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Conditionally-replicating adenovirus (CRAd) therapy is currently being tested against pancreatic cancer and has shown some promise. To improve the efficacy, a novel virus CRAd-Cans was designed by deletion of E1B-55kDa gene for selective replication in tumor cells, as well as carrying a new angiogenesis inhibitor gene, canstatin. CRAd-Cans mediated higher expression of canstatin in BxPC-3 pancreatic cancer cell line compared to the replication-deficient adenovirus Ad5-Cans. The modified CRAd-Cans manifested the same selective replication and cytocidal effects in pancreatic cancer cells as ONYX-015 in vitro, yet showed greater reduction of tumor growth in nude mice with markedly prolonged survival rate in vivo (P<0.05), compared to that of either ONYX-015 or Ad5-Cans. Pathological examination revealed viral replication, decreased microvessel density and increased cancer cell apoptosis in CRAd-Cans-treated xenografts. The results suggest that the novel oncolytic virus CRAd-Cans, showing synergistic effects of oncolytic therapy and anti-angiogenesis therapy, is a new promising therapeutics for pancreatic cancer. [ABSTRACT FROM AUTHOR]

This case report describes a rare occurrence of a 25-year-old female diagnosed with both systemic sclerosis (SSc) and ankylosing spondylitis (AS), two distinct autoimmune diseases. The patient presented with a combination of symptoms, including progressive skin tightening, lumbosacral pain, and Raynaud's phenomenon, which complicated the diagnosis. Despite the challenges posed by the coexistence of SSc and AS, a multidisciplinary treatment approach involving corticosteroids, immunosuppressants, and supportive therapies led to significant clinical improvement. Over the course of 3 weeks, the patient's Rodnan Skin Score improved from 18 to 11, and her pain and overall disease activity were markedly reduced. Although skin sclerosis showed substantial improvement, pulmonary involvement remains a concern that requires long-term monitoring. This case highlights the complexities in diagnosing and managing overlap syndromes, emphasizing the need for personalized treatment strategies and further investigation into the underlying genetic and immunological mechanisms., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

We report a case of a 72-year-old female who presented with fever, abdominal pain, and diarrhea accompanied by leukopenia, anemia, and thrombocytopenia. The diagnosis of acute aplastic anemia was confirmed through bone marrow aspiration. Treatment included glucocorticoids, immunoglobulin therapy, and plasma exchange. Subsequently, the patient developed gastrointestinal bleeding and abdominal Computed Tomography (CT) revealed perforation of the transverse colon. Pathological examination of surgically removed diseased tissue confirmed mucor infection. Despite receiving antifungal therapy with amphotericin B, the patient's condition deteriorated due to the sepsis progression. Mucor infection in immunocompromised patients should be vigilant, and early diagnosis may help improve prognosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

To analyze the factors associated with the overall patient condition and explore the clinical value of the Patient Global Assessment (PGA) index for assessing the disease state in patients with Ankylosing Spondylitis (AS). This cross-sectional study used a standardized questionnaire to record the basic information of patients with AS. The collected data included the Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-reactive protein (CRP), ASDAS-erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), PGA, and other clinical indicators. Statistical analysis was performed using SPSS 25.0 software, and the scale was assessed for retest reliability and structural validity. The Kruskal-Wallis H test and Spearman or Pearson correlation analysis were used to analyze the factors influencing PGA scores. The receiver operator characteristic (ROC) curve was used to identify the cutoff value of the PGA for predicting disease activity in AS. The patient age, disease duration, family history, and history of ocular inflammation significantly differed between PGA groups (P < .05). The median PGA was significantly lower in patients with disease remission than in those with disease activity (P < .01). The various clinical indexes significantly differed between PGA groups (P < .01). The PGA was significantly correlated with various clinical indicators (P < .01). The area under the ROC curve (AUC) for disease activity based on the ASDAS-CRP was 0.743 (P < .01) with a PGA cutoff value of 1.38; the AUC for disease activity based on the BASDAI was 0.715 (P < .01) with a PGA cutoff value of 1.63. The PGA was significantly correlated with patient-reported outcomes, disease activity, function, and psychological status, and may indicate the level of inflammation in patients with AS. A PGA of around 1.5 indicates disease activity., Competing Interests: None of the authors has any conflicts of interest to declare., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Hepatocellular carcinoma (HCC) is a highly prevalent and lethal tumor worldwide and its late discovery and lack of effective specific therapeutic agents necessitate further research into its pathogenesis and treatment. Organoids, a novel model that closely resembles native tumor tissue and can be cultured in vitro, have garnered significant interest in recent years, with numerous reports on the development of organoid models for liver cancer. In this study, we have successfully optimized the procedure and established a culture protocol that enables the formation of larger-sized HCC organoids with stable passaging and culture conditions. We have comprehensively outlined each step of the procedure, covering the entire process of HCC tissue dissociation, organoid plating, culture, passaging, cryopreservation, and resuscitation, and provided detailed precautions in this paper. These organoids exhibit genetic similarity to the original HCC tissues and can be utilized for diverse applications, including the identification of potential therapeutic targets for tumors and subsequent drug development.

Weighted gene co-expression network analysis (WGCNA) is a method for analysing gene expression patterns across multiple samples, clustering genes with similar expression patterns and identifying key genes associated with specific traits or phenotypes. In this study, we investigated the effects of fucoxanthin accumulation in Phaeodactylum tricornutum in response to abiotic stresses of phosphorus deficiency, red light, and yellow light using transcriptome sequencing and weighted gene co-expression network analysis. The results showed that compared to the control, the fucoxanthin content of P. tricornutum was significantly increased after phosphorus deficiency and red light treatment ( P <0.05), but significantly decreased after yellow light treatment ( P <0.05). A weighted gene co-expression network was constructed using 10,392 genes obtained from transcriptome sequencing, and β=18 (R 2 >0.8) was chosen as a soft threshold in order to ensure a scale-free network. A total of 10 co-expression modules were identified by correlation analysis of fucoxanthin content, with the purple module positively correlated with fucoxanthin content ( r =0.9, P =1E-200), and 9 key genes were identified, including five genes in the fucoxanthin biosynthesis pathway ( DXR , PSY , PDS1 , ZEP2 , VDL2 ) and 4 transcription factors ( bHLH5 , HOX2 , CCHH13 , HSF1b ). Further qRT-PCR confirmed that key genes were more highly expressed in the phosphorus deficiency treatment and linear regression analysis showed that the relative gene expressions were all highly correlated with the transcriptome data. The results of this study provide a basis for further investigation of the complex regulatory mechanisms of fucoxanthin in P. tricornutum.

