPL, and this difference remained unchanged after adjusting for systemic factors (all p＜0.01). Conclusions Our study suggests that retinal function is worse in diabetic eyes with PPL. These findings challenged the conventional ETDRS protocols which ignored peripheral retina in determining DR severity. Furthermore, combining UWF imaging with RETeval system to detect more retinal abnormalities may be helpful in DR management. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus-associated lymphoepithelioma-like intrahepatic cholangiocarcinoma (EBVa LEL-ICC) is a rare tumor, characterized by a rich tumor immune microenvironment (TIME). While this tumor is reportedly sensitive to immunotherapy, its response has been inconsistent. This decreased sensitivity was associated with reduced TIME abundance. We report the case of a 53-year-old woman with EBVa LEL-ICC having reduced TIME abundance. The patient presented with a liver lesion, which was detected using ultrasound. Initially, the tumor was sensitive to immunotherapy and chemotherapy (IC), but resistance developed after a short interval. Subsequently, stereotactic ablative radiotherapy (SABR) was added to the patient's treatment, which now consisted of ICSABR. Successful tumor shrinkage was achieved with the combination therapy regimen. Thus, surgery and ICSABR are effective adjuncts to the first-line IC therapy in improving the survival rate of patients with EBVa LEL-ICC. The results of this study support multidisciplinary treatment as a viable treatment strategy for EBVa LEL-ICC. [ABSTRACT FROM AUTHOR]

Purpose: We constructed a zebrafish xenograft tumor model to compare and quantify the antiangiogenic efficacy and safety of nine vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), axitinib, lenvatinib, pazopanib, apatinib, cabozantinib, sunitinib, semaxanib, sorafenib, and regorafenib, in parallel. Methods: CT26 and GL261 tumor cells were implanted into the perivitelline space of Tg (flk1: eGFP) zebrafish to construct a xenograft tumor model. VEGFR-TKIs' antiangiogenic efficacy was quantified using AngioTool software, and the median effective dose (ED50) was calculated. The toxicity was evaluated by calculating the median lethal dose (LD50) and gross morphological changes. Cardiac toxicity was further assessed by heart rate, heart rhythm, the distance between the sinus venosus (SV) and bulbus arteriosus (BA), and pericardial edema. Results: Using the zebrafish xenograft tumor model, we found that all nine VEGFR-TKIs exhibited antiangiogenic abilities, but the effectiveness of semaxanib was worse than that of other VEGFR-TKIs. Meanwhile, the zebrafish toxicity assay showed that all tested VEGFR-TKIs were associated with cardiac-related toxicity, especially apatinib and axitinib, which caused serious pericardial edema in zebrafish at relatively low concentrations. A narrow therapeutic window was found for most VEGFR-TKIs, and the simultaneous occurrence of toxic effects of semaxanib was recognized. Conclusion: Our findings showed the potential of using a zebrafish xenograft tumor model to accelerate VEGFR-TKI screening and further the development of more efficient and less toxic VEGFR-TKIs. [ABSTRACT FROM AUTHOR]

Background: Previous studies have explored the relationship between the geriatric nutritional risk index (GNRI) and survival outcomes of diffuse large Bcell lymphoma (DLBCL) cases, but the results were inconsistent. Consequently, the present meta-analysis was conducted to investigate how GNRI affects DLBCL and its function in terms of prognosis. Methods: TheWeb of Science, PubMed, Embase, and Cochrane Library databases were thoroughly searched until January 18, 2023. We calculated combined hazard ratios (HRs) and 95% confidence intervals (CIs) to estimate the relationship between the GNRI and survival outcomes of patients with DLBCL. Results: This meta-analysis included seven articles involving 2,353 cases. A lower level of GNRI predicted dismal overall survival (HR=1.40, 95% CI=1.25-1.56, p<0.001) and inferior progression-free survival (HR=1.46, 95% CI=1.19-1.80, p<0.001) of DLBCL patients. Moreover, a low GNRI was significantly related to Eastern Cooperative Oncology Group Performance Status =2 (odds ratio [OR] =4.55, 95% CI=2.75-7.54, p<0.001), Ann Arbor stage III-IV (OR=2.91, 95% CI=2.38-3.57, p<0.001), B symptoms (OR=3.51, 95% CI=2.34-5.29, p<0.001), and extranodal disease (OR=2.90, 95% CI=2.32-3.63, p<0.001). Conclusion: A lower GNRI level predicted poorer short- and long-term prognosis in patients with DLBCL. A low GNRI was correlated with clinical factors of disease progression in DLBCL patients. [ABSTRACT FROM AUTHOR]

