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Acute respiratory distress syndrome (ARDS) is a critical disease with a high mortality rate, characterized by obstinate hypoxemia caused by accumulation of alveolar fluid and excessive uncontrolled inflammation. Na,K-ATPase α1 (ATP1A1) subunit is an important component of Na,K-ATPase that transports Na

Background Rheumatoid arthritis (RA) is an autoimmune disease, which compromises the synovial membrane resulting in chronic inflammation. Increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) are implicated in the pathogenesis of RA. This study investigated the role of lncRNA ZNF667-AS1 in RA progression. Methods Synovial tissues and fibroblast-like synoviocytes (FLSs) were obtained from patients with RA. Gene expression was measured using RT-qPCR. Chondrocytes were treated with lipopolysaccharide (LPS) to establish in vitro models of OA. Cell counting kit-8 (CCK-8), western blot, and enzyme-linked immunosorbent assay (ELISA) were used to examine the proliferation and inflammatory cytokine production in chondrocytes. Animal models of OA were established in SD rats. Peripheral blood mononuclear cells (PBMCs) were isolated from the OA rats. Flow cytometry was used to measure the changes of the inflammatory T-helper cell 17 (Th17) cells. The relationship between ZNF667-AS1 and miR-523-3p was verified by luciferase reporter assay. Results ZNF667-AS1 was downregulated in RA-FLSs and LPS-stimulated chondrocytes. ZNF667-AS1 overexpression significantly promoted cell proliferation and inhibited the production of IL-6, IL-17 and TNF-α in LPS-stimulated chondrocytes. Additionally, ZNF667-AS1 overexpression reduced the generation of CD4 + IL-17+ cells. In mechanism, ZNF667-AS1 acted a sponge for miR-523-3p. MiR-523-3p overexpression reversed the ZNF667-AS1-mediated regulation of cell proliferation and inflammation. Furthermore, miR-523-3p overexpression abolished the inhibitory effects of ZNF667-AS1 on the JAK/STAT signalling activation. Conclusion ZNF667-AS1 exerts protective effects during RA development by sponging miR-523-3p and inactivating the JAK/STAT signalling.

Objectives Tonkinensine B, a novel compound with cytisine–pterocarpan skeleton isolated from the root of Sophora tonkinensis Gagnep, was reported to have a significant antitumor effect. The effect and intrinsic mechanism of tonkinensine B on tumour need to be further investigated. Methods With the help of cell cytotoxicity, the effect of tonkinensine B on MDA-MB-231 cells was investigated. By observing mitochondrial function changes, the intrinsic mechanism was further studied. The levels of key apoptosis-associated proteins Bcl-2, Bax, caspase-9, caspase-3 and AKT in MDA-MB-231 cells were analysed to determine whether tonkinensine B caused apoptosis via the mitochondrial pathway. Key findings After treated with tonkinensine B, MDA-MB-231 cells multiplication was repressed, and the decreased mitochondrial membrane potential, loss of ATP synthesis and elevated ROS generation were detected. Furthermore, the proportions of Bax/Bcl-2, cleaved caspase-3 and caspase-9 proteins production were up-regulated, indicating that tonkinensine B acted on intrinsic mitochondrial-mediated apoptosis pathway. In addition, tonkinensine B also reduced phosphorylation levels of AKT, and thus the activation of apoptosis might likewise be correlated with the inhibition of the PI3K/AKT pathway. Conclusions Tonkinensine B may be a hopeful candidate for human triple-negative breast cancer, and further structural optimization is expected to improve its anti-tumour activity.

MicroRNAs (miRNAs) are key players in human hepatocellular carcinoma (HCC) tumorigenesis. Therefore, small molecules targeting components of miRNA biogenesis may provide new therapeutic means for HCC treatment. By a high-throughput screening and structural simplification, we identified a small molecule, CIB-3b, which suppresses the growth and metastasis of HCC

Biofilms contribute to bacterial infection and drug resistance and are a serious threat to global human health. Antibacterial nanomaterials have attracted considerable attention, but the inhibition of biofilms remains a major challenge. Herein, we propose a nanohole-boosted electron transport (NBET) antibiofilm concept. Unlike known antibacterial mechanisms (e.g., reactive oxygen species production and cell membrane damage), nanoholes with atomic vacancies and biofilms serve as electronic donors and receptors, respectively, and thus boost the high electron transport capacity between nanomaterials and biofilms. Electron transport effectively destroys the critical components (proteins, intercellularly adhered polysaccharides and extracellular DNA) of biofilms, and the nanoholes also significantly downregulate the expression of genes related to biofilm formation. The anti-infection capacity is thoroughly verified both in vitro (human cells) and in vivo (rat ocular and mouse intestinal infection models), and the nanohole-enabled nanomaterials are found to be highly biocompatible. Importantly, compared with typical antibiotics, nanomaterials are nonresistant and thereby exhibit high potential for use in various applications. As a proof-of-principle demonstration, these findings hold promise for the use of NBET in treatments for pathogenic bacterial infection and antibiotic drug resistance., Nanomaterials have attracted attention as antibacterial agents and have several modes of action. Here, the authors report on 2D transition metal disulphide nanosheets with hole boosted electron donation/withdrawal for enhanced antibacterial and biofilm activity caused by electron damage.

Background Laparoscopic procedure has inherent merits of smaller incisions, better cosmesis, less postoperative pain, and earlier recovery. In the current study, we presented our method of purely laparoscopic feeding jejunostomy and compared its results with that of conventional open approach. Methods We retrospectively reviewed our patients from 2012 to 2019 who had received either laparoscopic jejunostomy (LJ, n = 29) or open ones (OJ, n = 94) in Chang Gung Memorial Hospital, Linkou. Peri-operative data and postoperative outcomes were analyzed. Results In the current study, we employed 3-0 Vicryl, instead of V-loc barbed sutures, for laparoscopic jejunostomy. The mean operative duration of LJ group was about 30 min longer than the OJ group (159 ± 57.2 mins vs 128 ± 34.6 mins; P = 0.001). There were no intraoperative complications reported in both groups. The patients in the LJ group suffered significantly less postoperative pain than in the OJ group (mean NRS 2.03 ± 0.9 vs. 2.79 ± 1.2; P = 0.002). The majority of patients in both groups received early enteral nutrition (P = 0.143). Conclusions Our study demonstrated that purely laparoscopic feeding jejunostomy is a safe and feasible procedure with less postoperative pain and excellent postoperative outcome. It also provides surgeons opportunities to enhance intracorporeal suture techniques.

