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BackgroundN6-methyladenosine (m6A) modification is a critical epigenetic modification in eukaryotes and involves several biological processes and occurrences of diseases. However, the roles and regulatory mechanisms of m6A regulators in osteoporosis (OP) remain unclear. Thus, the purpose of this study is to explore the roles and mechanisms of m6A regulators in OP.MethodsThe mRNA and microRNA (miRNA) expression profiles were respectively obtained from GSE56815, GSE7158, and GSE93883 datasets in Gene Expression Omnibus (GEO). The differential expression of 21 m6A regulators between high-bone mineral density (BMD) and low-BMD women was identified. Then, a consensus clustering of low-BMD women was performed based on differentially expressed (DE)-m6A regulators. The m6A-related differentially expressed genes (DEGs), the differentially expressed miRNAs (DE-miRNAs), and biological functions were investigated. Moreover, a weighted gene co-expression network analysis (WGCNA) was constructed to identify the OP-related hub modules, hub genes, and the functional pathways. Then, an m6A regulator–target–pathway network and the competing endogenous RNA (ceRNA) network in key modules were constructed. A least absolute shrinkage and selection operation (LASSO) Cox regression model and a Support Vector Machine-Recursive Feature Elimination (SVM-RFE) model were constructed to identify the candidate genes for OP prediction. The receiver operator characteristic (ROC) curves were used to validate the performances of predictive models and candidate genes.ResultsA total of 10,520 DEGs, 13 DE-m6A regulators, and 506 DE-miRNAs between high-BMD and low-BMD women were identified. Two m6A-related subclusters with 13 DE-m6A regulators were classified for OP. There were 5,260 m6A-related DEGs identified between two m6A-related subclusters, the PI3K-Akt, MAPK, and immune-related pathways, and bone metabolism was mainly enriched in cluster 2. Cell cycle-related pathways, RNA methylation, and cell death-related pathways were significantly involved in cluster 1. Five modules were identified as key modules based on WGCNA, and an m6A regulator–target gene–pathway network and the ceRNA network were constructed in module brown. Moreover, three m6A regulators (FTO, YTHDF2, and CBLL1) were selected as the candidate genes for OP.ConclusionM6A regulators play an important role in the occurrences and diagnosis of OP.

Background and Aims: To investigate the association between obstructive sleep apnea (OSA) severity and baseline serum cystatin C (Cys-C) concentration and to explore the association between baseline serum Cys-C and long-term cardiovascular outcomes and mortality in older patients with OSA.Methods: Between January 2015 and October 2017, a total of 1107 consecutive eligible older patients (≥60 years) with OSA were included in this multicenter, prospective cohort study, and baseline demographics, clinical characteristics, sleep parameters, and follow-up outcomes were collected. Participants were divided into different groups based on baseline serum Cys-C levels. The primary end point was major adverse cardiovascular events (MACE) and the secondary end point was all-cause mortality. The correlation between OSA severity and baseline serum Cys-C was evaluated by Spearman correlation analysis. Multivariate Cox regression was used to analyze the association between Cys-C and the incidence of MACE and mortality.Results: Participants included 672 men and 435 women, with a median age of 66 (range, 60–96) years. At baseline, apnea–hypopnea index (AHI) (r = 0.128, p < 0.05), oxygen desaturation index (ODI) (r = 0.116, p < 0.05), and the lowest pulse oxygen saturation (LSpO2) (r = −0.097, p < 0.05) were correlated with serum Cys-C concentration. During the median follow-up period of 42 months, 97 patients (8.8%) experienced MACE and 40 patients (3.6%) experienced death. The association between serum Cys-C levels and the risk of MACE and all-cause mortality was slow rising shaped. The multivariable Cox regression analysis showed patients with a serum Cys-C concentration of ≥1.14 mg/L had higher risks of MACE (HR = 5.30, 95% CI: 2.28–12.30, p < 0.05) and all-cause mortality (HR = 9.66, 95% CI: 2.09–44.72, p < 0.05) compared with patients with serum Cys-C of ≤0.81 mg/L in older patients with OSA. The receiver-operating characteristic curve showed baseline serum Cys-C levels exhibited moderately capable of identifying patients with a long-term risk of clinical adverse events (MACE and mortality).Conclusion: OSA severity was positively correlated with serum Cys-C concentration. High levels of Cys-C were independently associated with increased risks of MACE and all-cause mortality in older patients with OSA, suggesting that lowering Cys-C levels should be considered as a therapeutic target, and monitoring serum Cys-C may be beneficial to the favorable prognosis of older patients with OSA.

BackgroundNeoadjuvant intraperitoneal and systemic chemotherapy (NIPS) has shown promising results in gastric cancer (GC) with peritoneal metastasis. However, clinical practice experience of NIPS is still lacking in China. In this study, we investigate the efficacy and safety of NIPS in Chinese patients.MethodsEligible patients received NIPS every 3 weeks. Gastrectomy was performed for patients who met the criteria of conversion surgery. The primary end point was 1-year overall survival (OS) rate. Secondary end points were the response rate, toxic effects, conversion surgery outcomes and median survival time (MST).ResultsSixty-seven patients were enrolled. The primary endpoint was achieved with 1-year OS rate reached 67.2% (95% CI, 56.8%-79.4%). Conversion surgery was performed in 42 patients (62.9%), and R0 resection was achieved in 23 patients (54.8%) with the MST of 31.3 months (95% CI, 24.3-38.3). And the MST was 19.3 months (95% CI, 16.4-22.2) for all patients. Toxicity and surgical complications were well-tolerated. Moreover, sex, R0 resection, pathological nodal stage and tumor regression grade (TRG) were independent prognostic factors for patients who underwent conversion surgery.ConclusionThe NIPS is effective and safe in treating GC patients with peritoneal metastasis. Male patients, patients who underwent R0 resection, patients with ypN0-1 or TRG 1 after conversion surgery are more likely to benefit from the NIPS.Clinical Trial Registrationhttp://www.chictr.org.cn/, identifier https://clinicaltrials.gov/ ().

Abstract Dysregulations in transcription factors (TFs) and their genetic products play important roles in tumorigenesis, tumor progression and metastasis. However, prognostic value of the transcriptional regulatory networks in different cancers has not been investigated in depth. The purpose of our study was to identify and validate a potential predictive signature that combines TFs and their regulatory products in eight solid tumors. We used bioinformatics analysis to identify MET Transcriptional Regulator (MACC1) and Serine Peptidase Inhibitor Kunitz Type 1 (SPINT1) as candidate TFs with the respective downstream regulatory proteins for patient prognosis in pan‐cancer. Subsequent molecular analysis of clinical gastric cancer tissue samples further verified the negative correlation between MACC1 and SPINT1. Further, we showed that mechanistically, MACC1/SPINT1 mediated the pro‐HGF proteolysis and c‐Met phosphorylation in HGF/c‐MET signaling pathway. Kaplan‐Meier plots and receiver operating characteristics analysis revealed that the two‐gene signature combining MACC1 with SPINT1 was effective in predicting survival in all eight cancer cohorts tested. In conclusion, our study clarified the regulatory relationship between MACC1 and SPINT1 in the context of the HGF/c‐MET signaling pathway and determined MACC1/SPINT1 panel as a valuable signature for the prediction of prognosis in patients for multiple solid cancer types.

Abstract Peripheral biomarkers indicative of brain pathology are critically needed for early detection of Parkinson’s disease (PD). In this study, using NanoString and digital PCR technologies, we began by screening for alterations in genes associated with PD or atypical Parkinsonism in erythrocytes of PD patients, in which PD-related changes have been reported, and which contain ~ 99% of blood α-synuclein. Erythrocytic CHCHD2 mRNA was significantly reduced even at the early stages of the disease. A significant reduction in protein and/or mRNA expression of CHCHD2 was confirmed in PD brains collected at autopsy as well as in the brains of a PD animal model overexpressing α-synuclein, in addition to seeing a reduction of CHCHD2 in erythrocytes of the same animals. Overexpression of α-synuclein in cellular models of PD also resulted in reduced CHCHD2, via mechanisms likely involving altered subcellular localization of p300 histone acetyltransferase. Finally, the utility of reduced CHCHD2 mRNA as a biomarker for detecting PD, including early-stage PD, was validated in a larger cohort of 205 PD patients and 135 normal controls, with a receiver operating characteristic analysis demonstrating > 80% sensitivity and specificity.