The human placenta is a unique temporary organ with a mysterious immune tolerance. The formation of trophoblast organoids has advanced the study of placental development. HLA-G is uniquely expressed in the extravillous trophoblast (EVT) and has been linked to placental disorders. With older experimental methodologies, the role of HLA-G in trophoblast function beyond immunomodulation is still contested, as is its role during trophoblast differentiation. Organoid models incorporating CRISPR/Cas9 technology were used to examine the role of HLA-G in trophoblast function and differentiation. JEG-3 trophoblast organoids (JEG-3-ORGs) were established that highly expressed trophoblast representative markers and had the capacity to differentiate into EVT. CRISPR/Cas9 based on HLA-G knockout (KO) significantly altered the trophoblast immunomodulatory effect on the cytotoxicity of natural killer cells, as well as the trophoblast regulatory effect on HUVEC angiogenesis, but had no effect on the proliferation and invasion of JEG-3 cells and the formation of TB-ORGs. RNA-sequencing analysis further demonstrated that JEG-3 KO cells followed similar biological pathways as their wild-type counterparts during the formation of TB-ORGs. In addition, neither HLA-G KO nor the exogenous addition of HLA-G protein during EVT differentiation from JEG-3-ORGs altered the temporal expression of the known EVT marker genes. Based on the JEG-3 KO (disruption of exons 2 and 3) cell line and the TB-ORGs model, it was determined that HLA-G has a negligible effect on trophoblast invasion and differentiation. Despite this, JEG-3-ORG remains a valuable model for studying trophoblast differentiation. [ABSTRACT FROM AUTHOR]

Background: An increasing number of innovations have been discovered for treating hepatocellular carcinoma (HCC or commonly called HCC) therapy, Ferroptosis and mitochondrial metabolism are essential mechanisms of cell death. These pathways may act as functional molecular biomarkers that could have important clinical significance for determining individual differences and the prognosis of HCC. The aim of this study was to construct a stable and reliable comprehensive model of genetic features and clinical factors associated with HCC prognosis. Methods: In this study, we used RNA-sequencing (fragments per kilobase of exon model per million reads mapped value) data from the Cancer Genome Atlas (TCGA) database to establish a prognostic model. We enrolled 104 patients for further validation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analyses (KEGG) analysis were used for the functional study of differentially expressed genes. Pan-cancer analysis was performed to evaluate the function of the Differentially Expressed Genes (DEGs). Thirteen genes were identified by univariate and least absolute contraction and selection operation (LASSO) Cox regression analysis. The prognostic model was visualized using a nomogram. Results: We found that eight genes, namely EZH2, GRPEL2, PIGU, PPM1G, SF3B4, TUBG1, TXNRD1 and NDRG1, were hub genes for HCC and differentially expressed in most types of cancer. EZH2, GRPEL2 and NDRG1 may indicate a poor prognosis of HCC as verified by tissue samples. Furthermore, a gene set variation analysis algorithm was created to analyze the relationship between these eight genes and oxidative phosphorylation, mitophagy, and FeScontaining proteins, and it showed that ferroptosis might affect inflammatory-related pathways in HCC. Conclusion: EZH2, GRPEL2, NDRG1, and the clinical factor of tumor size, were included in a nomogram for visualizing a prognostic model of HCC. This nomogram based on a functional study and verification by clinical samples, shows a reliable performance of patients with HCC. [ABSTRACT FROM AUTHOR]