There is less clinical data on multiple myeloma (MM) in China, and the aim of this study was to collect and analyze the clinical data of newly diagnosed multiple myeloma (NDMM) patients in Hunan Province during 1 year, to understand the real clinical features and treatment outcome for Hunan Province patients with MM, and to strengthen the understanding of the standardized diagnosis process and treatment plan of MM.The clinical data of 529 patients with NDMM in 12 large-scale general hospitals in Hunan Province from January 1 to December 31, 2019 were collected and analyzed, including baseline data, treatment regimens, duration of treatment, and adverse reactions. The clinical characteristics, treatment, and safety of patients were analyzed by SPSS 21.0.Among the 529 NDMM patients, the age was 33-90 (median 64) years and the male-female ratio was 1.38꞉1. The clinical features ranged from high to low were as follows: Bone pain (77.7%), anemia (66.8%), renal insufficiency (40.6%), hypercalcemia (15.1%). Typing: IgG 46.5%, IgA 24.6%, IgD 2.6%, IgM 0.8%, light chain 15.7%, double clone 3.0%, no secretion 0.6%, absence 6.2%. Staging: Durie-Salmon stage I, II, and III were 4.5%, 10.6%, 77.3%, respectively, and 40 cases (7.6%) missed this data. International Staging System (ISS) stage I, II, and III were 10.4%, 24.4%, and 47.6%, respectively, and 93 cases (17.6%) were missing. Revised International Staging System (R-ISS) stage I, II, and III were 5.5%, 27.0%, 23.1%, respectively, and 235 cases (44.4%) missed this data. Among the 98 NDMM patients in the Third Xiangya Hospital, Central South University, Durie-Salmon (DS) stage missing 2.0%, ISS stage missing 12.3%, and R-ISS stage missing 12.3%.Treatment: Among the 529 patients,475 received treatment, the rate of treatment was 89.8%; 67.4% of the patients were able to complete four courses of chemotherapy at induction phase, 90.3% of the patients received proteasome inhibitor based combination chemotherapy regimen more than once, 67.2% received immunomodulator based regimen more than once, and 59.8% of the patients received proteasome inhibitor and immunomodulator based combination chemotherapy regimen more than once. Curative: Overall response rate (ORR) and high quality response rate (HQR) of the 4-course group were better than those of the 2-course group (ORR: 85% vs 65%,In 2019, the missed diagnosis rate of MM patients was high, the medium age of diagnosis was older, and the accuracy of patient diagnosis was not high. There is a great difference among medical centers, especially in the stage and risk stratified, nearly half of NDMM patients are not diagnosed with R-ISS stage; the lack of cytogenetic data needs to be supplemented by follow-up studies. A high proportion of patients with NDMM present with bone pain and anemia.Patients received treatment have higher use of chemotherapy regimens containing proteasome inhibitors and/or immunomodulators, but there is a significant gap among different medical centers, and standardized treatment needs to be strengthened. The safety during chemotherapy is controllable.

PurposeTo estimate the frequency of age-related macular degeneration (AMD) among people who underwent health examination in Hunan, China and to determine the relationship between dietary pattern and the risk of AMD.MethodsThe Questionnaire was used to collect dietary data from 56,775 study participants of ≥ 50 years old who underwent health examination at the Department of Health Management, the Third Xiangya Hospital of Central South University between January 2017 and December 2019. The diagnosis of AMD was based on the results of color fundus photography (CFP), spectral-domain optical coherence tomography (OCT) and multispectral imaging (MSI). After excluding participants with incomplete records or other ocular disease that may affect the results of fundus examination, a total of 43,672 study participants were included. The univariate and multivariate logistic regression analyses were used to determine the relationship between dietary pattern and the frequency of AMD.ResultsAmong the 43,672 study participants, 1080 (2.5%) had early AMD: the frequencies were 2.6% (n = 674) in men and 2.3% (n = 406) in women; the frequencies were 1.0% (n = 289), 3.6% (n = 401), 9.1% (n = 390) in 50–59, 60–69, ≥ 70 years old, respectively. And the age-standard frequency was 6.6% over the 60 years old in Hunan China. The high-salt intake increased the risk of early AMD [odds ratio (OR) = 1.61, 95% confidence interval (CI) = 1.54–1.68], whereas the intake of meat decreased the risk (OR = 0.90, 95% CI = 0.81–0.99).ConclusionIn Hunan China,there was a high frequency of early AMD detected through health examination over the 60 years old. And high-salt intake increases the risk of early AMD, whereas intake of meat decreases the risk. Modulating the dietary pattern and reducing the salt intake as an AMD prevention strategy warrant further study.

ObjectivesOur study aimed to investigate the relationship between the severity of frailty and the long-term care (LTC) needs of older adults from Chinese communities.DesignA cross-sectional study.SettingThree Chinese community health centres. All data were collected by trained researchers through face-to-face collection.ParticipantsWe surveyed a total of 540 older residents who aged 60 or older from community in Guangzhou, China.MeasuresThe Chinese version of the Tilburg frailty indicator was used to assess the frailty status of participants. LTC needs was evaluated by Integrated Home Care Services Questionnaire. Using non-adjusted and multivariate adjusted logistic regression analysis to evaluate frailty and LTC needs, then smoothed plots, threshold effect analysis and P for trend were used to further investigate the relationship between them.ResultsThe prevalence of frailty was 45.2% among the 540 older adults enrolled (aged 70.4±8.3 years; 65.7% females). 27% had higher LTC needs, which increased to 65.1% for individuals with frailty. Logistic regression analysis showed that frailty was strongly associated with LTC needs (OR 3.06, 95% CI 2.06 to 4.55, pConclusionThere is a linear relationship between frailty and LTC needs. With the increasing degree of frailty, the LTC needs of older adults dramatically increases.

Background Although research on the effects of comorbidities on coronavirus disease 2019 (COVID-19) patients is increasing, the risk of cancer history has not been evaluated for the mortality of patients with COVID-19. Methods In this retrospective study, we included 3232 patients with pathogen-confirmed COVID-19 who were hospitalized between January 18th and March 27th, 2020, at Tongji Hospital in Wuhan, China. Propensity score matching was used to minimize selection bias. Results In total, 2665 patients with complete clinical outcomes were analyzed. The impacts of age, sex, and comorbidities were evaluated separately using binary logistic regression analysis. The results showed that age, sex, and cancer history are independent risk factors for mortality in hospitalized COVID-19 patients. COVID-19 patients with cancer exhibited a significant increase in mortality rate (29.4% vs. 10.2%, P < 0.0001). Furthermore, the clinical outcomes of patients with hematological malignancies were worse, with a mortality rate twice that of patients with solid tumors (50% vs. 26.1%). Importantly, cancer patients with complications had a significantly higher risk of poor outcomes. One hundred nine cancer patients were matched to noncancer controls in a 1:3 ratio by propensity score matching. After propensity score matching, the cancer patients still had a higher risk of mortality than the matched noncancer patients (odds ratio (OR) 2.98, 95% confidence interval (95% CI) 1.76–5.06). Additionally, elevations in ferritin, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, procalcitonin, prothrombin time, interleukin-2 (IL-2) receptor, and interleukin-6 (IL-6) were observed in cancer patients. Conclusions We evaluated prognostic factors with epidemiological analysis and highlighted a higher risk of mortality for cancer patients with COVID-19. Importantly, cancer history was the only independent risk factor for COVID-19 among common comorbidities, while other comorbidities may act through other factors. Moreover, several laboratory parameters were significantly different between cancer patients and matched noncancer patients, which may indicate specific immune and inflammatory reactions in COVID-19 patients with cancer.

Salmonella enterica serovar Typhimurium, an intracellular Gram-negative bacterial pathogen, employs two type III secretion systems to deliver virulence effector proteins to host cells. One such effector, SseK3, is a Golgi-targeting arginine GlcNAc transferase. Here, we show that SseK3 colocalizes with cis-Golgi via lipid binding. Arg-GlcNAc-omics profiling reveals that SseK3 modifies Rab1 and some phylogenetically related Rab GTPases. These modifications are dependent on C-termini of Rabs but independent of the GTP- or GDP-bound forms. Arginine GlcNAcylation occurs in the switch II region and the third α-helix and severely disturbs the function of Rab1. The arginine GlcNAc transferase activity of SseK3 is required for the replication of Salmonella in RAW264.7 macrophages and bacterial virulence in the mouse model of Salmonella infection. Therefore, this SseK3 mechanism of action represents a new understanding of the strategy adopted by Salmonella to target host trafficking systems., Meng, Zhuang, Peng et al. study the role of a Golgi-targeting arginine GlcNAc transferase, SseK3, in the pathogenesis of Salmonella enterica. Through R-GlcNAcylated proteome analysis, they identify Rab proteins as targets for SseK3 as well as their modification sites. They demonstrate that SseK3 GlcNAc transferase activity is required for bacterial virulence in vitro and in vivo.