In this work, TiO2-MXene/poly (3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT:PSS) composite was utilized as an electrode material for the sensitive electrochemical detection of baicalein. The in-situ growth of TiO2 nanoparticles on the surface of MXene nanosheets can effectively prevent their aggregation, thus presenting a significantly large specific surface area and abundant active sites. However, the partial oxidation of MXene after calcination could reduce its conductivity. To address this issue, herein, PEDOT:PSS films were introduced to disperse the TiO2-MXene materials. The uniform and dense films of PEDOT:PSS not only improved the conductivity and dispersion of TiO2-MXene but also enhanced its stability and electrocatalytic activity. With the advantages of a composite material, TiO2-MXene/PEDOT:PSS as an electrode material demonstrated excellent electrochemical sensing ability for baicalein determination, with a wide linear response ranging from 0.007 to 10.0 μM and a lower limit of detection of 2.33 nM. Furthermore, the prepared sensor displayed good repeatability, reproducibility, stability and selectivity, and presented satisfactory results for the determination of baicalein in human urine sample analysis.

Celiac disease is an immune-mediated disorder triggered by hypersensitivity to gluten occurring in genetically susceptible individuals. A high-index of suspicion is needed for diagnosis as patients can be asymptomatic or present with atypical symptoms or extra-intestinal manifestations. Typical 18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)/Computed Tomography (CT) gastrointestinal manifestations of celiac disease include increased multifocal or diffuse jejunal and ileal uptake; focal duodenal uptake is less common. Splenomegaly with increased splenic FDG uptake is also uncommon in celiac disease in the absence of portal hypertension; small-sized spleen and functional hyposplenism are more typical. We report a case of celiac disease diagnosed after PET/CT showed FDG uptake in the duodenum and enlarged spleen. Follow-up after gluten-free diet showed complete metabolic resolution and regression of splenomegaly. The combination of focal bowel and splenic uptake is unusual in celiac disease and may be mistaken for a lymphoproliferative disorder. Awareness of this entity may avoid misdiagnosis and guide appropriate management.

Abstract Circular RNAs (circRNAs) is one type of important non-coding RNAs that participate in tumorigenesis and cancer progression. In our previous study, we performed a microarray analysis of circRNAs between the tumor tissues and the adjacent normal tissues of hepatocellular carcinoma (HCC) patients, and found that the circRNA hsa_circ_0007456 is significantly downregulated in the tumor tissues and correlated with the prognosis of HCC. We further investigated the relationship between the expression levels of hsa_circ_0007456 in HCC and the susceptibility of NK cells, and found that the expression levels of hsa_circ_0007456 in HCC cell lines significantly influenced their susceptibility to NK cells. Through a series of screening and validation, we found that hsa_circ_0007456 mainly functioned through sponging miR-6852-3p and regulating the expression of intercellular adhesion molecule-1 (ICAM-1) in HCC. The miR-6852-3p/ICAM-1 axis is essential for the NK cytotoxicity toward HCC mediated by hsa_circ_0007456. In conclusion, we identify here hsa_circ_0007456 as a promising biomarker of HCC, and highlight hsa_circ_0007456/miR-6852-3p/ICAM-1 axis as an important signaling pathway in the process of tumor immune evasion and the tumorigenesis of HCC.

Gastric cancer (GC) is a common gastrointestinal cancer with a high global mortality. Recent reports have suggested that long noncoding RNA (lncRNA) are implicated in multiple aspects of GC, including pathogenesis, progression, and therapeutic response. Herein, we investigated the function of FOXD1‐AS1 in GC progression and chemoresistance. Expression of FOXD1‐AS1 was low in normal stomach tissues but was upregulated in GC cell lines. Silencing of FOXD1‐AS1 impaired GC cell proliferation and motility in vitro, and repressed tumor growth and metastasis in vivo. Importantly, FOXD1‐AS1 upregulation increased the resistance of GC cells to cisplatin. Moreover, we found that FOXD1‐AS1 promoted FOXD1 protein translation through the eIF4G‐eIF4E‐eIF4A translational complex. We also demonstrated that FOXD1‐AS1 released eIF4E from phosphorylated 4E‐BP1 and thereby strengthened the interaction of eIF4E with eIF4G by activating the PI3K/AKT/mTOR pathway. Activation of the PI3K/AKT/mTOR pathway was due to the post‐transcriptional upregulation of PIK3CA, in turn induced by FOXD1‐AS1‐mediated sequestering of microRNA (miR)‐466. Furthermore, we verified that FOXD1‐AS1 facilitated GC progression and cisplatin resistance in a FOXD1‐dependent manner. In conclusion, FOXD1‐AS1 aggravates GC progression and chemoresistance by promoting FOXD1 translation via PIK3CA/PI3K/AKT/mTOR signaling. These findings highlight a novel target for treatment of patients GC, particularly patients with cisplatin resistance.

Parasitism is a widespread evolutionary strategy. A study that spans functional and evolutionary genomics identifies the molecular basis and history underlying two genes that have mediated divergent parasitic strategies (specialist vs generalist) between two sister species of parasitoid wasp.

Abstract This study was to detect the expression level of transferrin receptor 2 (TfR2) in gastric cancer and to analyze its value in predicting the prognosis of gastric cancer patients. Real‐time PCR (RT‐qPCR) was applied to detect the mRNA expression of TfR2 in gastric cancer tissues and paired adjacent nontumorous tissues. Immunohistochemistry (IHC) and western blotting were used to determine the protein expression of TfR2 in gastric cancer, and the relationship with the prognosis of gastric cancer patients was analyzed. The results were: (1) The mRNA and protein levels of TfR2 in gastric cancer tissues were remarkably lower than those in adjacent nontumorous gastric tissue (P

Abstract Recent studies have shown that long-term alcohol intake from food can lead to numerous mental disorders in humans, and the social and health effects of excessive intake of alcohol currently represent serious problems for governments and families worldwide. However, to date, it has not been determined how alcohol affects the hypothalamic–pituitary–adrenal (HPA) axis. The zebrafish offers a good model for studying the toxicology of food-grade ethanol. In the present study, using zebrafish larvae exposed to 1% ethanol, we performed zebrafish behavioral analysis. Samples were collected for enzyme-linked immunosorbent assay (ELISA) and quantitative real time-polymerase chain reaction (qRT-PCR) experiments, and statistical analysis was performed. We found that ethanol decreased the locomotor activity of zebrafish larvae, which showed a more intense reaction to external stimuli. Ethanol also increased the level of HPA axis hormones in zebrafish larvae, influenced the level of neurotransmitters, and altered the expression of key genes in neurotransmitter metabolism. Ethanol exposure affects zebrafish behavior, increases the level of HPA axis hormones in zebrafish larvae, affects the level of neurotransmitters, and affects the expression of key genes in dopamine and serotonin metabolism. These findings may help to elucidate the effects of ethanol on HPA axis activity.

Previously network representation learning methods mainly focus on exploring the microscopic structure, i.e., the pairwise relationship or similarity between nodes. However, the mesoscopic structure, i.e., community structure, an essential property in real networks, has not been thoroughly studied in the network representation learning. We here propose a deep attributed network representation learning with community awareness (DANRL-CA) framework. Specifically, we design a neighborhood enhancement autoencoder module to capture the 2-step relations between node pairs. To explore the multi-step relations, we construct a community-aware skip-gram module based on the encoder. We introduce two variants of DANRL-CA, namely, DANRL-CA-AM and DANRL-CA-CSM, which incorporate the community information and attribute semantics into node neighbors with different methods. We compare two variant models with the state-of-the-art methods on four datasets for node classification and link prediction. Especially, we apply our models on a brain network. The superiority indicates the scalability and effectiveness of our method on various networks. Compared with DANRL-CA-AM, DANRL-CA-CSM can more flexibly coordinate the role of node attributes and community information in the process of network representation learning, and shows superiority in the networks with sparse topological structure and node attributes.