Background: Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a group of rare but highly aggressive malignancies. The standard chemotherapy regimens composed of etoposide and cisplatin/carboplatin (EP/EC) are of limited efficacy. This prospective, multicenter, phase II study is conducted to explore the effectiveness and safety of first-line anti-PD-1 antibody (camrelizumab) combined with chemotherapy in advanced GEP-NEC patients. Methods: Patients with unresectable or metastatic GEP-NEC will receive camrelizumab combined with standard first-line chemotherapy every 3 weeks (camrelizumab 200 mg, administered intravenously on day 1; etoposide 100 mg/m2, administered intravenously on days 1–3; cisplatin 75 mg/m2, administered intravenously on day 1 or carboplatin area under the curve 5 mg/ml per min, administered intravenously on day 1). All patients were naïve to systemic therapy in the advanced setting. The primary endpoint is a 6-month progression-free survival (PFS) rate. The secondary endpoints are objective response rate, PFS, overall survival and adverse reactions. Discussion: This is the first study to investigate the therapeutic potential of camrelizumab plus chemotherapy for advanced GEP-NEC. It is expected that this trial will propose a new and effective treatment strategy for GEP-NEC in the first-line setting. [ABSTRACT FROM AUTHOR]

Background: NADH: ubiquinone oxidoreductase subunit C1(NDUFC1) encodes a subunit of the Complex I, whichmay support the structural stability of Complex I and assist in its biogenesis. The expression and functional roles of NDUFC1 in hepatocellular carcinoma (HCC) remain unknown. Result: We knocked down the expression of NDUFC1 in HCC cell lines to explore the effects of NDUFC1 downregulation on HCC in vitro. MTT assay determined that downregulation of NDUFC1 significantly inhibited cell proliferation. Flow cytometry with (propidium iodide) PI staining indicated silencing of NDUFC1 arrested cell cycle of BEL-7404 cells at G2 phase and SK-HEP-1 cells at S/G2 phase. Annexin V-PI double staining and flow cytometric analysis showed that the downregulation of NDUFC1 significantly increased the population of apoptotic cells. Wound-healing assay and transwell assay indicated that the downregulation of NDUFC1 suppressed the migration and invasion of HCC cells. According to the detection of complex1 activity, we found that the activity of NDUFC1 silenced group decreased, whereas the content of ROS increased. Furthermore, combined with bioinformatics analysis of senescence-related genes, we found that the silence of NDUFC1 in HCC could induce senescence and inhibit autophagy. In addition, NDUFC1 could correlate positively with cancer-related pathways, among which the p53 pathways and the PI3K/Akt/mTOR pathways. Finally, NDUFC1 is high expression in HCC specimens. High NDUFC1 expression was associated with poor prognosis and was an independent risk factor for reduced overall survival (OS). Conclusions: Our study indicated, for the first time, that NDUFC1 is an independent risk factor for the poor prognosis of HCC patients. NDUFC1 may promote tumor progression by inhibiting mitochondrial Complex I and up-regulating ROS through multiple cancer-related and senescence-related pathways of HCC, including p53 pathways and PI3K/Akt/mTOR pathways. We suppose that NDUFC1 might be a potential target for the mitochondrial metabolism therapy of HCC. [ABSTRACT FROM AUTHOR]