Cyclic nucleotide phosphodiesterase 4 (PDE4) specifically hydrolyzes cyclic adenosine monophosphate (cAMP) and plays vital roles in biological processes such as cancer development. To date, PDE4 inhibitors have been widely studied as therapeutics for the treatment of various diseases such as chronic obstructive pulmonary disease, and many of them have progressed to clinical trials or have been approved as drugs. Herein, we review the advances in the development of PDE4 inhibitors in the past decade and will focus on their pharmacophores, PDE4 subfamily selectivity, and therapeutic potential. Hopefully, this analysis will lead to a strategy for development of novel therapeutics targeting PDE4.

Significance The protein corona affects the clinical applications, organ targeting, and safety assessment of nanomaterials, and prediction of the protein corona would be valuable for the design of ideal nanomaterials. However, no methods to predict the protein corona are available. Overcoming the numerous quantitative and qualitative factors influencing corona formation, the present work builds models that precisely predict the functional composition of the protein corona and the cell recognition of nanoparticles (NPs) integrating machine learning and meta-analysis. This workflow provides an effective method to predict the functional composition of the protein corona that determines cell recognition to guide the synthesis and applications of NPs., Protein corona formation is critical for the design of ideal and safe nanoparticles (NPs) for nanomedicine, biosensing, organ targeting, and other applications, but methods to quantitatively predict the formation of the protein corona, especially for functional compositions, remain unavailable. The traditional linear regression model performs poorly for the protein corona, as measured by R2 (less than 0.40). Here, the performance with R2 over 0.75 in the prediction of the protein corona was achieved by integrating a machine learning model and meta-analysis. NPs without modification and surface modification were identified as the two most important factors determining protein corona formation. According to experimental verification, the functional protein compositions (e.g., immune proteins, complement proteins, and apolipoproteins) in complex coronas were precisely predicted with good R2 (most over 0.80). Moreover, the method successfully predicted the cellular recognition (e.g., cellular uptake by macrophages and cytokine release) mediated by functional corona proteins. This workflow provides a method to accurately and quantitatively predict the functional composition of the protein corona that determines cellular recognition and nanotoxicity to guide the synthesis and applications of a wide range of NPs by overcoming limitations and uncertainty.

To evaluate a radiomic approach for the stratification of diffuse gliomas with distinct prognosis and provide additional resolution of their clinicopathological and molecular characteristics. For this retrospective study, a total of 704 radiomic features were extracted from the multi-channel MRI data of 166 diffuse gliomas. Survival-associated radiomic features were identified and submitted to distinguish glioma subtypes using consensus clustering. Multi-layered molecular data were used to observe the different clinical and molecular characteristics between radiomic subtypes. The relative profiles of an array of immune cell infiltrations were measured gene set variation analysis approach to explore differences in tumor immune microenvironment. A total of 6 categories, including 318 radiomic features were significantly correlated with the overall survival of glioma patients. Two subgroups with distinct prognosis were separated by consensus clustering of radiomic features that significantly associated with survival. Histological stage and molecular factors, including IDH status and MGMT promoter methylation status were significant differences between the two subtypes. Furthermore, gene functional enrichment analysis and immune infiltration pattern analysis also hinted that the inferior prognosis subtype may more response to immunotherapy. A radiomic model derived from multi-parameter MRI of the gliomas was successful in the risk stratification of diffuse glioma patients. These data suggested that radiomics provided an alternative approach for survival estimation and may improve clinical decision-making.

Background Evidence for the association of thyroid dysfunction and autoantibody positivity with preterm birth remains controversial. We aimed to study the association of maternal thyroid dysfunction and autoantibody positivity with the risk of preterm birth. Method A hospital-based cohort study of 40,214 women was conducted. Gestational age-specific percentiles of the FT4 and TSH concentrations were used for the definition of thyroid dysfunction. Autoantibody positivity was identified when the concentration > the threshold. The association of thyroid dysfunction and autoantibody positivity with the risk of preterm birth was estimated. Results No significant higher risk of preterm birth was found for women with variants of thyroid dysfunction or autoantibody positive than euthyroid women. Sensitivity and stratification analyses indicated that thyroperoxidase antibody (TPOAb) positivity in the first trimester (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.17–1.90) and overt hypothyroidism restricted to women negative for TPOAb (OR, 4.94; 95%CI: 1.64–14.84) was associated with an increased risk of preterm birth. Modification effects of gestational age were found for women who had the test ≤18 and > 18 weeks. Continuous FT4 measurements tested ≤18 weeks of gestation were associated with a higher risk of preterm birth (OR, 1.13, 95% CI: 1.00–1.28), while a negative relationship for FT4 concentrations tested > 18 weeks of gestation (OR = 0.68, 95% CI: 0.48–0.97). Conclusions Some specific thyroid function abnormalities were associated with an increased risk of preterm birth. Interaction between gestational age and FT4 concentration on the risk of preterm birth was identified, with a critical node of 18 weeks of gestation.

Effective treatment of advanced invasive cervical cancer remains challenging nowadays. Herein, single-nucleus RNA sequencing (snRNA-seq) and SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq) technology are used to investigate the immunological microenvironment of cervical squamous cell carcinoma (CSCC), a major type of cervical cancers. The expression levels of most immune checkpoint genes in tumor and inflammation areas of CSCC were not significantly higher than those in the non-cancer samples except for LGALS9 and IDO1. Stronger signals of CD56+ NK cells and immature dendritic cells are found in the hypermetabolic tumor areas, while more eosinophils, immature B cells, and Treg cells are found in the hypometabolic tumor areas. Moreover, a cluster of cancer-associated fibroblasts (CAFs) are identified around some tumors, which highly expressed ACTA2, POSTN, ITGB4, and FAP. The CAFs might support the growth and metastasis of tumors by inhibiting lymphocyte infiltration and remodeling the tumor extracellular matrix. Furthermore, CAFs are associated with poorer survival probability in CSCC patients and might be present in a small fraction (∼20%) of advanced cancer patients. Collectively, these findings might enhance understanding of the CSCC immunological microenvironment and shed some light on the treatment of advanced CSCC.

Objectives To investigate the reproducibility, stability, internal consistency and the ability to grade malnutrition of Subjective Global Nutritional Assessment (SGNA) in outpatient children with cerebral palsy. Methods This was a part of a larger, cross-sectional study (ChiCTR2000033869) at the outpatient of a tertiary hospital. The recruitment and data collection of children with Cerebral Palsy aged from 1 to 18 years were from August 2020 to March 2021. The concurrent validity, inter-rater reliability, test-retest reliability and internal consistency of SGNA were tested. To analyze data, specificity, sensitivity, Kendall coefficient, Cohen's kappa coefficient, Spearman coefficient and Cronbach's α coefficient were used. Results The agreement between SGNA and anthropometric data was moderate to strong (k = 0.540-0.821). The sensitivity (71.70% to 89.74%) and specificity (77.67% to 91.03%) of SGNA to identify participants with z-score ≤-2 were good. The sensitivity of SGNA to identify participants with weight for age z-score ≤-3 was poor (30.00%). The interrater reliability (k = 0.703) and test-retest reliability (k = 0.779) were good. The item of edema was with poor agreement to SGNA nutritional grades (rs = 0.072), and after deleting it from SGNA, the Cronbach's α coefficient of SGNA increased from 0.715 to 0.886. Findings SGNA is good at identifying malnourished outpatient children with cerebral palsy, with excellent reproducibility and short-time stability. However, the ability to grade malnutrition is unsatisfactory. For further application in this group, a more appropriate item should be designed to replace the item of edema.