A dynamic and mutualistic interplay between tumor cells and the surrounding tumor microenvironment (TME) triggered the initiation, progression, metastasis, and therapy response of solid tumors. Recent clinical breakthroughs in immunotherapy for gastrointestinal cancer conferred considerable attention to the estimation of TME, and the maturity of next-generation sequencing (NGS)-based technology contributed to the availability of increasing datasets and computational toolbox for deciphering TME compartments. In the current review, we demonstrated the components of TME, multiple methodologies involved in TME detection, and prognostic and predictive TME signatures derived from corresponding methods for gastrointestinal cancer. The TME evaluation comprises traditional, radiomics, and NGS-based high-throughput methodologies, and the computational algorithms are comprehensively discussed. Moreover, we systemically elucidated the existing TME-relevant signatures in the prognostic, chemotherapeutic, and immunotherapeutic settings. Collectively, we highlighted the clinical and technological advances in TME estimation for clinical translation and anticipated that TME-associated biomarkers may be promising in optimizing the future precision treatment for gastrointestinal cancer.

Parasitoids are widespread in natural ecosystems and normally equipped with diverse viral factors to defeat host immune responses. On the other hand, parasitoids can enhance the antibacterial abilities and improve the hypoimmunity traits of parasitized hosts that may encounter pathogenic infections. These adaptive strategies guarantee the survival of parasitoid offspring, yet their underlying mechanisms are poorly understood. Here, we focused on Cotesia vestalis, an endoparasitoid of the diamondback moth Plutella xylostella, and found that C. vestalis parasitization decreases the number of host hemocytes, leading to disruption of the encapsulation reaction. We further found that one bracovirus C-type lectin gene, CvBV_28-1, is highly expressed in the hemocytes of parasitized hosts and participates in suppressing the proliferation rate of host hemocytes, which in turn reduces their population and represses the process of encapsulation. Moreover, CvBV_28-1 presents a classical bacterial clearance ability via the agglutination response in a Ca2+-dependent manner in response to gram-positive bacteria. Our study provides insights into the innovative strategy of a parasitoid-derived viral gene that has dual functions to manipulate host immunity for a successful parasitism.

BackgroundThe pathogenic mechanisms underlying the autonomic nervous system (ANS) dysfunction in patients with chronic migraine (CM) remain unclear. This study investigated the pathogenesis of ANS dysfunction in this population.MethodsA total of 60 patients diagnosed with CM and 60 healthy subjects were recruited to participate in this study. The pupil diameter, pupil contraction velocity, latency, amplitude, and the maximum gradient recovery time were examined before, at 2 min and at 5 min after the cold pressor test, which was combined with the pupillary light reflex method. A brain 3D T1-weighted structural imaging scan, resting-state functional magnetic resonance imaging scan, and diffusion tensor imaging (DTI) scan were also acquired.ResultsPatients with CM exhibited a longer recovery time to the maximum gradient at 2 min and at 5 min after cold pressing compared with the control group (P < 0.01 and P < 0.05, respectively). There was no significant difference in the pupil diameter, pupillary contraction velocity, latency, amplitude, blood pressure, or heart rate between the two groups (all P > 0.05). In the CM group, the regional homogeneity (ReHo) values of the left amygdala and left lateral hypothalamic area were significantly higher than those of other brain areas (P < 0.001, Alphasim corrected). The DTI scan of the whole brain area showed a lack of significant difference in DTI indices, including FA, MD, AD, and RD values between the two groups (P > 0.05, Alphasim corrected).ConclusionThe dysfunction of the left amygdala and left lateral hypothalamic area may be related to ANS dysfunction in patients with CM.

Endothelial cell dysfunction is the main contributing factor of diabetic foot ulcer (DFU). Circulating exosomes have been found to play an important role in many processes, such as cell senescence and angiogenesis. However, the underlying roles and mechanism of circulating exosomes in the onset and progression of DFU remain unclear. In this study, we isolated exosomes from the plasma of patients with DFU (DFU-Exos) and non-diabetic foot wounds (NDF-Exos). DFU-Exos promoted cell senescence and inhibited tube formation in Human Umbilical Vein Endothelial Cells (HUVECs), unlike NDF-Exos. Several datasets suggest that miR-181b-5p expression might be enriched in exosomes from DFU; this was verified using quantitative real-time PCR (qRT-PCR). We also found that miR-181b-5p, which was taken up by HUVECs, promoted cell senescence and inhibited tube formation. Dual luciferase reporter assay, qRT-PCR, Western blotting, and immunofluorescence staining confirmed that miR-181b-5p could negatively regulate nuclear factor erythroid 2-related factor 2 (NRF2) expression by binding to its 3′ UTR, thus further suppressing heme oxygenase-1 (HO-1) expression. In addition, NRF2 and HO-1 inhibitors could also rescue the effects of senescence and tube formation exerted by miR-181b-5p inhibitor. In vivo experiments showed that exosomes isolated from HUVECs which inhibited miR-181b-5p expression promoted angiogenesis to further restore the capacity of wound healing. In conclusion, this study indicated that circulating exosomal miR-181b-5p promoted cell senescence and inhibited angiogenesis to impair wound healing in DFU by regulating the NRF2/HO-1 pathway.

IntroductionLeptomeningeal metastasis (LM) commonly occurs in non-small cell lung cancer (NSCLC) patients and has a poor prognosis. Due to limited access to leptomeningeal lesions, the genetic characteristics of LM have not been explored to date. Cerebrospinal fluid (CSF) may be the most representative liquid biopsy medium to obtain genomic information from LM in NSCLC.MethodsCSF biopsies and matched peripheral blood biopsies were collected from 33 NSCLC patients with LM. We profiled genetic alterations from LM by comparing CSF cell-free DNA (cfDNA) with plasma cfDNA. Somatic mutations were examined using targeted sequencing. Genomic instability was analyzed by low-coverage whole-genome sequencing (WGS).ResultsDriver mutations were detected in 100% of CSF cfDNA with much higher variant allele frequency than that in matched plasma cfDNA (57.5%). Furthermore, we found that the proportions of CSF cfDNA fragments below 150 bp were significantly higher than those in plasma cfDNA. These findings indicate enrichment of circulating tumor DNA (ctDNA) in CSF and explain the high sensitivity of mutation detection in the CSF. The absence of some mutations in CSF cfDNA—especially the first-/second-generation mutation T790M, which confers resistance to epidermal growth factor receptor (EGFR)-Tyrosine kinase inhibitors (TKIs)—that were present in plasma cfDNA samples indicates different mechanisms of cancer evolution between LM and extracranial lesions. In addition, 86.6% of CSF ctDNA samples revealed high levels of genomic instability compared with 2.5% in plasma cfDNA samples. A higher number of large-scale state transitions (LSTs) in CSF cfDNA were associated with a shorter overall survival (OS).ConclusionOur results suggest that LM and extracranial lesions develop independently. Both CSF cfDNA genetic profiling and plasma cfDNA genetic profiling are necessary for clinical decision-making for NSCLC patients with LM. Through CSF-based low-coverage WGS, a high level of LSTs was identified as a potential biomarker of poor prognosis.

