Network Pharmacology Prediction: The Possible Mechanisms of Cinobufotalin against Osteosarcoma

Objective. To explore the active compounds and targets of cinobufotalin (huachansu) compared with the osteosarcoma genes to obtain the potential therapeutic targets and pharmacological mechanisms of action of cinobufotalin on osteosarcoma through network pharmacology. Methods. The composition of cinobufotalin was searched by literature retrieval, and the target was selected from the CTD and TCMSP databases. The osteosarcoma genes, found from the GeneCards, OMIM, and other databases, were compared with the cinobufotalin targets to obtain potential therapeutic targets. The protein-protein interaction (PPI) network of potential therapeutic targets, constructed through the STRING database, was inputted into Cytoscape software to calculate the hub genes, using the NetworkAnalyzer. The hub genes were inputted into the Kaplan-Meier Plotter online database for exploring the survival curve. Functional enrichment analysis was identified using the DAVID database. Results. 28 main active compounds of cinobufotalin were explored, including bufalin, adenosine, oleic acid, and cinobufagin. 128 potential therapeutic targets on osteosarcoma are confirmed among 184 therapeutic targets form cinobufotalin. The hub genes included TP53, ACTB, AKT1, MYC, CASP3, JUN, TNF, VEGFA, HSP90AA1, and STAT3. Among the hub genes, TP53, ACTB, MYC, TNF, VEGFA, and STAT3 affect the patient survival prognosis of sarcoma. Through function enrichment analysis, it is found that the main mechanisms of cinobufotalin on osteosarcoma include promoting sarcoma apoptosis, regulating the cell cycle, and inhibiting proliferation and differentiation. Conclusion. The possible mechanisms of cinobufotalin against osteosarcoma are preliminarily predicted through network pharmacology, and further experiments are needed to prove these predictions.

Surgical Resection is Preferred in Selected Solitary Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis

Backgrounds: Sorafenib is the standard care for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT), though it offers limited survival. This study was designed to compare clinical outcomes between liver resection (surgery) and trans-arterial chemoembolization plus radiotherapy (TACE-RT) as the initial treatment modality for resectable treatment-naïve solitary HCC combined with subsegmental (Vp1), segmental (Vp2), and lobar (Vp3) PVTT. Methods: From the institutional HCC registry, we identified 116 patients diagnosed with resectable treatment-naïve HCC with Vp1-Vp3 PVTT based on radiologic images who received surgery (n=44) or TACE-RT (n=72) as a primary treatment between 2010 and 2015. A propensity score matching (PSM) model was created. Results: The TACE-RT group had a higher tumor burden (tumor size, extent, and markers) than the surgery group. Cumulative patient survival curve in the surgery group was significantly higher than in the TACE-RT group before and after PSM. Liver function was relatively well-preserved in the surgery group compared with the TACE-RT group. TACE-RT group, male, increased alkaline phosphatase, and increased platelet count were predisposing factors for patient death in resectable treatment-naïve solitary HCC with PVTT. Conclusions: The present study suggests that surgery should be considered as an initial treatment in resectable treatment-naïve solitary HCC with Vp1-Vp3 PVTT.

Use and safety of prophylactic endoscopy from a single center serving urban and rural children with portal hypertension

Prophylactic endoscopy is routine in adults with portal hypertension (PHTN), but there is limited data in pediatrics. We sought to describe our experience with prophylactic endoscopy in pediatric PHTN. This is a retrospective study of 87 children who began surveillance endoscopy prior to gastrointestinal bleeding (primary prophylaxis) and 52 who began after an episode of bleeding (secondary prophylaxis) from 01/01/1994 to 07/01/2019. Patients who underwent primary prophylaxis had a lower mean number of endoscopies (3.897 vs 6.269, p = 0.001). The primary prophylaxis group was less likely to require a portosystemic shunt (6% vs 15%, p < 0.001) with no difference in immediate complications (1% vs 2%, p = 0.173) or 2-week complications (1% vs 2%, p = 0.097). No deaths were related to variceal bleeding or endoscopy. Kaplan–Meier Survival Curve suggests improved transplant and shunt free survival in the primary prophylaxis group (log-rank p < 0.001). Primary and secondary endoscopic prophylaxis should be considered safe for the prevention of variceal hemorrhage in pediatric portal hypertension. There are differences in outcomes in primary and secondary prophylaxis, but unclear if this is due to patient characteristics versus treatment strategy. Further study is needed to compare safety and efficacy to watchful waiting.