Paclitaxel remains the first-line chemotherapy regimen for many malignant tumors. However, prognosis and adverse events under different dosing regimens (one-week versus three-week treatment) remain contradictory in many randomized controlled trials (RCTs). Here, we performed a comprehensive meta-analysis to measure the efficacy and toxicities of these two dosing regimens. Four databases were systematically retrieved. RCTs comparing two paclitaxel dosing regimens for advanced malignant tumors with assessable outcomes (e.g., overall survival (OS), progression-free survival (PFS), toxicities, response rates) were included. In total, 19 eligible RCTs involving 9 674 patients were included. Meta-analysis of pan-cancers revealed that weekly paclitaxel treatment was more beneficial regarding PFS compared to three-week paclitaxel treatment (hazard ratio (HR) = 0.90, 95% confidence interval (CI) = 0.82-0.99

Natural killer (NK) cells are lymphocytes that are involved in controlling tumors or microbial infections through the production of interferon gamma (IFN-γ). Granulocyte colony-stimulating factor (G-CSF) inhibits IFN-γ secretion by NK cells, but the mechanism underlying this effect remains unclear. Here, by comparing the multi-omics profiles of human NK cells before and after in vivo G-CSF treatment, we identify a pathway that is activated in response to G-CSF treatment, which suppresses IFN-γ secretion in NK cells. Specifically, glucocorticoid receptors (GRs) activated by G-CSF inhibit secretion of IFN-γ by promoting interactions between SOCS1 promoters and enhancers, as well as increasing the expression of SOCS1. Experiments in mice confirm that G-CSF treatment significantly downregulates IFN-γ secretion and upregulates GR and SOCS1 expression in NK cells. In addition, GR blockade by the antagonist RU486 significantly reverses the effects of G-CSF, demonstrating that GRs upregulate SOCS1 and inhibit the production of IFN-γ by NK cells.

Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in Taiwan. Chronic obstructive pulmonary disease (COPD) is associated with CRC mortality in several population-based studies. However, this effect of COPD on CRC shows no difference in some studies and remains unclear in Taiwan’s population. Methods: We conducted a retrospective cohort study using Taiwan’s nationwide database. Patients newly diagnosed with CRC were identified from 2007 to 2012 via the Taiwan Cancer Registry dataset and linked to the National Health Insurance research database to obtain their medical records. Propensity score matching (PSM) was applied at a ratio of 1:2 in COPD and non-COPD patients with CRC. The 5-year overall survival (OS) was analyzed using the Cox regression method. Results: This study included 43,249 patients with CRC, reduced to 13,707 patients after PSM. OS was lower in the COPD group than in the non-COPD group. The adjusted hazard ratio (aHR) for COPD was 1.26 (95% confidence interval (CI), 1.19–1.33). Moreover, patients with CRC plus preexisting COPD showed a higher mortality risk in all stage CRC subgroup analysis. Conclusions: In this 5-year retrospective cohort study, patients with CRC and preexisting COPD had a higher mortality risk than those without preexisting COPD, suggesting these patients need more attention during treatment and follow-up.

Purpose The aim of this study was to construct and verify a computed tomography (CT) radiomics model for preoperative prediction of synchronous distant metastasis (SDM) in clear cell renal cell carcinoma (ccRCC) patients. Methods Overall, 172 patients with ccRCC were enrolled in the present research. Contrast-enhanced CT images were manually sketched, and 2994 quantitative radiomic features were extracted. The radiomic features were then normalized and subjected to hypothesis testing. Least absolute shrinkage and selection operator (LASSO) was applied to dimension reduction, feature selection, and model construction. The performance of the predictive model was validated through analysis of the receiver operating characteristic curve. Multivariate and subgroup analyses were performed to verify the radiomic score as an independent predictor of SDM. Results The patients randomized into a training (n = 104) and a validation (n = 68) cohort in a 6:4 ratio. Through dimension reduction using LASSO regression, 9 radiomic features were used for the construction of the SDM prediction model. The model yielded moderate performance in both the training (area under the curve, 0.89; 95% confidence interval, 0.81-0.97) and the validation cohort (area under the curve, 0.83; 95% confidence interval, 0.69-0.95). Multivariate analysis showed that the CT radiomic signature was an independent risk factor for clinical parameters of ccRCC. Subgroup analysis revealed a significant connection between the SDM and radiomic signature, except for the lower pole of the kidney subgroup. Conclusions The CT-based radiomics model could be used as a noninvasive, personalized approach for SDM prediction in patients with ccRCC.

The prognostic impact and treatment responses among cervical cancer patients with different histological types remains inconclusive. To determine the prognostic effects of different histologic types, we identified 39,088 patients with a diagnosis of cervical cancer between 2004 and 2016 from the Surveillance, Epidemiology, and End Results program.Variables related to the prognosis of cervical cancer were evaluated using log-rank method and univariate/multivariate Cox models before and after propensity score matching.Of the 36,310 patients, Squamous cell carcinoma (SCC) was the most common histological type (n = 27,043, 74.5%), followed by adenocarcinoma (AC, n = 7755, 21.4%) and adenosquamous carcinoma (ASC, n = 1512, 4.1%). Compared to SCC patients, patients with AC (HR = 1.14, 95%CI = 1.09-1.20, P 0.01) and ASC (HR = 1.28, 95%CI = 1.18-1.40, P 0.01) showed significantly poorer prognosis. Subgroup analyses indicated that the differences in prognosis between AC and SCC were only observed in stage II and III patients (P 0.01). In patients with concurrent chemoradiotherapy, survival rates of patients with AC were significantly worse compared with similar patients with SCC (HR = 1.14, 95%CI = 1.03-1.27; P 0.01).The prognostic impact of histologic types among patients with cervical cancer depends on tumor stages and therapeutic approaches. Tailored treatment and follow-up planning need to be developed across patients with different histological types and stages.

ObjectiveThis article aims to study the influencing factors of pgRNA and its change magnitude based on the real world.MethodsA total of 421 patients who were tested for pgRNA were selected. According to the baseline data, the subjects were divided into negative and positive groups. The Chi-square test and logistic regression were used to analyze the influencing factors of pgRNA status. Based on the follow-up data, the rank-sum test and linear regression were used to analyze the influencing factors of pgRNA change magnitude.ResultsA total of 153 (36.3%) of the 421 subjects were pgRNA-negative and 268 (63.7%) were pgRNA-positive. Logistic regression analysis showed that positive HBV DNA (OR: 40.51), positive HBeAg (OR: 66.24), tenofovir treatment (OR: 23.47), and entecavir treatment (OR: 14.90) were the independent risk factors for positive pgRNA. Univariate linear regression showed that the pgRNA change magnitude of patients treated with entecavir was higher than that of patients treated with tenofovir. Multivariate linear regression showed that age was an independent factor influencing pgRNA change magnitude.ConclusionsThe pgRNA of patients who were young, female, HBV DNA-positive, high-HBsAg, HBeAg-positive is higher than the detection line. HBV DNA and HBeAg are the independent risk factors of positive pgRNA. Different antiviral regimens and disease stages have significantly different effects on pgRNA status. There was a significant correlation between pgRNA and FIB-4, suggesting that pgRNA is related to liver fibrosis. The decrease in pgRNA was greater in young patients than in non-young patients. The decrease in pgRNA was greater in patients treated with tenofovir than in patients treated with entecavir.

Linderane (LDR) is a main furan-containing sesquiterpenoid of the common herbal medicine Lindera aggregata (Sims) Kosterm. Our early study indicated that LDR led to mechanism-based inactivation (MBI) of CYP2C9 in vitro, implying possible drug-drug interactions (DDIs) in clinic. In the present study, influence of LDR on the pharmacokinetics of the corresponding hydroxylated metabolites of CYP2C9 substrates in rats was investigated. Pharmacokinetic studies revealed that pretreatment with LDR at 20 mg/kg for 15 days inhibited the metabolism of both tolbutamide and warfarin catalyzed by CYP2C9. As for 4-hydroxytolbutamide, the Cmax was decreased, the t1/2z was prolonged, and the Vz/F was increased, all with significant difference. As for 7-hydroxywarfarin, the AUC0-t/AUC0-∞ and CLz/F were significantly decreased and increased, respectively. Furthermore, the underlying molecular mechanisms based on MBI of CYP2C9 by LDR were revealed. Two reactive metabolites of LDR, furanoepoxide and γ-ketoenal intermediates were identified in CYP2C9 recombinant enzyme incubation systems. Correspondingly, covalent modifications of lysine and cysteine residues of CYP2C9 protein were discovered in the CYP2C9 incubation system treated with LDR. The formation of protein adducts exhibited obvious time- and dose-dependence, which is consistent with the trend of enzyme inhibition caused by LDR in vitro. In addition to the apoprotein of CYP2C9, the heme content was significantly reduced after co-incubation with LDR. These data revealed that modification of both apoprotein and heme of CYP2C9 by reactive metabolites of LDR led to MBI of CYP2C9, therefore resulting in the inhibition of biotransformation of CYP2C9 substrates to their corresponding metabolites in vivo.