In order to promote the rapid development of the meat sheep industry, a three-way crossbred combination experiment was carried out with Australian White, Dorper, and Charollais sheep as terminal male parents and the elite F1 hybrids of Australian White  ×  Small-tailed Han (Han), Dorper  ×  Han, and Charollais  ×  Han as female parents, which was based on the screening of a two-way crossbred combination in meat sheep. The growth performance of six groups of three-way crossbred combinations and Han lambs was measured and analyzed, and the effect of a polymorphism in the CLPG gene on the growth performance of three-way crossbred lambs was also studied. The results showed that under the same rearing conditions, weight at 3 and 6 months of age and average daily gain from birth to 3 months and from 3 to 6 months of age were all the largest for Australian  ×  (Charollais  ×  Han) crossbred lambs. They were significantly or extremely significant different from the other three-way crossbred combinations and Han lambs ( P < 0.05 , P < 0.01 ). The body height, body length, chest girth, and cannon bone circumference at 3 months of age and body length, chest girth, and cannon bone circumference at 6 months of age were also the largest for Australian  ×  (Charollais  ×  Han) crossbred lambs. Among them, body length, chest girth, and cannon bone circumference at 3 months of age were significantly different from the other three-way crossbred combinations and Han lambs ( P < 0.05 ), and body length, chest girth, and cannon bone circumference at 6 months of age were significantly or extremely significant different from the other three-way crossbred combinations and Han lambs ( P < 0.05 , P < 0.01 ). The potential genetic effects of the CLPG gene on the growth performance indicators of three-way crossbred lambs showed that a mutation site ( g .232 C   >   T ) of this gene had two genotypes: CC and CT . Among them, the data of body weights and body sizes from CT genotype individuals at birth, 3 months old, and 6 months old were significantly higher than those of CC genotype individuals, and some indicators showed significant or extremely significant differences ( P < 0.05 , P < 0.01 ), suggesting that higher growth performance was observed in individuals with T alleles. To sum up, the crossbred combination of Australian  ×  (Charollais  ×  Han) could be suggested as the optimal choice. The T allele of the CLPG gene showed potential advantages in the performance of meat production in meat sheep. Based on the current results, we recommend that the offspring of Australian  ×  (Charollais  ×  Han) with the T allele should be preferentially utilized for meat sheep production., Competing Interests: The contact author has declared that none of the authors has any competing interests., (Copyright: © 2022 Jian Tao Wang et al.)

Objective: The study aimed to determine the prevalence and pathogens of invasive fungal infection (IFI) among intensive care unit (ICU) patients. The next goal was to investigate the association between empirical antifungal treatment and mortality in ICU patients., Methods: Using microbiological events, we identified all ICU patients with IFI and then retrieved electronic clinical data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The data were statistically analyzed using t -tests, chi-square tests, log-rank tests, and Cox regression., Results: The most commonly reported fungi were Candida (72.64%) and Aspergillus (19.08%). The most frequently prescribed antifungal medication was fluconazole (37.57%), followed by micafungin (26.47%). In the survival study of ICU patients and patients with sepsis, survivors were more likely to receive empirical antifungal treatment. In contrast, non-empirical antifungal therapy was significantly associated with poor survival in patients with positive blood cultures. We found that the current predictive score makes an accurate prediction of patients with fungal infections challenging., Conclusions: Our study demonstrated that empirical antifungal treatment is associated with decreased mortality in ICU patients. To avoid treatment delays, novel diagnostic techniques should be implemented in the clinic. Until such tests are available, appropriate empirical antifungal therapy could be administered based on a model that predicts the optimal time to initiate antifungal therapy. Additional studies should be conducted to establish more accurate predictive models in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Rao, Ma, Tang, Xu, He, Li, Liu, Xu, Yang, Gong, Xue, Wu and Xue.)

Background: Antibody-based cancer therapeutics is developing rapidly in recent years for its advantages in precisely targeting the tumor cells. However, tumor-specific cell surface antigens are still lacking, and the heterogeneity of tumor mass greatly impeded the development of effective drugs. Methods: In the present study, single-cell RNA sequencing was used to dissect tumor heterogeneity in human hepatocellular carcinoma (HCC). Tissues from different spatial regions including the tumor, para-tumor, and distant normal liver tissues were dissociated into single cells, and the gene expressions were compared in a different subpopulation of cells from these regions and validated in independent cohorts. Results: A total of 28 cell clusters with different distribution patterns and gene expression profiles were identified within a heterogenous tumor and its paired liver tissues. Differentially expressed genes encoding the plasma membrane in cells with hepatic lineage were further extracted from single-cell transcriptome sequencing and validated in TCGA database. A 3-gene signature was identified to be significantly upregulated in dominant HCC tumor cell subpopulations with prognostic significance and validated in multiple independent patient cohorts. Conclusion: The composition of the three plasma membrane proteins on the surface of HCC tumor cells within a heterogenous tumor might indicate poor prognostic tumor subpopulations during cancer evolution and potential therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tang, Yuan, Gong, Zhang, Liu and Luo.)

The purpose of this study is to examine preservice Chinese language teachers' cognition in teaching intercultural communicative competence. In the study we collected data through in-depth interviews with seven preservice teachers in a Master of Education program (Teaching Chinese as a Second Language, TCSL) at a university in Hong Kong SAR, China. The findings indicated that the participants had a relatively positive attitude and inclination toward the development of students' intercultural communicative competence, while their conceptualizations of culture tended to be static and ambiguous. In addition, the participants' objectives in teaching intercultural communicative competence were found to be more attitude-than knowledge- or skill-oriented. The study offers valuable insights that preservice language teachers' cognition plays a crucial role in their future professional development and calls for curricular innovations with intercultural aims in teacher education programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gong, Lai, Gao, Li, Huang and Lin.)

Objective: To predict the trends for fine-scale spread of Oncomelania hupensis based on supervised machine learning models in Shanghai Municipality, so as to provide insights into precision O. hupensis snail control., Methods: Based on 2016 O. hupensis snail survey data in Shanghai Municipality and climatic, geographical, vegetation and socioeconomic data relating to O. hupensis snail distribution, seven supervised machine learning models were created to predict the risk of snail spread in Shanghai, including decision tree, random forest, generalized boosted model, support vector machine, naive Bayes, k-nearest neighbor and C5.0. The performance of seven models for predicting snail spread was evaluated with the area under the receiver operating characteristic curve (AUC), F1-score and accuracy, and optimal models were selected to identify the environmental variables affecting snail spread and predict the areas at risk of snail spread in Shanghai Municipality., Results: Seven supervised machine learning models were successfully created to predict the risk of snail spread in Shanghai Municipality, and random forest (AUC = 0.901, F1-score = 0.840, ACC = 0.797) and generalized boosted model (AUC= 0.889, F1-score = 0.869, ACC = 0.835) showed higher predictive performance than other models. Random forest analysis showed that the three most important climatic variables contributing to snail spread in Shanghai included aridity (11.87%), ≥ 0 °C annual accumulated temperature (10.19%), moisture index (10.18%) and average annual precipitation (9.86%), the two most important vegetation variables included the vegetation index of the first quarter (8.30%) and vegetation index of the second quarter (7.69%). Snails were more likely to spread at aridity of < 0.87, ≥ 0 °C annual accumulated temperature of 5 550 to 5 675 °C, moisture index of > 39% and average annual precipitation of > 1 180 mm, and with the vegetation index of the first quarter of > 0.4 and the vegetation index of the first quarter of > 0.6. According to the water resource developments and township administrative maps, the areas at risk of snail spread were mainly predicted in 10 townships/subdistricts, covering the Xipian, Dongpian and Tainan sections of southern Shanghai., Conclusions: Supervised machine learning models are effective to predict the risk of fine-scale O. hupensis snail spread and identify the environmental determinants relating to snail spread. The areas at risk of O. hupensis snail spread are mainly located in southwestern Songjiang District, northwestern Jinshan District and southeastern Qingpu District of Shanghai Municipality.