Predictors of mortality among TB-HIV co-infected children attending anti-retroviral therapy clinics of selected public hospitals in southern, Ethiopia: retrospective cohort study

Background Co-infection of tuberculosis and HIV has a significant impact on public health. TB is the most common opportunistic infection and the leading cause of death in HIV-positive children worldwide. But there is paucity of studies concerning the predictors of mortality among TB-HIV co-infected children. This study aimed to determine the predictors of mortality among TB-HIV co-infected children attending ART clinics of public hospitals in Southern Nation, Nationalities and Peoples Region (SNNPR), Ethiopia. Methods A hospital-based retrospective cohort study design was used among 284 TB-HIV co-infected children attending ART clinics at selected public hospitals in SNNPR, Ethiopia, from January 2009 to December 2019. Then, medical records of children who were TB/HIV co-infected and on ART were reviewed using a structured data extraction tool. Data were entered using Epidata 4.6 and analyzed using SPSS version 23. The Kaplan Meier survival curve along with log rank tests was used to estimate and compare survival time. Bivariable and multivariable analyses were conducted to identify predictors of mortality among TB/HIV co-infected children. Adjusted Hazard Ratio with p value < 0.05 and 95% confidence interval was considered statistically significant. Result A total of 284 TB/HIV co-infected children were included in the study. Among these, 35 (12.3%) of them died during the study period. The overall mortality rate was 2.78 (95%CI = 1.98-3.99) per 100 child years of observation. The predictors of mortality were anemia (AHR = 3.6; 95%CI: 1.39-9.31), fair or poor ART drug adherence (AHR = 2.9; 95%CI = 1.15-7.43), extrapulmonary TB (AHR = 3.9; 95%CI: 1.34-11.45) and TB drug resistance (AHR = 5.7; 95%CI: 2.07-15.96). Conclusion Mortality rate of TB/HIV co-infected children in selected public hospitals in SNNPR, Ethiopia was documented as 2.78 per child years of observation as a result of this study. Moreover, Anemia, drug resistant tuberculosis, extrapulmonary TB and poor adherence to ART drugs were identified as the predictors of mortality among these children.

High score of LDH plus dNLR predicts poor survival in patients with HER2-positive advanced breast cancer treated with trastuzumab emtansine

Objective To investigate the prognostic value of derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) in patients with advanced HER2 positive breast cancer treated with trastuzumab emtansine. Methods Fifty one patients with advanced HER2 positive breast cancer who received T-DM1 treatment in Harbin Medical University Cancer Hospital were selected. The clinical data and blood test indexes were collected, and the ROC curve determined the optimal cut-off value. Kaplan-Meier survival curve and Cox regression model was used to analyze the effect of different levels of dNLR,LDH,LNI (dNLR combined with LDH index) before and after T-DM1 treatment on the survival of patients. Results The median PFS and OS of the patients with advanced HER2 positive breast cancer who received T-DM1 treatment were 6.9 months and 22.2 months, respectively. The optimal cut-off value of LDH and dNLR before T-DM1 treatment was 244 U / L (P = 0.003) and 1.985 (P = 0.013), respectively. Higher LDH and dNLR were significantly correlated with shorter median PFS and OS (P < 0.05). The median PFS of patients with LNI (0), LNI (1) and LNI (2) were 8.1 months, 5.5 months and 2.3 months, respectively, P = 0.007. Univariate and multivariate analysis showed that LDH > 244 U / L, dNLR > 1.985, LNI > 0, ECOG ≥1 and HER-2 (IHC2 +, FISH+) before the T-DM1 treatment were the poor prognostic factors. LDH uptrend after the T-DM1 treatment also predicted poor prognosis. Conclusion Serum LDH > 244 U / L and dNLR > 1.985 before the T-DM1 treatment were prognostic risk factors for patients with advanced HER2 positive breast cancer receiving T-DM1 treatment. The higher LNI score was significantly associated with shorter PFS and OS. LDH uptrend after T-DM1 treatment was also related to the poor prognosis.