Dietary supplements and medications containing polyvalent cations can interact with integrase strand transfer inhibitors (INSTIs) and decrease exposure to INSTIs. In this cross-sectional study of 513 people living with HIV (PLWH) who were on stable antiretroviral therapy, 57.5% and 6.6% reported concurrent use of dietary supplements and antacids, respectively. In the multivariable analysis, the use of antacids, but not dietary supplements containing polyvalent cations, was associated with HIV viremia in PLWH who received INSTI-based ART.

Preterm labour is a common pregnancy complication contributing to major maternal and fetal morbidity and mortality. We have found microRNA (miR)-212-3p, a potential infection-associated molecule, was significantly over-expressed during human preterm labour. However, the mechanism remains unknown. In this study, we have adopted a lipopolysaccharide (LPS)-induced Institute of Cancer Research murine preterm model to examine the role of miR-212-3p in the infection-induced preterm labour. Myometrial miR-212-3p expression was increased by nearly 4-fold in the term labour group (P = 0.10) and 12-fold (P = 0.03) in the LPS-induced preterm labour group compared with the non-labour group. In vitro cellular experiments confirmed that a series of pro-inflammatory cytokines, including interleukin (IL)1B (P = 0.02) and IL-6 (P = 0.01), rather than LPS (P = 0.08) itself could significantly upregulate miR-212-3p expression in human myometrial smooth muscle cells. Methyl-CpG-binding protein 2 (MeCP2), as a target gene of miR-212-3p confirmed by our dual luciferase assay, influenced myocyte contractility and connexin 43 expression which is an important contraction-associated protein. Therefore, we conclude that miR-212-3p may be involved in infection-induced preterm labour through MeCP2 and it is a promoting molecule and novel target for the diagnosis and treatment of preterm labour in the future.

The mitogen-activated protein kinase (MAPK) signaling pathway member T-LAK cell–originated protein kinase/PDZ-binding kinase (TOPK/PBK) is closely involved in tumorigenesis and progression. Its overexpression in colorectal carcinoma (CRC) exacerbates tumor malignancy, promotes metastasis and results in dismal prognosis. Therefore, targeting TOPK is a promising approach for CRC therapy. Here, we report the development of a TOPK selective inhibitor SKLB-C05, with subnanomolar inhibitory potency. In vitro, SKLB-C05 exhibited excellent cytotoxicity and anti-migration and invasion activity on TOPK high-expressing CRC cells and induced cell apoptosis. These activities could attribute to its inhibition of TOPK downstream signaling including extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1, 2, and 3 (JNK1/2/3), as well as downregulation of FAK/Src- MMP signaling. Furthermore, SKLB-C05 disrupted cell mitosis and blocked CRC cell cycle. In vivo, oral administration of SKLB-C05 at concentrations of 20 and 10 mg kg−1·day−1 dramatically attenuated CRC tumor xenograft growth and completely suppressed hepatic metastasis of HCT116 cells, respectively. Thus, these findings suggest that SKLB-C05 is a specific TOPK inhibitor with potent anti-CRC oncogenic activity in vitro and in vivo.

Eight new platinum(II) complexes Pt1–Pt8 with substituted 3‑(2′‑benzimidazolyl) coumarins were successfully synthesized and characterized by single crystal X-ray diffraction analysis, nuclear magnetic resonance spectroscopy (NMR), electrospray ionization-mass spectrometry (ESI-MS), infrared spectrophotometry (IR) and elemental analysis. Crystallographic data of these Pt1–Pt8 complexes showed that the Pt(II) has distorted four-coordinated square planar geometry. Pt1–Pt8 were found to display high cytotoxic activity in vitro against the cisplatin-resistant SK-OV-3/DDP cancer cells with a low IC50 from 1.01–10.32 μM, but low cytotoxicity on the normal HL-7702 cells. Further studies revealed that Pt1–Pt3 induced apoptosis in SK-OV-3/DDP cancer cells via mitochondria dysfunction signaling pathways. Our findings also indicated that Pt1 was a telomerase inhibitor targeting c-myc promoter elements.

Imbalance miRNAs contribute to tumor formation; therefore, the development of small-molecule compounds that regulate miRNA biogenesis is an important strategy in oncotherapy. Here, (-)-Gomisin M1 (GM) was found to modulate miRNA biogenesis to inhibit the proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells. GM modulated expression profiles of miRNA and protein in HCC cells and suppressed tumor growth in a mouse model. Mechanistically, GM affected miRNA maturation by targeting TAR RNA-binding protein 2 (TRBP), with an efficacy higher than that of enoxacin, and promoted the binding of TRBP with Dicer. Structural simplification and a preliminary structure-activity relationship study via the synthesis of 20 GM derivatives showed that compound 9 exhibited more potent inhibitory activity in HCC cell proliferation and affinity for TRBP than did GM. These results suggest that TRBP may be a novel potential therapeutic target in HCC and compound 9 may be a potential drug candidate for the treatment of HCC.

Cyanide detection methods are urgently needed due to the highly lethal to human beings. Herein, we report two fluorescence probes (Probe 1 and Probe 2) based on cyanoethylene group for cyanide anion (CN−) detection. The selective recognition for CN− was confirmed by the completely opposite green fluorescence of Probe 1 and red fluorescence of Probe 2 observed by fluorescence spectra and naked eyes. The probes take advantages of the large Stokes shift (~160 nm), rapid response (30 s), anti-interference performance and low detection limit (Probe 1: 12.4 nM, Probe 2: 101 nM). The sensing mechanism is certificated to the nucleophilic attack of CN− to electron-deficient cyanoethylene group of probes, which was demonstrated by 1H NMR titration, HR-MS, Job's plot and IR spectroscopy. Density functional theory (DFT) calculations were carried out to analyze the mechanism in theory. Further, practical applications were studied. Easy-to-use test strips treated with Probe 1 or Probe 2 are capable of CN− detection in pure drinking water. The good biocompatibility and membrane penetrability have achieved the bioimaging capability of Probe 1 and Probe 2 in living HepG-2 cells, making the probes promising for use in real lives.

BACKGROUND: Tribbles pseudokinase 3 (TRIB3) is a member of the tribbles-related family, which has been determined in various cancers, including renal cell carcinoma, acute promyelocytic leukemia, colorectal cancer, endometrial cancer, and glioma. However, its role in retinoblastoma (RB) has not yet been explored. METHODS: The expression level of TRIB3 was detected in RB tissues and cell lines using qRT-PCR. The effects of TRIB3 on cell proliferation and invasion capacities were analyzed with MTT, crystal violet, and transwell assays. Western blot and rescue assays were conducted to explore the underlying mechanism. RESULTS: This study found that TRIB3 was upregulated in human RB tissues compared to adjacent normal tissues both at the mRNA and protein levels. Overexpression of TRIB3 significantly promoted cell proliferation and invasion of RB cells, while TRIB3 knockdown inhibited these processes. Moreover, the mechanism deciphering experiments showed that TRIB3 overexpression can increase AKT and mTOR phosphorylation. Conversely, TRIB3 knockdown decreased the phosphorylation of AKT and mTOR. Additionally, MK2206, a potent AKT inhibitor, blocked the promotive effects of TRIB3 in RB cells. CONCLUSION: This study demonstrated that TRIB3 acts as an oncogene and plays a crucial role in the proliferation and invasion of RB cells via regulating the AKT/mTOR signaling pathway. Therefore, TRIB3 may serve as a potential target in the diagnosis and/or treatment of RB.

