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BACKGROUND The advantages and disadvantages of robotic technology compared with conventional surgery for low rectal cancer have been discussed extensively. However, a few studies on the efficacy of total mesorectal excision (TME) with different robotic technologies have been reported. The aim of this study was to evaluate the efficacy of two types of robot-assisted TME (R-TME) compared with laparoscopic TME (L-TME). METHODS A prospective comparative study was conducted comparing da Vinci R-TME, Micro Hand S R-TME, and L-TME for rectal cancer. This study was registered with "Clinicaltrials.gov" (ID: NCT02752698) and approved by the Association for the Accreditation of Human Research Protection Program (AAHRPP) (Project number: T16007). Between January 2017 and May 2019, patients with rectal cancer (cT1-3NxM0) were prospectively registered in the Third Xiangya Hospital. The integrity of the TME sample served as the primary outcome. Secondary outcomes included the involvement of the circumferential and distal resection margins (CRM and DRM), number of lymph nodes retrieved, blood loss, operative time, conversion rate, comprehensive complication index score, the International Prostate Symptom score, the International Index of Erectile Function, and the Female Sexual Function Index. RESULTS Of 134 patients with rectal cancer (74 males, mean age [SD] 59.1 ± 8.27 years), 46 patients underwent laparoscopic TME, 45 patients underwent da Vinci R-TME, and 43 patients underwent Micro Hand S R-TME. There were no differences in results between the two types of R-TME. Compared with laparoscopic TME, significant reductions in blood loss (median 65.50 ml da Vinci; median 66.54 ml Micro Hand S vs median 95.04 ml L-TME p = 0.037 and p = 0.041, respectively) and conversion rate (2.2% da Vinci; 2.3% Micro Hand S vs 6.8% L-TME p = 0,040 for the comparison daVinci L-TME and p = 0.038 for the comparison Micro Hand S vs. L-TME) with da Vinci Si and Micro Hand S R-TME were noted, and significant increases in operation time (230.05 min da Vinci; 235.03 min Micro Hand S vs. 205.53 min L-TME p = 0.045 and p = 0.043, respectively) was observed. Additionally, more patients underwent TME with sphincter-preserving methods in the two R-TME groups based on the type of operation (da Vinci 97.7%; Micro Hand S 97.9% vs. L-TME 82% resulting in p = 0.033 for the comparison daVinci L-TME and p = 0.035 for the comparison Micro Hand S vs. L-TME). In comparison with L-TME, there was a larger number of lymph nodes retrieved (da Vinci mean 17.54; Micro Hand S mean 17.32 vs. L-TME mean 14.96 p = 0.031 for the comparison daVinci L-TME and p = 0.033 for the comparison Micro Hand S vs L-TME) and less blood loss (da Vinci mean 65.50 ml; Micro Hand S mean 66.54 ml vs. L-TME mean 95.04 ml, p = 0.037 for the comparison daVinci L-TME and p = 0.041 for the comparison Micro Hand S vs. L-TME), and incidence of severe postoperative complications was similar among three TME groups except for the earlier recovery of urogenital function (mean IPSS score da Vinci 7.73±1.35; Micro Hand S7.75±1.47 vs L-TME 14.26±1.41 p

Weiling Leng,1 Danlan Pu,2 Juan Jiang,2 Xiaotian Lei,1 Qinan Wu,3,&ast; Bing Chen1,&ast; 1Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China; 2Endocrinology and Nephrology Department, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, People’s Republic of China; 3Endocrinology Department, Chongqing Medical University Affiliated Dazu Hospital, Dazu District People’s Hospital, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qinan Wu; Bing Chen Email wqn11@126.com; chenbingxnyy@126.comBackground: This study investigated the effects of metformin on breast density in overweight/obese premenopausal women.Methods: Overweight/obese premenopausal women (n=120) were randomly assigned to the metformin or placebo group, and all women received lifestyle interventions. The outcomes included weight, BMI, FPG, FIN, glucose, HOMA-IR, LDL-C, HDL-C, TG, TC, SBP, DBP, FSH, E, AD, and the BIRADS grade, and the incidence of breast cancer was assessed by pathological biopsy and BIRADS grade greater than 4.Results: In total, 120 overweight/obese women completed the 1-year trial. Seven patients had a BIRADS grade greater than 4, including 5 patients who were biopsy positive, in the control group, and 2 patients had a BIRADS grade greater than 4, including 1 patient who was biopsy positive, in the metformin group. Compared with those in the control group, the body weight, BMI, FIN, FPG, HOMA-IR, TC, BIRADS grade and positive pathological biopsy rate in the metformin group were significantly decreased (P< 0.05), while AD was significantly increased (P< 0.05). The correlation analysis indicated that the BIRADS grade was significantly correlated with weight, BMI, FPG, FIN, HOMA-IR, SBP, AD and the positive pathological biopsy rate, and the positive pathological biopsy rate was significantly correlated with weight, BMI, HOMA-IR, SBP, AD and BIRADS grade. The logistic regression analysis revealed that the BIRADS grade was significantly correlated with the positive pathological biopsy rate and AD and that the positive pathological biopsy rate was significantly correlated with the BIRADS grade.Conclusion: As adjunctive therapy, the combination of lifestyle changes and metformin was found to be a safe strategy for improving related metabolic markers and increasing adiponectin. The BIRADS grade was significantly correlated with the positive pathological biopsy rate and AD, and the positive pathological biopsy rate was significantly correlated with the BIRADS grade.Keywords: metformin, breast density, overweight/obese, adiponectin

Ethyl ferulate (EF) is abundant in Rhizoma Chuanxiong and grains (e.g., rice and maize) and possesses antioxidative, antiapoptotic, antirheumatic, and anti-inflammatory properties. However, its effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) is still unknown. In the present study, we found that EF significantly alleviated LPS-induced pathological damage and neutrophil infiltration and inhibited the gene expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) in murine lung tissues. Moreover, EF reduced the gene expression of TNF-α, IL-1β, IL-6, and iNOS and decreased the production of NO in LPS-stimulated RAW264.7 cells and BMDMs. Mechanistic experiments revealed that EF prominently activated the AMPK/Nrf2 pathway and promoted Nrf2 nuclear translocation. AMPK inhibition (Compound C) and Nrf2 inhibition (ML385) abolished the beneficial effect of EF on the inflammatory response. Furthermore, the protective effect of EF on LPS-induced ALI was not observed in Nrf2 knockout mice. Taken together, the results of our study suggest that EF ameliorates LPS-induced ALI in an AMPK/Nrf2-dependent manner. These findings provide a foundation for developing EF as a new anti-inflammatory agent for LPS-induced ALI/ARDS therapy. [Image: see text]

Malignant tumors are a major cause of death, and their incidence is increasing worldwide. Although the survival rate for some cancers has improved, treatments for other malignant tumors are limited, and their mortality rate continues to increase. People with type 2 diabetes have a higher risk of malignant tumors and a higher mortality rate than those without diabetes. Metformin is a commonly used hypoglycemic drug. In recent years, a growing number of studies have indicated that metformin has antitumor effects and increases the sensitivity of malignant tumors to chemotherapy. However, the effect of metformin on different tumors is currently controversial, and the mechanism of metformin’s antitumor action is not fully understood. Insights into the effect of metformin on malignant tumors and the possible mechanism may contribute to the development of antitumor drugs., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/MWKNn8872gg

Subarachnoid hemorrhage (SAH) can cause acute neuronal injury and chronic neurocognitive deficits; biomarkers reflecting its associated neuronal injury are of potential prognostic value. Sortilin, a member of the vacuolar protein sorting 10p (Vps10p) family, is enriched in neurons and is likely involved in neurodegenerative diseases. Here, we explored sortilin in the cerebrospinal fluid (CSF) as a potential biomarker for early neuronal injury after SAH. Sortilin levels in the CSF of SAH patients (n = 11) and controls (n = 6) were analyzed by immunoblot. SAH rats surviving 3–72 h (h) were evaluated neurologically, with their brain and CSF samples examined histologically and biochemically. Sortilin protein ~100 kDa was detected in the CSF from SAH patients only, with its levels correlated to Hunt-Hess scale. Rats in the SAH groups showed poorer Garcia score and beam balancing capability than sham controls. Sortilin ~100 kDa was detectable in the CSF of the SAH, but not sham, animals. Levels of sortilin ~100 kDa and fragments ~40 kDa in cortical lysates were elevated in the SAH relative to control rats. Levels of cortical glial fibrillary acidic protein (GFAP) were also elevated in the SAH rats. In immunohistochemistry, the pattern of sortilin labeling in the brain was largely comparable between the SAH and control rats, whereas an increased astrocytic GFAP immunolabeling was evident in the former. Together, these results suggest that SAH can cause an early and remarkable rise of sortilin products in CSF, likely reflecting neuronal change. Sortilin could be further explored as a potential biomarker in some brain disorders.