Objective: Cervical cancer remains a leading cause of gynecological cancer-related death. In this study, we aimed to investigate the expression pattern of miR-599 and its prognostic significance in cervical cancer., Materials and Methods: The RT-qPCR analysis was used to detect the expression levels of miR-599 in cervical cancer tissues and cell lines. The association between miR-599 expression and clinical characteristics of cervical cancer patients was analyzed using the χ 2 test. The Kaplan-Meier analysis and multivariate Cox proportional hazards model were used to explore the prognostic significance of miR-599. Then, CCK-8 assays, transwell migration, and invasion assays were used to assess the effects of miR-599 on tumor cell proliferation, migration, and invasion of cervical cancer cells, respectively., Results: miR-599 expression was significantly downregulated in cervical cancer tissues and cells compared with non-cancerous tissues and HaCaT cells, respectively. Statistical analysis revealed that miR-599 expression was associated with lymph node metastasis and FIGO stage. The miR-599 expression was an independent prognostic factor for overall survival. Functionally, overexpression of miR-599 suppressed cell proliferation, migration, and invasion of cervical cancer cells, while downregulation of miR-599 had opposite effects., Conclusion: miR-599 acts as a tumor suppressor in cervical cancer that inhibiting cell proliferation, migration, and invasion of cervical cancer cells, suggesting that miR-599 may be a potential prognostic biomarker and novel targeted strategy for cervical cancer., Competing Interests: Declaration of competing interest The author(s) have no conflicts of interest relevant to this article., (Copyright © 2022. Published by Elsevier B.V.)

Tumour lineage plasticity is an emerging hallmark of aggressive tumours. Tumour cells usually hijack developmental signalling pathways to gain cellular plasticity and evade therapeutic targeting. In the present study, the secreted protein growth and differentiation factor 1 (GDF1) is found to be closely associated with poor tumour differentiation. Overexpression of GDF1 suppresses cell proliferation but strongly enhances tumour dissemination and metastasis. Ectopic expression of GDF1 can induce the dedifferentiation of hepatocellular carcinoma (HCC) cells into their ancestral lineages and reactivate a broad panel of cancer testis antigens (CTAs), which further stimulate the immunogenicity of HCC cells to immune-based therapies. Mechanistic studies reveal that GDF1 functions through the Activin receptor-like kinase 7 (ALK7)-Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signalling cascade and suppresses the epigenetic regulator Lysine specific demethylase 1 (LSD1) to boost CTA expression. GDF1-induced tumour lineage plasticity might be an Achilles heel for HCC immunotherapy. Inhibition of LSD1 based on GDF1 biomarker prescreening might widen the therapeutic window for immune checkpoint inhibitors in the clinic., (© 2021. The Author(s).)

(1) Background: Sleep problems have become one of the current serious public health issues. Pillow height affects the alignment of the cervical spine and is closely related to the mechanical environment of the cervical spine. An appropriate pillow height can provide adequate support for the head and neck to reduce the stress in the cervical spine and relax the muscles of the neck and shoulder, thereby relieving pain and improving sleep quality. (2) Methods: We reviewed the current trends, research methodologies, and determinants of pillow height evaluation, summarizing the evidences published since 1997. In particular, we scrutinized articles dealing with the physiological and mechanical characteristics of the head-neck-shoulder complex. (3) Results: Through the investigation and analysis of these articles, we presented several quantitative and objective determinants for pillow height evaluation, including cervical spine alignment, body dimension, contact pressure, and muscle activity. The measurement methods and selection criteria for these parameters are described in detail. However, the suggested range for achieving optimal cervical spine alignment, appropriate pressure distribution, and minimal muscle activity during sleep cannot yet be identified considering the lack of sufficient evidence. Moreover, there remain no firm conclusions about the optimal pillow height for the supine and lateral positions. (4) Conclusions: A comprehensive evaluation combining the above determinants provides a unique solution for ergonomic pillow design and proper pillow height selection, which can effectively promote the public sleep health. Therefore, it is necessary to develop a reasonable algorithm to weigh multiple determinants.

Hepatic impairment in coronavirus disease 2019 (COVID-19) may derive from cholangiocyte damage in the beginning, but not from direct infection of hepatocytes. Chronic liver disease patients co-infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited overexpression of angiotensin-converting enzyme 2 receptors and overwhelming cytokine storm. Consensus has been reached that we should encourage as many people as possible to be vaccinated in order to achieve herd immunity. SARS-CoV-2 vaccines can prevent or alleviate severe infection and cytokine storm. It is recommended that all adult patients with chronic liver diseases and liver transplant recipients should receive COVID-19 vaccines using the standard dose and schedule. Data is not yet sufficient to compare the efficacy of different types of vaccines used in chronic liver disease patients., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest and financial support for this work., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Sanguinarine is the main active component of the Papaver plants, and protopine-6-hydroxylase(P6 H), involved in the sanguinarine biosynthetic pathway, can oxidize protopine to 6-hydroxyprotopine. The investigation on the diversity of P6 H genes in the medicinal Papaver plants contributes to the acquirement of P6 H with high activity to increase the biosynthesis of sanguinarine. Five P6 H genes in P. somniferum, P. orientale, and P. rhoeas were discovered based on the re-sequencing data of the Papaver species, followed by bioinformatics analysis. With the elongation factor 1α(EF-1α), which exhibits stable expression in the root and stem, as the internal reference gene, the transcription levels of P6H genes in roots and stems of the Papaver plants were detected by real-time fluorescent quantitative PCR. As indicated by the re-sequencing results, there were two genotypes of P6H in P. somniferum and P. orientale, respectively, and only one in P. rhoeas. The bioinformatics analysis showed that the P6 H proteins of the three Papaver plants contained the conserved domain cl12078, which is the characteristic of p450 supergene family, and transmembrane regions. The existence of signal peptide remained verification. Real-time fluorescent quantitative PCR results revealed that the transcription level of P6 H in roots of P. somniferum was about 1.44 times of that in stems(α=0.05). The present study confirmed genetic diversity of P6 H in the three medicinal Papaver plants, which lays a basis for the research on the biosynthesis pathway and mechanism of sanguinarine in Papaver species.