Backgrounds: Immune checkpoint inhibitors (ICIs) are considered cornerstones of oncology treatment with durable anti-tumor efficacy, but the increasing use of ICIs is associated with the risk of developing immune-related adverse events (irAEs). Although ICI-associated pancreatic adverse events (AEs) have been reported in patients treated with ICIs, the clinical features and spectrum of pancreatic AEs are still not well-defined. Therefore, this study aimed to identify the association between pancreatic AEs and ICIs treatments and to characterize the main features of ICI-related pancreatic injury (ICIPI) based on the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: Data from the first quarter of 2015 to the first quarter of 2021 in the database were extracted to conduct a disproportionality analysis. The selection of AEs related to the pancreas relied on previous studies and preferred terms from the Medical Dictionary for Regulatory Activities. Two main disproportionality analyses—the reporting odds ratio (ROR) and information component (IC)—were used to evaluate potential associations between ICIs and pancreatic AEs. Results: In total, 2,364 cases of pancreatic AEs in response to ICIs were extracted from the FAERS database, of which, 647 were identified as ICI-associated pancreatitis and 1,293 were identified as ICI-associated diabetes mellitus. Generally, significant signals can be detected between pancreatic AEs and all ICIs treatments (ROR025 = 3.30, IC025 = 1.71). For monotherapy, the strongest signal associated with pancreatitis was reported for anti-PD-L1 (ROR025 = 1.75, IC025 = 0.76), whereas that with diabetes mellitus was reported for anti-PD-1 (ROR025 = 6.39, IC025 = 2.66). Compared with monotherapy, combination therapy showed stronger associations with both ICI-associated pancreatitis (ROR025 = 2.35, IC025 = 1.20 vs. ROR025 = 1.52, IC025 = 0.59) and ICI-associated diabetes mellitus (ROR025 = 9.53, IC025 = 3.23 vs. ROR025 = 5.63, IC025 = 2.48), but lower fatality proportion. Conclusions: ICIs were significantly associated with the over-reporting frequency of pancreatic AEs, in which combination therapy posed a higher reporting frequency. Therefore, patients should be informed of these potential toxicities before ICIs medications are administered.

MicroRNAs (miRNAs), a class of endogenous, non-coding RNAs, which is 20–24 nucleotide long, regulate the expression of its target genes post-transcriptionally and play critical roles in plant normal growth, development, and biotic and abiotic stresses. In cells, miRNA biogenesis and stability control are important in regulating intracellular miRNA abundance. In addition, research on these two aspects has achieved fruitful results. In this review, we focus on the recent research progress in our understanding of miRNA biogenesis and their stability control in plants.

The neutrophil-to-lymphocyte ratio (NLR) plays an important role in the progression of intracerebral hemorrhage (ICH). An increasing number of studies have reported that a high NLR is correlated with poor clinical outcomes among patients with ICH. Here, we conducted a systematic review and meta-analysis to evaluate the prognostic value of NLR in the setting of ICH. We performed a comprehensive search of electronic literature databases to identify all relevant studies evaluating the prognostic role of NLR in patients with ICH. Two researchers independently screened the studies and extracted relevant data. We extracted, pooled, and weighted odds ratio (OR) and 95% confidence interval (CI) values using a generic inverse-variance method, and then evaluated the heterogeneity among studies using Q test and I2 statistic. Finally, we selected a total of 26 studies including 7,317 patients for the current study. Overall, our results indicated that a high NLR was significantly associated with a poor outcome (OR, 1.32; 95% CI, 1.19–1.46; P < 0.00001), mortality (OR, 1.05; 95% CI, 1.01–1.09; P = 0.02), and neurological deterioration (OR, 1.65; 95% CI, 1.08–2.52; P = 0.02). We did not observe a significant association between NLR and hematoma expansion (OR, 1.04; 95% CI, 0.99–1.08; P = 0.09). Our study indicated that a high NLR is significantly associated with poor clinical outcomes in patients with ICH. As NLR is a simple and easily available biomarker, future studies should focus on exploring its application in the prognostic evaluation of patients with ICH.

Background: This meta-analysis aimed to assess the efficacy and safety of ginkgo terpene lactone preparations including ginkgo diterpene lactone meglumine injection, ginkgolide injection, and ginkgolide B injection for ischemic stroke (IS).Methods: We searched the randomized controlled trials (RCTs) with publication date earlier than 31 August 2021 in PubMed, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journals Database (VIP), Chinese Biomedical Literature Database (CBM), Wanfang Database, Embase, and the Cochrane Library. RevMan 5.3 software was applied to analyze the data and generate the forest plot and funnel plot. Meanwhile, publication bias was also assessed by Egger’s test with STATA 12 software.Results: A total of 28 RCTs were eligible for inclusion. Among them, 23 RCTs were used to evaluate the efficacy of ginkgo terpene lactone preparations as the main treatment intervention for IS. To be specific, ginkgo diterpene lactone meglumine injection was superior to control drug in improving clinical efficacy [RR = 1.18, 95% CI (1.12, 1.24), Z = 6.36, p < 0.001] and neurological function [MD = −1.42, 95% CI (−1.91, −0.93), Z = 5.66, p < 0.001]. However, the effectiveness of the ginkgolide B injection group was equivalent to that of the control group. Additionally, ginkgolide injection achieved better clinical efficacy [RR = 1.10, 95% CI (1.02, 1.18), Z = 2.36, p = 0.02], but the changes of neurological function deficit was not obviously different between two groups [MD = −0.43, 95% CI (−4.32, 3.46), Z = 0.22, p = 0.83]. Furthermore, meta-analysis of five trials on ginkgo diterpene lactone meglumine injection combined with recombinant tissue plasminogen activator (rt-PA) thrombolytic therapy for acute IS showed that combination therapy was better in improving clinical efficacy [OR = 1.91, 95% CI (1.13, 3.22), Z = 2.41, p = 0.02] and neurological function [MD = −3.31, 95% Cl (−3.64,−2.98), Z = 19.63, p < 0.001]. Importantly, no serious adverse drug reactions/adverse drug events (ADRs/ADEs) were reported.Conclusion: Ginkgo terpene lactone preparations have good therapeutic effects on patients with IS. For acute IS, ginkgo diterpene lactone meglumine injection can be used as a complementary therapy to improve the clinical efficacy of rt-PA.

Cloke-Wilson rearrangement has been well studied, in which cyclopropyl ketones or cyclopropyl imines could be transformed to dihydrofuran or dihydropyrrole derivatives through a tandem ring-opening/recyclization process. Herein, we report a new version of Cloke-Wilson rearrangement, in which the ring-opening/recyclization of cyclopropyl ketones upon visible-light-induced photoredox catalysis can provide oxy-bridged macrocyclic frameworks under mild reaction conditions, and the reagent XRf plays dual roles in the catalytic cycle. The reaction proceeds through a ring-opening and an interrupted recyclization by intramolecular nucleophilic attack with the in situ generated radical cation. The reaction mechanism was proposed on the basis of control, deuterium labeling, Stern–Volmer quenching and CV measuring experiments. This protocol can afford a series of oxy-bridged macrocyclic frameworks with broad substrate scope and good functional-group tolerance. In addition, a variety of 2,2-disubstituted oxy-bridged macrocyclic indolinones can be obtained efficiently by simple manipulation from the products.

Neoadjuvant FLOT regimen has shown promising results for the treatment of locally advanced gastric cancer, however SOX regimen remains the preferred chemotherapy in Eastern countries. Here the authors report that the two therapies result in similar outcomes, measured as clinical downstaging and pathological response, in a phase II randomized clinical trial.

Abstract Background Obesity, a risk factor for many chronic diseases, is a potential independent risk factor for iron deficiency. Evidence has shown that chronic intermittent hypobaric hypoxia (CIHH) has protective or improved effects on cardiovascular, nervous, metabolic and immune systems. We hypothesized that CIHH may ameliorate the abnormal iron metabolism in obesity. This study was aimed to investigate the effect and the underlying mechanisms of CIHH on iron metabolism in high-fat-high-fructose-induced obese rats. Methods Six to seven weeks old male Sprague-Dawley rats were fed with different diet for 16 weeks, and according to body weight divided into four groups: control (CON), CIHH (28-day, 6-h daily hypobaric hypoxia treatment simulating an altitude of 5000 m), dietary-induced obesity (DIO; induced by high fat diet and 10% fructose water feeding), and DIO + CIHH groups. The body weight, systolic arterial pressure (SAP), Lee index, fat coefficient, blood lipids, blood routine, iron metabolism parameters, interleukin6 (IL-6) and erythropoietin (Epo) were measured. The morphological changes of the liver, kidney and spleen were examined. Additionally, hepcidin mRNA expression in liver was analyzed. Results The DIO rats displayed obesity, increased SAP, lipids metabolism disorders, damaged morphology of liver, kidney and spleen, disturbed iron metabolism, increased IL-6 level and hepcidin mRNA expression, and decreased Epo compared to CON rats. But all the aforementioned abnormalities in DIO rats were improved in DIO + CIHH rats. Conclusions CIHH improves iron metabolism disorder in obese rats possibly through the down-regulation of hepcidin by decreasing IL-6 and increasing Epo.

