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The prognosis for cervical cancer (CC) patients with lymph node metastasis (LNM) is extremely poor. Lipid droplets (LDs) have a pivotal role in promoting tumor metastasis. The crosstalk mechanism between LDs and LNM modulated in CC remains largely unknown.This study aimed to construct a miRNA-dependent progonostic model for CC patients and investigate whether miR-532-5p has a biological impact on LNM by regualting LDs accumulation.LASSO-Cox regression was applied to establish a prognostic prediction model. miR-532-5p had the lowest P-value in RNA expression (P 0.001) and prognostic prediction (P 0.0001) and was selected for further study. The functional role of the prognostic miR-532-5p-correlated competing endogenous RNA (ceRNA) network was investigated to clarify the crosstalk between LDs and LNM. The underlying mechanism was determined using site-directed mutagenesis, dual luciferase reporter assays, RNA immunoprecipitation assays, and rescue experiments. A xenograft LNM model was established to evaluate the effect of miR-532-5p and orlistat combination therapy on tumor growth and LNM.A novel 5-miRNAs prognostic signature was constructed to better predict the prognosis of CC patient. Further study demonstrated that miR-532-5p inhibited epithelial-mesenchymal transition and lymphangiogenesis by regulating LDs accumulation. Interestingly, we also found that LDs accumulation promoted cell metastasis in vitro. Mechanistically, we demonstrated a miR-532-5p-correlated ceRNA network in which LINC01410 was bound directly to miR-532-5p and effectively functioned as miR-532-5p sponge to disinhibit its target gene-fatty acid synthase (Our findings highlight a LD accumulation-dependent mechanism of miR-532-5p-modulated LNM and support treatment with miR-532-5p/orlistat as novel strategy for treating patients with LNM in CC.

BACKGROUND Right ventricular outflow tract (RVOT) obstruction relief is one of the major procedures during the total correction of tetralogy of Fallot (TOF). Pulmonary insufficiency (PI) is usually inevitable after a transannular incision with a patch repair is performed. Therefore, some surgeons advocate to place a monocusp valve within the transannular patch (TAP) in order to decrease the severity of the PI. However, the monocusp valve seemed not be very effective in some patients who underwent the complete TOF repair. METHODS Patients who had the classic form of TOF between January 2009 and January 2017 and underwent the corrective surgery with a TAP by the same cardiovascular surgeon were identified for further analysis. Clinical information including demographics at operation, perioperative data, and postoperative outcome were collected retrospectively and compared between the group with and without a monocusp valve. RESULTS A total of 24 TOF cases were included in the final analysis, and 16 (66.7%) patients received a monocusp valve placement. The patients' characteristics before and during the surgery were similar between the two groups. The median duration of chest tube drainage after the total correction in the monocusp group was longer than those without the valve (p = 0.04). There was no difference in the immediate postoperative data, including the inflammation/infection status, the duration of mechanical ventilation, and the length of ICU and hospital stay. CONCLUSION Implantation of a monocusp valve during the total TOF correction using a TAP did not bring benefit to improve the immediate postoperative outcomes, especially the duration of the pleural drainage. Further study with a prospective design and a larger number of cases is needed.

Background The overwhelming majority of hangman’s fractures cause anterior dislocation of C2. Hangman’s fracture with C2 posterior dislocation is extremely rare, only one paediatric case was reported in 2018 to date. This kind of injury cannot be catalogued using current classification schemes and no established treatment recommendations exist. The purpose of this article is to report a rare case of a hangman's fracture with C2 posterior dislocation, which does not fit into existing classification systems and discuss management technical notes to avoid pitfalls. Methods Description of case, review of relevant literatures and share our experience. Results A 31-year-old male sustained hangman’s fracture with C2 posterior dislocation after fell into a 50cm deep roadside ditch when riding a motorcycle. Radiograph and computed tomography (CT) on admission showed fractures through both pars of C2 and C2 posterior dislocation. Magnetic resonance imaging (MRI) on admission showed high T2-weighted signal intensity of cervical spinal cord and compression of cervical spinal cord by posterior dislocation of C2 vertebral body. A C2-3 anterior cervical discectomy and fusion (ACDF) was performed. At 6 months after operation, bony fusion was achieved, and MRI showed the T2-weighted signal hyperintensity of cervical spinal cord before surgery disappeared. Conclusion C2–C3 ACDF is recommended for hangman's fractures with C2 posterior dislocation. Traction before surgery is not recommended.

Lung adenocarcinomas manifesting as subsolid nodules usually have a favorable prognosis. This study aimed to have a comprehensive investigation of the radiological and clinicopathologic features and oncological outcomes of subsolid nodules. Between March 2010 and December 2015, 865 patients with surgically resected clinical IA subsolid lung adenocarcinoma were retrospectively reviewed. Patients were classified into the pure ground-glass nodules (GGN) (pGGN [n = 358], without solid component on lung and mediastinal windows), heterogeneous GGN (hGGN [n = 65], only with solid components on lung window), and real part-solid nodule (rPSN [n = 442], with solid component on both lung and mediastinal windows) groups. The clinicopathological features and survival time of the three groups were compared between groups. There was a significant increase in median tumor size (P0.001), solid component size measured at lung window (LW-SCS) (P0.001), and the proportion of invasive adenocarcinoma subtypes (P0.001) from pGGNs to hGGNs to rPSNs. After adjustment for LW-SCS, adenocarcinomas with predominant lepidic patterns were still more common in hGGNs than in rPSNs (P = 0.009). Patients with rPSNs had a significantly worse recurrence-free survival (RFS) than those with pGGNs and hGGNs (5-year: 91.9% versus 100% versus 100%, P0.001). Multivariate Cox analyses revealed that gender (both P0.05) and clinical T category (based on lung window [LW-cT] [P = 0.002] or mediastinal window [MW-cT] [P0.001]) were independent prognostic factors of RFS in the rPSN group. HGGNs represented as an intermediate subtype between pGGNs and rPSNs. Both pGGNs and hGGNs had excellent outcomes, while rPSNs exhibited a worse prognosis than them. Clinical T category and gender had prognostic implications for rPSNs.

The ninth edition of lung cancer staging system recommends that specific driver mutations should be considered as prognostic factors in survival models. This study comprehensively investigated the prognostic value of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in patients with resected lung adenocarcinomas according to different clinicopathologic and radiologic characteristics.In total, 1464 patients with completely resected primary lung adenocarcinomas were examined for KRAS mutations from November 2008 to March 2015. Age, sex, smoking status, performance status, tumor-node-metastasis stage, radiologic features, and histologic subtypes were collected. Competing risk model was used to estimate the cumulative incidence rate of recurrence. Cox regression multivariable analyses on recurrence-free survival (RFS) and overall survival (OS) were performed.KRAS mutations were more frequent in male subjects (P .001), current/former smokers (P .001), invasive mucinous adenocarcinoma (P .001), and solid tumors (P .001). In general, KRAS-mutated patients had greater cumulative recurrence rate (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.23-3.08; P .001) and worse overall survival (OS; HR, 1.88; 95% CI, 1.23-2.87; P .001) than KRAS wild-type patients. The OS (P .001) of patients harboring KRAS-G12C/V mutations was shorter than that of other KRAS-mutated patients. Cox multivariable analyses demonstrated that KRAS mutations were independently associated with worse RFS (HR, 5.34; 95% CI, 2.53-11.89; P = .001) and OS (HR, 2.63; 95% CI, 1.03-6.76; P = .044) in part-solid lung adenocarcinomas. For stage I patients, Cox multivariable analyses revealed that KRAS mutation was an independent risk factor for RFS (HR, 2.05; 95% CI, 1.19-3.56; P = .010) and OS (HR, 2.38; 95% CI, 1.29-4.40; P = .005).In this study, we revealed that KRAS mutations was an independent prognostic factor in part-solid tumors and in stage I lung adenocarcinomas. These findings may contribute to the ninth edition of lung cancer staging project.