Purpose: Recurrent implantation failure (RIF) is an enormous challenge for in vitro fertilization (IVF) clinicians. An understanding of the molecular mechanisms of RIF helps to predict prognosis and develop new therapeutic strategies. The study is designed to identify diagnostic biomarkers for RIF as well as the potential mechanisms underlying RIF by utilizing public databases together with experimental validation. Methods: Two microarray datasets of RIF patients and the healthy control endometrium were downloaded from the Gene Expression Omnibus (GEO) database. First, differentially expressed microRNAs (miRNAs) (DEMs) were identified and their target genes were predicted. Then, we identified differentially expressed genes (DEGs) and selected hub genes through protein-protein interaction (PPI) analyses. Functional enrichment analyses of DEGs and DEMs were conducted. Furthermore, the key DEMs which targeted these hub genes were selected to obtain the key miRNA–target gene network. The key genes in the miRNA-target gene network were validated by a single-cell RNA-sequencing dataset of endometrium from GEO. Finally, we selected two miRNA–target gene pairs for further experimental validation using dual-luciferase assay and quantitative polymerase chain reaction (qPCR). Results: We identified 49 DEMs between RIF patients and the fertile group and found 136,678 target genes. Then, 325 DEGs were totally used to construct the PPI network, and 33 hub genes were selected. Also, 25 DEMs targeted 16 key DEGs were obtained to establish a key miRNA–target gene network, and 16 key DEGs were validated by a single-cell RNA sequencing dataset. Finally, the target relationship of hsa-miR-199a-5p-PDPN and hsa-miR4306-PAX2 was verified by dual-luciferase assay, and there were significant differences in the expression of those genes between the RIF and fertile group by PCR (p < 0.05). Conclusion: We constructed miRNA–target gene regulatory networks associated with RIF which provide new insights regarding the underlying pathogenesis of RIF; hsa-miR 199a-5p-PDPN and hsa-miR-4306-PAX2 could be further explored as potential biomarkers for RIF, and their detection in the endometrium could be applied in clinics to estimate the probability of successful embryo transfer. [ABSTRACT FROM AUTHOR]

Gastric cancer is the second most prevalent cancer and the second leading cause of cancer-related death in China. The prognosis of metastatic gastric cancer is poor with a median overall survival of 8-10 months. Apatinib, an oral small-molecule, selective vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, is approved as third-line or subsequent therapy for gastric cancer in China. Several recent small-scale studies and case reports showed that it may be great help in improvement of prognosis as second-line treatment in patients with advanced or metastatic gastric cancer. Here, we present a case of advanced gastric adenocarcinoma with multiple hepatic metastases who was treated with apatinib plus paclitaxel as second-line therapy, realized a long progression-free survival of 37 months. Until 29 January 2022, the disease remains an efficacy of partial response. We believe that the good outcome of this case is not an accident, because of the typically hyper-vascular of his liver metastases, the treatment toxicities of hypertension and proteinuria, all may be potential predictive biomarkers for anti-angiogenic treatments. [ABSTRACT FROM AUTHOR]

In order to solve the problem of peel between display panel and backlight module in new display products such as four-sided borderless display and curved display, in this paper, the peel strength of foam tape was studied through experiment and simulation, and the peel stress strength of the foam tape was established to guide product design. Firstly, the peel stress of foam tape was obtained by peel strength experiment of foam tape samples. Then, the simulation model was established by using finite element software, and the load weight corresponding to the tilt experiment of the 27-inch four-sided borderless display was calculated. Finally, the accuracy of the simulation model was verified by the tilt experiment of 27-inch display, and the peel stress strength of the foam tape was established. The peel stress was about 1.94×10 -2 MPa. Based on the peel stress strength, the minimum width of foam tape for 23.8-inch four-sided borderless display was 1.5 mm. The display passed the 60 ℃/90% RH HTHHS 500 hours experiment, meeting the product quality requirements. This method can guide the size design of foam tape for new display products such as four-sided borderless display and curved display, and enhance the ultimate design competitiveness of products. [ABSTRACT FROM AUTHOR]

The hippocampus is a locus of working memory (WM) with anterior and posterior subregions that differ in their transcriptional and external connectivity patterns. However, the involvement and functional connections between these subregions in WM processing are poorly understood. To address these issues, we recorded intracranial EEG from the anterior and the posterior hippocampi in humans (seven females and seven males) who maintained a set of letters in their WM. We found that WM maintenance was accompanied by elevated low-frequency activity in both the anterior and posterior hippocampus and by increased theta/alpha band (3-12 Hz) phase synchronization between anterior and posterior subregions. Cross-frequency and Granger prediction analyses consistently showed that the correct WM trials were associated with theta/alpha band-coordinated unidirectional influence from the posterior to the anterior hippocampus. In contrast, WM errors were associated with bidirectional interactions between the anterior and posterior hippocampus. These findings imply that theta/alpha band synchrony within the hippocampus may support successful WM via a posterior to anterior influence. A combination of intracranial recording and a fine-grained atlas may be of value in understanding the neural mechanisms of WM processing. [ABSTRACT FROM AUTHOR]