Abstract Background Microglial function is vital for maintaining the health of the brain, and their activation is an essential component of neurodegeneration. There is significant research on factors that provoke “reactive” or “inflammatory” phenotypes in conditions of injury or disease. One such factor, exposure to the aggregated or oligomeric forms of α-synuclein, an abundant brain protein, plays an essential role in driving microglial activation; including chemotactic migration and production of inflammatory mediators in Lewy body (LB) diseases such as Parkinson’s disease. On the other hand, it is increasingly recognized that microglia also undergo changes, dependent on the cellular environment, that promote mainly reconstructive and anti-inflammatory functions, i.e., mostly desirable functions of microglia in a physiological state. What maintains microglia in this physiological state is essentially unknown. Methods In this study, using in vitro and in vivo models, we challenged primary microglia or BV2 microglia with LPS + IFN-γ, IL-4 + IL-13, α-synuclein monomer, and α-synuclein oligomer, and examined microglia phenotype and the underlying mechanism by RT-PCR, Western blot, ELISA, IF, IHC, Co-IP. Results We described a novel physiological function of α-synuclein, in which it modulates microglia toward an anti-inflammatory phenotype by interaction with extracellular signal-regulated kinase (ERK) and recruitment of the ERK, nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor γ (PPARγ) pathways. Conclusions These findings suggest a previously unrecognized function of monomeric α-synuclein that likely gives new insights into the pathogenesis and potential therapies for Lewy body-related diseases and beyond, given the abundance and multiple functions of α-synuclein in brain tissue.

Abstract Parkinson’s disease is a neurodegenerative disorder characterized by the transmission and accumulation of toxic species of α-synuclein (α-syn). Extracellular vesicles (EVs) are believed to play a vital role in the spread of toxic α-syn species. Recently, peripheral α-syn pathology has been investigated, but little attention has been devoted to erythrocytes, which contain abundant α-syn. In this study, we first demonstrated that erythrocyte-derived EVs isolated from Parkinson’s disease patients carried elevated levels of oligomeric α-syn, compared to those from healthy controls. Moreover, human erythrocyte-derived EVs, when injected into peripheral blood in a mouse model of Parkinson’s disease, were found to readily cross the blood-brain barrier (BBB). These EVs accumulated in astrocyte endfeet, a component of the BBB, where they impaired glutamate uptake, likely via interaction between excitatory amino acid transporter 2 (EAAT2) and oligomeric α-syn. These data suggest that erythrocyte-derived EVs and the oligomeric α-syn carried in them may play critical roles in the progression or even initiation of Parkinson’s disease. Additionally, the mechanisms involved are attributable at least in part to dysfunction of astrocytes induced by these EVs. These observations provide new insight into the understanding of the mechanisms involved in Parkinson’s disease.

Salvia miltiorrhiza Bunge is an herb rich in bioactive tanshinone and salvianolic acid compounds. It is primarily used as an effective medicine for treating cardiovascular and cerebrovascular diseases. Liposoluble tanshinones and water-soluble phenolic acids are a series of terpenoids and phenolic compounds, respectively. However, the regulation mechanism for the simultaneous promotion of tanshinone and salvianolic acid biosynthesis remains unclear. This study identified a R2R3-MYB subgroup 20 transcription factor (TF), SmMYB98, which was predominantly expressed in S. miltiorrhiza lateral roots. The accumulation of major bioactive metabolites, tanshinones, and salvianolic acids, was improved in SmMYB98 overexpression (OE) hairy root lines, but reduced in SmMYB98 knockout (KO) lines. The qRT-PCR analysis revealed that the transcriptional expression levels of tanshinone and salvianolic acid biosynthesis genes were upregulated by SmMYB98-OE and downregulated by SmMYB98-KO. Dual-Luciferase (Dual-LUC) assays demonstrated that SmMYB98 significantly activated the transcription of SmGGPPS1, SmPAL1, and SmRAS1. These results suggest that SmMYB98-OE can promote tanshinone and salvianolic acid production. The present findings illustrate the exploitation of R2R3-MYB in terpenoid and phenolic biosynthesis, as well as provide a feasible strategy for improving tanshinone and salvianolic acid contents by MYB proteins in S. miltiorrhiza. Keywords: Plant secondary metabolism, Transcriptional regulation, R2R3-MYB transcription factor, Traditional Chinese Medicine, Metabolic engineering

Abstract Background Brain metastases are one of the most common intracranial neoplasms. Increasing evidence have indicated that systemic immunotherapy may provide long‐term benefits for brain metastases. Herein, we presented the results of an immune oncology panel RNA sequencing platform for patients with brain metastases from different primary sites. Methods We investigated 25 samples of human brain metastases from lung cancer (n = 12), breast cancer (n = 6), and colorectal cancer (n = 7). Besides, 13 paired samples of adjacent noncancerous brain tissue (10 from patients with lung cancer and 3 from patients with breast cancer) were collected as controls. By comparing the brain metastases and paired samples of adjacent noncancerous brain tissue from 13 patients, we detected three upregulated and six downregulated genes, representing the malignant properties of cancer cells and increased immune infiltration in the microenvironment. Next, we profiled the immune‐related genes in brain metastases from three primary cancer types. Results A group of genes were significantly overexpressed in the microenvironment of brain metastases from lung cancer, covering the checkpoint pathways, lymphocyte infiltration, and TCR‐coexpression. Especially, immune checkpoint molecules, PD‐L1, PD‐L2, and IDO1 were expressed at higher levels in brain metastases from lung cancer than those from the other two cancer types. Conclusions This study presents an immune landscape of brain metastases from different cancer types. With high RNA expression levels of PD‐1/PD‐L1 axis and immune infiltration in brain metastases, it would be worthwhile to explore the efficacy of immune checkpoint blockade for lung cancer patients with intracranial metastases.

Abstract Background The aim of this study is to demonstrate that capecitabine metronomic chemotherapy is non-inferior to capecitabine conventional chemotherapy as maintenance treatment, in patients who have responded to 16–18 weeks first-line chemotherapy in metastatic colorectal cancer (mCRC). Methods The study design is a prospective, randomized, open label, phase II clinical trial. Those patients with mCRC who respond well after 16–18 weeks of standard doublet chemotherapy as induction may be enrolled into this study, and randomly assigned to the capecitabine metronomic group or standard dosage group. The duration of disease control after randomization and progression-free survival after enrollment are the primary endpoints. Overall survival, safety, and quality of life are the secondary endpoints. The sample size required to achieve the research objectives of this project is 79 patients in each group. The study recently started on 1 January 2018, and will last for 36 months. Discussion This project is intended to study the efficacy and safety of capecitabine metronomic chemotherapy in the maintenance treatment of advanced colorectal cancer, and to explore the strategy of “low toxicity, high efficiency, economy, and individualization”, which is suitable for China’s national conditions and pharmacoeconomics. It has great prospects for clinical application and a clear socioeconomic value. Trial registration ClinicalTrials.gov: NCT03158610 . Registered on 15 May 2017.

Abstract In this paper, the exponential stability for a class of delayed competitive neural networks is studied. By applying the inequality technique and non-reduced-order approach, some novel and useful criteria of global exponential stability for the addressed network model are established. Moreover, a numerical example is presented to show the feasibility and effectiveness of the theoretical results.