LncRNAs play an important role in a variety of biological processes, such as cancer pathogenesis. The lncRNA zinc ribbon domain containing 1 antisense RNA 1 (ZNRD1-AS1) is a natural antisense transcript of ZNRD1. In this study, we found that ZNRD1-AS1 levels were significantly upregulated in gastric cancer tissues compared to those in adjacent healthy gastric tissues. ZNRD1-AS1 levels were correlated with lymph node metastasis, distal metastasis, and TNM stage, but were not correlated with age and sex. ZNRD1-AS1 knockdown suppressed cell proliferation, migration, and invasion, and promoted apoptosis. ZNRD1-AS1 overexpression had the opposite effect. ZNRD1-AS1 knockdown suppressed tumor growth and pulmonary metastasis in a nude mouse model ZNRD1-AS1 can bind to miR-9-5p and ZNRD1-AS1 knockdown can decrease the protein level of heat shock protein 90 alpha family class A member 1 (HSP90AA1), which is the target of miR-9-5p. The miR-9-5p inhibitor rescued the effect of ZNRD1-AS1 knockdown, and the mutant of miR-9-5p binding site on ZNRD1-AS1 sequence blocked the effect of ZNRD1-AS1 overexpression. In conclusion, ZNRD1-AS1 levels were upregulated in gastric cancer tissues, and knockdown of ZNRD1-AS1 suppressed gastric cancer cell proliferation and metastasis by targeting the miR-9-5p/HSP90AA1 axis. Our findings provide novel insights into the mechanism underlying the role of ZNRD1-AS1 in gastric cancer.

Background: Schistosomiasis control is striving forward to transmission interruption and even elimination, evidence-lead control is of vital importance to eliminate the hidden dangers of schistosomiasis. This study attempts to identify high risk areas of schistosomiasis in China by using information value and machine learning., Methods: The local case distribution from schistosomiasis surveillance data in China between 2005 and 2019 was assessed based on 19 variables including climate, geography, and social economy. Seven models were built in three categories including information value (IV), three machine learning models [logistic regression (LR), random forest (RF), generalized boosted model (GBM)], and three coupled models (IV + LR, IV + RF, IV + GBM). Accuracy, area under the curve (AUC), and F1-score were used to evaluate the prediction performance of the models. The optimal model was selected to predict the risk distribution for schistosomiasis., Results: There is a more prone to schistosomiasis epidemic provided that paddy fields, grasslands, less than 2.5 km from the waterway, annual average temperature of 11.5-19.0 °C, annual average rainfall of 1000-1550 mm. IV + GBM had the highest prediction effect (accuracy = 0.878, AUC = 0.902, F1 = 0.920) compared with the other six models. The results of IV + GBM showed that the risk areas are mainly distributed in the coastal regions of the middle and lower reaches of the Yangtze River, the Poyang Lake region, and the Dongting Lake region. High-risk areas are primarily distributed in eastern Changde, western Yueyang, northeastern Yiyang, middle Changsha of Hunan province; southern Jiujiang, northern Nanchang, northeastern Shangrao, eastern Yichun in Jiangxi province; southern Jingzhou, southern Xiantao, middle Wuhan in Hubei province; southern Anqing, northwestern Guichi, eastern Wuhu in Anhui province; middle Meishan, northern Leshan, and the middle of Liangshan in Sichuan province., Conclusions: The risk of schistosomiasis transmission in China still exists, with high-risk areas relatively concentrated in the coastal regions of the middle and lower reaches of the Yangtze River. Coupled models of IV and machine learning provide for effective analysis and prediction, forming a scientific basis for evidence-lead surveillance and control.

Tumor lineage plasticity is emerging as a critical mechanism of therapeutic resistance and tumor relapse. Highly plastic tumor cells can undergo phenotypic switching to a drug-tolerant state to avoid drug toxicity. Here, we investigate the transmembrane tight junction protein Claudin6 (CLDN6) as a therapeutic target related to lineage plasticity for hepatocellular carcinoma (HCC). CLDN6 was highly expressed in embryonic stem cells but markedly decreased in normal tissues. Reactivation of CLDN6 was frequently observed in HCC tumor tissues as well as in premalignant lesions. Functional assays indicated that CLDN6 is not only a tumor-associated antigen but also conferred strong oncogenic effects in HCC. Overexpression of CLDN6 induced phenotypic shift of HCC cells from hepatic lineage to biliary lineage, which was more refractory to sorafenib treatment. The enhanced tumor lineage plasticity and cellular identity change were potentially induced by the CLDN6/TJP2 (tight junction protein 2)/YAP1 (Yes-associated protein 1) interacting axis and further activation of the Hippo signaling pathway. A de novo anti-CLDN6 monoclonal antibody conjugated with cytotoxic agent (Mertansine) DM1 (CLDN6-DM1) was developed. Preclinical data on both HCC cell lines and primary tumors showed the potent antitumor efficiency of CLDN6-DM1 as a single agent or in combination with sorafenib in HCC treatment., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

This article reports on an inquiry that investigated the development of ba constructions in early childhood Mandarin. All cases of ba construction were extracted from the Early Childhood Mandarin Corpus collected from 168 preschoolers aged 2;6, 3;6, 4;6, and 5;6 (year; month; Li and Tse, 2011). Early Childhood Mandarin Corpus, University of Hong Kong. Data analysis indicated that: (1) Mandarin-speaking children produced a repertoire of 11 types of ba construction, and the children in the youngest age group (age 2;6) were able to produce six types of them; (2) children at 4 years old (age 4;6) experienced a critical developmental period of pragmatic use, and at 5 years old (age 5;6) they had attained cognitive and linguistic maturity in understanding the semantic and syntactic features of ba constructions; and (3) there was a significant age effect on the production of three types of ba construction, but no significant association between the children's gender and their production of ba constructions. These findings offer fresh insights into understanding Chinese children's innate capacity to understand the co-occurrence constraints concerning the syntactic, semantic and verb features inherent in ba construction, and their developmental ability to denote telic events by resorting to the appropriate ba sentence patterns., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tsung and Gong.)