Background/Purpose: Hypertension is a risk factor of incident diabetes. In 2017, the ACC/AHA updated the definition of hypertension to above 130/80 mmHg, while the 2018 ESC/ESH guideline and the JNC7 criteria remained the cutoff of 140/90 mmHg. This study was aimed to investigate how different cutoffs of hypertension affect the association of hypertension to incident diabetes and the progression of insulin resistance. Methods: A total of 1177 subjects without diabetes at baseline were followed for 4.5 years. Diabetes was diagnosed by the results of oral glucose tolerance tests and hemoglobin A1c, or if anti-diabetic agents were used. Results: Hypertension by both criteria was associated with incident diabetes. Change of HOMA2-IR every 5 years (ΔHOMA2-IR/5 yr) was higher in subjects with hypertension than those without (adjusted p = 0.044). Subjects with treated hypertension had the highest risk of diabetes (HR 2.98, p

Background: Curcumin possesses multiple bioactivities that have beneficial effects on diabetic foot ulcers. Herein, we aimed to conduct a preclinical systematic review of 9 studies, including a total of 262 animals, to assess the possible mechanisms of curcumin for wound healing in diabetic animals. Methods: Five databases were searched from inception to May 12, 2020; Rev-Man 5.3 software was applied for data analyses. Cochrane Collaboration’s tool 10-item checklist was used to evaluate the methodological quality, and data revealed scores of risk of bias ranging from 2 to 5. Results: Meta-analysis indicated that curcumin had significant effects on wound healing rate and blood vessel density when compared with control (P < 0.05). The wound regeneration properties of curcumin for diabetic wounds are thought to mainly work through the possible mechanisms of antioxidation, enhanced cell proliferation, increased collagen formation, and angiogenesis. However, the anti-inflammatory effect on wounds in diabetic animals remain controversial. Conclusions: The findings indicate that more randomized controlled trials should be pursued to obtain more reliable results regarding inflammatory response. Overall, curcumin might be a probable candidate for diabetic foot ulcers and may contribute to future clinical trials. Prospero Registration: CRD42020188981.

The human microflora is a complex ecosystem composed of diverse microorganisms mainly distributed in the epidermal and mucosal habitats of the entire body, including the mouth, lung, intestines, skin, and vagina. These microbial communities are involved in many essential functions, such as metabolism, immunity, host nutrition, and diseases. Recent studies have focused on the microbiota associated with cancers, particularly the oral and intestinal microbiota. Radiotherapy, the most effective cytotoxic modality available for solid tumors, contributes to the treatment of cancer patients. Mounting evidence supports that the microbiota plays pivotal roles in the efficacy and prognosis of tumor radiotherapy. Here, we review current research on the microbiota and cancer development, and describe knowledge gaps in the study of radiotherapy and the microbiota. Better understanding of the effects of the microbiome in tumorigenesis and radiotherapy will shed light on future novel prevention and treatment strategies based on modulating the microbiome in cancer patients.

On December 18, 2020, the FDA approved osimertinib as adjuvant therapy in patients with non–small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) mutations, as detected by an FDA-approved test. The approval was based on the ADAURA study, in which 682 patients with NSCLC were randomized to receive osimertinib (n = 339) or placebo (n = 343). Disease-free survival (DFS) in the overall population (stage IB–IIIA) was improved for patients who received osimertinib, with an HR of 0.20; 95% confidence interval (CI), 0.15–0.27; P < 0.0001. Median DFS was not reached for the osimertinib arm compared with 27.5 months (95% CI, 22.0–35.0) for patients receiving placebo. Overall survival data were not mature at the time of the approval. This application was reviewed under FDA's Project Orbis, in collaboration with Australia Therapeutic Goods Administration, Brazil ANVISA, Health Canada, Singapore Health Sciences Authority, Switzerland Swissmedic, and the United Kingdom Medicines and Healthcare products Regulatory Agency. This is the first targeted therapy adjuvant approval for NSCLC and has practice-changing implications.

Micro-RNA has a very important role in gene regulation. The stem gene Oct4 is related with the growth, mobility, and infiltration of skin cancer cells. Studying the regulatory mechanism of micro-RNAs of Oct4 in skin cancer cells is of important clinical significance. Oct4 gene was analyzed using bioinformatics methods to find mir-RNA with regulatory functions. mir-RNA high-expression vector and suppression vector with pcDNA3.1-EGFP was transfected to skin cancer cell line HS-4 followed analysis of Oct4 expression 24 h and 48 h after transfection and transwell in-vitro cell invasion assay. Bioinformatics showed that mir-335 has relationship with the Oct4 gene. pcDNA3.1-EGFP-335-up and pcDNA3.1-EGFP-335-down were successfully constructed. 24 and 48 hours after transfection, the Oct4 expression in the high-expression group was gradually and significantly decreased (P < 0.05). Meanwhile, the cell migration and infiltration capacity was decreased significantly and showed time dependence with significant differences between groups (P < 0.05). mir-335 expression in suppression group was reduced without change of Oct4 (P > 0.05). Increased mir-335 can decrease the performance of Oct4 in skin cancer cells and inhibit the infiltration ability of cells without affecting cell infiltration capability.

Flavonoid glycoside scutellarin (SCU) has been widely applied in the treatment of cerebral ischemic diseases in China. In this article, we conducted research on the working mechanisms of SCU in hypoxia reoxygenation (HR) injury of isolated cerebral basilar artery (BA) and erebral ischemia reperfusion (CIR) injury in rat models. In isolated rat BA rings, HR causes endothelial dysfunction (ED) and acetylcholine (ACh) induces endothelium-dependent vasodilation. The myography result showed that SCU (100 µM) was able to significantly improve the endothelium-dependent vasodilation induced by Ach. However, SCU did not affect the ACh-induced relaxation in normal BA. Further studies suggested that SCU (10–1000 µM) dose-dependently induced relaxation in isolated BA rings which were significantly blocked by the cGMP dependent protein kinase (PKG) inhibitor Rp-8-Br-cGMPs (PKGI-rp, 4 µM). Pre-incubation with SCU (500 µM) reversed the impairment of endothelium-dependent vasodilation induced by HR, but the reversing effect was blocked if PKGI-rp (4 µM) was added. The brain slice staining test in rats’ model of middle cerebral artery occlusion (MCAO) induced CIR proved that the administration of SCU (45, 90 mg/kg, iv) significantly reduced the area of cerebral infarction. The Western blot assay result showed that SCU (45 mg/kg, iv) increased brain PKG activity and PKG protein level after CIR surgery. In conclusion, our findings suggested that SCU possesses the ability of protecting brain cells against CIR injury through vascular endothelium protection and PKG signal. Graphic Abstract

Our work was to evaluate Exosome CircRNA EIF4G2 in cervical cancer development. Methods: Using Hela and Siha in our present study. Transfection vector, exosome cirEIF4G2, exosome si-NC or exosome si-circEIF4G2 in cells. Using RT-qPCR to measure circEIF4G2 gene expression in difference cell groups. Evaluating cell proliferation, apoptosis, invasion and wound healing rate by MTT, flow cytometry, transwell and wound healing assay. The relative proteins, HPV16 E6 and HPV16 E7, were evaluated by WB assay. With Exosome CircRNA EIF4G2 transfection, Hela and Siha cells proliferation, invasion cells number and wound healing rates were significantly increased and cells apoptosis were significantly depressed (P < 0.001, respectively) with HPV16 E6 and HPV16 E7 proteins expression were significantly up-regulation (P < 0.001, respectively). However, with Exosome si-CircRNA EIF4G2 transfection, Hela and Siha cells proliferation, invasion cells number and wound healing rates were significantly depressed and cells apoptosis were significantly increased (P < 0.001, respectively) with HPV16 E6 and HPV16 E7 proteins expression were significantly down-regulation (P < 0.001, respectively). Exosome CircRNA EIF4G2 as an oncology role in cervical cancer via regulation HPV16 E6/E7 up-regulation in vitro study.