Background The distribution characteristics of gender, age, and season and the influence of season on the length of hospitalization stay (LOS) were analyzed based on the information of inpatients about various diseases. Methods A total of 5575 patients’ basic information (gender, age, hospitalization time, season of onset) of five diseases was classified according to spring, summer, autumn, winter. Their distribution characteristics were analysed using T‐test, one‐way ANOVA, Chi‐square test. Then the data were incorporated into SPSS 21.0 for statistical analysis. Results Most cases of cranial chronic vascular disease (CCVD) were found in summer (53% of cases), less in spring, and no cases in winter. The LOS was longer for middle‐aged men, elderly men, and elderly women in the fall group than in the spring group (p < 0.05). The LOS was longer in the fall group than in the summer group for older men and older women (p < 0.05). Herpes zoster cases were more frequent in summer (43%) and autumn (56.30%), less frequent in spring (1.20%), and no cases in winter. Middle‐aged and elderly men in the summer group had longer LOS than the autumn group (p < 0.05). The most cases of cervical spondylosis were found in the spring (42.00%), the fewest were found in the fall (0.10%). Cases of knee osteoarthritis were the most in winter (53.40%) and fewer in summer (7%) and autumn (9.80%). Conclusion CCVD, herpes zoster, cervical spondylosis, and knee osteoarthritis have an obvious seasonal distribution, and seasons have a certain impact on the hospitalization time of patients with CCVD or herpes zoster, especially in older men.

Abstract Background Metastasis and recurrence, wherein circulating tumour cells (CTCs) play an important role, are the leading causes of death in colorectal cancer (CRC). Metastasis-initiating CTCs manage to maintain intravascular survival under anoikis, immune attack, and importantly shear stress; however, the underlying mechanisms remain poorly understood. Methods In view of the scarcity of CTCs in the bloodstream, suspended colorectal cancer cells were flowed into the cyclic laminar shear stress (LSS) according to previous studies. Then, we detected these suspended cells with a CK8+/CD45−/DAPI+ phenotype and named them mimic circulating tumour cells (m-CTCs) for subsequent CTCs related researches. Quantitative polymerase chain reaction, western blotting, and immunofluorescence were utilised to analyse gene expression change of m-CTCs sensitive to LSS stimulation. Additionally, we examined atonal bHLH transcription factor 8 (ATOH8) expressions in CTCs among 156 CRC patients and mice by fluorescence in situ hybridisation and flow cytometry. The pro-metabolic and pro-survival functions of ATOH8 were determined by glycolysis assay, live/dead cell vitality assay, anoikis assay, and immunohistochemistry. Further, the concrete up-and-down mechanisms of m-CTC survival promotion by ATOH8 were explored. Results The m-CTCs actively responded to LSS by triggering the expression of ATOH8, a fluid mechanosensor, with executive roles in intravascular survival and metabolism plasticity. Specifically, ATOH8 was upregulated via activation of VEGFR2/AKT signalling pathway mediated by LSS induced VEGF release. ATOH8 then transcriptionally activated HK2-mediated glycolysis, thus promoting the intravascular survival of colorectal cancer cells in the circulation. Conclusions This study elucidates a novel mechanism that an LSS triggered VEGF-VEGFR2-AKT-ATOH8 signal axis mediates m-CTCs survival, thus providing a potential target for the prevention and treatment of hematogenous metastasis in CRC.

Human facial expression is the core carrier of feedback. Facial expression recognition(FER) has been introduced into mickle fields, such as auxiliary medical care, safe driving, marketing assistance, distance education. However, in the real production process, facial expression image samples collected in different scenarios have problems such as complex backgrounds, which causes the FER model to train very slowly, low recognition rate, and insufficient generalization, so it cannot meet the actual production requirements. As the originator of the clustering algorithm, fuzzy C-means clustering(FCM) algorithm has stable performance and good results. It is applied to the convolutional layer of a convolutional neural network(CNN) to obtain a convolution kernel with an initial value, so as to extract the expression image features in the training set and the test set. This can solve the problem of random initialization of the convolution kernel. Based on the CNN, this paper introduces FCM to optimize the feature extraction (FE) capability of the model, and proposes a novel FER algorithm using an improved CNN(F-CNN). Because traditional CNN has problems such as irrational layer settings and too many parameters. The proposed F-CNN first adjusts the CNN network structure to improve the nonlinear expression ability of CNN. Then, replace the Softmax classifier that comes with CNN with a support vector machine (SVM) to improve the model's classification ability. The comparison experiments with other models show that the improved model improve the FER rate. The introduced FCM algorithm can effectively improve the model's FE performance and shorten the time of F-CNN during training. On the whole, F-CNN has reference value.

Momilactones are diterpenoid phytoalexins with allelopathic functions, which have been found in the widely distributed bryophyte Calohypnum plumiforme. Clustered genes containing CpDTC1/HpDTC1, CpCYP970A14, CpCYP964A1, and CpMAS are involved in momilactone biosynthesis. Besides, momilactone concentration in C. plumiforme is affected by heavy metal treatment such as CuCl2. However, transcription factors which might regulate momilactone biosynthesis are unclear. WRKY transcription factors (TFs) regulate phytoalexin biosynthesis in many plant species. In this study, a systematic analysis of the WRKY TFs was performed according to the C. plumiforme genome. A total of 19 CpWRKY genes were identified and categorized into five subgroups based on their phylogenetic relationship. Conserved domain and motif analysis suggested that the WRKY domain was highly conserved, but there were some variations. Cis-acting elements and binding sites analysis implied that CpWRKY genes might be induced by stress and further regulate the biosynthesis of momilactones. Our study lays a foundation for further functional characterization of the candidate CpWRKY genes involved in the regulation of momilactone biosynthesis, and provides new strategies for increasing momilactone production.

Deep learning-based object counting models have recently been considered preferable choices for plant counting. However, the performance of these data-driven methods would probably deteriorate when a discrepancy exists between the training and testing data. Such a discrepancy is also known as the domain gap. One way to mitigate the performance drop is to use unlabeled data sampled from the testing environment to correct the model behavior. This problem setting is also called unsupervised domain adaptation (UDA). Despite UDA has been a long-standing topic in machine learning society, UDA methods are less studied for plant counting. In this paper, we first evaluate some frequently-used UDA methods on the plant counting task, including feature-level and image-level methods. By analyzing the failure patterns of these methods, we propose a novel background-aware domain adaptation (BADA) module to address the drawbacks. We show that BADA can easily fit into object counting models to improve the cross-domain plant counting performance, especially on background areas. Benefiting from learning where to count, background counting errors are reduced. We also show that BADA can work with adversarial training strategies to further enhance the robustness of counting models against the domain gap. We evaluated our method on 7 different domain adaptation settings, including different camera views, cultivars, locations, and image acquisition devices. Results demonstrate that our method achieved the lowest Mean Absolute Error on 6 out of the 7 settings. The usefulness of BADA is also supported by controlled ablation studies and visualizations.

Despite the high burden of household air pollution from biomass fuel in sub-Saharan Africa, the association of prenatal biomass fuel exposure and birth weight as a continuous variable among term births has not been extensively studied. In this study, our primary aim is to estimate the association between biomass cooking fuel and birth weight among term births in Kaduna, northwestern Nigeria. For replication, we also evaluated this association in a larger and nationally representative sample from the 2018 Nigerian Demographic and Health Survey (DHS). Our primary analysis included 1,514 mother-child pairs recruited from Kaduna, in northwestern Nigeria, using the Child Electronic Growth Monitoring System (CEGROMS). Replication analysis was conducted using data from 6,975 mother-child pairs enrolled in 2018 Nigerian DHS. The outcome variable was birth weight, and the exposure was cooking fuel type, categorized in CEGROMS as liquefied petroleum gas, kerosene, or biomass fuel, and in the DHS as low pollution fuel, kerosene, or biomass fuel. We estimated covariate adjusted associations between birth weight and biomass fuel exposure in CEGROMS using linear regression and using linear mixed model in the DHS. In CEGROMS, adjusting for maternal age, education, parity, BMI at birth, and child sex, mothers exposed to biomass fuel gave birth to infants who were on average 113g lighter (95% CI -196 to -29), than those using liquified petroleum gas. In the 2018 Nigeria DHS data, compared to low pollution fuel users, mothers using biomass had infants weighing 50g (95% CI -103 to 2) lower at birth. Exposure to biomass cooking fuel was associated with lower birth weight in our study of term newborns in Kaduna, Nigeria. Data from the nationally representative DHS provide some support for these findings.