Introduction This study aimed to evaluate the utility of metagenomic next-generation sequencing (mNGS) for the diagnosis of Pneumocystis jirovecii pneumonia (PJP) in non-human immunodeficiency virus-infected patients. Methods We conducted a retrospective study. A total of 60 non-human immunodeficiency virus-infected PJP patients and 134 patients diagnosed with non-PJP pneumonia were included. P. jirovecii and other co-pathogens identified by mNGS in bronchoalveolar lavage fluid and/or blood samples were analyzed. Using clinical composite diagnosis as the reference standard, we compared the diagnostic performance of mNGS in PJP with conventional methods, including Gomori methenamine silver staining and serum (1,3)-β-d-glucan. Modifications of antimicrobial treatment for PJP patients after the report of mNGS results were also reviewed. Results mNGS reached a sensitivity of 100% in diagnosing PJP, which was remarkably higher than Gomori methenamine silver staining (25.0%) and serum (1,3)-β-d-glucan (67.4%). The specificity of mNGS (96.3%) significantly surpassed serum (1,3)-β-d-glucan (81.4%). Simultaneous mNGS of bronchoalveolar lavage fluid and blood samples was performed in 21 out of 60 PJP patients, and it showed a concordance rate of 100% in detecting P. jirovecii. Besides, mNGS showed good performance in identifying co-pathogens of PJP patients, among which cytomegalovirus and Epstein-Barr virus were most commonly seen. Initial antimicrobial treatment was modified in 71.7% of PJP patients after the report of mNGS results. Conclusion mNGS is a useful diagnostic tool with good performance for the diagnosis of PJP and the detection of co-pathogens. mNGS of bronchoalveolar lavage fluid and/or blood samples is suggested in patients with presumptive diagnosis of PJP. Blood samples may be a good alternative to bronchoalveolar lavage fluid for mNGS when bronchoscopic examination is not feasible.

There is a high incidence of tooth injury or loss due to endotracheal intubation or extubation. Tooth injury may be costly or even life threatening. In particular, tooth aspiration may cause airway obstruction, aspiration pneumonitis, or lung collapse, but tooth aspiration after tracheal extubation is rarely reported and easily overlooked. A missing tooth after extubation can be more dangerous. However, there are no practical guidelines and standard intervention strategies to deal with a loose or missing tooth. This article presents the case of a 67-year-old man who underwent laparoscopic colectomy for a colonic tumor under general anesthesia, and whose left maxillary incisor was loose. After surgery, the loose tooth was missing and we had to go through a difficult process to find it. Finally, a chest X-ray revealed a foreign body located in the trachea, and it was successfully removed by fiber-bronchoscopy. The patient woke up with no discomfort and was discharged without complications on the third day after surgery. Based on our experience in this case, we put forward a complete and effective flowchart named "VICTOR" as an option for the prevention of tooth loss and aspiration during surgical procedures and for locating a missing tooth in a timely, appropriate and safe way during the perioperative period.

Juan Jiang,* Danlan Pu,* Renzhi Hu, Mingyang Hu, Qinan Wu Department of Endocrinology and Nephrology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, 400030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qinan WuDepartment of Endocrinology and Nephrology, Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, People’s Republic of ChinaEmail wqn11@126.comObjective: To explore the efficacy of the hospital glycemic management system with information integration in patients with malignant tumors and hyperglycemia.Methods: Three hundred ninety-three patients diagnosed with malignant tumors with hyperglycemia and hospitalized in the non-endocrinology department of a specialized cancer hospital from March 2019 to November 2020 were recruited. All the patients were diagnosed and treated according to the clinical department and disease course. In total, 196 patients were divided into the control group, who received the conventional blood glucose management mode, and 197 patients were divided into the intervention group, who received the hospital glycemic management system with information integration. The average daily glucose levels were recorded before and after breakfast, lunch, and dinner, at bedtime and at night. The average glucose level, glucose compliance rate, hypoglycemia rate, hyperglycemia rate, glucose measurements per day, average number of hospitalization days and patient satisfaction were compared between the groups.Results: In the intervention group, the average glucose level was significantly lower than that in the control group (P< 0.05). The hyperglycemia and hypoglycemia rates in the intervention group were lower than those in the control group (P< 0.05). The glucose compliance rate in the intervention group was higher than that in the control group (P< 0.05). The highest blood glucose level in the intervention group was lower than that in the control group (P< 0.05), and the lowest blood glucose level was higher than that in the control group (P< 0.05). The glucose measurements per day in the intervention group were higher than those in the control group, and the average number of hospitalization days in the intervention group was lower than that in the control group (P< 0.05). Patient satisfaction in the intervention group was higher than that in the control group (P< 0.05).Conclusion: The hospital glycemic management system with information integration significantly improved the glycemic management of patients with malignant non-endocrine tumors and hyperglycemia, including their glucose level and glucose compliance rate, as well as patient satisfaction, and reduced the average number of hospitalization days and risk of hyperglycemia/hypoglycemia.Keywords: information integration, malignant tumor with hyperglycemia, hospital glycemic management system

Background: Cervical cancer (CC) is one of the most common cancers among women worldwide. Circular RNAs (circRNAs) are recently identified as important gene regulators with critical roles in cancer biology. In this study, we explored the effects of circ_0000388 on the malignant phenotypes of CC cells and its mechanism. Materials and Methods: Circ_0000388 expression and miR-337-3p expression in CC tissue samples were measured using quantitative real time polymerase chain reaction. CCK-8 was adopted to assess the effect of circ_0000388 on CC cell line proliferation. TUNEL assay was employed to probe the effect of circ_0000388 on apoptosis. Wound healing assay and transwell assay were conducted to detect the effect of circ_0000388 on migration and invasion. Further, interaction among circ_0000388, miR-337-3p, and TCF12 (transcription factor 12) was determined by bioinformatics analysis, RT-PCR, Western blot, RNA immunoprecipitation assay, and luciferase reporter assay. Results: Circ_0000388 expression in CC clinical samples was upregulated and this was correlated with unfavorable pathological indexes. Circ_0000388 remarkably enhanced the proliferation and metastasis of CC cells. Circ_0000388 overexpression dramatically impeded miR-337-3p expression and it was identified as a sponge of miR-337-3p. Furthermore, circ_00003888 also enhanced the TCF12 expression, while the effect could be reversed by co-transfection with miR-377-3p. Conclusions: Circ_0000388 was a novel oncogenic circRNA in CC, and promoted cancer progression via regulating miR-337-3p and TCF12, and could be potentially used as a diagnostic biomarker and therapy target.

Graphical abstract, Lung adenocarcinoma (LUAD) has a high mortality rate and is difficult to diagnose and treat in its early stage. Previous studies have demonstrated that small nucleolar RNAs (snoRNAs) play a critical role in tumor immune infiltration and the development of a variety of solid tumors. However, there have been no studies on the correlation between tumor-infiltrating immune-related snoRNAs (TIISRs) and LUAD. In this study, we filtered six immune-related snoRNAs based on the tissue specificity index (TSI) and expression profile of all snoRNAs between all LUAD cell lines from the Cancer Cell Line Encyclopedia and 21 types of immune cells from the Gene Expression Omnibus database. Further, we performed real-time quantitative polymerase chain reaction (RT-qPCR) to validate the expression status of these snoRNAs on peripheral blood mononuclear cells (PBMCs) and lung cancer cell lines. Next, we developed a TIISR signature based on the expression profiles of snoRNAs from 479 LUAD patients filtered by the random survival forest algorithm. We then analyzed the value of this TIISR signature (TIISR risk score) for assessing tumor immune infiltration, immune checkpoint inhibitor (ICI) treatment response, and the prognosis of LUAD between groups with high and low TIISR risk score. Further, we found that the TIISR risk score groups showed significant differences in biological characteristics and that the risk score could be used to assess the level of tumor immune cell infiltration, thereby predicting prognosis and responsiveness to immunotherapy in LUAD patients.