Purpose As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib has a powerful ability to penetrate the blood-brain barrier and a high potency for controlling brain metastases (BMs) from EGFR-mutant non-small cell lung cancer (NSCLC). The clinical value of cranial radiation therapy in osimertinib-treated NSCLC with BMs remains largely unknown. Methods and Materials Patients with NSCLC and BMs and receiving osimertinib treatment as the standard of care were retrospectively enrolled from 2 institutions. Cranial radiation therapy (RT; whole-brain radiation therapy [WBRT] or/and stereotactic radiosurgery [SRS]) performed before disease progression (PD) to osimertinib was categorized as upfront cranial radiation therapy (ucRT group), excluding those treatments performed during prior EGFR-TKI treatment. Overall survival (OS), progression-free survival (PFS), and the time to intracranial progression (iTTP) were compared between the 2 groups, with adjustment by covariates in propensity-score matched (PSM) analyses. The state of having 1 to 3 BM lesions, with a maximal size of ≤3 cm, was defined as having oligo-BM; otherwise; the cases were defined as having multiple BMs. Results Of the 205 patients enrolled, osimertinib was used as first-line therapy in 74 and second-line therapy in 131. There were 48 patients who received ucRTs, including WBRT in 24 and SRS in 24. All patients with oligo-BM in the ucRT group received SRS alone (n = 17), whereas most (n = 28; 90.3%) patients with multiple BMs received WBRT. Failure pattern analyses indicated that in the non-ucRT group, 40.2% of the initial PD involved the brain and 76.9% of the cranial PD involved the original sites, indicating the potential roles of ucRT. Indeed, the iTTP was significantly prolonged (P = .010) in the ucRT group among the whole population. In the PSM oligo-BM cohort, the ucRT group showed superior PFS (P = .033) and OS (P = .026) compared with the non-ucRT group, and the differences remained after multivariate Cox analyses. No such differences were observed in the subpopulation with multiple BMs. Conclusions In osimertinib-treated NSCLC patients with BMs, oligo-BM status could be used as a potential factor to select patients for upfront cranial RT. Further investigation by well-designed clinical trials is warranted.

Background China is facing big challenges to achieve the “90–90-90 targets”. The HIV prevalence of elderly (≥50 years) men have been steadily increasing in China, mainly through the sexual transmission route, but sexual behaviors of them are far from well-studied. In 2019, elderly men accounted for 59.2% of HIV/AIDS cases in Sichuan, China. Methods The research design is a cross-sectional study. Face-to-face interviews were conducted among 795 HIV negative elderly men from rural Chengdu, capital City of Sichuan. Bivariate and multivariate logistic regression models were applied to examine factors associated with commercial heterosexual behavior from a modified Knowledge-Attitude-Practice (KAP) perspective. Results 129 (16.23%) respondents admitted high-risk sexual behaviors, including 11.07% commercial heterosexual behavior, 6.16% extramarital, 2.89% casual and 0.25% homosexual behavior, and no one used condom consistently. 427(68.43%) had ever gotten HIV-related Health Education (HRHE), mainly through mass media (70.49%). The HIV-related knowledge awareness rate was only 31.41%. Migration history (AOR =2.46,95% CI = 1.02–5.91), age(≥60 vs. 50–59, OR = 0.41, 95% CI = 0.19–0.91), receiving HRHE from mass media (OR = 0.37, 95%CI = 0.16–0.85), marital status (married vs. never married, OR = 0.04, 95%CI = 0–0.52), and undecided (AOR =0.02, 95%CI = 0.01–0.09) and objection (AOR =0.04, 95%CI = 0.01–0.1) attitude toward commercial sex were related to lifetime commercial heterosexual behavior. Conclusions High-risk sexual behaviors are common among elderly men from rural areas in Chengdu. Receiving HRHE from mass media and undecided and objection attitude toward commercial sex prevent elderly from being involving in commercial heterosexual behavior. According to the results, health facilities should continue to conduct systematic interventions, paying more attention to 50–59 years old group. Sex and condom use need to be talked in public. Working with mass media, health facilities give elderly men education not only focusing on HIV/AIDS, but also on knowledge and skills of condom use.

There are around 300 million adolescent pregnancies worldwide, accounting for 11% of all births worldwide. Accumulating evidence demonstrates that many adverse perinatal outcomes are associated with adolescent pregnancies. However, how and why these abnormalities occur remain to be defined. In this study, pregnancy at different stages was compared between 25- and 30- day-old and mature female mice. We found that the litter size of adolescent pregnancy is significantly decreased from F1 to F3 generations compared to mature pregnancy. On days 8 and 12 of pregnancy, multiple abnormalities in decidual and placental development appear in F3 adolescent pregnancy. On days 5 and 8, uterine endoplasmic reticulum stress is dysregulated in F3 adolescent pregnancy. Embryo implantation and decidualization are also compromised in adolescent pregnancy. Many genes are abnormally expressed in adolescent estrous uteri. The abnormal endocrine environment and abnormal implantation from uterine immaturity may result in multiple pregnancy failures in adolescent pregnancy. The aim of this study is to shed light on human adolescent pregnancy.

Background. Colorectal cancer (CRC) is the third most common tumor worldwide. Aberrant N6-methyladenosine (m6A) modification can influence the progress of the CRC. Additionally, long noncoding RNA (lncRNA) plays a critical role in CRC and has a close relationship with m6A modification. However, the prognostic potential of m6A-related lncRNAs in CRC patients still remains to be clarified. Methods. We use “limma” R package, “glmnet” R package, and “survival” R package to screen m6A-related-lncRNAs with prognostic potential. Then, we comprehensively analysed and integrated the related lncRNAs in different TNM stages from TCGA database using the LASSO Cox regression. Meanwhile, the relationship between functional enrichment of m6A-related lncRNAs and immune microenvironment in CRC was also investigated using the TCGA database. A prognostic model was constructed and validated to determine the association between m6A-related lncRNAs in different TNM stages and the prognosis of CRC. Result. We demonstrated that three related m6A lncRNAs in different TNM stages were associated with the prognosis of CRC patients. Patients from the TCGA database were classified into the low-risk and the high-risk groups based on the expression of these lncRNAs. The patients in the low-risk group had longer overall survival than the patients in the high-risk group ( P < 0.001 ). We further constructed and validated a prognostic nomogram based on these genes with a C-index of 0.80. The receiver operating characteristic curves confirmed the predictive capacity of the model. Meanwhile, we also found that the low-risk group has the correlation with the dendritic cell (DC). Finally, we discovered the relationship between the m6A regulators and the three lncRNAs. Conclusion. The prognostic model based on three m6A-related lncRNAs exhibits superior predictive performance, providing a novel prognostic model for the clinical evaluation of CRC patients.

To explore the significance of Fluorine-18 labeled fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in diagnosing connective tissue diseases (CTDs) in fever of unknown origin (FUO) or inflammation of unknown origin (IUO) patients.Clinical and image data of 242 consecutive FUO/IUO patients who underwent PET/CT examination and eventually diagnosed CTDs were retrospectively analyzed, including distribution of diseases, clinical characteristics, and PET/CT imaging findings. The role of FDG PET/CT in differential diagnosis of CTDs was evaluated through clinical questionnaire survey.Patients diagnosed as CTDs accounted for 48.1% of FUO/IUO patients. Among them, adult-onset Still's disease was most frequently diagnosed. Other common diseases included systemic vasculitis, undifferentiated connective tissue disease, rheumatoid arthritis, idiopathic inflammatory myopathy, systemic lupus erythematosus, and polymyalgia rheumatica. On FDG PET/CT examination, 97.9% of the patients had positive findings. Inflammatory lesions were detected in 66.5% and non-specific abnormal uptakes were found in 31.4%. Detected lesions distributed consistently with corresponding susceptible organs and tissues in various diseases. Clinical questionnaire results shown that FDG PET/CT excluded malignant tumors, focal infections, or other typical CTDs in 45.5% of the patients; indicated important diagnostic clues or appropriate biopsy sites in 20.6% of patients; and directly suggested the diagnosis of a CTD in 33.1% of patients.FDG PET/CT could reveal inflammatory lesions in organs and tissues that reflect the clinical characteristics in different CTDs, thus providing an objective evidence for differential diagnosis, classification, and treatment decision of these diseases. Key Points • FDG PET/CT is a useful tool for differential diagnosing connective tissue diseases among patients with fever of unknown origin/inflammatory of unknown origin.

Atherosclerotic cardiovascular disease resulting from dysregulated lipid metabolism is the leading cause of morbidity and mortality worldwide. Apolipoprotein E (ApoE) plays a critical role in cholesterol metabolism. Knockouts in lipid-metabolizing proteins including ApoE in multiple model organisms such as mice and rats exhibiting elevated levels of cholesterol have been widely used for dissecting the pathology of atherosclerosis, but few of these animal models exhibit advanced atherosclerotic plaques leading to ischemia-induced clinical symptoms, limiting their use for translational studies. Here we report hypercholesterolemia and severe atherosclerosis characterized by stenosis and occlusion of arteries, together with clinical manifestations of stroke and gangrene, in ApoE knockout dogs generated by CRISPR/Cas9 and cloned by somatic cell nuclear transfer technologies. Importantly, the hypercholesterolemia and atherosclerotic complications in F0 mutants are recapitulated in their offspring. As the ApoE-associated atherosclerosis and clinical manifestations in mutant dogs are more similar to that in human patients compared with those in other animal models, these mutant dogs will be invaluable in developing and evaluating new therapies, including endovascular procedures, against atherosclerosis and related disorders.