Obesity is a leading global health problem contributing to various chronic diseases, including type II diabetes mellitus (T2DM). The aim of this study was to investigate whether blueberries, yoghurt, and their respective bioactive components, Cyanidin-3-O-β-glucoside (C3G) and peptides alone or in combinations, alter the expression of genes related to glucose metabolism in skeletal muscles from diet-induced obese mice. In extensor digitorum longus (EDL), yoghurt up-regulated the expression of activation of 5'adenosine monophosphate-activated protein kinase (AMPK), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-3 kinase (PI3K) and glucose transporter 4 (GLUT4), and down-regulated the expression of angiotensin II receptor type 1 (AGTR-1). The combination of blueberries and yoghurt down-regulated the mRNA expression of AGTR-1 and Forkhead box protein O1 (FoxO1) in the EDL. Whereas the combination of C3G and peptides down-regulated AGTR-1 and up-regulated GLUT4 mRNA expression in the EDL. In the soleus, blueberries and yoghurt alone, and their combination down-regulated AGTR-1 and up-regulated GLUT4 mRNA expression. In summary blueberries and yoghurt, regulated multiple genes associated with glucose metabolism in skeletal muscles, and therefore may play a role in the management and prevention of T2DM.

Tranexamic acid has been shown to reduce rebleeding after aneurysmal subarachnoid hemorrhage; however, whether it can reduce mortality and improve clinical outcomes is controversial. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of the tranexamic acid in aneurysmal subarachnoid hemorrhage. We conducted a comprehensive literature search of PubMed, Embase, Web of Science, and Cochrane Library from inception to March 2021 for randomized controlled trials (RCTs) comparing tranexamic acid and placebo in adults with aneurysmal subarachnoid hemorrhage. The risk of bias was evaluated using the Cochrane Handbook, and the quality of evidence was evaluated using the GRADE approach. This meta-analysis included 13 RCTs, involving 2,888 patients. In patients with aneurysmal subarachnoid hemorrhage tranexamic acid had no significant effect on all-cause mortality (RR = 0.96; 95% CI = 0.84–1.10, p = 0.55, I2 = 44%) or poor functional outcome (RR = 1.04; 95% CI = 0.95–1.15, p = 0.41) compared with the control group. However, risk of rebleeding was significantly lower (RR = 0.59; 95% CI = 0.43–0.80, p = 0.0007, I2 = 53%). There were no significant differences in other adverse events between tranexamic acid and control treatments, including cerebral ischemia (RR = 1.17; 95% CI = 0.95–1.46, p = 0.15, I2 = 53%). At present, routine use of tranexamic acid after subarachnoid hemorrhage cannot be recommended. For a patient with subarachnoid hemorrhage, it is essential to obliterate the aneurysm as early as possible. Additional higher-quality studies are needed to further assess the effect of tranexamic acid on patients with subarachnoid hemorrhage.

Background Despite enormous progress in the stage IV esophageal cancer (EC) treatment, some patients experience early death after diagnosis. This study aimed to identify the early death risk factors and construct models for predicting early death in stage IV EC patients. Methods Stage IV EC patients diagnosed between 2010 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were selected. Early death was defined as death within 3 months of diagnosis, with or without therapy. Early death risk factors were identified using logistic regression analyses and further used to construct predictive models. The concordance index (C-index), calibration curves, and decision curve analyses (DCA) were used to assess model performance. Results Out of 4411 patients enrolled, 1779 died within 3 months. Histologic grade, therapy, the status of the bone, liver, brain and lung metastasis, marriage, and insurance were independent factors for early death in stage IV EC patients. Histologic grade and the status of the bone and liver metastases were independent factors for early death in both chemoradiotherapy and untreated groups. Based on these variables, predictive models were constructed. The C-index was .613 (95% confidence interval (CI), [.573–.653]) and .635 (95% CI, [.596–.674]) in the chemoradiotherapy and untreated groups, respectively, while calibration curves and DCA showed moderate performance. Conclusions More than 40% of stage IV EC patients suffered from an early death. The models could help clinicians discriminate between low and high risks of early death and strategize individually-tailed therapeutic interventions in stage IV EC patients.

Background: We investigated the mutational landscape of circulating tumor DNA (ctDNA) in predicting tumor response to first-line treatment in patients with metastatic colorectal cancer (mCRC). Methods: We included 41 patients with initially unresectable mCRC, treated with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX)/5-fluorouracil/leucovorin/irinotecan (FOLFIRI) with/without bevacizumab (Bev)/cetuximab (Cet). Blood samples were prospectively collected at two timepoints: at baseline and after four cycles of first-line treatment. Mutational status of 1086 genes were studied in ctDNA by targeted next-generation sequencing (NGS). Molecular mutational burden (MMB) was defined as mean mutation frequency among obtained mutations for each gene. To evaluate the association between molecular characteristics of cfDNA and therapeutic response better, we divided these patients into MMB-high and MMB-low group according to the median value of MMB (0.3). Results: Among the 41 enrolled patients, alterations of six genes ( TRIM24 , SPEN , RNF43 , PRKAR1A , KRAS , and KDM5 C ) were found at baseline. Baseline MMB of six genes was significantly lower in partial response (PR)/stable disease (SD) patients than progression disease (PD) patients ( p = 0.0012). Further analysis demonstrated that genomic profiling of ctDNA from pretreatment blood samples was significantly different between PR/SD (non-PD) group and PD group. By comparing the baseline levels of KRAS MMB in the two subgroups, we found that PD cases were all MMB-high, whereas non-PD cases were mainly in MMB-low subgroup. Furthermore, patients with low-KRAS MMB had superior response rate, significantly longer progression-free survival (PFS) and longer overall survival (OS) than high-KRAS MMB group. Conclusions: This prospective and serial genomic profiling study revealed the utility of ctDNA in predicting clinical outcomes in mCRC patients under first-line treatment. Levels of KRAS MMB might aid in monitoring therapeutic efficacy in mCRC patients at pretreatment/after four cycles of first-line treatment.

BackgroundPromising development in immune checkpoint blockade (ICB) therapy has shown remarkable results in the treatment of gastric cancer (GC). However, the objective response rate in GC remains unsatisfactory. Noninvasive imaging to predict responses to ICB therapy via tumor microenvironment (TME) assessment is needed. Accordingly, this study aimed to evaluate the role of 68Ga-FAPI-04 PET/CT in the assessment of the immunosuppressive TME in GC and to cross-correlate imaging findings with responses to ICB therapy.MethodsThe correlation between fibroblast-activation-protein (FAP) expression and immunosuppressive cell infiltration was analyzed using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) database, and GC tissue microarrays. To characterize the TME, TMEscores were calculated based on RNA-seq data from four GC patients. A total of 21 patients with GC underwent 68Ga-FAPI-04 PET/CT before ICB treatment, and two of them were imaged after ICB therapy.ResultsFAP expression was found to be closely correlated with poor prognosis and infiltration of immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), exhausted T cells, and regulatory T cells (Tregs) in GC. We also found a strong relationship (R2 = 0.9678, p = 0.0162) between 68Ga-FAPI-04 uptake and TMEscore. Further analyses indicated that high 68Ga-FAPI-04 uptake was correlated with reduced therapeutic benefits from ICB therapy.Conclusions68Ga-FAPI-04 PET/CT may be used to noninvasively image the cancer-associated fibroblasts immunosuppressive TME in vivo and also potentially serve as a predictive biomarker of survival and antitumor immune response among patients who received ICB therapies.