BACKGROUND The sleep quality of patients with postoperative glioma at home has not been reported worldwide. In this study, the sleep quality of postoperative glioma patients at home was explored through telephone interviews. AIM To investigate the sleep quality of patients with postoperative glioma. METHODS Glioma patients who were treated and operated on at Nanjing Brain Hospital from May 2012 to August 2019 were selected as participants via convenience sampling. A total of 549 patients were recruited by telephone, and 358 of those patients responded to the Pittsburgh Sleep Quality Index (PSQI). RESULTS The total PSQI score was 5.19 ± 3.39 in all patients with postoperative glioma, which was higher than that of the normal group. There were 135 patients with poor sleep quality (PSQI > 7), which accounted for 37.7% of all respondents. The scores of the seven dimensions of the PSQI were sleep latency (1.22 ± 1.05), sleep disturbance (1.12 ± 0.98), subjective sleep quality (1.03 ± 0.92), habitual sleep efficiency (1.02 ± 0.91), daytime dysfunction (0.95 ± 0.43), sleep persistence (0.83 ± 0.76), and use of sleeping medication (0.25 ± 0.24). The results showed that the subjective sleep quality of the patients who underwent an operation 1-2 years ago was worse than that of the patients who underwent an operation more than 2 years ago (P < 0.05). Older patients had worse sleep latency and sleep duration scores than younger patients (P < 0.05). Sleep disturbance and daytime dysfunction were worse in patients who received postoperative radiotherapy/ chemotherapy (P < 0.05). CONCLUSION The sleep quality of patients with postoperative glioma at home is worse than that of normal adults. Moreover, difficulty falling asleep and sleep disorders are common complications among these patients, and age, postoperative duration, and postoperative chemoradiotherapy could affect sleep quality.

Gonorrhea is one of the main sexually transmitted diseases in China. It mainly affects the genitourinary tract, and its clinical manifestations vary from asymptomatic to complicated types. The diagnosis of gonorrhea should be based on the patient's epidemiological history, clinical manifestations, and laboratory examination results. Treatment should be prompt and standardized and should involve the recommended treatment regimens. Patients should be appropriately followed up after treatment. The antimicrobial resistance of gonococcal isolates has become a severe problem of clinical concern. In order to provide technical guidance of the diagnosis and treatment of gonorrhea for health care workers, the authors developed the guidelines based on the version of 2014, which will be of important in the standardizing medical care of gonorrhea, and further facilitating control and prevention of the disease.

The purpose of this study was to investigate whether TXA can effectively reduce blood loss after HTO and related complications and to evaluate its safety.From March 2016 to March 2018, 100 patients who underwent medial opening wedge HTO in the Department of Orthopedics, the second affiliated hospital of xi'an jiaotong university, with an average age of 52.8 ± 3.2 years, were randomly divided into the TXA group (using intravenous TXA) and the control group (using the same amount of normal saline), with 50 patients in each group. The postoperative wound drainage volume, decrease in hemoglobin and hematocrit value, total blood loss, wound healing, blood transfusion, deep venous thrombosis (DVT) and pulmonary embolism (PE) were compared between the two groups.The drainage volume on the first postoperative day and the total drainage volume of the TXA group were significantly lower compared with those of the control group (145.7 vs 264.5 ml, 282.3 vs 413.2 ml, P 0.05). The decreases in the hemoglobin and hematocrit values on the postoperative first, second and fifth days were lower in the TXA group than those in the control group (1.4 VS 3.5, 2.6 vs 3.3, 1.9 vs 2.9 g, P 0.05; 3.3 vs 5.5, 5.0 vs 9.1, 3.8 vs 7.2%, P 0.05), and the mean total blood loss was also lower in the TXA group than that in the control group (477.9 vs 834.6 ml, P 0.05). In the control group, 1 patient had wound hematoma requiring additional paracentesis and pressure dressing, 1 patient had superficial wound infection requiring additional debridement, and 1 patient had postoperative blood transfusion compared to none in the TXA group (P 0.05). There was no symptomatic DVT or PE in either of the groups.Intravenous TXA can effectively and safely reduce blood loss and bleeding-related complications after HTO and was beneficial for the blood management of HTO.

Ovarian cancer (OC) is a common gynecological malignant carcinoma worldwide. Accumulating research has revealed that multiple microRNAs (miRNAs) are abnormally expressed at different levels in various malignancies, playing vital roles in tumorigenesis. This study investigated the regulatory functions and potential mechanism of miR-126 in OC proliferation, invasion and migration. It was found that miR-126 was prominently downregulated in OC. Moreover, the decrease of miR-126 promoted the aggressive phenotypes and indicated poor prognosis of OC patients. Functional assays demonstrated that restoration of miR-126 dramatically repressed OC cell proliferation, migration and invasion. Furthermore, luciferase reporter assay was conducted to verify putative binding sites of miR-126 in the epidermal growth factor-like domain 7 (EGFL7) 3 untranslated region (3′UTR), indicating that EGFL7 was a target gene of miR-126 in OC cells. It was further discovered that miR-126 exerts its function on regulating ERK/MAPK pathway and epithelial-to-mesenchymal transition (EMT) in OC cells. The above findings suggested that miR-126 served as a cancer suppressor in OC, suggesting a promising application of miR-126 in the clinical diagnosis and therapeutics of OC.

Background EDP‐305 is a novel and potent farnesoid X receptor (FXR) agonist, with no/minimal cross‐reactivity to TGR5 or other nuclear receptors. Herein we report therapeutic efficacy of EDP‐305, in direct comparison with the first‐in‐class FXR agonist obeticholic acid (OCA), in mouse models of liver disease. Methods EDP‐305 (10 and 30 mg/kg/day) or OCA (30mg/kg/day) was tested in mouse models of pre‐established biliary fibrosis (BALBc.Mdr2‐/‐, n = 9‐12/group) and steatohepatitis induced by methionine/choline‐deficient diet (MCD, n = 7‐12/group). Effects on biliary epithelium were evaluated in vivo and in primary EpCAM + hepatic progenitor cell (HPC) cultures. Results In a BALBc.Mdr2‐/‐ model, EDP‐305 reduced serum transaminases by up to 53% and decreased portal pressure, compared to untreated controls. Periportal bridging fibrosis was suppressed by EDP‐305 at both doses, with up to a 39% decrease in collagen deposition in high‐dose EDP‐305. In MCD‐fed mice, EDP‐305 treatment reduced serum ALT by 62% compared to controls, and profoundly inhibited perisinusoidal ‘chicken wire’ fibrosis, with over 80% reduction in collagen deposition. In both models, treatment with 30mg/kg OCA reduced serum transaminases up to 30%, but did not improve fibrosis. The limited impact on fibrosis was mediated by cholestasis‐independent worsening of ductular reaction by OCA in both disease models; OCA but not EDP‐305 at therapeutic doses promoted ductular proliferation in healthy mice and favoured differentiation of primary HPC towards cholangiocyte lineage in vitro. Conclusions EDP‐305 potently improved pre‐established liver injury and hepatic fibrosis in murine biliary and metabolic models of liver disease, supporting the clinical evaluation of EDP‐305 in fibrotic liver diseases including cholangiopathies and non‐alcoholic steatohepatitis.

Introduction: Ultrasound-guided thoracic paravertebral block (US-TPVB) is generally used for postoperative analgesia. We hypothesized that single-injection US-TPVB could be used as the principal anesthetic technique for a peritoneal dialysis catheter (PDC) procedure (implantation or removal). The anesthetic effect and venous ropivacaine level after a TPVB would be compared with that after local anesthetic infiltration (LAI). Methods: Patients undergoing PDC procedures were randomized into Group LAI or TPVB. In Group LAI, 40 mL of 0.25% ropivacaine were used. In Group TPVB, single-injection of US-TPVB at T10–T11 level was performed with 20 mL of 0.25% ropivacaine. The quality of anesthesia, visual analogue scale of pain, and venous total plasma ropivacaine level were compared between the 2 groups. Results: Seventy-four eligible patients were enrolled and 38 in Group TPVB. Thirty patients in Group TPVB and 26 patients in Group LAI underwent PDC procedures successfully. Higher satisfaction rates by nephrologists and patients (76.3 and 78.9%) were reported in Group TPVB (44.4 and 44.4% in Group LAI, respectively). The peak venous total plasma ropivacaine concentrations were below the reported toxic threshold in the 2 groups. Conclusions: A single-injection US-TPVB with 20 mL of 0.25% ropivacaine at T10–T11 could be the principal anesthetic technique for PDC procedures, which provided a comparable anesthetic effect to that of LAI with 40 mL ropivacaine. Higher satisfaction rates by nephrologists and patients were observed in Group TPVB. The 20 mL dose of 0.25% ropivacaine used for an US-TPVB was safe in end-stage renal diseases patients.

The authors have requested that this preprint be removed from Research Square.