Hypertrophic scar (HS) is a dermal fibroproliferative disease that often occurs following abnormal wound healing. To date, there is no satisfied treatment strategies for improvement of scar formation with few side effects. The effects of gambogenic acid (GNA) on scar hypertrophy has not been studied previously. The present study was undertaken to find out the scar-reducing effects of GNA (0.48, 0.96 or 1.92 mg/ml) on skin wounds in rabbit ears. Scar evaluation index (SEI), collagen I (Col1) and collagen III (Col3), microvascular density (MVD), CD4+T cells and macrophages, vascular endothelial growth factor receptor 2 (VEGFR2), fibroblast growth factor receptor 1 (FGFR1), phospho-VEGFR 2 (p-VEGFR2) and p-FGFR1, interleukin (IL)-1β, IL-6, IL-10 and tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF) in scar tissue were detected using various methods, respectively. Our data showed that GNA significantly reduced SEI, and the expression of Col1 and Col3 in scar tissue in a concentration-dependent manner. Also, it decreased MVD, the infiltration of CD4+T cells and macrophages, and the levels of VEGFR2, p-VEGFR2, FGFR1, p-FGFR1, TGF-β1, CTGF, IL-1β, IL-6, TNF-α, in addition to upregulated IL-10 in scar tissue. As a result, this study revealed that GNA reduced HS formation, which was associated with the inhibition of neoangiogenesis, local inflammatory response and growth factor expression in scar tissue during wound healing. These findings suggested that GNA may be considered as a preventive and therapeutic candidate for HS., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: We aimed to identify and represent factors associated with thrombocytopenia in intensive care unit, especially the pathogens and drugs related to severe and extremely thrombocytopenia. Then, we aim to compare the mortality of platelet transfusion and non-transfusion in patients with different degrees of thrombocytopenia., Methods: We identified all thrombocytopenic patients in intensive care unit by using platelet-specific values and then extracted electronic health records from our Hospital Information System. Data were statistically analyzed with t test, chi-square test, and logistic regression., Results: We found that infections (32.7%) were the most frequent cause associated with thrombocytopenia, followed by sepsis shock (3.93%) and blood loss (2.99%). Meanwhile, antifungals ( p  = 0.002) and bacterial infection ( p  = 0.037) were associated with severe and extremely severe thrombocytopenia. Finally, we found that the mortality of platelet transfusion and non-transfusion in patients was statistically significant for patients with platelet counts between 30 and 49/nL (χ 2  = 9.719, p  = 0.002)., Conclusion: Infection and sepsis emerged as two primary factors associated with thrombocytopenia in intensive care unit. Meanwhile, antifungals and bacterial infection were associated with platelet counts less than 49/nL. Finally, platelet transfusion may be associated with reduced mortality in patients with platelet counts between 30 and 49/nL., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Objective: To understand the status of chronic filariasis patients in Jiangxi Province in 2018, so as to provide insights into the follow-up care of the patients., Methods: In 2018, a case follow-up study was conducted in all registered patients with chronic filariasis in previously endemic areas of Jiangxi Province, and a clue investigation was done for identifying the missing patients. In addition, the data of caring sites for chronic filarisis patients were collected and analyzed in the province., Results: A total of 802 chronic filariasis patients were identified in 56 counties (districts) of Jiangxi Province in 2018. The patients had a male/female ratio of 1∶1, and 85.41% had ages of over 70 years. There were 58.60%, 93.89%, 17.21% and 3.62% of chronic filariasis patients with lymphangitis, lymphedema/elephantiasis, chyluria and hydrocele, respectively. A total of 273 caring sites were assigned in 56 counties (districts) of Jiangxi Province, and 306 caring activities were carried out in 2018., Conclusions: The number of chronic filariasis patients has significantly decreased in Jiangxi Province; however, the care remains to be intensified for chronic filariasis patients.

Background: Loss of terminal differentiation markers and gain of stem cell-like properties are a major hallmark of cancer malignant progression. Identification of novel biomarkers representing tumor developmental progeny and predictive of patients' prognosis would greatly benefit clinical cancer management., Methods: Human embryonic stem cells were induced to differentiate into hepatocytes along hepatic lineages. Transcriptomic data from different liver developmental stages were analyzed combining with the RNA-seq data from The Cancer Genome Atlas (TCGA) project. Kaplan-Meier survival analysis and Cox regression analyses were used to analyze the clinical significance in HCC patients., Results: A shifted expression pattern of claudin (CLDN) family genes were identified to be closely associated with liver development and tumor progression. Claudins with hepatic features were found to be significantly down-regulated and predicted better prognosis in HCC patients. Conversely, another set of claudins with embryonic stem cell features were found to be significantly up-regulated and predicted worse prognosis in HCC patients. A claudin signature score system was further established by combining the two sets of claudin genes. The newly established claudins signature could robustly predict HCC patients' prognosis in the training, testing, and independent validation cohorts., Conclusions: In the present study, we developed a novel embryonic developmental claudins signature to monitor the extent of tumor dedifferentiation in HCC from an in vitro hepatocyte differentiation model. The claudins signature might present a great potential in predicting prognostic significance in HCC as cell surface biomarkers, and provide novel therapeutic targets for precision oncology further in the clinic.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by synovial inflammation and hyperplasia resulting from an imbalance between the proliferation and apoptosis of fibroblast-like synoviocytes (FLSs). Our previous study found that sorafenib had inhibitory effects in rats with adjuvant arthritis (AA). The present study investigated the role of sorafenib in the induction of AA FLS apoptosis in vitro. FLSs obtained from AA rats were cultured in vitro and identified. Cell apoptosis was detected using terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) labeling methods. Real-time PCR and Western blotting assays were used to quantify the expression levels of Fas, Caspase-3, Mcl-1, NF-κB and C-jun gene products in AA FLSs. Our data revealed that sorafenib (4 μmol/L) induced apoptosis in AA FLSs, and flow cytometry analysis showed that AA FLSs treated with sorafenib (4 μmol/L) in vitro accumulated in early and late apoptosis. There were significant increases in the expression levels of Fas, Caspase-3 and Mcl-1, and significant decreases in NF-κB and C-jun expression in AA FLSs treated with sorafenib. In summary, these results demonstrate that sorafenib promotes AA FLS apoptosis, which may be related to the upregulation of Fas and Caspase-3 and downregulation of NF-κB and C-jun. All of these findings suggest that sorafenib exerts an inhibitory effect on AA rats in vivo via AA FLS apoptotic induction, which has potential therapeutic implications for RA., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of tumors with complicated treatment options that depend on pathological grading, clinical staging, and presence of symptoms related to hormonal secretion. With regard to diagnosis, remarkable advances have been made: Chromogranin A is recommended as a general marker for pNETs. But other new biomarker modalities, like circulating tumor cells, multiple transcript analysis, microRNA profile, and cytokines, should be clarified in future investigations before clinical application. Therefore, the currently available serum biomarkers are insufficient for diagnosis, but reasonably acceptable in evaluating the prognosis of and response to treatments during follow-up of pNETs. Surgical resection is still the only curative therapeutic option for localized pNETs. However, a debulking operation has also been proven to be effective for controlling the disease. As for drug therapy, steroids and somatostatin analogues are the first-line therapy for those with positive expression of somatostatin receptor, while everolimus and sunitinib represent important progress for the treatment of patients with advanced pNETs. Great progress has been achieved in the combination of systematic therapy with local control treatments. The optimal timing of local control intervention, planning of sequential therapies, and implementation of multidisciplinary care remain pending., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Clinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy., Competing Interests: The authors declare no competing interest.

Ovarian cancer (OC) is one of the most common gynecological malignancies, with the highest mortality rate in women worldwide. LINC00662, a long non-coding RNA (lncRNA), was shown to play a vital role in many malignancies, while little is known about its role in OC. Firstly, our study determined the expression of LINC00662 in OC tissues and cells. Upregulation or downregulation of LINC00662 were performed in OC cells to explore its effects on cell proliferation and glycolysis of OC. The interaction between LINC00662 and miR-375 was verified using luciferase assays and RNA immunoprecipitation. Results showed that LINC00662 was highly expressed in OC tissues and cells, and patients with increased expression of LINC00662 were associated with shorter overall survival. Furthermore, functional assays proved that LINC00662 was essential for OC cell proliferation and glycolysis. Subsequently, our study further revealed that LINC00662 acted as a competitive RNA and it could modulate the expression of HIF-1α through directly binding with miR- 375. Collectively, upregulation of LINC00662 in ovarian cancer tissues is closely correlated to poor survival. LINC00662 might regulate HIF-1α expression via miR-375. These findings suggested that LINC00662 has the potential to be explored as a diagnostic biomarker for OC., (Copyright 2020 Biolife Sas. www.biolifesas.org.)