The crystal-facet effect on the structural stability and electronic properties of wurtzite InP nanowires (NWs) with different side-facets are investigated by using first-principles calculation within density-function theory. The surface-energy calculation suggests that side-facet structures of InP NWs are unreconstructed due to the fact that the low-index {1̄100} and {11̄20} facets with paired In-P dimers satisfy the electron counting rule. The calculated formation energies indicate that the structural stability of InP NWs strongly depends on their side-facets. Among considered InP NWs with different side-facets, the {1̄100} faceted NWs present the highest stability due to the relative low surface atom ratio, which is in good agreement with experimental observations where wurtzite InP NWs prefer to be surrounded by {1̄100} facets. The size dependence of NW band gap indicates that the band gap (Eg) of uniform-sized InP NWs with different side-facets follows the trend, Eg-{11̄20}>Eg-{1̄100}-{11̄20} >Eg-{1̄100}, when NW diameter is larger than 3nm and a reverse trend is found in the smaller sized NWs (d<3 nm). Our result opens the possibility to engineer the band gap of wurtzite InP NWs by controlling their side-facets. [ABSTRACT FROM AUTHOR]

Objective: To understand the real experience of nursing students majoring in geriatric nursing in learning the course of geriatric nursing, so as to provide reference for the design of this course. Methods: The semi-structured interview was used to interview 27 sophomore nursing students in the department of geriatric nursing in a a Chinese medicine college to understand their experience of learning the course of "Geriatric Nursing", and to apply a seven-step phenomenological analysis method for data analysis. Results: Refined 8 themes: Lack of cognition of physiological aging; focus on social issues and daily life care; adopting a blended teaching style to stimulate nursing students' interest in learning; understanding the life of the elderly from a professional point of view after class; reverence for life and realisation of life values; little attention is paid to the career of the elderly in China; Geriatric Nursing program expands the scope of employment; and fostering nursing students' willingness to engage with the elderly. Conclusion: The nursing students can understand and experience to the elderly and their lives through learning the course of Geriatric Nursing, but lack the motivation to learn actively. Teachers should guide nursing students to pre-study before class, enrich the course content, expand their knowledge outside of class, and adopt blended teaching to cultivate their perception of the elderly. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a nervous disorder, affects physical movement, and leads to difficulty in balancing, walking, and coordination. A novel sensor is mandatory to determine PD and monitor the progress of the treatment. Neurofilament light chain (NfL) has been recognized as a good biomarker for PD and also helps to distinguish between PD and atypical PD syndromes. Immunosensor was generated by current-volt measurement on gap-fingered interdigitated electrode with silicon dioxide surface to determine NfL level. To enhance the detection, anti-NfL antibody was complexed with gold-nanourchin and immobilized on the sensing electrode. The current-volt response was gradually increased at the linear detection range from100 fM to 1nM. Limitof detection and sensitivitywere 100 fMwith the signal-to-noise ratioat n=3 on a linear curve (y=0.081x+1.593; R²=0.9983). Limit of quantification falls at 1pMand high performance of the sensorwas demonstrated by discriminating against other neurogenerative disease markers, in addition, it was reproducible even in serum-spiked samples. This method of detection system aids to measure the level of NfL and leads to determine the condition with PD. [ABSTRACT FROM AUTHOR]

Plant host defense peptides (HDPs), also known as antimicrobial peptides (AMPs), are regarded as one of the most prevalent barriers elaborated by plants to combat various infective agents. Among the multiple classes of HDPs, the Snakin class attracts special concern, as they carry 12 cysteine residues, being the foremost cysteine-rich peptides of the plant HDPs. Also, their cysteines are present at very highly conserved positions and arranged in an extremely similar way among different members. Like other plant HDPs, Snakins have been shown to exhibit strong antifungal and antibacterial activity against a wide range of plant pathogens. Moreover, they display diversified biological activities in many aspects of plant growth and the development process. This review is devoted to present the general characters of the Snakin class of plant HDPs, as well as the individual features of different Snakin family members. Specifically, the sequence properties, spatial structures, distributions, expression patterns and biological activities of Snakins are described. In addition, further detailed classification of the Snakin family members, along with their possible mode of action and potential applications in the field of agronomy and pathology are discussed. [ABSTRACT FROM AUTHOR]