Background: Lung cancer is the most common cancer and one of the main causes of cancer-related deaths, and it manifests as metastatic disease in most cases. Considering frequent gene mutation and/or signaling deregulation in lung adenocarcinoma, identifying novel factors or agents targeting these signaling pathways might be promising strategies for lung adenocarcinoma therapy. Methods: GEO datasets were analyzed to identify differentially expressed genes (DEGs) in lung adenocarcinoma. The specific effects of candidate gene overexpression or knockdown on lung adenocarcinoma cell phenotypes were examined. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) are used to connect the genomic and functional information of DEGs. The dynamic effects of candidate gene and signaling pathway agonist on lung adenocarcinoma malignant behaviors were investigated. Finally, clinical lung adenocarcinoma and adjacent non-cancerous tissues were collected and the levels of candidate gene were examined in tissue samples.Results: Inhibitor of DNA binding 2 (ID2) was identified as an aberrantly downregulated gene in lung adenocarcinoma. ID2 overexpression suppressed lung adenocarcinoma cell viability, colony formation capacity, and migration. ID2 overexpression also reduced the protein levels of N-cadherin, MMP2, MMP9, and the phosphorylation of AKT and mTOR. The PI3K/AKT/mTOR signaling agonist exerted opposite effects on lung adenocarcinoma cells to those of ID2 overexpression, and partially reversed the effects of ID2 overexpression. In tissue samples, ID2 protein levels and mRNA expression were also downregulated compared with those in adjacent non-cancerous tissues. Conclusion: ID2 exerts its tumor-suppressive effects on lung adenocarcinoma cell malignant behaviors through inhibiting the activation of the PI3K/AKT/mTOR signaling pathway. Restoring ID2 expression in lung adenocarcinoma cells might improve the curative effect of lung adenocarcinoma therapies.

Juan Jiang,1,2 Xia Wang,3 Jian He,3 Donglei Liao,3 Xiaolu Deng3 1Department of Respiratory Medicine (National Key Clinical Specialty), Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Hunan Provincial Clinical Research Center for Respiratory Diseases, Changsha, People’s Republic of China; 3Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Xiaolu DengDepartment of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of ChinaTel +86 13786113654Email dengxiaolu1019@163.comBackground: Pneumocystis jirovecii pneumonia (PCP) is a serious opportunistic infection in immunocompromised children. Real-time polymerase chain reaction (PCR) is widely used for the diagnosis of PCP due to its good accuracy. However, the diagnostic performance of multiplex real-time PCR on sputum in children with PCP has never been explored.Methods: Medical records of 63 consecutive pediatric patients were analyzed retrospectively, including 13 cases with PCP and 50 with non-PCP pneumonia. Pneumocystis jirovecii (P. jirovecii) and other co-pathogens detected by multiplex real-time PCR in sputum samples were summarized. Using clinical composite diagnosis as the reference standard, we further compared the diagnostic performance of multiplex real-time PCR to combined serological markers (1,3)-β-D-glucan plus lactate dehydrogenase. Additionally, modifications of antimicrobial treatment for pediatric PCP patients after the report of multiplex real-time PCR results were reviewed.Results: In children with PCP, nonproductive cough and shortness of breath were more common, lymphocyte count in peripheral blood was markedly lower, and serum levels of (1,3)-β-D-glucan and lactate dehydrogenase were much higher than non-PCP group. Multiplex real-time PCR reached a sensitivity of 100% in diagnosing PCP, which was better than serum (1,3)-β-D-glucan plus lactate dehydrogenase (76.9%). Its specificity (98.0%) significantly surpassed serum (1,3)-β-D-glucan plus lactate dehydrogenase (84.4%). Furthermore, multiplex real-time PCR showed a good performance in identifying co-pathogens in sputum of pediatric PCP patients. Cytomegalovirus, Epstein–Barr virus and Streptococcus pneumoniae were the most common co-pathogens in these patients. Initial antimicrobial treatment was modified in 76.9% of children with PCP after the report of PCR results.Conclusion: Multiplex real-time PCR on sputum is a diagnostic tool with good performance for the identification of P. jirovecii as well as co-pathogens in children with PCP. Sputum may be an alternative to bronchoalveolar lavage fluid for PCR assay in children when bronchoscopic examination is not feasible.Keywords: immunocompromised population, children, Pneumocystis jirovecii pneumonia, multiplex real-time polymerase chain reaction, sputum

Weiling Leng,1,* Juan Jiang,2,* Bing Chen,1 Qinan Wu3 1Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China; 2Endocrinology and Nephrology Department, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, People’s Republic of China; 3Endocrinology Department, Dazu Hospital of Chongqing Medical University, The People’s Hospital of Dazu, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qinan WuEndocrinology Department, Dazu Hospital of Chongqing Medical University, The People’s Hospital of Dazu, Chongqing Email wqn11@126.com View the original paper by Dr Leng and colleagues This is in response to the Letter to the Editor

Introduction:The risk of mortality is higher in pediatric intensive care units (PICU). To prevent mortality in critically ill infants, optimal clinical management and risk stratification are required.Aims and Objectives:To assess the accuracy of PELOD-2, PIM-3, and PRISM-III/IV scores to predict outcomes in pediatric patients.Results:A total of 29 studies were included for quantitative synthesis in meta-analysis. PRISM-III/IV scoring showed pooled sensitivity of 0.78; 95% CI: 0.72–0.83 and pooled specificity of 0.75; 95% CI: 0.68–0.81 with 84% discrimination performance (SROC 0.84, 95% CI: 0.80–0.87). In the case of PIM-3, pooled sensivity 0.75; 95% CI 0.71–0.79 and pooled specificity 0.76; 95% CI 0.73–0.79 were observed with good discrimination power (SROC, 0.82, 95% CI 0.78–0.85). PELOD-2 scoring system had pooled sensitivity of 0.78 (95% CI: 0.71–0.83) and combined specificity of 0.75 (95% CI: 0.68–0.81), as well as good discriminating ability (SROC 0.83, 95% CI: 0.80–0.86) for mortality prediction in PICU patients.Conclusion:PRISM-III/IV, PIM-3, and PELOD-2 had good performance for mortality prediction in PICU but with low to moderate certainty of evidence. More well-designed studies are needed for the validation of the study results.

IntroductionEpidermal growth factor receptor (EGFR) 19del and L858R mutation are known as “common mutations” in non-small cell lung cancer (NSCLC) and predict sensitivities to EGFR tyrosine kinase inhibitors (TKIs), whereas 20ins and T790M mutations confer drug-resistance to EGFR-TKIs. The role of the remaining uncommon EGFR mutations remains elusive.MethodsWe retrospectively screened a group of NSCLC patients with uncommon EGFR mutations other than 20ins and T790M. The mutation patterns, use of different generations of EGFR-TKIs, and concurrent genetic alterations were analyzed. Meanwhile, a cohort of patients with single 19del or L858R were included for comparison.ResultsA total of 180/1,300 (13.8%) patients were identified. There were 102 patients with advanced or recurrent NSCLC that received first-line therapy of gefitinib/erlotinib/icotinib and afatinib and were eligible for analysis. The therapeutic outcomes among patients with common mutations (EGFRcm, n = 97), uncommon mutation plus common mutations (EGFRum+EGFRcm, n = 52), complex uncommon mutations (complex EGFRum, n = 22), and single uncommon mutations (single EGFRum, n = 28) were significantly different (ORRs: 76.3%, 61.5%, 54.5%, and 50.0%, respectively, p = 0.023; and mPFS: 13.3, 14.7, 8.1, and 6.0 months, respectively, p = 0.004). Afatinib showed superior efficacy over gefitinib/erlotinib/icotinib in EGFRcm (ORR: 81.0% vs. 75.0%, p = 0.773; mPFS: 19.1 vs. 12.0m, p = 0.036), EGFRum+EGFRcm (ORR: 100% vs. 54.5%, p = 0.017; mPFS: NE vs. 13.6m, p = 0.032), and single EGFRum (ORR: 78.6% vs. 21.4%, p = 0.007; mPFS: 10.1 vs. 3.0m, p = 0.025) groups. Comprehensive genomic profiling by Next Generation Sequencing encompassing multiple cancer-related genes was performed on 51/102 patients; the mPFS of patients without co-mutation (n = 16) and with co-mutations of tumor-suppressor genes (n = 31) and driver oncogenes (n = 4) were 31.1, 9.2, and 12.4 months, respectively (p = 0.046). TP53 mutation was the most common co-alteration and showed significantly shorter mPFS than TP53 wild-type patients (7.0 vs. 31.1m, p < 0.001). Multivariate analysis revealed that concurrent 19del/L858R and tumor-suppressor gene alterations independently predicted better and worse prognosis in patients with uncommon mutations, respectively.ConclusionsUncommon EGFR mutations constitute a highly heterogeneous subgroup of NSCLC that confer different sensitivities to EGFR-TKIs with regard to the mutation patterns. Afatinib may be a better choice for most uncommon EGFR mutations. Concurrent 19del/L858R and tumor-suppressor gene alterations, especially TP53, can be established as prognostic biomarkers.