The oxidative state of intestinal tracts of healthy animals were investigated after short-term intake of half-fin anchovy hydrolysates (HAHp) and their thermal or Maillard reaction products (MRPs). After one month of continuous oral gavage of HAHp, HAHp-heated products (HAHp-H), the MRPs of HAHp with 3% of glucose (HAHp-3%G MRPs), and the MRPs of HAHp with 3% of fructose (HAHp-3%F MRPs) at a dose of 1.0 g/kg of body weight per day into healthy ICR male mice, the concentrations of serum low-density and high-density lipoprotein cholesterol did not significantly change compared to the control group (CK, gavage with saline). Similar results were found for the interleukin-6 concentrations of all groups. By comparison, HAHp-H, HAHp-3%G MRPs, and HAHp-3%F MRPs administration decreased serum tumor necrosis factor-α concentration as compared to the CK group (p < 0.05). No histological damage was observed in the jejunum, ileum, and colonic tissues of all groups. However, HAHp-H treatment induced higher upregulation of Kelch-like ECH-associated protein 1, transcription factors Nrf-2, associated protective phase-II enzymes of NAD(P)H: quinine oxidoreductase-1, and hemoxygenase-1 in colon tissue, as well as higher upregulation of endogenous antioxidant enzymes, including copper/zinc superoxide dismutase, manganese superoxide dismutase, catalase, and glutathione peroxidase 2 than other groups (p < 0.05). Additionally, increases in Nε-carboxymethyllysine expression in the colonic tissues of all groups were consistent with their increased oligopeptide transporter 1 expressions. Our results suggest that the thermal products of HAHp might have a broad application prospect in improving antioxidant defense in vivo in healthy animals.

The use of adjuvant corticosteroids with surgery for chronic subdural hematoma (CSDH) has received considerable attention in recent years. However, there is no conclusive evidence regarding its effectiveness and safety for CSDH. Therefore, we performed a meta-analysis and systematic review to evaluate the effectiveness and safety of corticosteroids as an adjuvant treatment for the treatment of CSDH. We comprehensively searched electronic databases (PubMed, EMBASE, Cochrane Library, and Web of Science) to identify relevant trials that investigated the efficacy and safety of adjuvant corticosteroids with surgery for CSDH, published from inception until May 2021. Outcome measures included recurrence rate, all-cause mortality, good functional outcome, length of hospitalization, and adverse events. We used the Cochrane risk of bias method to evaluate the quality of randomized controlled trials (RCTs), and the Newcastle Ottawa Scale to evaluate the quality of observational studies. We included nine studies, consisting of three RCTs and six observational studies, that compared corticosteroids as an adjuvant treatment to surgery with surgery alone. Pooled results revealed that the risk of recurrence was significantly reduced in patients who received adjuvant corticosteroids with surgery compared to those who underwent surgery alone (relative risk [RR] = 0.52, 95% confidence interval [CI] = 0.39–0.69, p < 0.00001). However, no statistically significant difference was observed between these groups in all-cause mortality (RR = 0.91, 95% CI = 0.37–2.23, p = 0.83), good functional outcome (RR = 1.03, 95% CI = 0.96–1.10, p = 0.47), length of hospitalization (MD = 0.35, 95% CI = –2.23 to 1.67, p = 0.83), and infection rates (RR = 0.99, 95% CI = 0.64–1.53, p = 0.95). Adjuvant corticosteroids with surgery reduce the risk of recurrence of CDSH, but do not improve the all-cause mortality or functional outcome, as compared to surgery alone. These findings support the use of adjuvant corticosteroids with surgery for CSDH patients. Further high-quality RCTs are required to confirm the efficacy and safety of adjuvant corticosteroids in the treatment of CSDH patients.

Anthracnose is a disease caused by Colletotrichum species. They are well known as major plant pathogens, and a black stem disease, specifically caused by Colletotrichum truncatum and primarily infecting sword bean (Canavalia gladiata), was observed in the Yunnan province, China. To aid disease management and to determine pathogenic characteristics, the species causing the leaf spot disease of hairy vetch was verified as C. truncatum. A sequence analysis of the ITS, ACT, GAPDH, and HIS3 genes was conducted, as well as morphological and cultural characteristics, to identify this Colletotrichum species, which has curved conidia. C. truncatum isolates from sword bean formed a distinctive group among Colletotrichum species, including those that infect other forage and field crops. Artificially inoculated sword bean seedlings showed typical symptoms of anthracnose, which were similar to field observations. To the best of our knowledge, this is the first report of C. truncatum causing black stem disease on sword beans in China.

Superovulation is a common approach to maximize the number of eggs available for either clinical assisted reproductive technologies or experimental animal studies. This procedure provides supraphysiological amounts of gonadotropins to promote continued growth and maturation of ovarian follicles that otherwise would undergo atresia. There is evidence in mice, cows, sheep, and humans that superovulation has a detrimental impact on the quality of the resulting ovulated eggs or embryos. Here we tested the hypothesis that eggs derived from superovulation have a reduced capacity to support calcium oscillations, which are a critical factor in the success of embryo development. Eggs were obtained from mice that were either naturally cycling or underwent a standard superovulation protocol. The eggs were either parthenogenetically activated using strontium or fertilized in vitro while undergoing monitoring of calcium oscillatory patterns. Following parthenogenetic activation, superovulated eggs had a slightly delayed onset and longer duration of the first calcium transient, but no differences in oscillation persistence, frequency, or total calcium signal. However, in vitro fertilized superovulated eggs had no differences in any of these measures of calcium oscillatory behavior relative to spontaneously ovulated eggs. These findings indicate that although subtle differences in calcium signaling can be detected following parthenogenetic activation, superovulation does not disrupt physiological calcium signaling at fertilization, supporting the use of this method for both clinical and experimental purposes.

The neutrophil–to-lymphocyte ratio (NLR), as an essential systemic inflammation factor, has been widely used as a prognostic indicator in various diseases, such as malignant tumors, cardiovascular disease, and intracranial hemorrhage. An increasing number of studies have believed that NLR is a valuable predictor of prognosis for patients with aneurysmal subarachnoid hemorrhage (aSAH). However, these results remain controversial. In the current study, we planned to carry out a systematic review and meta-analysis to investigate the association between NLR and poor outcome, and the occurrence of delayed cerebral ischemia (DCI). We carried out a comprehensive search for published literatures on PubMed, EMBASE, Cochrane Library, and Web of Science databases from inception to April 1, 2021. We conducted an assessment of all included studies based on the principles proposed in the Newcastle-Ottawa Quality Assessment Scale (NOS). Poor outcome and the occurrence of DCI were considered as the main outcome measure. We calculated the pooled odds ratio (OR) and corresponding 95% confidence interval (CI) to examine the strength of the association of NLR with poor outcome or the occurrence of DCI. We strictly selected a total of 10 studies comprising 4,989 patients. Nine studies reported the association between NLR and poor outcome, and five studies reported the association between NLR and the occurrence of DCI. The pooled results indicated higher NLR was significantly associated with both poorer outcomes (OR = 1.32, 95%CI 1.11–1.57; P = 0.002, I2 = 87%), and the occurrence of DCI (OR = 1.72, 95%CI 1.22–2.41; P = 0.002, I2 = 82%) in aSAH patients. The NLR is a valuable indicator of inflammation to independently predict poor outcome and occurrence of DCI after aSAH, where a higher NLR is significantly associated with poor outcomes and occurrence of DCI. These findings suggest that the NLR can help clinicians evaluate the prognosis and identify potentially severe patients early, which may contribute to better management and improve poor prognosis of aSAH patients.

Ophiorrhiza pumila (O. pumila; Op) is a medicinal herbaceous plant, which can accumulate camptothecin (CPT). CPT and its derivatives are widely used as chemotherapeutic drugs for treating malignant tumors. Its biosynthesis pathway has been attracted significant attention. Teosinte branched 1/cycloidea/proliferating cell factors 1/2 (TCP) transcription factors (TFs) regulate a variety of physiological processes, while TCP TFs are involved in the regulation of CPT biosynthesis remain unclear. In this study, a systematic analysis of the TCP TFs family in O. pumila was performed. A total of 16 O. pumila TCP (OpTCP) genes were identified and categorized into two subgroups based on their phylogenetic relationships with those in Arabidopsis thaliana. Tissue-specific expression patterns revealed that nine OpTCP genes showed the highest expression levels in leaves, while the other seven OpTCPs showed a higher expression level in the stems. Co-expression, phylogeny analysis, and dual-luciferase (Dual-LUC) assay revealed that OpTCP15 potentially plays important role in CPT and its precursor biosynthesis. In addition, the subcellular localization experiment of candidate OpTCP genes showed that they are all localized in the nucleus. Our study lays a foundation for further functional characterization of the candidate OpTCP genes involved in CPT biosynthesis regulation and provides new strategies for increasing CPT production.