Background: To compare the efficacy of 3 chemotherapeutic combinations for laparoscopic hyperthermic intraperitoneal perfusion chemotherapy (HIPPC) in the treatment of malignant ascites secondary to unresectable gastric cancer (GC)., Materials and Methods: From January 2010 to December 2013, 38 GC patients were randomly divided into 3 groups and treated by laparoscopic HIPPC with 1 of the 3 following chemotherapy combinations: raltitrexed (Ra) with oxaliplatin (L-OHP), Ra with cisplatin (DDP), and Ra with mitomycin C (MMC). Perioperative complications, patients' quality of life, and survival were recorded and compared among the 3 groups., Results: The intraoperative course was successful in all patients, and no perioperative death or complication related to laparoscopic HIPPC was documented. The median follow-up period was 9 months and the median survival was 7.5 months for all patients. Patients in the Ra/L-OHP group had a median survival of 8.7 months, the Ra/DDP group had a median survival of 5.6 months, and the Ra/MMC group had a median survival of 7.5 months. Patients' median survival in the Ra/L-OHP group and Ra/MMC group is significantly longer than Ra/DDP group (P<0.05). No significant difference was found in total remission rate of ascites, increase in the Karnofsky performance scale, and incidence rate of port-site metastases among the 3 groups., Conclusions: Laparoscopy-assisted HIPPC provide modest yet encouraging efficacy for malignant ascites secondary to disseminated GC. Our preliminary data indicate that the chemotherapeutical combination of Ra/L-OHP and Ra/MMC might be more beneficial compared with Ra/DDP in terms of patients' survival.

Gastric cancer (GC) is a highly prevalent type of metastatic tumor. The mechanisms underlying GC metastasis are poorly understood. Some long noncoding RNAs (lncRNAs) reportedly play key roles in regulating metastasis of GC. However, the biological roles of five natural antisense lncRNAs (AC093818.1, CTD-2541M15.1, BC047644, RP11-597M12.1, and RP11-40A13.1) in GC metastasis remain unclear. In this study, the expression of these lncRNAs was measured by quantitative reverse transcription-polymerase chain reaction. Migration and invasion were evaluated by wound-healing and the Transwell assay, respectively. Stable cells were injected into the tail veins of nude mice. Sections of collected lung and liver tissues were stained using hematoxylin and eosin. Protein expression was analyzed by western blot. RNA immunoprecipitation (RIP) assay was used to verify whether the STAT3 and SP1 transcription factors bound to AC093818.1 in GC cells. Expression levels of the five lncRNAs, especially AC093818.1, were significantly upregulated in metastatic GC tissues relative to those in nonmetastatic GC tissues. AC093818.1 expression was correlated with invasion, lymphatic metastasis, distal metastasis, and tumor-node-metastasis stage. AC093818.1 expression was highly sensitive and specific in the diagnosis of metastatic or nonmetastatic GC. AC093818.1 overexpression promoted GC migration and invasion in vitro and in vivo. AC093818.1 overexpression increased PDK1, p-AKT1, and p-mTOR expression levels. AC093818.1 silencing decreased these expressions. AC093818.1 bound to transcription factors STAT3 and SP1, and SP1 or STAT3 silencing could alleviated the effect of AC093818.1 overexpression. The data demonstrate that lncRNA AC093818.1 accelerates gastric cancer metastasis by epigenetically promoting PDK1 expression. LncRNA AC093818.1 may be a potential therapeutic target for metastatic GC.

Stroke is a leading cause of disability and death in the worldwide. Therefore, prevention of stroke is critically important. Genistein, a natural phytoestrogen extracted from soybeans, has been found to be a potential neuroprotective agent for stroke prevention. However, the role of genistein and its underlying mechanism in ovariectomized rats has been rarely evaluated. In this study, ovariectomized rats were treated with genistein (10 mg/kg) or vehicle daily for two weeks before they received middle cerebral artery occlusion (MCAO) and reperfusion. Seventy-two hours after reperfusion, the neurological function was evaluated by Garcia test, infarct volumes were detected by 2,3,5-triphenyltetrazolium chloride staining; and neuronal damage and cell apoptosis were detected by Nissl and Tunel staining in the ischemic penumbra, respectively. In addition, Western blotting was used to detect the activity of PI3K-Akt-mTOR signal pathway in the ischemic penumbra in different groups. And we found that genistein treatment in ovariectomized rats significantly improved neurological outcomes, reduced infarct volumes, decreased neuronal damage and cell apoptosis, and increased the activity of PI3K-Akt-mTOR signal pathway. Our findings indicated that treatment genistein could alleviate neuronal apoptosis induced by cerebral ischemia in ovariectomized rats via promoting the activity of PI3K-Akt-mTOR signal pathway, which provides a new molecular mechanism for the neuroprotective effects of genistein against stroke.

Astragali Radix (AR) is a widely used traditional Chinese medicine for healing the cardiovascular, liver and immune systems. Recently, superfine pulverizing technology has been applied to developing novel formulations to improve bioavailability of the active constituents in herbs, such as ultrafine granular powder of AR. In this study, a universal and sensitive quantitative method based on LC-MS/MS was employed for determining formononetin, the main flavonoid in AR, in human plasma for comparative pharmacokinetics of three oral formulations of AR. Formononetin and IS (quercetin) were extracted by ethyl acetate from human plasma and were separated on a C 18 column with a mobile phase consisting of acetonitrile and 0.1% formic acid. Positive-ion electrospray-ionization mode was applied in mass spectrometric detection. The quantitative method was validated with regards to selectivity, linearity, accuracy and precision, matrix effect, extraction recovery and stability, and was applied to comparing the pharmacokinetics of ultrafine granular powder (UGP), ultrafine powder (UP) and traditional decoction pieces (TDP) of AR after oral administration. The peak concentration and areas under the concentration-time curve of formononetin in UGP and UP were significantly higher than those of TDP. UGP and UP could significantly improve the bioavailability of AR in human compared with TDP after oral administration., (© 2019 John Wiley & Sons, Ltd.)