Breast cancer, a hormone‐dependent tumour, generally includes four molecular subtypes (luminal A, luminal B, HER2 enriched and triple‐negative) based on oestrogen receptor, progesterone receptor and human epidermal growth factor receptor‐2. Multiple hormones in the body regulate the development of breast cancer. Endocrine therapy is one of the primary treatments for hormone‐receptor‐positive breast cancer, but endocrine resistance is the primary clinical cause of treatment failure. Prolactin (PRL) is a protein hormone secreted by the pituitary gland, mainly promoting mammary gland growth, stimulating and maintaining lactation. Previous studies suggest that high PRL levels can increase the risk of invasive breast cancer in women. The expression levels of PRL and PRLR in breast cancer cells and breast cancer tissues are elevated in most ER+ and ER− tumours. PRL activates downstream signalling pathways and affects endocrine therapy resistance by combining with prolactin receptor (PRLR). In this review, we illustrated and summarized the correlations between endocrine therapy resistance in breast cancer and PRL, as well as the pathophysiological mechanisms and clinical practices. The study on PRL and its receptor would help explore reversing endocrine therapy‐resistance for breast cancer.

ATM (ataxia–telangiectasia mutated) is an important cell-cycle checkpoint kinase required for cellular response to DNA damage. Activated by DNA double strand breaks, ATM regulates the activities of many downstream proteins involved in various carcinogenic events. Therefore, ATM or its genetic variants may have a pleiotropic effect on cancer development. We conducted a pleiotropic analysis to evaluate associations between genetic variants of ATM and risk of multiple cancers. With genotyping data extracted from previously published genome-wide association studies of various cancers, we performed multivariate logistic regression analysis, followed by a meta-analysis for each cancer site, to identify cancer risk-associated single-nucleotide polymorphisms (SNPs). In the ASSET two-sided analysis, we found that two ATM SNPs were significantly associated with risk of multiple cancers. One tagging SNP (rs1800057 C>G) was associated with risk of multiple cancers (two-sided P = 5.27 × 10−7). Because ATM rs1800057 is a missense variant, we also explored the intermediate phenotypes through which this variant may confer risk of multiple cancers and identified a possible immune-mediated effect of this variant. Our findings indicate that genetic variants of ATM may have a pleiotropic effect on cancer risk and thus provide an important insight into common mechanisms of carcinogenesis.

Introduction We aimed to validate the use of the novel grading system proposed by the International Association for the Study of Lung Cancer pathology committee for prognosis stratification of invasive pulmonary adenocarcinomas (ADCs) in Chinese patients. Correlations between the grading system, common driver mutations, and adjuvant chemotherapy (ACT) were also investigated. Methods From 2008 to 2016, the histologic patterns of a large cohort of 950 patients with invasive ADCs (stage I–III) were retrospectively analyzed and classified according to the proposed grading system. Subsequently, tumor grading was correlated with genetic data, ACT, and patient outcome. Results Compared with conventional predominant pattern-based groups, the novel grading system carried improved survival discrimination (area under the curve = 0.768 for recurrence-free survival and 0.775 for overall survival). The area under the curve was not further improved when incorporated lymphovascular invasion status. EGFR mutations (p Conclusions The novel International Association for the Study of Lung Cancer grading system is a practical and efficient discriminator for patient prognosis and should be part of an integrated pathologic-genetic subtyping to improve survival prediction. In addition, it may support patient stratification for aggressive adjuvant chemotherapy.

Osimertinib is the standard treatment for advanced non-small cell lung cancer (NSCLC) patients with T790M mutation after the failure of first-/second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). We comprehensively analyzed factors that affect the therapeutic efficacy of the osimertinib treatment in NSCLC patients. 351 NSCLC patients with T790M mutation receiving osimertinib treatment were included. We investigated the value of different factors in predicting the clinical outcomes of the osimertinib therapy, including progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Logistic and COX regression were used to identify prognosticators. In osimertinib therapy, EGFR mutation status (19Del/L858R) at initial diagnosis and the therapeutic choice of prior EGFR-TKI agent was not associated with patients’ prognosis. Notably, the PFS of the prior EGFR-TKI was independently related to ORR (OR, 95% CI 0.98, 0.96–1.00, p = 0.030), PFS (HR, 95% CI 0.98, 0.97–1.00, p = 0.009) and OS (HR, 95% CI 0.96, 0.93–0.98, p

BACKGROUND Maternal sepsis is a major cause of gestational morbidity and neonatal mortality worldwide and particularly in China. AIM To evaluate the etiology of maternal sepsis and further identify its risk factors. METHODS In this retrospective study, we evaluated 70698 obstetric patients who were admitted to the Third Affiliated Hospital of Guangzhou Medical University between January 1, 2009 and June 30, 2018. Subjects were divided into sepsis group and non-sepsis group based on the incidence of sepsis. Data about medical history (surgical and obstetric history) and demographic information were collected. The Mann-Whitney U test was used to compare patient age, gestational age and duration of hospitalization between the two groups. Univariate and multivariate logistic regression models were used to analyze the etiology and the risk factors for maternal sepsis. Unadjusted and adjusted odds ratios (OR) are reported. RESULTS A total of 561 of 70698 obstetric patients were diagnosed with infection; of the infected patients, 492 had non-sepsis associated infection (87.7%), while 69 had sepsis (12.3%). The morbidity rate of maternal sepsis was 9.76/10000; the fatality rate in the sepsis group was 11.6% (8/69). Emergency admission (OR = 2.183) or transfer (OR = 2.870), irregular prenatal care (OR = 2.953), labor induction (OR = 4.665), cervical cerclage (OR = 14.214), first trimester (OR = 6.806) and second trimester (OR = 2.09) were significant risk factors for maternal sepsis. CONCLUSION Mode of admission, poor prenatal care, labor induction, cervical cerclage, first trimester and second trimester pregnancy were risk factors for maternal sepsis. Escherichia coli was the most common causative organism for maternal sepsis, and the uterus was the most common site of infection.

BACKGROUND The most commonly ingested foreign body in Asians is fish bone. The vast majority of patients have obvious symptoms and can be timely diagnosed and treated. Cases of pyogenic cervical spondylitis and diskitis with retropharyngeal and epidural abscess resulting in incomplete quadriplegia due to foreign body ingestion have been rarely reported. The absence of pharyngeal or esophageal discomfort and negative computed tomography (CT) findings of fish bone have not been reported. We report the case of an elderly female patient with delayed cervical infection and incomplete quadriplegia who had a history of fish bone ingestion. CASE SUMMARY A 73-year-old woman presented with right neck pain and weakness of four limbs for a week, and had a history of fish bone ingestion and negative findings on laryngoscopic examination one month previously. She did not complain of any pharyngeal or esophageal discomfort. Cervical magnetic resonance imaging showed C4/C5 spondylitis and diskitis along with retropharyngeal and ventral epidural abscesses. No sign of fish bone was detected on lateral cervical radiography and CT scans. The muscle strength of the patient’s right lower limb receded to grade 1 and other limbs to grade 2 suddenly on the 10th day of hospitalization. Emergency surgery was performed to drain the abscess and decompress the spinal cord by removing the anterior inflammatory necrotic tissue. Simultaneously, flexible esophagogastroduodenoscopy was carried out and a hole in the posterior pharyngeal wall was found. The motor weakness of the right lower limb improved to grade 3 and the other limbs to grade 4 within 2 d postoperatively. CONCLUSION This rare case highlights the awareness of the posterior pharyngeal or esophageal wall perforation in patients with cervical pyogenic spondylitis along with a history of fish bone ingestion, even though local discomfort symptoms are absent and the radiological examinations are negative.