Epilepsy is a high incidence neurological disease, and its repeated attacks cause serious physical and psychological damage to the patient. Differentially expressed in normal and neoplastic cells (DENN) domain containing 5B (DENND5B) is a lipoprotein binding protein that mediates synaptic vesicle transport and regulates neuroplasticity and lipid metabolism. Nevertheless, the effect of DENND5B on seizures remains unclear. We aimed to investigate the association of DENND5B with epilepsy, detect its expression and distribution in the nervous system, and explore its role in epileptogenesis through western blot, immunofluorescence staining, and behavioral studies. In this experiment, two C57BL/6 mice models, which induced seizures by pentylenetetrazole and kainic acid, were established. We observed that the expression of DENND5B was reduced in the brains of patients with temporal lobe epilepsy, and its expression was also similarly decreased in both chronic epileptic mice. The findings strongly suggest that DENND5B may be associated with epileptic seizures. Results of immunofluorescence showed that DENND5B was mainly expressed in the hippocampal region and co-located with neurons but not with astrocytes. Next, we used lentivirus to induce both lentiviral vector-mediated overexpression and knockdown of DENND5B in mice to test the change of susceptibility and severity of seizures in the two chronic seizure models. Knockdown of DENND5B was found to promote epileptic seizures, increase chronic spontaneous recurrent epileptic seizures and epileptic discharge, and reduce the incubation period. However, overexpression of DENND5B showed the opposite effect. These results suggest that DENND5B overexpression decreased the behavioral phenotype of epileptic seizures, but DENND5B downregulation had the opposite effect. In summary, our findings suggest that DENND5B can regulate epileptic seizures and may provide a new target for antiepileptic therapy.

Background A lack of information on specific and interventional factors for stillbirth has made designing preventive strategies difficult, and the stillbirth rate has declined more slowly than the neonatal death rate. We compared the prevalence of stillbirth among the offspring of women with or without abnormal placental perfusion (APP). Methods We conducted a hospital-based retrospective cohort study involving women with a singleton pregnancy between 2012 and 2016 (N = 41,632). Multivariate analysis was performed to compare the prevalence of stillbirth in infants exposed to APP (defined as any abnormality in right or left uterine artery pulsatility index or resistance index [UtA-PI, −RI] [e.g., > 95th percentile] or presence of early diastolic notching) with that in those not exposed to APP. Results Stillbirths were more common among women with APP than among those with normal placental perfusion (stillbirth rate, 4.3 ‰ vs 0.9 ‰; odds ratio (OR), 4.2; 95% confidence interval (CI), 2.2 to 8.0). The association strengths were consistent across groups of infants exposed to APP that separately defined by abnormality in right or left UtA-PI or -RI (OR ranged from 3.2 to 5.3; all P ≤ 0.008). The associations were slightly stronger for the unexplained stillbirths. Most of the unexplained stillbirth risk was attributed to APP (59.0%), while a foetal sex disparity existed (94.5% for males and 58.0% for females). Women with normal placental perfusion and a male foetus had higher credibility (e.g., higher specificities) in excluding stillbirths than those with APP and a female foetus at any given false negative rate from 1 to 10% (93.4% ~ 94.1% vs. 12.3% ~ 14.0%). Conclusions APP is associated with and accounts for most of the unexplained stillbirth risk. Different mechanisms exist between the sexes. The performance of screening for stillbirth may be improved by stratification according to sex and placental perfusion.

Background Escalation of commitment is a common bias in human decision making. The present study examined (1) differences in neural recruitment for escalation and de-escalation decisions of prior investments, and (2) how the activations of these brain networks are affected by two factors that can arguably modulate escalation decisions: (i) self-responsibility, and (ii) framing of the success probabilities. Results Imaging data were obtained from functional magnetic resonance imaging (fMRI) applied to 29 participants. A whole-brain analysis was conducted to compare brain activations between conditions. ROI analysis, then, was used to examine if these significant activations were modulated by two contextual factors. Finally, mediation analysis was applied to explore how the contextual factors affect escalation decisions through brain activations. The findings showed that (1) escalation decisions are faster than de-escalation decisions, (2) the corresponding network of brain regions recruited for escalation (anterior cingulate cortex, insula and precuneus) decisions differs from this recruited for de-escalation decisions (inferior and superior frontal gyri), (3) the switch from escalation to de-escalation is primarily frontal gyri dependent, and (4) activation in the anterior cingulate cortex, insula and precuneus were further increased in escalation decisions, when the outcome probabilities of the follow-up investment were positively framed; and activation in the inferior and superior frontal gyri in de-escalation decisions were increased when the outcome probabilities were negatively framed. Conclusions Escalation and de-escalation decisions recruit different brain regions. Framing of possible outcomes as negative leads to escalation decisions through recruitment of the inferior frontal gyrus. Responsibility for decisions affects escalation decisions through recruitment of the superior (inferior) gyrus, when the decision is framed positively (negatively).

Mental retardation autosomal dominant 7 (MRD7), or DYRK1A Related Intellectual Disability Syndrome (OMIM 614104) is a developmental syndrome with microcephaly, intellectual disability, language delay and epileptic seizures. Haploinsufficiency of DYRK1A is the cause of MRD7. Here, we generated an induced pluripotent stem cell (iPSC) line with the mutation (DYRK1Ac.1730T>A) from the Peripheral blood mononuclear cell (PBMC) of a MRD7 patient along with an isogenic gene-corrected control iPSC line by CRISPR/Cas9 genome editing. Both iPSC lines showed full pluripotency, normal karyotype and differentiation capacity without integrating vectors. These DYRK1A mutant and isogenic gene-corrected iPSC control line provides a useful model to study the underlying molecular mechanisms of MRD7.

Pan-HER inhibitors exhibit extensive biological activity and offer unique advantages and usually bind to targets in an irreversible manner. Owing to the off-target toxicity of irreversible inhibitors, reversible pan-HER inhibitors are desirable. Herein, we describe the process of N-(ring structure fused phenyl)quinazoline-4-amine-based design, synthesis, and biological evaluation of pan-HER inhibitors in vitro and in vivo. Compound C5, with the molecular skeleton of N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine, displayed irreversible binding just like other effective pan-HER inhibitors. To our surprise, compound C6, which possessed the same skeleton, was found to be a high-strength reversible pan-HER inhibitor. This compound was capable of inhibiting HER1s (such as EGFR T790M/L858R and WT), HER2, and HER4 and can be considered as a breakthrough in the development of pan-HER inhibitors. Altogether, N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine can serve as an effective molecular skeleton for developing both reversible and irreversible pan-HER inhibitors in the following discovery of antitumor drugs.

We report a comprehensive proteomic study of a 90-case cohort of paired samples of triple-negative breast cancer (TNBC) in quantification, phosphorylation, and DNA-binding capacity. Four integrative subtypes (iP-1-4) are stratified on the basis of global proteome and phosphoproteome, each of which exhibits distinct molecular and pathway features. Scaffold and co-expression network analyses of three proteomic datasets, integrated with those from genome and transcriptome of the same cohort, reveal key pathways and master regulators that, characteristic of TNBC subtypes, play important regulatory roles within and between scaffold sub-structures and co-expression communities. We find that NAE1 is a potential drug target for subtype iP-1, and a series of key molecules in fatty acid metabolism, such as AKT1/FASN, are plausible targets for subtype iP-2. Libraries of proteins, pathways and networks of TNBC provide a valuable molecular infrastructure for further clinical exploration and in-depth studies of the molecular mechanisms of the disease.