Based on first-principles calculations, the magnetoelectric effect and the critical thickness for ferroelectricity in Co/BaTiO3/Co multiferroic tunnel junctions were investigated. The calculated results show that the ferroelectricity of multiferroic tunnel junctions can be maintained until a critical thickness of 1.6 nm. The magnetic moments of interface atoms are sensitive to the ferroelectric displacements, which leads to a sizable magnetoeletric effect in multiferroic tunnel junctions. The multiferroic tunnel junctions may opens an avenue for the development of novel electronic devices. [ABSTRACT FROM AUTHOR]

Introduction The optimal dose-fractionation schedule of palliative radiotherapy has been debated in patients with bone metastases. Our objective is to comprehensively compare multiple fraction schedules with single fraction radiotherapy in terms of efficacy and toxicities by performing a systematic review and network meta-analysis. Methods and analysis Electronic searches of titles/abstracts of palliative radiotherapy for bone metastases will be performed, using PubMed, Cochrane Library, Embase, clinical trials, American Society for Therapeutic Radiology and Oncology and European Society of Radiotherapy and Oncology. The primary outcome of interest is the incidence of skeletal-related event following palliative radiotherapy for bone metastases in prospective studies. The risk of bias and quality of evidence will be evaluated based on Cochrane Collaboration’s tool and Grades of Recommendation, Assessment, Development and Evaluation in the network meta-analysis. We will conduct subgroup analysis and sensitivity analysis regardless of heterogeneity estimates. Ethics and dissemination This study will synthesise the evidence regarding dose-fractionation schedule of palliative radiotherapy in patients with bone metastases. We hope the findings from this study will help clinicians and patients select optimum palliative radiotherapy by identifying the optimal dose-fractionation schedule of palliative radiotherapy with the most value in terms of patient-important outcomes. The evidence obtained from network meta-analysis will help to guide head-to- head research in the future. The results will be disseminated through international conference reports and peer-reviewed manuscripts. Ethics review board is not required for this network meta-analysis. [ABSTRACT FROM AUTHOR]

Aims To investigate the function and the corresponding neurovascular structures in patients with diabetes without clinically detectable retinopathy. Methods Sixty-six patients with type 2 diabetes without retinopathy (NDR) and 62 healthy controls were recruited. The 16 and 32 Tds flicker electroretinography (ERG) was performed using a mydriasis-free, full-field flicker ERG recording device (RETeval). The vessel density (VD) of superficial capillary plexus (SCP) and deep capillary plexus (DCP), FD300 and ganglion cell complex (GCC) thickness in the macula were quantified using optical coherence tomography angiography (OCTA). The retinal nerve fibre layer (RNFL) thickness and the radial peripapillary capillary (RPC) density in the peripapillary area were also measured with OCTA. results Parafoveal and perifoveal VD in both SCP and DCP decreased in NDR group in comparison to control group (all p<0.01). However, macular GCC thickness was comparable between the two groups (p=0.661). Peripapillary RNFL thickness and RPC density were significantly lower in NDR group (p<0.001 and p=0.009, respectively). With regard to ERG parameters, delayed implicit time and decreased amplitude were found in NDR group in comparison to the control group (all p<0.01). In the multiple linear regression analyses, delayed implicit time for 16 and 32 Tds stimuli was significantly correlated with increased HbA1c (β=0.350, p<0.001; β=0.328, p<0.001, respectively) and decreased VD of SCP in the parafoveal region (β=-0.266, p=0.013; β=-0.253, p=0.005, respectively). However, delayed implicit time for 16 and 32 Tds stimuli was not correlated with the thickness of GCC (β=-0.008, p=0.818) in multiple linear regression analyses. Conclusion Functional and structural impairments have already started in diabetic retina even in the absence of visible retinal lesions. Subtle microvascular abnormalities rather than ganglion cell loss might be associated with early functional changes in NDR patients. Poor control of blood glucose was associated with delayed implicit time of flicker ERG in preclinical diabetic retinopathy. [ABSTRACT FROM AUTHOR]