Objective To explore the development and pregnancy potential of non-pronuclear (0PN) zygote-derived embryos in conventional in vitro fertilization (IVF) cycles. Study design Embryonic development in 1039 oocyte retrieval cycles and clinical outcomes of 659 frozen-thawed blastocyst transfer cycles were retrospectively studied. Results Developmental potential of embryos with different blastomere numbers on day 3 were inconsistent in 0PN and 2PN groups. For 0PN-derived embryos, blastocyst rate of fast developing embryos (75.4%) was similar to that of intermediately developing embryos (72.9%), but good quality blastocyst rate of the former (49.2%) was significantly higher than that of the later (39.6%). In 2PN group, intermediately developing embryos had the highest blastocyst rate (77.9%) and good quality blastocyst rate (51.5%) (statistically significant). Comparison of frozen-thawed transfer was carried out between 0PN- and 2PN-derived blastocysts. For both single (SBT) and double blastocyst transfer (DBT) groups, no statistical differences existed between 0PN- and 2PN-derived blastocysts in clinical pregnancy rates (45.2% and 49.1% in SBT group, 64.7% and 66.4% in DBT group), implantation rates (45.2% and 49.1% in SBT group, 41.2% and 47.7% in DBT group) and live birth rates (35.5% and 36.8% in SBT group, 52.9% and 51.2% in DBT group). Conclusion The developmental characteristic of 0PN-derived embryos was different from that of 2PN-derived embryos in IVF cycles. 0PN-derived blastocysts could obtain acceptable clinical pregnancy and live birth, but more studies are needed to confirm the safety..

Daoming Zhang,1 Yuan Li,1 Haoyue Li,2 Tian Tang,1 Yongfa Zheng,1 Xufeng Guo,1 Ximing Xu1 1Cancer Center, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of ChinaCorrespondence: Ximing XuCancer Center, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, People’s Republic of ChinaTel +86-13707120651Email doctorxu120@aliyun.comObjective: To evaluate the value of serum complement component 1q (C1q) levels in predicting the efficacy of combined immunotherapy in patients with lung cancer.Methods: A total of 42 patients with lung cancer who received combined immunotherapy in the cancer center of Renmin Hospital of Wuhan University were included in this study. The clinical data of serum C1q and lactate dehydrogenase (LDH) levels before and three weeks after immunotherapy were collected.Results: Response evaluation showed that the number of patients with complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) was 0 (0%), 26 (61.9%), 14 (33.3%), and 2 (4.8%), respectively. The CR/PR group (patients with CR or PR) showed higher pC1q (C1q level before immunotherapy) and iC1q (C1q level 3 weeks after immunotherapy) than the SD/PD group (patients with SD or PD). The LDH reduction (96.2%) and C1q increment (84.6%) in the CR/PR group 3 weeks after immunotherapy were higher than those of the SD/PD group, and the differences were statistically significant. Logistic regression analysis indicated that pC1q, iC1q, and LDH level trends 3 weeks after the treatment were significantly correlated to the efficacy of combined immunotherapy with odds ratios of 8.185, 5.500, and 0.031, respectively.Conclusion: High C1q levels before immunotherapy and increased C1q levels and decreased LDH levels 3 weeks afterward suggest good therapeutic effects of combined immunotherapy in patients with lung cancer. Serum C1q levels have certain clinical significance in predicting the efficacy of combined immunotherapy.Keywords: immunotherapy, efficacy prediction, complement component 1q

Background Perivascular epithelioid cell tumor (PEComa) is an uncommon tumor of mesenchymal origin. Cases of PEComa in the liver are extremely rare. Aim To analyze the clinicopathological features and treatment of hepatic PEComa and to evaluate the prognosis after different treatments. Methods Clinical and pathological data of 26 patients with hepatic PEComa were collected. All cases were analyzed by immunohistochemistry and clinical follow-up. Results This study included 17 females and 9 males, with a median age of 50 years. Lesions were located in the left hepatic lobe in 13 cases, in the right lobe in 11, and in the caudate lobe in 2. The median tumor diameter was 6.5 cm. Light microscopy revealed that the tumor cells were mainly composed of epithelioid cells. The cytoplasm contained heterogeneous eosinophilic granules. There were thick-walled blood vessels, around which tumor cells were radially arranged. Immunohistochemical analysis of pigment-derived and myogenic markers in PEComas revealed that 25 cases were HMB45 (+), 23 were Melan-A (+), and 22 SMA (+). TFE3 and Desmin were negative in all cases. All the fluorescence in situ hybridization samples were negative for TFE3 gene break-apart probe. Tumor tissues were collected by extended hepatic lobe resection or simple hepatic tumor resection as the main treatments. Median follow-up was 62.5 mo. None of the patients had metastasis or recurrence, and there were no deaths due to the disease. Conclusion Hepatic PEComa highly expresses melanin and smooth muscle markers, and generally exhibits an inert biological behavior. The prognosis after extended hepatic lobe resection and simple hepatic tumor resection is semblable.

A binucleating Schiff base ligand 2-methoxy-6-(iminomethyl)phenol (HL) and two new M(II) complexes [Zn4L4(N3)4](H2O)2 (1) and [Co4L4Cl4] (2) are synthesized. These metal complexes are characterized using various physicochemical techniques, e.g. elemental analyses and single crystal X-ray diffraction. Furthermore, both CCK-8 assay and cell colony formation results indicate that the inhibitory activity of compound 1 against Y79 retinoblastoma cancer cells is stronger than that of compound 2. In addition to this, we also reveal that compound 1 can significantly increase the ROS accumulation in Y79 retinoblastoma cancer cells, which is higher than that in the group treated with compound 2. All the results above suggest a stronger anticancer activity of compound 1 compared to compound 2 and that it has the potential of being a novel candidate for retinoblastoma cancer treatment.

The treatment of patients with advanced non-small-cell lung cancer (NSCLC) in recent years has been increasingly guided by biomarker testing. Testing has centered on driver genetic alterations involving the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangements. The presence of these mutations is predictive of response to targeted therapies such as EGFR tyrosine kinase inhibitors (TKIs) and ALK TKIs. However, there are substantial challenges for the implementation of biomarker testing, particularly in emerging countries. Understanding the barriers to testing in NSCLC will be key to improving molecular testing rates worldwide and patient outcomes as a result. In this article, we review EGFR mutations and ALK rearrangements as predictive biomarkers for NSCLC, discuss a selection of appropriate tests and review the literature with respect to the global uptake of EGFR and ALK testing. To help improve testing rates and unify procedures, we review our experiences with biomarker testing in China, South Korea, Russia, Turkey, Brazil, Argentina and Mexico, and propose a set of recommendations that pathologists from emerging countries can apply to assist with the diagnosis of NSCLC.

BACKGROUND Intestinal barrier breakdown, a frequent complication of intestinal ischemia-reperfusion (I/R) including dysfunction and the structure changes of the intestine, is characterized by a loss of tight junction and enhanced permeability of the intestinal barrier and increased mortality. To develop effective and novel therapeutics is important for the improvement of outcome of patients with intestinal barrier deterioration. Recombinant human angiopoietin-like protein 4 (rhANGPTL4) is reported to protect the blood-brain barrier when administered exogenously, and endogenous ANGPTL4 deficiency deteriorates radiation-induced intestinal injury. AIM To identify whether rhANGPTL4 may protect intestinal barrier breakdown induced by I/R. METHODS Intestinal I/R injury was elicited through clamping the superior mesenteric artery for 60 min followed by 240 min reperfusion. Intestinal epithelial (Caco-2) cells and human umbilical vein endothelial cells were challenged by hypoxia/ reoxygenation to mimic I/R in vitro. RESULTS Indicators including fluorescein isothiocyanate-conjugated dextran (4 kilodaltons; FD-4) clearance, ratio of phosphorylated myosin light chain/total myosin light chain, myosin light chain kinase and loss of zonula occludens-1, claudin-2 and VE-cadherin were significantly increased after intestinal I/R or cell hypoxia/reoxygenation. rhANGPTL4 treatment significantly reversed these indicators, which were associated with inhibiting the inflammatory and oxidative cascade, excessive activation of cellular autophagy and apoptosis and improvement of survival rate. Similar results were observed in vitro when cells were challenged by hypoxia/reoxygenation, whereas rhANGPTL4 reversed the indicators close to normal level in Caco-2 cells and human umbilical vein endothelial cells significantly. CONCLUSION rhANGPTL4 can function as a protective agent against intestinal injury induced by intestinal I/R and improve survival via maintenance of intestinal barrier structure and functions.