Shank3 is a postsynaptic scaffolding protein of excitatory synapses. Mutations or variations of SHANK3 are associated with various psychiatric and neurological disorders. We set to determine its normal expression pattern in the human brain, and its change, if any, with age and Alzheimer’s disease (AD)-type β-amyloid (Aβ) and Tau pathogenesis. In general, Shank3 immunoreactivity (IR) exhibited largely a neuropil pattern with differential laminar/regional distribution across brain regions. In youth and adults, subsets of pyramidal/multipolar neurons in the cerebrum, striatum, and thalamus showed moderate IR, while some large-sized neurons in the brainstem and the granule cells in the cerebellar cortex exhibited light IR. In double immunofluorescence, Shank3 IR occurred at the sublemmal regions in neuronal somata and large dendrites, apposing to synaptophysin-labeled presynaptic terminals. In aged cases, immunolabeled neuronal somata were reduced, with disrupted neuropil labeling seen in the molecular layer of the dentate gyrus in AD cases. In immunoblot, levels of Shank3 protein were positively correlated with that of the postsynaptic density protein 95 (PSD95) among different brain regions. Levels of Shank3, PSD95, and synaptophysin immunoblotted in the prefrontal, precentral, and cerebellar cortical lysates were reduced in the aged and AD relative to youth and adult groups. Taken together, the differential Shank3 expression among brain structures/regions indicates the varied local density of the excitatory synapses. The enriched Shank3 expression in the forebrain subregions appears inconsistent with a role of this protein in the modulation of high cognitive functions. The decline of its expression in aged and AD brains may relate to the degeneration of excitatory synapses.

Doublecortin (DCX) is transiently expressed in new-born neurons in the subventricular zone (SVZ) and subgranular zone (SGZ) related to adult neurogenesis in the olfactory bulb (OB) and hippocampal formation. DCX immunoreactive (DCX+) immature neurons also occur in the cerebral cortex primarily over layer II and the amygdala around the paralaminar nucleus (PLN) in various mammals, with interspecies differences pointing to phylogenic variation. The tree shrews (Tupaia belangeri) are phylogenetically closer to primates than to rodents. Little is known about DCX+ neurons in the brain of this species. In the present study, we characterized DCX immunoreactivity (IR) in the forebrain of Chinese tree shrews aged from 2 months- to 6 years-old (n = 18). DCX+ cells were present in the OB, SVZ, SGZ, the piriform cortex over layer II, and the amygdala around the PLN. The numerical densities of DCX+ neurons were reduced in all above neuroanatomical regions with age, particularly dramatic in the DG in the 5–6 years-old animals. Thus, DCX+ neurons are present in the two established neurogenic sites (SVZ and SGZ) in the Chinese tree shrew as seen in other mammals. DCX+ cortical neurons in this animal exhibit a topographic pattern comparable to that in mice and rats, while these immature neurons are also present in the amygdala, concentrating around the PLN as seen in primates and some nonprimate mammals.

Object: Exploring the effect of Tetrahydropalmatine (THP) on diabetic neuropathic pain (DNP) and its possible mechanism. Methods: The type 2 diabetic (T2DM) rat models were prepared by high-fat and high-sugar feeding combined with a single small-dose intraperitoneal injection of streptozotocin (STZ). When the mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL) of T2DM model rats decreased to less than 85% which were judged as DNP-bearing rats. After treatment with or without THP, the protein expression of hypertonic glycerol reactive kinase (p38), phosphorylated hypertonic glycerol-responsive kinase (p-p38) and OX42 (a specific marker of microglia) were detected by Western Blot and and the mRNA content of p38 and OX42 were detected by qRT-PCR. The expression of pro-inflammatory factors IL-1β, IL-6, TNF-α, as well as chemotactic factors and their receptors including CXCL1, CXCR2, CCL2 and CCR2 in spinal tissues were detected by ELISA. Serum FINS and GSP content were also detected by ELISA. Double-label immunofluorescence were used to observe the expression of OX42 and p-p38 in the spinal dorsal horn. Results: Results showed that THP inhibited microglial activation of spinal in DNP rats. And after THP intervention, the MWT and TWL of DNP rats decreased, the expression of p38, p-p38 and OX42 in the spinal cord tissues of rats was significantly reduced while the mRNA of p38 and OX42 also reduced. The expression of IL-1β, IL-6, TNF-α, CXCL1, CXCR2, CCL2 and CCR2 in the spinal cord tissues of rats was significantly reduced (P Conclusions: THP significantly alleviates pain symptoms in DNP rats, and this effect may be achieved by inhibiting the inflammatory response caused by the activation of microglia mediated by the p38-MAPK signaling pathway.

Jin-Ping Zheng,1,* Jing Zhang,2,* Li-Jun Ma,3 Ping Chen,4 Mao Huang,5 Xue-Mei Ou,6 Zi-Wen Zhao,7 Shu-Juan Jiang,8 Jie Cao,9 Wanzhen Yao2 1State Key Laboratory of Respiratory Disease, National Clinical Research Center, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Respiratory Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 3Department of Respiratory Medicine, Henan Provincial People’s Hospital, Henan, People’s Republic of China; 4Department of Internal Medicine, The Second Xiangya Hospital, Hunan, People’s Republic of China; 5Jiangsu Province Hospital, Jiangsu, People’s Republic of China; 6Department of Respiratory Medicine, West China Hospital, Chengdu, People’s Republic of China; 7Department of Respiratory Medicine, Guangzhou First People’s Hospital, Guangzhou, People’s Republic of China; 8Department of Respiratory Medicine, Shandong Provincial Hospital, Shandong, People’s Republic of China; 9Department of Respiratory Medicine, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wanzhen YaoDepartment of Respiratory Medicine, Peking University Third Hospital, 49 North Garden Road, Beijing 100191, People’s Republic of ChinaTel +86 156 1190 8216Email yaowanzhen11@edusbm.comPurpose: The current guidelines recommend the use of systemic corticosteroids (SCS) as the optimal treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The aim of this real-world study was to evaluate whether nebulized budesonide (NBS) could also be used as an initial treatment for AECOPD.Patients and methods: AECOPD patients initially treated with NBS or SCS (oral/intravenous) were enrolled. A large-scale, long-term multicenter cohort study of AECOPD patients was performed to analyze outcomes for each treatment (NCT02051166).Results: Initial NBS and SCS treatment resulted in similar outcomes in terms of improvements in FEV1, PaO2, SaO2, and PaCO2. Disease severity affected outcome similarly in both groups. When the groups were stratified according to whether the initial treatment was subsequently intensified or reduced, more intubation was seen in the groups in which initial treatment was intensified. NBS escalation and SCS reduction groups spent more days in the hospital. The NBS escalation group was associated with the highest medical expenditure and a relatively higher rate of new-onset pneumonia. The NBS maintenance/reduction group showed the lowest mortality rate between groups. Stratification according to initial PaCO2 level showed more intubation in the groups with high initial PaCO2 concentrations.Conclusion: These results indicate that NBS may be used as an initial treatment in certain AECOPD patients, and further studies are needed to better define those most likely to benefit.Keywords: nebulized budesonide, systemic corticosteroids, chronic obstructive pulmonary disease, AECOPD &nbsp

The present work exhibits the adsorptive potential of hydroxyapatite coated activated carbon (C-HAP) composite for the removal of Pb(II) from aqueous solution. The composite was prepared by co-precipitating CaCl2 and activated carbon mixture with (NH4)2HPO4 solution. The adsorbent was characterized by Scanning electron microscopy (SEM), Fourier infrared spectroscopy (FTIR), X-ray diffraction (XRD), and gas sorption analyzer. The effects of several factors, such as pH, initial concentration, adsorbent dose, contact time, and co-existing ions on the degree of adsorption performance were discussed in batch experiments. The adsorption process of Pb(Ⅱ) on C-HAP followed the pseudo-second order kinetic model, and the equilibrium data at different temperatures were best fitted to Langmuir isotherm model. The mechanism of Pb (II) removal by C-HAP was a complex physicochemical process, and the maximum adsorption capacity of was 416.67 mg/g, which was significantly higher than that of many other adsorbents. The thermodynamic calculations suggested that the Pb(II) adsorption process was spontaneous and exothermic in nature. According to this study, the composite of C-HAP with high adsorption capacity could be explored as a newly developed adsorbent for future column application in Pb(II) removal.