To retrospectively analyze the symptoms and characteristics of nervous system damage in severe/critically severe patients with coronavirus disease 2019 (COVID-19) in Sichuan province, with a view to providing basic references for the prevention and treatment of COVID-19.A total of 90 patients with severe/critically severe COVID-19 were included, who were diagnosed and treated in COVID-19 designated hospital of Sichuan province from 11 January 2020 to 20 March 2020. Clinical features, test results, treatment options and clinical outcomes were analyzed retrospectively.Of 90 patients, there were 54 males and 36 females, with an average age of (53.90±16.92) years. In addition to the classic symptoms such as fever and/or respiratory symptoms, 53 patients also had various degrees of neurologic manifestations, including 33 cases of fatigue, 21 muscle soreness, 12 dizziness, 8 headaches, 3 mental disorders, and 1 consciousness disorders and 1 case of neck pain. Compared with the patients without neurologic manifestations, those with neurologic manifestations took a longer time from admission to diagnosis of COVID-19 (Neurological symptoms are not uncommon in severe/critically severe patients with COVID-19, and it's relatively difficult in the treatment. It should be paid attention in order to avoid misdiagnosis.

Calcium-responsive transactivator (CREST), a nuclear protein highly expressed in postmitotic neurons, is involved in the regulation of cell cycle, differentiation and dendritic development of neuronal cells. Its mRNA has been detected in the testis of adult rat, whilst its protein expression and distribution pattern in the testis remain to be elucidated. In this study, we examined the distribution of CREST in the adult testes of both rats and human as well as the expression pattern of CREST in the testes of postnatal developing rats. In the adult testes of both human and rats, immunohistochemical analysis revealed that CREST was selectively distributed in the mature Sertoli cells but not in the spermatogenic cells. In the testes of postnatal developmental rats, CREST was expressed not only in Sertoli cells but also in the gonocytes and spermatogenic cells at the initial stage of spermatogenic cell differentiation. CREST immunoreactivity continued to increase in Sertoli cells during differentiation, reaching its peak in adulthood. However, CREST immunostaining intensity dramatically decreased as the spermatogenic cells differentiate, disappearing in the post-differentiation stage. Furthermore, Brg1 and p300, two CREST-interacting proteins ubiquitously expressed in the body, are found to be colocalized with CREST in the spermatogenic epithelial cells including Sertoli cells. The unique expression pattern of CREST in developing testis suggests that CREST might play regulatory roles in the differentiation of spermatogenic epithelial cells. The Sertoli cell-specific expression of CREST in the adulthood hints that CREST might be a novel biomarker for the mature Sertoli cells. Supplementary Information The online version of this article (10.1007/s00418-020-01942-1) contains supplementary material, which is available to authorized users.

In this study, black geotextile inter-row mulch, a weed control practice, was applied under a semi-arid climate to attenuate solar reflection in 2015-2017, and it concurrently increased soil temperature and fruit-zone high temperature duration and decreased low temperature duration. Inter-row mulch decreased anthocyanins concentrations in grapes in 2015-2016, and consistently inhibited flavonols accumulation in 2015-2017. Correlation analysis between microclimate parameters and flavonoids concentrations reflected the importance of solar reflection, fruit-zone high and low temperature duration, heat accumulation and soil temperature to flavonoids accumulation. Basal leaf removal, a widely applied practice to increase fruit-zone light exposure, was applied to mulch-treated grapevines to investigate if increasing incident light could mitigate the impact of inter-row mulch on flavonoids, and it had limited influence on anthocyanins whereas compensated the loss of flavonols in grapes caused by inter-row mulch. Notably, inter-row mulch wines showed less red and more yellow color than controls because of lower anthocyanins concentrations.

To estimate the association of maternal thyroid dysfunction with the risk of gestational hypertension and diabetes. Whether the association was affected by gestational age at diagnosis and thyroid autoimmunity was further explored.A cohort study of 41 647 participants was conducted. Thyroid function (ie, thyroid-stimulating hormone [TSH] and free thyroxine [FT4]) was measured by electrochemiluminescence immunoassay. Thyroid antibody positivity (eg, thyroperoxidase, thyroglobulin, and TSH receptor antibody) was indicated if the values of these antibodies exceeded the upper targets of the reference range. The relationship between maternal thyroid dysfunction and the risk of pre-eclampsia (PE) and gestational diabetes mellitus (GDM) was assessed by multivariate logistic regression.Isolated hypothyroxinemia (defined as 5th ≤ TSH ≤ 95th percentile, FT45th percentile) was associated with the risk of PE (odds ratio [OR], 1.32; 95% CI, 1.10-1.58). Overt hypothyroidism (TSH95th percentile; FT45th percentile) was related to the risk of severe PE (OR, 2.59; 95% CI, 1.05-6.37). Being positive for TSH receptor antibody was associated with a decreased risk of GDM (OR, 0.49; 95% CI, 0.35-0.70). A marginally significant association between overt hypothyroidism detected at the first trimester and the risk of GDM was found (OR, 1.60; 95% CI, 1.00-2.83). The association of thyroid dysfunction with the risk of PE and GDM was stronger among pregnant women who were negative for autoantibodies.Some types of thyroid dysfunction during pregnancy were associated with the risk of PE and GDM. The associations varied by gestational age at diagnosis and by thyroid autoantibody status.

Background The association between immune-related adverse events (irAEs) and survival outcomes in patients with advanced melanoma receiving therapy with immune checkpoint inhibitors (ICIs) has not been well established, particularly in Asian melanoma. Methods We retrospectively reviewed 49 melanoma patients undergoing therapy with ICIs (anti-PD-1 monotherapy), and analyzed the correlation between irAEs and clinical outcomes including progression-free survival (PFS) and overall survival (OS). Results: Overall, the patients who experienced grade 1–2 irAEs had longer PFS (median PFS, 4.6 vs. 2.5 months; HR, 0.52; 95% CI: 0.27–0.98; p = 0.042) and OS (median OS, 15.2 vs. 5.7 months; HR, 0.50; 95% CI: 0.24–1.02; p = 0.058) than the patients who did not experience irAEs. Regarding the type of irAE, the patients with either skin/vitiligo or endocrine irAEs showed better PFS (median PFS, 6.1 vs. 2.7 months; HR, 0.40, 95% CI: 0.21–0.74; p = 0.003) and OS (median OS, 18.7 vs. 4.5 months; HR, 0.34, 95% CI: 0.17–0.69, p = 0.003) than patients without any of these irAEs. Conclusions Melanoma patients undergoing anti-PD-1 monotherapy and experiencing mild-to-moderate irAEs (grade 1–2), particularly skin (vitiligo)/endocrine irAEs had favorable survival outcomes. Therefore, the association between irAEs and the clinical outcomes in melanoma patients undergoing anti-PD-1 ICIs may be severity and type dependent.