Functional implications of aging-related lncRNAs for predicting prognosis and immune status in glioma patients

Glioma, is the most prevalent intracranial tumor with high recurrence and mortality rate. Long noncoding RNAs (lncRNAs) play a critical role in the occurrence and progression of tumors as well as in aging regulation. Our study aimed to establish a new glioma prognosis model by integrating aging-related lncRNAs expression profiles and clinical parameters in glioma patients from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) datasets. The Pearson correlation analysis ( |R|> 0.6, P＜0.001) was performed to explore the aging-related lncRNAs, and univariate cox tregresion and least absolute shrinkage and selection operator (LASSO) regression were used to screening prognostic signature in glioma patients. Based on the fifteen lncRNAs, we can divide glioma patients into three subtypes, and developed a prognostic model. Kaplan-Meier survival curve analysis showed that low-risk patients had longer survival time than high-risk group. Principal component analysis indicated that aging-related lncRNAs signature had a clear distinction between high- and low-risk groups. We also found that fifteen target lncRNAs were closely correlated with 119 genes by establishing a co-expression network. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis displayed different function and pathways enrichment in high-and low-risk groups. The different missense mutations were observed in two groups, and the most frequent variant types were single nucleotide polymorphism (SNP). This study demonstrated that the novel aging-related lncRNAs signature had an important prognosis prediction and may contribute to individual treatment for glioma.

Impact of Extended and Restricted Antibiotic Deescalation on Mortality

Background: More data are needed about the safety of antibiotic de-escalation in specific clinical situations as a strategy to reduce exposure to broad-spectrum antibiotics. This study aims to compare the survival curve of patient de-escalated (early or late) against those not de-escalated on antibiotics, to determine the association of patient related, clinical related, and pressure sore/device related characteristics on all-cause 30-day mortality and determine the impact of early and late antibiotic de-escalation on 30-day all-cause mortality. Methods: This is a retrospective cohort study on patients in medical ward Hospital Kuala Lumpur, admitted between January 2016 and June 2019. A Kaplan–Meier survival curve and Fleming–Harrington test were used to compare the overall survival rates between early, late, and those not de-escalated on antibiotics while multivariable Cox proportional hazards regression was used to determine prognostic factors associated with mortality and the impact of de-escalation on 30-day all-cause mortality. Results: Overall mortality rates were not significantly different when patients were not de-escalated on extended or restricted antibiotics, compared to those de-escalated early or later (p = 0.760). Variables associated with 30-day all-cause mortality were a Sequential Organ Function Assessment (SOFA) score on the day of antimicrobial stewardship (AMS) intervention and Charlson’s comorbidity score (CCS). After controlling for confounders, early and late antibiotics were not associated with an increased risk of mortality. Conclusion: The results of this study reinforce that restricted or extended antibiotic de-escalation in patients does not significantly affect 30-day all-cause mortality compared to continuation with extended and restricted antibiotics.

From Model Organisms to Humans, the Opportunity for More Rigor in Methodologic and Statistical Analysis, Design, and Interpretation of Aging and Senescence Research

This review identifies frequent design and analysis errors in aging and senescence research and discusses best practices in study design, statistical methods, analyses, and interpretation. Recommendations are offered for how to avoid these problems. The following issues are addressed: 1) errors in randomization, 2) errors related to testing within-group instead of between-group differences, 3) failing to account for clustering, 4) failing to consider interference effects, 5) standardizing metrics of effect size, 6) maximum lifespan testing, 7) testing for effects beyond the mean, 8) tests for power and sample size, 9) compression of morbidity versus survival curve-squaring, and 10) other hot topics, including modeling high-dimensional data and complex relationships and assessing model assumptions and biases. We hope that bringing increased awareness of these topics to the scientific community will emphasize the importance of employing sound statistical practices in all aspects of aging and senescence research.