Background Asthma is associated with multiple psychiatric comorbidities. However, the relationship between asthma and suicidality has not be well established. Methods According to the PRISMA guidelines, protocol of the study was registered in the PROSPERO database (CRD42019123150). A systematic search of the PubMed, Embase and PsycINFO databases was performed for relevant studies published from its inception to January 25, 2019. Studies that reported the risk of suicidal ideation, attempts and mortality in asthmatics compared with non-asthmatics were included. A random-effects model was used to synthesize the estimates and the quality of the included studies was assessed under the Newcastle-Ottawa Scale. Results Twenty-eight studies including 2,759,841 asthmatic patients and 16,290,362 non-asthmatic controls were pooled and analyzed in the current study. The pooled data showed that asthmatic patients had increased risk of exhibiting suicidal ideation (OR, 1.52; 95%CI, 1.37–1.70), suicide attempts (OR, 1.60; 95%CI, 1.33–1.92) and suicide mortality (OR, 1.31; 95%CI, 1.11–1.55) compared to non-asthmatic controls. Noticeably, adolescent asthmatic patients had a more than 2-fold risk of suicide mortality compared to non-asthmatic controls (OR, 2.14; 95%CI, 1.61–2.83). Limitations The limitations of the present study were variability in study designs and various measures of asthma and suicidality, which possibly contribute to notable heterogeneity. Conclusions Patients with asthma have a significantly increased risk of suicidal ideation, suicide attempts and suicide mortality. Clinical physicians should pay more attention to the increased risk of suicidality in asthmatics, screen for these suicidal thoughts and behaviors, and make appropriate mental health referrals when necessary.

Increasing evidence suggests that cancer progression is strongly influenced by the host immune response, which is represented by immune cell infiltrates. The T-lymphocyte-based Immunoscore is reported to be a reliable prognostic factor in colon cancer, but its significance in urothelial carcinoma of the bladder (UCB) is at an early stage of exploration. This study aimed to determine whether the tumor immune infiltrate, as evaluated by the Immunoscore, could act as a useful prognostic marker for UCB patients who have undergone radical cystectomy (RC). In this study, immunohistochemistry was used to examine the Immunoscore of 221 UCB patients who underwent RC. The Immunoscore of the patients was determined by the densities of CD3+ and CD8+ T cells at the tumor center and the invasive margin. A highly significant association between a low Immunoscore and a shortened patient survival (P

Worldwide, the most prevalent metabolic disorder is diabetes mellitus (DM), an important condition that has been widely studied. Diabetic peripheral neuropathy (DPN), a complication that can occur with DM, is associated with pain and can result in foot ulcers and even amputation. DPN treatments are limited and mainly focus on pain management. There is a clear need to develop treatments for DPN at all stages. To make this progress, it is necessary to understand the molecular signaling pathways related to DPN. For this review, we aimed to concentrate on the main signaling cascades that contribute to DPN. In addition, we provide information with regard to treatments that are being explored.

Accumulating evidence suggests that long noncoding RNA (lncRNA) plays important regulatory roles in cancer biology. However, the involvement of lncRNA in colorectal carcinoma progression remains largely unknown, especially in colorectal carcinoma metastasis. In this study, we investigated the changes in lncRNA expression in colorectal carcinoma and identified a new lncRNA, the antisense transcript of SATB2 (SATB2-AS1), as a key regulator of colorectal carcinoma progression. SATB2-AS1 was frequently downregulated in colorectal carcinoma cells and tissues, and patients whose tumors expressed SATB2-AS1 at low levels had a shorter overall survival and poorer prognosis. Downregulation of SATB2-AS1 significantly promoted cell proliferation, migration, and invasion in vitro and in vivo, demonstrating that it acts as a tumor suppressor in colorectal carcinoma. SATB2-AS1 suppressed colorectal carcinoma progression by serving as a scaffold to recruit p300, whose acetylation of H3K27 and H3K9 at the SATB2 promoter upregulated expression of SATB2, a suppressor of colorectal carcinoma growth and metastasis. SATB2 subsequently recruited HDAC1 to the Snail promoter, repressing Snail transcription and inhibiting epithelial-to-mesenchymal transition. Taken together, these data reveal SATB2-AS1 as a novel regulator of the SATB2-Snail axis whose loss facilitates progression of colorectal carcinoma. Significance: These data show that the lncRNA SATB2-AS1 mediates epigenetic regulation of SATB2 and Snail expression to suppress colorectal cancer progression. See related commentary by Li, p. 3536

Background Ageing, chronic diseases, prolonged inactivity, and inadequate nutrition pose a severe threat to skeletal muscle health and function. To date, experimental evidence suggests that ageing‐related subclinical inflammation could be an important causative factor in sarcopenia. Although inflammatory signalling has been implicated in the pathogenesis of experimental animal models of sarcopenia, few studies have surveyed the clinical association between circulating factors and muscle mass in patients before and after lifestyle interventions. In this study, we evaluated whether proinflammatory cytokines are associated with the onset of sarcopenia, which circulating factors are associated with the severity of sarcopenia, and how these factors change after lifestyle interventions in sarcopenic elderly persons. Methods A total of 56 elderly subjects (age ≥ 60 years) with sarcopenia and 56 elderly non‐sarcopenic subjects, who met entry criteria and had given informed consent, were selected from the Peking Union Medical College Hospital multicentre prospective longitudinal sarcopenia study for testing relevant circulating factors. Thirty‐two elderly subjects from the sarcopenic cohort completed a 12 week intensive lifestyle intervention programme with whey supplements (30 g/day) and a personalized resistance training regimen. The levels of proinflammatory cytokines and metabolic hormones, pre‐intensive and post‐intensive lifestyle interventions, were measured. Results The sarcopenic group was significantly older (72.05 ± 6.54 years; P 11.15 pg/mL) and TWEAK (>1276.48 pg/mL) were associated with a 7.6‐fold and 14.3‐fold increased risk of sarcopenia, respectively. After adjustment for confounding variables, high levels of TWEAK were still associated with a 13.4‐fold increased risk of sarcopenia. Intensive lifestyle interventions led to significant improvements in sarcopenic patients' muscle mass and serum profiles of TWEAK, TNF‐α, IL‐18, insulin, and adiponectin (all P

Farnesoid X receptor (FXR) is a nuclear receptor that has emerged as a key regulator in the maintenance of hepatic steatosis, inflammation, and fibrosis. However, the role of FXR in renal fibrosis remains to be established. Here, we investigate the effects of the FXR agonist EDP‐305 in a mouse model of tubulointerstitial fibrosis via unilateral ureteral obstruction (UUO). Male C57Bl/6 mice received a UUO on their left kidney. On postoperative d 4, mice received daily treatment by oral gavage with either vehicle control (0.5% methylcellulose) or 10 or 30 mg/kg EDP‐305. All animals were euthanized on postoperative d 12. EDP‐305 dose‐dependently decreased macrophage infiltration as measured by the F4/80 staining area and proinflammatory cytokine gene expression. EDP‐305 also dose‐dependently reduced interstitial fibrosis as assessed by morphometric quantification of the collagen proportional area and kidney hydroxyproline levels. Finally, yes‐associated protein (YAP) activation, a major driver of fibrosis, increased after UUO injury and was diminished by EDP‐305 treatment. Consistently, EDP‐305 decreased TGF‐β1—induced YAP nuclear localization in human kidney 2 cells by increasing inhibitory YAP phosphorylation. YAP inhibition may be a novel antifibrotic mechanism of FXR agonism, and EDP‐305 could be used to treat renal fibrosis.—Li, S., Ghoshal, S., Sojoodi, M., Arora, G., Masia, R., Erstad, D. J., Ferriera, D. S., Li, Y., Wang, G., Lanuti, M., Caravan, P., Or, Y. S., Jiang, L.‐J., Tanabe, K. K., Fuchs, B. C. The farnesoid X receptor agonist EDP‐305 reduces interstitial renal fibrosis in a mouse model of unilateral ureteral obstruction. FASEB J. 33, 7103–7112 (2019). www.fasebj.org