Although some regulatory agencies have claimed that consumer exposures to tetrabromobisphenol A (TBBPA) are not likely to cause adverse health effects in humans or the environment, the safety of tetrabromobisphenol A (TBBPA) has been questioned. Here, we summarize the literature concerning in vivo and in vitro neurotoxicity of TBBPA over the past decades. Most laboratory rodent studies reported that gavage administration of TBBPA at doses below 1000 mg/kg/day generally exerted no or limited effects on neuropathology and locomotor behaviors, but increased anxiety and auditory impairments were observed in several studies. In fish and amphibians, waterborne exposure to TBBPA was generally reported to disrupt neurodevelopment and lead to neurobehavioral alterations. Moreover, in vitro studies support the observations that TBBPA could exert neurotoxic effects in vertebrates. Thus, we suggest that TBBPA could have adverse effects on the nervous system in vertebrates. Given rapid excretion and low availability of TBBPA in laboratory rodents following single gavage administration, we speculate that single-daily gavage could result in an underestimation of the neurotoxic effects of TBBPA in rodents. Thus, we propose to employ multiple-daily administration routes (such as dermal, inhalation, and drinking water), to further assess the neurotoxic effects of TBBPA in mammals.

Bone is the common extra-hepatic site for cancer metastasis. Hepatic cancer is associated with a higher incidence of pathological fracture. However, this important regulatory mechanism remains unexplored. Thus, exosome-mediated cell-cell communication between hepatocellular cancer and bone might be key to osteolytic bone destruction. Huh-7 exosomes were characterized for size and exosome marker expressions (CD63, Alix). Exosome mediated osteoclast differentiation in the RAW 264.7 cells was monitored from day 1 to 6 and multinucleated osteoclast formation and bone resorption activity were analyzed. The osteoclastogenic factor expressions in the exosomes and osteoclast differentiation markers such as tumor necrosis factor receptor 6 (TRAF6), nuclear factor κB (NF-κB), nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), and cathepsin K (CTSK) were analyzed using western blot. Exosomes released by liver cancer cells (Huh-7) promoted osteoclast differentiation in RAW 264.7 cells. Analysis of osteoclastogenic factors in the exosomes showed that exosomes were specifically enriched with tumor necrosis factor α (TNF-α). Huh-7 exosomes promoted osteoclast differentiation by significantly increasing the number of TRAP-positive multi nucleated osteoclasts and resorption pits. Importantly, exosomes upregulated osteoclast markers TRAF6, NF-κB, and CTSK expressions. Further, neutralizing exosomal TNF-α reverted exosome-mediated osteoclast differentiation in RAW 264.7 cells. Collectively, our findings show that cellular communication of exosomal TNF-α from hepatocellular cancer cells (Huh-7) regulates osteoclast differentiation through NF-κB/CTSK/TRAP expressions. Thus, exosomal TNF-α might act as an important therapeutic target to prevent hepatocellular cancer mediated pathological bone disease.

The red blood cell (RBC) lifespan is an important physiological indicator of clear significance in clinical research, used for the differential diagnosis of various diseases such as anemia, compensatory phase hemolysis, and polycythemia. The 15 N-glycine labeling technique is the gold standard method for determining RBC lifespans. However, the usefulness of this technique in clinical settings is seriously hindered by the several weeks required to complete the analyses. Levitt's CO breath test is another reliable technique for determining RBC lifespans, with a simpler protocol giving much faster results, making it more useful in clinical applications. To compare the CO breath test and 15 N-glycine labeling technique for measuring the human RBC lifespan. We investigated human RBC lifespans where each subject undertook both the 15 N-glycine labeling technique and the CO breath test. The correlation between the results from these two methods were analyzed. Eight of the ten subjects successfully completed the study. The RBC lifespan values obtained by Levitt's CO breath test were lower than those obtained by the 15 N-glycine labeling technique. The RBC lifespan values determined from the 15 N-glycine labeling technique and the CO breath test were significantly correlated, with a Pearson correlation coefficient of R=0.98 (p

Arterial stiffness, a consequence of smoking, is an underlying risk factor of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs), hydrolyzed by soluble epoxide hydrolase (sEH), have beneficial effects against vascular dysfunction. However, the role of sEH knockout in nicotine-induced arterial stiffness was not characterized. We hypothesized that sEH knockout could prevent nicotine-induced arterial stiffness. In the present study

Background Pulmonary fibrosis (PF) is a devastating disease characterized by remodeling of lung architecture and abnormal deposition of fibroblasts in parenchymal tissue and ultimately results in respiratory failure and death. Preclinical studies suggest that mesenchymal stem cell (MSC) administration may be a safe and promising option in treating PF. The objective of our meta-analysis is to assess the efficacy of MSC therapy in preclinical models of PF. Methods We performed a comprehensive literature search in PubMed, EMBASE, Web of Science, and Cochrane Library databases from inception to March 17, 2021. Studies that assessed the efficacy of MSC therapy to animals with PF were included. The SYRCLE bias risk tool was employed to evaluate the bias of included studies. The primary outcomes included survival rate and pulmonary fibrosis scores. Meta-analysis was conducted via Cochrane Collaboration Review Manager (version 5.4) and Stata 14.0 statistical software. Results A total of 1120 articles were reviewed, of which 24 articles met inclusion criteria. Of these, 12 studies evaluated the survival rate and 20 studies evaluated pulmonary fibrosis scores. Compared to the control group, MSC therapy was associated with an improvement in survival rate (odds ratios (OR) 3.10, 95% confidence interval (CI) 2.06 to 4.67, P < 0.001, I2 = 0%) and a significant reduction in pulmonary fibrosis scores (weighted mean difference (WMD) 2.05, 95% CI −2.58 to −1.51, P < 0.001, I2 = 90%). Conclusions MSC therapy is a safe and effective method that can significantly improve the survival and pulmonary fibrosis of PF animals. These results provide an important basis for future translational clinical studies.

Our previous study has shown that the transcription factor Kruppel-like factor 7 (KLF7) promotes peripheral nerve regeneration and motor function recovery after spinal cord injury. KLF7 also participates in traumatic brain injury, but its regulatory mechanisms remain poorly understood. In the present study, an HT22 cell model of traumatic brain injury was established by stretch injury and oxygen-glucose deprivation. These cells were then transfected with an adeno-associated virus carrying KLF7 (AAV-KLF7). The results revealed that, after stretch injury and oxygen-glucose deprivation, KLF7 greatly reduced apoptosis, activated caspase-3 and lactate dehydrogenase, downregulated the expression of the apoptotic markers B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and cleaved caspase-3, and increased the expression of βIII-tubulin and the antiapoptotic marker Bcl-2. Furthermore, KLF7 overexpression upregulated Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) phosphorylation in HT22 cells treated by stretch injury and oxygen-glucose deprivation. Immunoprecipitation assays revealed that KLF7 directly participated in the phosphorylation of STAT3. In addition, treatment with AG490, a selective inhibitor of JAK2/STAT3, weakened the protective effects of KLF7. A mouse controlled cortical impact model of traumatic brain injury was then established. At 30 minutes before modeling, AAV-KLF7 was injected into the ipsilateral lateral ventricle. The protein and mRNA levels of KLF7 in the hippocampus were increased at 1 day after injury and recovered to normal levels at 3 days after injury. KLF7 reduced ipsilateral hippocampal atrophy, decreased the injured cortex volume, downregulated Bax and cleaved caspase-3 expression, and increased the number of 5-bromo-2'-deoxyuridine-positive neurons and Bcl-2 protein expression. Moreover, KLF7 transfection greatly enhanced the phosphorylation of JAK2 and STAT3 in the ipsilateral hippocampus. These results suggest that KLF7 may protect hippocampal neurons after traumatic brain injury through activation of the JAK2/STAT3 signaling pathway. The study was approved by the Institutional Review Board of Mudanjiang Medical University, China (approval No. mdjyxy-2018-0012) on March 6, 2018.