Prospective Study of Serum Uric Acid Levels and First Stroke Events in Chinese Adults With Hypertension

Objectives: We investigated the association between serum uric acid (SUA) levels and the risk of the first stroke in Chinese adults with hypertension.Methods: A total of 11, 841 hypertensive patients were selected from the Chinese Hypertension Registry for analysis. The relationship between SUA levels and first stroke was determined using multivariable Cox proportional hazards regression, smoothing curve fitting, and Kaplan–Meier survival curve analysis.Results: During a median follow-up of 614 days, 99 cases of the first stroke were occurred. Cox proportional hazards models indicated that SUA levels were not significantly associated with the first stroke event [adjusted-hazard ratio (HR) per SD increase: 0.98, 95% CI 0.76–1.26, P = 0.889]. In comparison to the group without hyperuricemia (HUA), there were no significantly higher risks of first stroke events (adjusted-HR: 1.22, 95% CI 0.79–1.90, P = 0.373) in the population with HUA. However, in the population less than 60 years old, subjects with HUA had a significantly higher risk of the first stroke than the population without HUA (adjusted-HR: 4.89, 95% CI 1.36–17.63, P = 0.015). In subjects older than 60 years, we did not find a significant relationship between HUA and first stroke (adjusted-HR: 0.97, 95% CI 0.60–1.56, P = 0.886). Survival analysis further confirmed this discrepancy (log-rank P = 0.013 or 0.899 for non-aging or aging group).Conclusion: No significant evidence in the present study indicated that increased SUA levels were associated with the risk of first stroke in the Chinese adults with hypertension. Age played an interactive role in the relationship between HUA and the first stroke event.

Comparison of Tumor Seeding and Recurrence Rate After Laparoscopic vs. Open Nephroureterectomy for Upper Urinary Tract Transitional Cell Carcinoma

Introduction: Laparoscopic surgery for Upper Urinary Tract Urothelial Cell Carcinoma (UTUC) is still debated for its possible seeding risk and thus consequent oncological recurrences, especially for atypical ones. The aim of the study is to compare recurrence and survival after Laparoscopic vs. Open Radical Nephroureterectomy (RNU) for Upper Urinary Tract Urothelial Cancer (UTUC).Method: A retrospective evaluation of UTUC consecutive surgeries from 2008 to 2019 was conducted, including pT ≥ 2, High Grade UTUC who underwent RNU with bladder cuff excision without concomitant lymphadenectomy in three urological tertiary centers. Statistical analyses compared recurrence and cancer specific survival, based on surgical approach, while logistic multivariate analyses and Kaplan Meyer survival curve analyzed possible risk factors for recurrence and survival.Results: One hundred seven cases of RNU, 47 (43.9%) laparoscopic and 60 (56.1%) open, were included in this report. Preoperative characteristics were comparable between groups. However, tumor stage was higher in the Open arm [T3–T4 in 44 (73.3%) vs. 20 (43.4%) in Laparoscopic]. Mean follow-up was 91.6 months in laparoscopy RNU vs. 93.5 months in open RNU. Recurrence rate (RR) was comparable between groups (p = 0.594), and so was the site, although 3 (6.3%) peritoneal recurrences were found only in laparoscopic group (p = 0.057). At multivariate logistic regression, tumor stage and surgical approach were independent predictors of recurrence (p &lt; 0.05), while only tumor stage was predictor of cancer specific death (p = 0.029).Conclusion: Surgical approach has no impact on recurrence site, overall survival, and RR. Still, according to our data peritoneal carcinomatosis was present only in laparoscopic arm, despite how it didn't reach statistical significance.