Background: Gradual loss of terminal differentiation markers and gain of stem cell-like properties is a major hall mark of cancer malignant progression. The stem cell pluripotent transcriptional factor SOX family play critical roles in governing tumor plasticity and lineage specification. This study aims to establish a novel SOX signature to monitor the extent of tumor dedifferentiation and predict prognostic significance in hepatocellular carcinoma (HCC)., Methods: The RNA-seq data from The Cancer Genome Atlas (TCGA) LIHC project were chronologically divided into the training (n = 188) and testing cohort (n = 189). LIRI-JP project from International Cancer Genome Consortium (ICGC) data portal was used as an independent validation cohort (n = 232). Kaplan-Meier and multivariable Cox analyses were used to examine the clinical significance and prognostic value of the signature genes., Results: The SOX gene family members were found to be aberrantly expressed in clinical HCC patients. A five-gene SOX signature with prognostic value was established in the training cohort. The SOX signature genes were found to be closely associated with tumor grade and tumor stage. Liver cancer dedifferentiation markers (AFP, CD133, EPCAM, and KRT19) were found to be progressively increased while hepatocyte terminal differentiation markers (ALB, G6PC, CYP3A4, and HNF4A) were progressively decreased from HCC patients with low SOX signature scores to patients with high SOX signature scores. Kaplan-Meier survival analysis further indicated that the newly established SOX signature could robustly predict patient overall survival in both training, testing, and independent validation cohort., Conclusions: An oncogenic dedifferentiation SOX signature presents a great potential in predicting prognostic significance in HCC, and might provide novel biomarkers for precision oncology further in the clinic.

As important topographic factors, slope aspect and gradient affect plant growth and leaf functional traits by regulating the combination of water and heat. Exploring the response of leaf functional traits to topographic factors is helpful for understanding plant adaptation strategies. We investigated the effects of sunny slope (including half sunny slope) and shady slope (including half shady slope) and three slope gradient (15°-20°, 21°-25°, and 26°-30°) on the leaf functional traits of apricot (Prunus armeniaca L.), the main afforestation tree species on the Loess Plateau. The results showed that: 1) Slope aspect and gradient exerted significant effects on all functional traits. Except leaf water content (LWC), other leaf functional traits were not affected by the interaction of slope aspect and gradient. 2) The leaf area (LA) under the sunny slope was equivalent to that under the shady slope. Leaf dry matter content (LDMC) and LWC (0.27 g·g -1 and 67.0%, respectively) were significantly higher under the shady slope than under the sunny slope (0.24 g·g -1 and 59.6%, respectively), while specific leaf area (SLA) (163.05 cm 2 ·g -1 ) was significantly lower under the former than under the latter (183.72 cm 2 ·g -1 ). 3) At different slope gradients, SLA and LA reached a maximum value at 15°-20° (184.04 cm 2 ·g -1 ) and 26°-30° (21.14 cm 2 ), respectively. 4) Except no difference in soil water content (Θ) between 15°-20° and 26°-30°, it differed significantly between two slope aspects and among other slope gradients. The Θ was one of the main factors causing the differences in functional traits, especially in the 0-10 cm soil layer. 5) SLA was negatively correlated with LWC and LDW and positively correlated with LA. LDW was positively correlated with LWC and negatively correlated with LA. Θ was positively correlated with LWC but not with other leaf functional traits.

Background: A key issue in achieving and sustaining malaria elimination is the need to prevent local transmission arising from imported cases of malaria. The likelihood of this occurring depends on a range of local factors, and these can be used to allocate resources to contain transmission. Therefore, a risk assessment and management strategy is required to identify risk indexes for malaria transmission when imported cases occur. These risks also need to be quantified and combined to give a weighted risk index score. This can then be used to allocate the resources to each administrative region to prevent transmission according to the degree of risk., Methods: A list of potential risk indexes were generated from a literature review, expert consultation and panel discussion. These were initially classified into 4 first-level indexes including infection source, transmitting conditions, population vulnerability and control capacity. Each of these was then expanded into more detailed second-level indexes. The Delphi method was then used to obtain expert opinion to review and revise these risk indexes over two consecutive rounds to quantify agreement among experts as to their level of importance. Risk indexes were included in the final Transmission Risk Framework if they achieved a weighted importance score ≥ 4. The Analytic Hierarchy Process was then used to calculate the weight allocated to each of the final risk indexes. This was then used to create an assessment framework that can be used to evaluate local transmission risk in different areas., Results: Two rounds of Delphi consultation were conducted. Twenty-three experts were used at each round with 100% recovery rate of participant questionnaires. The coordination coefficients (W) for the two rounds of Delphi consultation were 0.341 and 0.423, respectively (P < 0.05). Three first-level indexes and 13 second-level indexes were identified. The Analytic Hierarchy Process was performed to calculate the weight of the indexes. For the first-level indexes, infection source, transmitting conditions, and control capacity, the index weight was 0.5396, 0.2970 and 0.1634 respectively. For the three top second-level indexes, number of imported malaria cases, Anopheles species, and awareness of timely medical visit of patient, the index weight was 0.3382, 0.2475, and 0.1509 respectively., Conclusions: An indexed system of transmission risk assessment for imported malaria was established using the Delphi method and the Analytic Hierarchy Process. This was assessed to be an objective and practical tool for assessing transmission risk from imported cases of malaria into China.

Indole- and azaindole-based glyoxylyl amide derivatives have been described as HIV-1 attachment inhibitors (AIs) that act by blocking the interaction between the viral gp120 coat protein and the human host cell CD4 receptor. As part of an effort to more deeply understand the role of the indole/azaindole heterocycle in the expression of antiviral activity, a survey of potential replacements was conducted using parallel synthesis methodology. The design and optimization was guided by a simple 2-dimensional overlay based on an overall planar topography between the indole/azaindole and C-7 substituents that had been deduced from structure-activity studies leading to the discovery of temsavir (3). 2-Substituted naphthalene- and quinoline-derived chemotypes emerged as the most interesting prototypes, with C-5 and C-6 substituents enhancing antiviral potency. Despite the fact that neither of these chemotypes incorporated a H-bond donor that has been shown to engage the side chain carboxylate of Asp 113 in gp120, the antiviral potency of several analogues met or exceeded that of 3, demonstrating that engaging Asp 113 is not a prerequisite for potent antiviral activity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Topography has major impacts on the trade-off of plant survival strategies. Exploring the differential pattern of leaf ecological stoichiometry along the elevation gradient contributes to a better understanding of plant's response to environmental changes and its ecological adaptability. We investigated leaf C, N, and P concentrations and stoichiometric ratios of Leontopodium leontopodioides at three elevations, including from 4400 m to 4700 m, from 4701 m to 5000 m, and from 5001 m to 5300 m, on the northeastern margin of the Qinghai-Tibetan Plateau in China. The results showed that the concentrations of leaf C, N, and P of L. leontopodioides were 405.36 g·kg -1 , 18.42 g·kg -1 and 0.94 g·kg -1 , respectively. Leaf C/N, C/P, and N/P were 22.67, 467.61 and 20.30, respectively. The concentrations of leaf N and P of L. leontopodioides consistently increased with the increases of elevation. The coefficient of variations for leaf C, N and P concentrations and ratios of L. leontopodioides were all less than 30%, with an order of P (30%) > C/P (29%) > C/N (18%) > N (17%) > N/P (15%) > C (3%). The growth of L. leontopodioides on the Qinghai-Tibetan Plateau was mainly limited by P availability.