INTRODUCTION Tuberculous empyema (TE) in children is common in high-TB burden and medical resource-limited areas. However, studies that evaluate the characteristics of TE in children are sparse. This study aimed to analyze the clinical features of pediatric TE receiving surgical intervention. METHODS We performed a retrospective study of children with empyema secondary to community-acquired pneumonia who underwent surgery in our institution. The clinical characteristics were compared between TE and empyema secondary non-tuberculosis infection (non-tuberculosis empyema, NTE). RESULTS One hundred patients were included (27 with TE and 73 with NTE). Stage 3 empyema occupied 81.5% and 45.2% of TE and NTE in this study. The TE children had older age, longer duration of illness, and milder symptoms. Pleural fluid culture was positive for Mycobacterium tuberculosis in 7.4% of patients with TE. Lymph node enlargement, lymph node calcification, and pleural nodules presented in TE with high specificity (93.2%, 98.6%, and 98.5%) but low sensitivity (33.3%, 14.8%, and 29.6%) on CT scan. Thoracoscopy surgery was performed in 14 (51.9%) in TE and 39 (53.4%) in NTE. Postoperative chest-tube indwelling time was longer (7.85 ± 5.00 vs. 4.89 ± 1.81 days, p < .001), and more patients had incomplete lung expansion after 3 months in TE. CONCLUSION Tuberculosis infection should be screened in management of children with empyema in high-TB burden areas. Pediatric TE usually presented at older age and with milder respiratory symptoms. Pleural biopsy during surgery is often necessary to confirm the cause of infection. Thoracotomy is still required in some pediatric TE or NTE with delayed treatment in medical resource-limited area.

Summary Objectives Tuberculosis (TB) remains one of the public health problems worldwide. Rapid, sensitive and cost-effective diagnosis of Mycobacterium tuberculosis (M.tb) is critical for TB control. Methods We developed a novel M.tb DNA detection platform (nominated as TB-QUICK) which combined loop-mediated isothermal amplification (LAMP) and CRISPR-Cas12b detection. TB-QUICK was performed on pulmonary or plasma samples collected from 138 pulmonary TB (PTB) patients, 21 non-TB patients and 61 close contacts to TB patients. Acid-fast bacillus (AFB) smear, M.tb culture and GeneXpert MTB/RIF (Xpert) assays were routinely conducted in parallel. Results By targeting M.tb IS6110, TB-QUICK platform could detect as low as 1.3 copy/μL M.tb DNA within 2 h. In pulmonary TB samples, TB-QUICK exhibited improved overall sensitivity of 86.8% over M.tb culture (66.7%) and Xpert (70.4%), with the specificity of 95.2%. More significantly, TB-QUICK exhibited a superior sensitivity in AFB-negative samples (80.5%) compared to Xpert (57.1%) and M.tb culture (46.2%). In the detection of plasma M.tb DNA by TB-QUICK, 41.2% sensitivity for AFB-positive and 31.7% for AFB-negative patients were achieved. Conclusion In conclusion, TB-QUICK exhibits rapidity and sensitivity for M.tb DNA detection with the superiority in smear-negative paucibacillary TB patients. The clinical application of TB-QUICK in TB diagnosis needs to be further validated in larger cohort.

Objective To observe the influence of transcutaneous auricular vagus nerve stimulation (taVNS) on fasting plasma glucose (FPG) and serum insulin (INS) in Zucker diabetes fatty (ZDF) rats and explore the regulatory effect of taVNS on blood glucose in ZDF rats. Methods A total of 20 male ZDF rats were randomized into a model group and a taVNS group, 10 rats in each one. Besides, the other 10 Zucker Lean (ZL) rats were selected to be a control group. The rats in the control group were fed with common forage and those in the model group and the taVNS group were fed with high-sugar and high-fat forage. The intervention of electric stimulation was applied in the rats of taVNS group, with 2/15 Hz in frequency, disperse-dense wave and 2 mA in intensity. Each intervention lasted 30 min, once a day, consecutively for 12 weeks. No any intervention was given in the control group and the model group. The body mass and FPG level were recorded once every 2 weeks in the rats. After the experiment, the rats were sacrificed and blood sample was collected. Enzyme linked immunosorbent assay (ELISA) was adopted to determine the level of serum INS in the rats. Results After the modeling, compared with the control group, the body mass and FPG level were all higher (P Conclusion taVNS apparently improves in hyperglycemia in ZDF rats and increases serum insulin concentration in the rats.

Background Functional mitral regurgitation (FMR) is one of the most common heart valve diseases in diabetes and may increase left ventricular (LV) preload and aggravate myocardial stiffness. This study aimed to investigate the aggravation of FMR on the deterioration of LV strain in type 2 diabetes mellitus (T2DM) patients and explore the independent indicators of LV peak strain (PS). Materials and methods In total, 157 T2DM patients (59 patients with and 98 without FMR) and 52 age- and sex-matched healthy control volunteers were included and underwent cardiac magnetic resonance examination. T2DM with FMR patients were divided into T2DM patients with mild (n = 21), moderate (n = 19) and severe (n = 19) regurgitation. LV function and global strain parameters were compared among groups. Multivariate analysis was used to identify the independent indicators of LV PS. Results The T2DM with FMR had lower LV strain parameters in radial, circumferential and longitudinal direction than both the normal and the T2DM without FMR (all P P Conclusion FMR may aggravate the deterioration of LV stiffness in T2DM patients, resulting in decline of LV strain and function. The regurgitation degree and months with diabetes were independently correlated with LV global PS in T2DM with FMR.

Aims Neointimal hyperplasia remains a major obstacle in vascular regeneration. Sca-1-positive progenitor cells residing within the vascular adventitia play a crucial role in the assemblage of vascular smooth muscle cell (VSMC) and the formation of the intimal lesion. However, the underlying mechanisms during vascular injury are still unknown. Methods and results Aneointimal formation rat model was prepared by carotid artery injury using 2F-Forgaty. After vascular injury, Meox1 expressions time-dependently increased during the neointima formation, with its levels concurrently increasing in the adventitia, media, and neointima. Meox1 was highly expressed in the adventitia on the first day after vascular injury compared to the expression levels in the media. Conversely, by the 14th day post-injury, Meox1 was extensively expressed more in the media and neointima than the adventitia. Analogous to the change of Meox1 in injured artery, Sca-1+ progenitor cells increased in the adventitia wall in a time-dependent manner and reached peak levels on the 7th day after injury. More importantly, this effect was abolished by Meox1 knockdown with shRNA. The enhanced expression of SDF-1α after vascular injury was associated with the markedly enhanced expression levels of Sca1+ progenitor cell, and these levels were relatively synchronously increased within neointima by the 7th day after vascular injury. These special effects were abolished by the knockdown of Meox1 with shRNA and inhibition of CXCR4 by its inhibitor, AMD3100. Finally, Meox1 concurrently regulated SDF-1α expressions in VSMC via activating CDC42, and CDC42 inhibition abolished these effects by its inhibitor, ZCL278. Also, Meox1 was involved in activation of the CXCR4 expression of Sca-1+ progenitor cells by CDC42. Conclusions Spatio-temporal model of Meox1 expression regulates theSca-1+progenitor cell migration during the formation of the neointima through the synergistic effect of Rho/CDC42 and SDF-1α/CXCR4.

The aim of this study was to identify a urine extracellular vesicle circular RNA (circRNA) classifier that could detect high-grade prostate cancer (PCa) of Grade Group (GG) 2 or greater. For this purpose, we used RNA sequencing to identify candidate circRNAs from urinary extracellular vesicles from 11 patients with high-grade PCa and 11 case-matched patients with benign prostatic hyperplasia. Using ddPCR in a training cohort (n = 263), we built a urine extracellular vesicle circRNA classifier (Ccirc, containing circPDLIM5, circSCAF8, circPLXDC2, circSCAMP1, and circCCNT2), which was evaluated in two independent cohorts (n = 497, n = 505). Ccirc showed higher accuracy than two standard of care risk calculators (RCs) (PCPT-RC 2.0 and ERSPC-RC) in both the training cohort and the validation cohorts. In all three cohorts, this novel urine extracellular vesicle circRNA classifier plus RCs was statistically more predictive than RCs alone for predicting ≥ GG2 PCa. This assay, which does not require precollection digital rectal examination nor special handling, is repeatable, noninvasive, and can be easily implemented as part of the basic clinical workflow.

As the most representative family of proteinases related to tumorigenesis, matrix metalloproteinase-9 (MMP-9) represents a key player in cancer cell migration and regulation of the tumor microenvironment. The inhibition of MMP-9 activity has been pursued as a target for anticancer therapy. However, most synthetic MMP-9 inhibitors have failed in clinical trials because of their lack of selectivity. Here, an abiotic mimic based on molecularly imprinted nanoparticles has been designed as an inhibitor for MMP-9. To attain fast mass transfer and facilitate multifunctional roles, we synthesized the imprinted polymer thin layer on the surface of gold nanorods by reversible addition-fragmentation chain transfer polymerization using MMP-9 as the template, which captures MMP-9 selectively and inhibits its activity by providing steric hindrance to the activity-related domain of MMP-9. In vitro cell experiments and in vivo studies in mice demonstrate that the imprinted artificial antibody suppresses the migration and growth of metastatic tumors. The tumor growth inhibition rate reaches up to 54 ± 15%. Compared with the typical photothermal therapy induced by gold nanorods, the use of MMP-9-imprinted synthetic antibody could better inhibit the lung tumor metastasis by quenching the enzyme activity of MMP-9. This study offers a new paradigm in the engineering of imprinted nanoparticles as inhibitors for cancer therapy.