Pengbo Deng, Chengping Hu, Zeng Xiong, Yuanyuan Li, Juan Jiang, Huaping Yang, Yongjun Tang, Liming Cao, Rongli Lu Department of Respiratory Medicine, Key Site of National Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China Purpose: Large-scale studies have revealed that appropriate antiangiogenic treatment enables the recovery of the normal structure and function of solid tumor vessels. Epigallocatechin-3-gallate (EGCG), a natural extract of green tea, has multiple effects on angiogenesis. However, normalization of blood vessels due to natural ingredients has not yet been reported. Therefore, we examined the microvasculature, microenvironment, and efficacy of EGCG combined with chemotherapy in a xenograft model. Methods: We treated A549 cell (human lung adenocarcinoma cell line) xenograft-bearing nude mice with EGCG in vivo. CD31, αSMA, and collagen IV were labeled and detected using quantum-dot double-labeled immunofluorescence to measure microvessel density, microvessel pericyte-coverage index, and collagen IV expression. Vessel-perfusion function was determined by lectin injection, permeability by Evans blue extravasation, interstitial fluid pressure using the wick-in-needle technique, and hypoxia levels using a polarographic electrode and immunohistochemical pimonidazole labeling. Cisplatin concentration in tumor tissue was detected using graphite-furnace atomic absorption spectrophotometry. Xenograft mice were randomized into five groups: treated with saline, cisplatin, EGCG, EGCG + cisplatin on day 1, or EGCG + cisplatin during the vascular normalization window. Tumor-growth delay and tumor-suppression rate were measured to evaluate tumor growth. Results: EGCG treatment in vivo caused temporary changes, including transient depression of microvessel density, microvessel pericyte-coverage index, and collagen IV expression, transient elevation of vessel perfusion and permeability, and decreased interstitial fluid pressure and hypoxia. During vascular normalization, pretreatment with EGCG increased cisplatin concentration in tumor tissue compared with treatment with cisplatin only. Tumor-growth delay after treatment in the five groups during the vascular normalization window was 6.3±1.51, 7.5±1.57, 8.3±1.79, 12.1±1.35, and 15.4±1.99 days, indicating synergistic EGCG–cisplatin effects, especially during the vascular normalization window (P

Background Pleural fibrosis is defined as excessive depositions of matrix components that result in pleural tissue architecture destruction and dysfunction. In severe cases, the progression of pleural fibrosis leads to lung entrapment, resulting in dyspnea and respiratory failure. However, the mechanism of pleural fibrosis is poorly understood. Methods miR-4739 levels were detected by miRNA array and real-time PCR. Real-time PCR, western blotting and immunofluorescence were used to identify the expression profile of indicators related to fibrosis. Target gene of miR-4739 and promoter activity assay was measured by using dual-luciferase reporter assay system. In vivo, pleural fibrosis was evaluated by Masson staining and miR-4739 level was detected by In situ hybridization histochemistry. Findings We found that bleomycin induced up-regulation of miR-4739 in pleural mesothelial cells (PMCs). Over-regulated miR-4739 mediated mesothelial-mesenchymal transition and increased collagen-I synthesis in PMCs. Investigation on the clinical specimens revealed that high levels of miR-4739 and low levels of bone morphogenetic protein 7 (BMP-7) associated with pleural fibrosis in patients. Then we next identified that miR-4739 targeted and down-regulated BMP-7 which further resulted in unbalance between Smad1/5/9 and Smad2/3 signaling. Lastly, in vivo studies revealed that miR-4739 over-expression induced pleural fibrosis, and exogenous BMP-7 prevented pleural fibrosis in mice. Interpretation Our data indicated that miR-4739 targets BMP-7 which mediates pleural fibrosis. The miR-4739/BMP-7 axis is a promising therapeutic target for the disease. Fund The National Natural Science Foundation of China.

Purpose There are limited therapeutic options for patients with advanced penile squamous cell carcinoma (PSCC) after chemotherapy failure. Thus, we evaluated the feasibility of salvage treatment using the epidermal growth factor receptor (EGFR) mono-antibody nimotuzumab in chemotherapy-failed PSCC patients and explored potential response or resistance biomarkers. Materials and methods Six chemotherapy-failed PSCC patients with locally advanced disease or distant metastasis were enrolled consecutively to nimotuzumab treatment. Clinical responses and side effects were evaluated, and genetic characteristics of cancer specimens were analyzed through the next-generation sequencing of hotspot regions in cancer-related genes. Results Two of 6 patients showed partial responses, one was identified as having stable disease, while the other 3 had disease progression after nimotuzumab therapy. Side effects were all welltolerated. Genetic analysis revealed that TP53, CDKN2A, RB1, SMAD4, FLT3, and PIK3CA were the most frequently mutated genes in PSCC specimens, while altered KRAS, HRAS, EGFR, ERBB2, and FLT3 may be correlated with nimotuzumab resistance. Furthermore, 3 patients that were human papillomavirus-positive each showed clinical response or stable disease. Conclusions EGFR mono-antibody may be a potential modality for locally advanced PSCC patients after chemotherapy failure. Further large-scale clinical studies are needed to elucidate the role of human papillomavirus status and critical gene mutations in the clinical response to EGFR-targeted therapy.

PURPOSE To evaluate the value of α-fetoprotein (AFP) classification criteria in predicting tumor response and patient survival and to discuss the agreement between AFP criteria and modified Response Evaluation Criteria In Solid Tumors (mRECIST). MATERIALS AND METHODS Between January 2011 and December 2014, 147 patients with unresectable hepatocellular carcinoma (HCC) with baseline AFP levels ≥ 400 ng/mL who underwent transarterial chemoembolization as initial treatment were retrospectively enrolled for AFP/imaging correlation analysis. AFP-based response was classified as complete response (CR) in cases of AFP level normalization, partial response (PR) in cases of > 50% decrease vs baseline, stable disease (SD) in cases of -50% to +30% change vs baseline, or progressive disease (PD) in cases of > 30% increase vs baseline. Intermethod agreement between the 2 methods was assessed by Cohen κ coefficient. Response rates according to AFP and mRECIST were compared, and the association between response rate and overall survival (OS) was evaluated. RESULTS The κ value for agreement between AFP criteria and mRECIST was 0.549 (ie, moderate), with objective response and disease control rates of 36.1% and 63.3% per AFP criteria and 34.7% and 46.3% per RECIST (P = .807 and P = .003), respectively. Although AFP criteria and mRECIST showed significantly prognostic strata for CR, PR, SD, and PD after chemoembolization (P < .001 for both), some overlap in radiologic PD survival curves was observed. The OS of AFP-based disease control (ie, CR/PR/SD) was significantly longer than that of AFP-based PD among patients with radiologic PD (9.0 vs 6.0 mo; P < .001). CONCLUSIONS The defined AFP response moderately correlated with mRECIST response and yielded accurate prognostic prediction in patients with HCC and AFP levels ≥ 400 ng/mL treated with chemoembolization.

Background: The current study analyzed resected stage I–IIIA pulmonary lymphoepithelioma-like carcinoma (LELC) cases to define the clinical characteristics, prognosis and long-term outcomes of resected LELC, with the purpose of guiding clinical management for this rare tumor.Methods: Resected stage I–IIIA LELC, adenocarcinoma (ADC) and squamous cell carcinoma (SCC) cases from our center were enrolled. Propensity score matching (PSM) was applied to minimize the selection bias. Overall survival (OS) and disease-free survival (DFS) were compared between groups. Multivariate analyses were performed to identify the prognostic factors, and a nomogram was developed.Results: A total of 159 LELCs, 2,757 ADCs, and 1,331 SCCs were included. LELC, dominated among younger patients and non-smokers. LELC was a poorly differentiated disease that lacked driver gene mutations and was positive for immunohistochemistry indicators of squamous cell lineage. Survival analyses revealed that OS was significantly better for LELC than for other common non-small cell lung cancers (NSCLCs) both before PSM (all P < 0.001) and after PSM (all P < 0.05). Further analyses revealed that early pathological node stage and preoperative albumin level ≥35 were identified as independent prognostic factors favoring OS and DFS.Conclusions: LELC, dominated among younger and non-smoking populations, lacked driver gene mutations and was positive for immunohistochemistry indicators of squamous cell lineage. The survival outcome of LELC was better than other common NSCLCs.

Objective This study aimed to evaluate the difference of two various robotic technology applied in R- Total mesorectal excision (TME). Methods From May 2017 to December 2018, consecutive patients with rectal cancer who underwent da Vinci R-TME or Micro Hand S R-TME were enrolled. The comparative study was conducted on Short-term Operative, Oncological, and Functional Outcomes between two type of R-TME. Results 47 patients underwent da Vinci R-TME, and 43 patients underwent Micro Hand S R-TME. No difference occured between two groups in TME completeness, CRM, DRM, CRM involvement and DRM involvement, operative time, blood loss, protective ileostomy, conversion rate, number of retrieved lymph nodes, Comprehensive Complication Index (CCI), International Prostate Symptom Score (IPSS) or Wexner scores. However, the setup time in the Micro Hand S group was longer. Conclusions In the present study, both da Vinci R-TME and Micro Hand S R-TME achieve excellent TME quality with acceptable morbidity and postoperative function.