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the synovial membrane of joints. In this study, we aimed to investigate whether sorafenib exerts antiarthritic effects on RA in vivo. Adjuvant arthritis (AA) was induced (day 0) in male Sprague-Dawley rats by intradermal injection of 0.1 mL of complete Freund's complete adjuvant into the left hind paw. Sorafenib (10, 20, or 40 mg/kg/day) was administered intragastrically from day 10 to 24. Body weight, paw volume, synovial inflammation, and tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-10, and IL-17 serum levels were detected. In addition, microvascular density (MVD) and the expression of vascular endothelial growth factor receptor 2 (VEGFR-2) and fibroblast growth factor receptor 1 (FGFR-1) in synovial tissues were analyzed. Our data revealed that sorafenib administration led to significant body weight gain in AA rats but suppressed paw swelling, synovial hyperplasia, and inflammatory infiltration. Furthermore, it decreased TNF-α, IL-1β, and IL-17 serum levels and upregulated IL-10. MVD and VEGFR-2 and FGFR-1 expression in synovial tissues were significantly reduced. Thus, this study shows that sorafenib exerts anti-arthritic effects in AA rats and therefore has potential in RA treatment. Anat Rec, 301:1519-1526, 2018. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

The optimization of the 4-methoxy-6-azaindole series of HIV-1 attachment inhibitors (AIs) that originated with 1 to deliver temsavir (3, BMS-626529) is described. The most beneficial increases in potency and pharmacokinetic (PK) properties were attained by incorporating N-linked, sp 2 -hybridized heteroaryl rings at the 7-position of the heterocyclic nucleus. Compounds that adhered to a coplanarity model afforded targeted antiviral potency, leading to the identification of 3 with characteristics that provided for targeted exposure and PK properties in three preclinical species. However, the physical properties of 3 limited plasma exposure at higher doses, both in preclinical studies and in clinical trials as the result of dissolution- and/or solubility-limited absorption, a deficiency addressed by the preparation of the phosphonooxymethyl prodrug 4 (BMS-663068, fostemsavir). An extended-release formulation of 4 is currently in phase III clinical trials where it has shown promise as part of a drug combination therapy in highly treatment-experienced HIV-1 infected patients.

After grasslands were contracted to individual households on the Qinghai-Tibetan Pla-teau, two grassland management patterns were formed, i.e., the single-household management pattern (SMP) and the multi-household management pattern (MMP). The soil nutrients and their spatial distributions under those two patterns were compared in the Nagchu Prefecture of Tibet. The results showed that the soil organic carbon, total nitrogen, and total phosphorus under the MMP (84.31, 6.87 and 0.59 g·kg -1 ) were all significantly higher than those under the SMP (73.57, 6.07 and 0.54 g·kg -1 ). On the vertical dimension, the variation coefficient of soil total phosphorous between 0-15 cm layer and 15-30 cm layer under SMP had no significant difference, while that of soil pH, soil organic carbon and total nitrogen in 15-30 cm layer were all higher than 0-15 cm layer under both patterns. On the horizontal dimension, the variation coefficients of soil organic carbon and total nitrogen under SMP were significantly higher than those under MMP, with the estimated values for the former being 25.7% and 23.5%, and for the latter being 19.3% and 18.6%, respectively. Compared with the MMP, the uneven distribution of nutrients could easily lead to soil nutrient loss under the SMP.

This study was conducted to determine the mechanism by which di-2-ethylhexyl phthalate (DEHP) exposure influences lipid metabolism of juvenile yellow catfish Tachysurus fulvidraco. Fish were exposed to three DEHP concentrations (0, 0·1 and 0·5 mg l -1 DEHP) for 8 weeks. Fatty acid synthase (FAS) activity significantly decreased with increasing DEHP concentrations, the highest value was in the Tween control group, whereas the lowest activities of carnitine palmitoyltransferase (CPT) and lipoprotein lipase (LPL) were in this group. The messenger (m)RNA levels of 6-phospho-gluconate dehydrogenase (6PGD), FAS and acetyl-CoA carboxylase a (ACCa) significantly increased with increasing DEHP concentration, the highest values were in the 0·5 mg l -1 DEHP group. The mRNA level of peroxisome proliferator-activated receptor γ (PPARγ) was lower in Tween control than in fish exposed to 0·1 and 0·5 mg l -1 DEHP. The highest mRNA level of ACCb was in the 0·1 mg l -1 DEHP group. These results indicate that DEHP exposure can disturb lipid metabolism at the enzymatic and mRNA levels in Pelteobagrus fulvidraco., (© 2017 The Fisheries Society of the British Isles.)

Long non-coding RNAs (lncRNAs), a variety of transcripts without protein coding ability, have recently been reported to play vital roles in gastric cancer (GC) development and progression. However, the biological role of long non-coding RNA LINC00673 in GC is not fully known. In the study, we found that LINC00673 expression was dramatically higher in gastric cancer tissues compared with adjacent normal tissues, and positively associated with lymph node metastasis, distant metastasis and TNM stage in patients. Higher LINC00673 expression predicted poor disease-free survival (DFS) and overall survival (OS) in GC patients. By univariate and multivariate Cox analysis, the results confirmed that higher LINC00673 expression was an independent risk factor of prognosis in patients. Knockdown of endogenous LINC00673 significantly inhibited cell proliferation, colony formation number, cell migration and invasion in GC. Furthermore, knockdown of endogenous LINC00673 reduced the expression levels of PCNA, CyclinD1 and CDK2 in GC cells. RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) proved that LINC00673 suppressed KLF4 expression by interacting with EZH2 and DNMT1 in GC cells. Moreover, we confirmed that LINC00673 promoted cell proliferation and invasion by partly repressing KLF4 expression in GC. Taken together, these results indicated that LINC00673 may be a prognostic biomarker and therapeutic target for GC patients., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Hypertrophic scar (HS) is a dermal fibroproliferative disorder characterized by the excessive proliferation of fibroblasts and is thought to result from a cellular imbalance caused by the increased growth and reduced apoptosis of hypertrophic scar fibroblasts (HSFs). Our recent study demonstrated that recombinant human endostatin (rhEndostatin) plays a key role in the inhibition of HSF proliferation in vitro, with a resulting decrease in dermal thickness and scar hypertrophy. However, the effect of this protein on HSF apoptosis is unknown. The present study was undertaken to directly examine the effect of rhEndostatin on HSF apoptosis in the rabbit ear model. Transmission electron microscopy and flow cytometry were used to investigate HSF apoptosis in scar tissues and cultured HSFs in vitro, respectively. The expression levels of the c-jun, c-fos, NF-κB, fas, caspase-3, and bcl-2 gene products in HSFs were quantified using real-time PCR and Western blotting assays. Our data reveal that rhEndostatin (2.5 or 5mg/ml) induces HSF apoptotic cell death in scar tissue. Additionally, HSFs treated with rhEndostatin (100mg/L) in vitro accumulated in early and late apoptosis and displayed significantly decreased expression of c-jun, c-fos, NF-κB, fas, caspase-3 and bcl-2. In sum, these results demonstrate that rhEndostatin induces HSF apoptosis, and this phenotypeis partially due to downregulation of NF-κB and bcl-2. These findings suggest that rhEndostatin may have an inhibitory effect on scar hypertrophy in vivo via HSF apoptotic induction and therefore has potential therapeutic use for the treatment of HS., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)