China is a major producer and consumer of green tea and possesses numerous high-quality tea cultivars, which can be used to make green tea. However, the green teas produced from these tea cultivars vary markedly in aroma. In this study, a sensory evaluation method and headspace solid-phase microextraction combined with GC-MS were employed to determine the primary substances that contribute to the aromas and key differences in the aroma components of green tea produced from 20 tea cultivars. The results revealed 57 major volatile components, among which aldehydes, alcohols, and esters were the most prevalent. For the volatile components, the linalool, nonanal, and geraniol contents were the highest, followed by dimethyl sulfide, methyl salicylate, heptanal, and caproicacidhexneylester. The volatile components varied considerably among the green tea samples, and some contained substances with a high content that gave off unique aromas. The correlation analysis revealed significant correlations between the sensory evaluation scores and contents of linalool, geraniol, methyl salicylate, cis-linalool oxide, 3-carene, phenethyl alcohol, limonene, (Z)-3-cis-3-hexenyl isovalerate, citral, (E)-β-ocimene, alcohols, esters, and alkenes, as well as between the sensory evaluation scores and total volatile component contents. Aromatic substances with the highest odor activity values were, in descending order, linalool, capraldehyde, dimethyl sulfide, β-ionone, geraniol, nonanal, heptanal, (E)-2-nonenal, and caproicacidhexneylester. These substances were the major contributors to aroma formation in the green tea samples. The principal component analysis and orthogonal projections to the latent structure-discriminant analysis suggested that the 20 tea cultivars could be grouped into 6 categories and that the high content of linalool, nonanal, and geraniol substantially contributed to the categorization of the tea cultivars. A key variable analysis revealed that 23 volatile components played a critical role in the categorization of the tea cultivars. [ABSTRACT FROM AUTHOR]

Green tea made from high amino acid content (HAAC) tea cultivars with different leaf colors exhibits many similar characteristics, such as slight bitterness, a rich aroma, and a refreshing and velvety taste. To determine differences in the key constituents of five HAAC tea cultivars with various leaf colors, the cultivars quality constituents were systematically analyzed and compared with that of a normal green tea cultivar. High theanine (Thea) content and the synthesis of Thea precursors are extremely important determinants of the character of these HAAC tea cultivars. The levels of most catechins, carotenoids, and chlorophylls in the HAAC tea cultivars were significantly lower than those in the normal tea cultivar, as was that of caffeine. The present study suggests that the inhibition of catechins (particularly epicatechins; ECs), chlorophylls, carotenoids, and caffeine biosyntheses in HAAC tea cultivars directs the metabolic network toward amino acid biosynthesis, particularly Thea biosynthesis. [ABSTRACT FROM AUTHOR]

The communication between tumor-derived elements and stroma in the metastatic niche has a critical role in facilitating cancer metastasis. Yet, the mechanisms tumor cells use to control metastatic niche formation are not fully understood. Here we report that in the lung metastatic niche, high-metastatic hepatocellular carcinoma (HCC) cells exhibit a greater capacity to convert normal fibroblasts to cancer-associated fibroblasts (CAFs) than low-metastatic HCC cells. We show high-metastatic HCC cells secrete exosomal miR-1247-3p that directly targets B4GALT3, leading to activation of β1-integrin-NF-κB signaling in fibroblasts. Activated CAFs further promote cancer progression by secreting pro-inflammatory cytokines, including IL-6 and IL-8. Clinical data show high serum exosomal miR-1247-3p levels correlate with lung metastasis in HCC patients. These results demonstrate intercellular crosstalk between tumor cells and fibroblasts is mediated by tumor-derived exosomes that control lung metastasis of HCC, providing potential targets for prevention and treatment of cancer metastasis. [ABSTRACT FROM AUTHOR]