Objective. To explore the potential mechanism of Huanglian Jiedu Decoction (HJD) treatment and prevention of metastatic Cutaneous Melanoma (CM) occurrence and metastasis based on network pharmacological methods and immune infiltration analysis. Methods. The GEO database was used to obtain metastatic CM disease targets, the TCMSP database and the HERB database were used to obtain HJD action targets, core genes were screened by protein interaction network, and the potential mechanism of HJD in the treatment of metastatic CM was explored by enrichment analysis, prognostic analysis and immune infiltration analysis. Results. HJD treatment of metastatic CM involved 60 targets, enrichment analysis showed that HJD treatment of metastatic CM involved Chemokine signaling pathway, NF-kappa B signaling pathway, and Fluid shear stress and atherosclerosis, etc. Prognostic analysis revealed that HJD had a certain ability to improve the prognosis of metastatic CM patients. Immune infiltration analysis showed that HJD could inhibit the immune cell infiltration of metastatic CM patients by acting on related targets. Conclusions. Our study identified the potential mechanism of HJD in the treatment of metastatic CM through network pharmacology, and revealed the mechanism of HJD in the prevention of Skin Cutaneous Melanoma metastasis through immune infiltration analysis and prognostic analysis.

Objective: Human endogenous retroviruses (HERVs) have been gradually confirmed to be involved in the onset and progression of motor neuron disease(MND). However, noninvasive detection of HERVs in the central nervous system is lacking. The aim of this study is to verify the relationship between the level of HERV-K env in neuronal extracellular vesicles in plasma and the onset and severity of MND. Methods: We extracted neuronal extracellular vesicles from plasma of 39 MND patients and 30 age- and sex-matched controls, and detected HERV-K env in extracellular vesicles by an enzyme-linked immunosorbent assay (ELISA). Results: Levels of HERV-K env in neuronal extracellular vesicles positively associated with range of lower motor neurons (LMNs) involved (1.66 �� 0.37 vs. 1.35 �� 0.34, p = 0.041), ALS phenotype (1.52 �� 0.31 vs. 1.24 �� 0.37, p = 0.013) and course of disease (1.83 �� 0.35 vs. 1.42 �� 0.22, p = 0.003), and increased in advanced-phase MND (definite and probable according to revised EI Escorial criteria) compared with early-phase MND (possible and lab-supported probable), albeit without very profound significance (1.52 �� 0.34 vs. 1.29 �� 0.36, p = 0.048). Conclusions: In conclusion, levels of HERV-K env in neuronal extracellular vesicles extracted from plasma can be used as a noninvasive biomarker of severity of MND.

Background: The impact of peritoneal dialysis-associated peritonitis (PD peritonitis) on long-term outcomes is uncertain. This nationwide retrospective study was conducted in Taiwan to understand the incidence, risk factors and long-term outcomes of PD peritonitis. Methods: A total of 11,202 incident adult peritoneal dialysis (PD) patients from 2000 to 2010 were collected from a Longitudinal Health Insurance Database and followed up until the end of 2011. Definition of peritonitis, the primary outcome, simultaneously met the diagnosis of peritonitis (International Classification of Diseases, Ninth Revision, Clinical Modification 567) and antibiotic use. Secondary outcomes included the impact of peritonitis on PD discontinuation and survival. Cox proportional hazards models with and without time-dependent variables were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: There were 7634 peritonitis episodes in 4245 patients during the follow-up period. The overall incidence of peritonitis was 0.18 episodes per patient-year. Peritonitis-associated risk factors included older age, female gender, chronic heart failure, cerebrovascular disease, liver cirrhosis and lower monthly income. In an adjusted Cox hazard proportional regression with the time-dependent model, peritonitis patients had a higher risk of PD discontinuation (HR 2.71, 95% CI 2.52–2.92) and mortality (HR 1.68, 95% CI 1.57–1.81) compared to patients without peritonitis. The adjusted HRs for mortality increased with each prior episode: one episode, two episodes and more than two episodes (all p < 0.05). The adjusted HRs for PD discontinuation also increased with the frequency of peritonitis. These negative effects were greatest during the first year and persisted significantly after 5 years. In a sensitivity analysis in which peritonitis within 30 days of death or PD discontinuation was excluded, peritonitis patients still had significantly increased risk of PD discontinuation and mortality compared to patients without peritonitis. Conclusions: Although peritonitis incidence was low, our findings reveal that peritonitis carried acute and long-term sequelae of higher PD discontinuation and lower patient survival.

Exosomes derived from mesenchymal stem cells (MSC-Exo) are effective in modulating immunity. However, the role of MSC-Exo in clear cell renal cell carcinoma (ccRCC) is unclear. Our study was performed to identify if exosomal microRNA (miRNA) can be used as potential noninvasive biomarkers for ccRCC therapy. An orthotopic ccRCC mouse model was established, followed by MSC-Exo injection (1 mL, 20 μg/mL). The metastases of tumors were observed using HE staining, while number of dendritic cells, natural killing (NK) T cells and CD8(+) T cells was measured using flow cytometry. It was observed that MSC-Exo treatment significantly inhibited metastasis and growth of tumors, and improved immune response in vivo. As for in vitro assay, naive T cells were treated with MSC-Exo, followed by detection of T cell proliferation using EdU staining and CFSE assay. Results also showed that MSC-Exo facilitated sensitivity of ccRCC cells to NK T cells. Our experimental data further showed that miR-182 could be delivered by MSC-Exo in ccRCC, which targeted vascular endothelial growth factor A (VEGFA), as dual-luciferase reporter assays validated. In conclusion, miR-182 contained in MSC-Exo promoted immune response of T cells by suppressing VEGFA expression, thus alleviating ccRCC development.

Introduction Programmed cell death ligand-1 (PD-L1) expression is a promising biomarker for identifying treatment related to non-small cell lung cancer (NSCLC). Automated image analysis served as an aided PD-L1 scoring tool for pathologists to reduce inter- and intrareader variability. We developed a novel automated tumor proportion scoring (TPS) algorithm, and evaluated the concordance of this image analysis algorithm with pathologist scores. Methods We included 230 NSCLC samples prepared and stained using the PD-L1(SP263) and PD-L1(22C3) antibodies separately. The scoring algorithm was based on regional segmentation and cellular detection. We used 30 PD-L1(SP263) slides for algorithm training and validation. Results Overall, 192 SP263 samples and 117 22C3 samples were amenable to image analysis scoring. Automated image analysis and pathologist scores were highly concordant [intraclass correlation coefficient (ICC) = 0.873 and 0.737]. Concordances at moderate and high cutoff values were better than at low cutoff values significantly. For SP263 and 22C3, the concordances in squamous cell carcinomas were better than adenocarcinomas (SP263 ICC = 0.884 vs 0.783; 22C3 ICC = 0.782 vs 0.500). In addition, our automated immune cell proportion scoring (IPS) scores achieved high positive correlation with the pathologists TPS scores. Conclusions The novel automated image analysis scoring algorithm permitted quantitative comparison with existing PD-L1 diagnostic assays and demonstrated effectiveness by combining cellular and regional information for image algorithm training. Meanwhile, the fact that concordances vary in different subtypes of NSCLC samples, which should be considered in algorithm development.

Gastric cancer (GC) is one of the most common cancers globally, threatening global health. The deregulation of the Hippo signaling pathway has been discovered in GC and may be related to cancer development, proliferation, metastasis, and drug resistance. Yes-associated protein (YAP), as a downstream effector of the Hippo signaling pathway and a crucial co-transcription factor in the nucleus, is a promising and vital potential drug target for the treatment of GC. A series of drugs or compounds that inhibit YAP has been developed or confirmed. Therefore, this review will focus on summarizing the drugs and small-molecule inhibitors that have been reported to inhibit YAP and discuss the clinical prospects of YAP inhibitors in GC.