Background Previous study indicated that transversus abdominis plane (TAP) block could be the principal anesthetic technique for peritoneal dialysis catheter (PDC) implantations. However, a TAP block could not provide an optimal anesthetic effect on catheter exit site during PDC implantation. We hypothesized that single-injection ultrasound-guided thoracic paravertebral block (US-TPVB) could be the principal anesthetic technique with better pain relief at catheter exit site during PDC implantation, compared to a TAP block. And anesthesia quality of a single-injection US-TPVB was compared with that of a TAP block and local anesthetic infiltration (LAI). Methods Patients undergoing PDC implantations were randomized into groups TPVB or TAP or LAI. In group TPVB, single-injection US-TPVB at T10-T11 level was performed with 20 ml of 0.25% ropivacaine. In group TAP, oblique subcostal TAP block was performed with 20 ml of 0.25% ropivacaine. In group LAI, 40 ml of 0.25% ropivacaine was used. Anesthesia quality was compared among the three groups, including general anesthesia conversion rate, cumulative rescuing sufentanil consumption, and satisfaction rate by nephrologists and patients. Results Eighty-eight eligible patients were enrolled. Visual analogue scale (VAS) at most time points (except for the catheter exit site) were lower in group TAP, compared with group TPVB. VAS at parietal peritoneum manipulation was 6 (5, 7), 3 (0, 6), and 7 (4.75, 9) in groups TPVB, TAP, and LAI, respectively (P P = 0.005). Lower general anesthesia conversion rate, less cumulative rescuing sufentanil consumption, and higher satisfaction rates by nephrologists and patients were recorded in group TAP, compared with groups TPVB and LAI. Conclusions Single-injection US-TPVB provided a better pain relief at catheter exit site. The quality and reliability of anesthesia after a single-injection US-TPVB was comparable to that of LAI, but not better than that of an oblique subcostal TAP block for PDC implantation. Trial registration TCTR20160911002. Registered on 8 September 2016.

Survival rates are usually used to evaluate the effect of cancer treatment and prevention. No study has focused on the characteristic of population-based cancer survival in Fujian, which is regarded as one of the high-risk areas of cancer in China. This study aims to analyze the 5-year relative survival of patients in Fujian Province using population-based cancer registry data. A total of 8 population-based registries in Fujian Province reported cancer cases diagnosed in 2012-2014. Relative survival was calculated as the ratio between observed survival and expected survival. The 5-year relative survival for all cancers combined was 36.19% and the age-standardized 5-year relative survival for all patients was 31.80%. Females had higher relative survival than males (38.90% and 27.00%). The patients in urban areas had higher relative survival than those in rural areas (32.34% and 31.29%). Lung, gastric, liver, colorectal, and esophageal cancers were the five most common cancers, with 5-year relative survival below 50%. This is the first study that evaluated the population-based cancer relative survival in Fujian, China. Our study suggests that the overall survival of cancer patients in Fujian Province is poor. Furthermore, the results of this study can be used as a baseline for further research in Fujian, and provide important evidence for cancer etiology research.

Dystrophic neurites (DNs) are found in many neurological conditions such as traumatic brain injury and age-related neurodegenerative diseases. In Alzheimer’s disease (AD) specifically, senile plaques containing silver-stained DNs were already described in the original literature defining this disease. These DNs could be both axonal and dendritic in origin, while axonal dystrophy relative to plaque formation has been more extensively studied. Here, we demonstrate an early occurrence of dendritic dystrophy in the hippocampal CA1 and subicular regions in human brains (n = 23) with primary age-related tauopathy (PART), with neurofibrillary tangle (NFT) burden ranging from Braak stages I to III in the absence of cerebral β-amyloid (Aβ) deposition. In Bielschowsky’s silver stain, segmented fusiform swellings on the apical dendrites of hippocampal and subicular pyramidal neurons were observed in all the cases, primarily over the stratum radiatum (s.r.). The numbers of silver-stained neuronal somata and dendritic swellings counted over CA1 to subiculum were positively correlated among the cases. Swollen dendritic processes were also detected in sections immunolabeled for phosphorylated tau (pTau) and sortilin. In aged and AD brains with both Aβ and pTau pathologies, silver- and immunolabeled dystrophic-like dendritic profiles occurred around and within individual neuritic plaques. These findings implicate that dendritic dystrophy can occur among hippocampal pyramidal neurons in human brains with PART. Therefore, as with the case of axonal dystrophy reported in literature, dendritic dystrophy can develop prior to Alzheimer-type plaque and tangle formation in the human brain.

Objective To evaluate the impact of robotic technology on the learning curve for robot-assisted gastrectomy in the initial clinical application stage and to compare RAG with laparoscopic-assisted gastrectomy using a short-term evaluation. Methods Between September 2016 and December 2018, 111 consecutive distal gastric cancer patients who were candidates for RAG or LAG were prospectively enrolled. Operative findings, morbidity, oncological findings, and the learning curve were analyzed. Results Thirty patients underwent RAG with the da Vinci Si robot system, and eighty-one patients underwent LAG. Blood loss was lower during RAG than during LAG (133.80 ± 95.28 vs. 178.83 ± 98.37, P = 0.046). The operative time for RAG was significantly longer (304.45 ± 42.08 vs. 281.17 ± 32.69, P = 0.015). The number of retrieved lymph nodes (LNs) was greater (37.33 ± 8.25 vs. 32.78 ± 5.98, P = 0.003) with RAG. Notably, RAG had an advantage in the dissection of No. 9 and 11p LNs (3.56 ± 1.76 vs. 2.78 ± 1.30, P = 0.038; 2.48 ± 0.93 vs. 1.99 ± 0.84, P = 0.015, respectively). Severe complications were less frequent in the RAG group (7 (8.6%) vs. 1 (3.3%), P = 0.003). No significant differences in terms of postoperative recovery were found between the two groups. The learning curve for RAG showed that the cumulative sum value decreased from the 10th case, while it decreased from the 28th case in the LAG group. Conclusion By means of robotic technology, RAG is better than LAG for the dissection of No. 9 and 11p LNs and for the alleviation of surgical trauma, and the technique is learned more rapidly during the preliminary stage than the LAG technique.

Diagnosing Alzheimer’s disease (AD) in the preclinical stage offers opportunities for early intervention; however, there is currently a lack of convenient biomarkers to facilitate the diagnosis. Using radiomics analysis, we aimed to determine whether the features extracted from multiparametric magnetic resonance imaging (MRI) can be used as potential biomarkers. This study was part of the Sino Longitudinal Study on Cognitive Decline project (NCT03370744), a prospective cohort study. All participants were cognitively healthy at baseline. Cohort 1 (n = 183) was divided into individuals with preclinical AD (n = 78) and controls (n = 105) using amyloid-positron emission tomography, and this cohort was used as the training dataset (80%) and validation dataset (the remaining 20%); cohort 2 (n = 51) was selected retrospectively and divided into “converters” and “nonconverters” according to individuals’ future cognitive status, and this cohort was used as a separate test dataset; cohort three included 37 converters (13 from the Alzheimer’s Disease Neuroimaging Initiative) and was used as another test set for independent longitudinal research. We extracted radiomics features from multiparametric MRI scans from each participant, using t-tests, autocorrelation tests, and three independent selection algorithms. We then established two classification models (support vector machine [SVM] and random forest [RF]) to verify the efficiency of the retained features. Five-fold cross-validation and 100 repetitions were carried out for the above process. Furthermore, the acquired stable high-frequency features were tested in cohort three by paired two-sample t-tests and survival analyses to identify whether their levels changed with cognitive decline and impact conversion time. The SVM and RF models both showed excellent classification efficiency, with an average accuracy of 89.7–95.9% and 87.1–90.8% in the validation set and 81.9–89.1% and 83.2–83.7% in the test set, respectively. Three stable high-frequency features were identified, all based on the structural MRI modality: the large zone high-gray-level emphasis feature of the right posterior cingulate gyrus, the variance feature of the left superior parietal gyrus, and the coarseness feature of the left posterior cingulate gyrus; their levels were correlated with amyloid-β deposition and predicted future cognitive decline (areas under the curve 0.649–0.761). In addition, levels of the variance feature at baseline decreased with cognitive decline and could affect the conversion time (p < 0.05). In conclusion, this exploratory study shows that the radiomics features of multiparametric MRI scans could represent potential biomarkers of preclinical AD.