Background New therapeutic options to address the ongoing COVID-19 pandemic are urgently needed. One possible strategy is the repurposing of existing drugs approved for other indications as antiviral agents for SARS-CoV-2. Due to the commercial unavailability of SARS-CoV-2 drugs for treating COVID-19, we screened approximately 250 existing drugs or pharmacologically active compounds for their inhibitory activities against feline infectious peritonitis coronavirus (FIPV) and human coronavirus OC43 (HCoV-OC43), a human coronavirus in the same genus (Betacoronavirus) as SARS-CoV-2. Methods FIPV was proliferated in feline Fcwf-4 cells and HCoV-OC43 in human HCT-8 cells. Viral proliferation was assayed by visualization of cytopathic effects on the infected Fcwf-4 cells and immunofluorescent assay for detection of the nucleocapsid proteins of HCoV-OC43 in the HCT-8 cells. The concentrations (EC50) of each drug necessary to diminish viral activity to 50% of that for the untreated controls were determined. The viabilities of Fcwf-4 and HCT-8 cells were measured by crystal violet staining and MTS/PMS assay, respectively. Results Fifteen out of the 252 drugs or pharmacologically active compounds screened were found to be active against both FIPV and HCoV-OC43, with EC50 values ranging from 11 nM to 75 μM. They are all old drugs as follows, anisomycin, antimycin A, atovaquone, chloroquine, conivaptan, emetine, gemcitabine, homoharringtonine, niclosamide, nitazoxanide, oligomycin, salinomycin, tilorone, valinomycin, vismodegib. Conclusion All of the old drugs identified as having activity against FIPV and HCoV-OC43 have seen clinical use in their respective indications and are associated with known dosing schedules and adverse effect or toxicity profiles in humans. Those, when later confirmed to have an anti-viral effect on SARS-CoV-2, should be considered for immediate uses in COVID-19 patients., Graphical abstract Image 1

Colorectal cancer (CRC) is a malignant cancer with high incidence and mortality in the world. Immunotherapy targeting neoantigens can induce durable tumor regression in cancer patients, but is almost limited to personalized precision therapy, due to the individual differences of unique neoantigens. With the discovery of many common oncogenic mutations, and such mutation-associated neoantigens could cover more patients, and hence are valuable in clinical field. However, whether the common neoantigens can be identified in CRC is unknown. Combining the somatic mutations data from 321 CRC patients with a filter standard and 7 predicted algorithms, we screened and obtained 25 HLA-A*1101-restricted common neoantigens with a high binding affinity (IC结直肠癌是世界高发和高致死率的恶性肿瘤。靶向新抗原的免疫治疗已被证实可以诱导癌症患者肿瘤持续消退,但这些特异性新抗原,仅适用于个体精准治疗。随着大量的高频肿瘤基因突变被发现,这些与突变相关的高频新抗原可覆盖更多人群,具有较强的临床意义。然而目前结直肠癌中是否也存在高频新抗原仍不清楚。本研究利用来源于321个结直肠癌患者的体细胞突变数据库,联合1种标准过滤和7种预测算法,筛选并获得了25个基于中国人高频分型HLA-A*1101限制性的高频新抗原,它们均具有高亲和力(IC

Background The effect and extent of abnormal placental perfusion (APP) on the risk of male hypospadias are poorly understood. We compared the prevalence of male hypospadias in the offspring of women with APP and quantify the extent of the APP effect on the anomaly. Methods A hospital-based retrospective analysis of births from 2012 to 2016 was conducted in 2018. Women of singleton pregnancy and male infants born to them were included (N = 21,447). A multivariate analysis was performed to compare the prevalence of male hypospadias in infants exposed to APP with those that were not exposed to APP. Results Compared with the infants of women without APP, infants of women with APP showed an increased risk of male hypospadias (odds ratio, 2.40; 95% confidence interval, 1.09–5.29). The male hypospadias cumulative risk increased with the severity of APP. Infants exposed to severe APP had a significantly higher risk of male hypospadias than those without APP exposure (9.2 versus 1.7 per 1000 infants, P Conclusions Male hypospadias risk was associated with APP and increased with APP severity, as measured in the second trimester. APP had an important role in the development of the anomaly.

AIM To establish an ultrasound-based radiomics model through machine learning methods and then to assess the ability of the model to differentiate infected focal liver lesions from malignant mimickers. MATERIALS AND METHODS A total of 104 patients with infected focal liver lesions and 485 patients with malignant hepatic tumours were included, consisting of hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), combined hepatocellular–cholangiocarcinoma (cHCC-CC), and liver metastasis. Radiomics features were extracted from grey-scale ultrasound images. Feature selection and predictive modelling were carried out by dimensionality reduction methods and classifiers. The diagnostic effect of the prediction mode was assessed by receiver operating characteristic (ROC) curve analysis. RESULTS In total, 5,234 radiomics features were extracted from grey-scale ultrasound image of every focal liver lesion. The ultrasound-based radiomics model had a favourable predictive value for differentiating infected focal liver lesions from malignant hepatic tumours, with an area under the curve (AUC) of 0.887 and 0.836 (HCC group), 0.896 and 0.766 (CC group), 0.944 and 0.754 (cHCC-CC group), 0.918 and 0.808 (liver metastasis group), and 0.949 and 0.745 (malignant hepatic tumour group) for the training set and validation set, respectively. CONCLUSIONS Ultrasound-based radiomics is helpful in differentiating infected focal liver lesions from malignant mimickers and has the potential for use as a supplement to conventional grey-scale ultrasound and contrast-enhanced ultrasound (CEUS).

Background The ongoing COVID-19 pandemic has caused more than 193,825 deaths during the past few months. A quick-to-be-identified cure for the disease will be a therapeutic medicine that has prior use experiences in patients in order to resolve the current pandemic situation before it could become worsening. Artificial intelligence (AI) technology is hereby applied to identify the marketed drugs with potential for treating COVID-19. Methods An AI platform was established to identify potential old drugs with anti-coronavirus activities by using two different learning databases; one consisted of the compounds reported or proven active against SARS-CoV, SARS-CoV-2, human immunodeficiency virus, influenza virus, and the other one containing the known 3C-like protease inhibitors. All AI predicted drugs were then tested for activities against a feline coronavirus in in vitro cell-based assay. These assay results were feedbacks to the AI system for relearning and thus to generate a modified AI model to search for old drugs again. Results After a few runs of AI learning and prediction processes, the AI system identified 80 marketed drugs with potential. Among them, 8 drugs (bedaquiline, brequinar, celecoxib, clofazimine, conivaptan, gemcitabine, tolcapone, and vismodegib) showed in vitro activities against the proliferation of a feline infectious peritonitis (FIP) virus in Fcwf-4 cells. In addition, 5 other drugs (boceprevir, chloroquine, homoharringtonine, tilorone, and salinomycin) were also found active during the exercises of AI approaches. Conclusion Having taken advantages of AI, we identified old drugs with activities against FIP coronavirus. Further studies are underway to demonstrate their activities against SARS-CoV-2 in vitro and in vivo at clinically achievable concentrations and doses. With prior use experiences in patients, these old drugs if proven active against SARS-CoV-2 can readily be applied for fighting COVID-19 pandemic.

Purpose: Several RAB family genes have been studied extensively and proven to play pivotal roles in the occurrence and development of certain cancers. Here, we explored commonly expressed RAB family genes in humans and their prognostic significance using bioinformatics, and then identified potential biomarkers of breast invasive carcinoma (BRCA). Materials and methods: The prognostic values (overall survival) of RAB family genes in BRCA were obtained using Gene Expression Profiling Interactive Analysis (GEPIA). The expression patterns of RAB family genes and their relationships with clinicopathological parameters in BRCA were measured using the ONCOMINE and UALCAN databases, respectively. Genetic mutations and survival analysis were investigated using the cBio Cancer Genomics Portal (c-BioPortal). Interacting genes of potential biomarkers were identified using STRING, and functional enrichment analyses were performed using FunRich v3.1.3. Results: In total, 64 RAB genes were identified and analyzed in our study. Results showed that RAB1B, RAB2A, and RAB18 were up-regulated and significantly associated with poor overall survival in BRCA. Furthermore, their higher expression was positively correlated with clinicopathological parameters (e.g. cancer stage and nodal metastasis status). DNA copy number amplifications and mRNA up-regulation were the main genetic mutations, and the altered group showed significantly poorer overall survival compared with the unaltered group. Functional enrichment analysis of RAB1B, RAB2A, and RAB18 indicated they were closely involved in GTPase activity. Conclusions:RAB1B, RAB2A, and RAB18 were up-regulated and significantly correlated with poor prognosis in BRCA. Thus, they could be applied as novel biomarkers of BRCA in future studies.