Modelling the dynamic gas/particle partitioning process of semi-volatile organic compounds emitted from point sources: Quantitative analysis and impact assessment.

The deleterious impact of pollution point sources on the surrounding environment and human has long been a focal point of environmental research. When considering the local atmospheric dispersion of semi-volatile organic compounds (SVOCs) around the emission sites, it is essential to account the dynamic process for the gas/particle (G/P) partitioning, which involves the transition from an initial state to a steady state. In this study, we have developed a model that enables the prediction of the dynamic process for G/P partitioning of SVOCs, particularly considering the influence from emission. It is important to note that the dynamic processes of the concentrations of SVOCs in particle phase (CP) and in gas phase (CG) differ significantly. These differences arise due to the influence of two critical factors: particulate proportion of SVOCs in the emissions (ϕ0) and octanol-air partitioning coefficient (KOA). The validity of our model was assessed by comparing its predictions of the extremum value of the G/P partitioning quotient (KP) with the results obtained from the steady-state model. Remarkably, the characteristic time (tC), used to evaluate the timescale required for SVOCs to reach steady state, demonstrated different variations with KOA for CP and CG. Additionally, the values of tC were quite different for CP and CG, which were markedly influenced by ϕ0. For some SVOCs with high KOA values, it took approximately 35 h to reach steady state. Furthermore, it was found that the time to achieve 95 % of steady state (t95 ≈ 3tC) could reach approximately 105 h. This duration is sufficient for chemicals to disperse from their emission site to the surrounding areas. Therefore, it is crucial to consider the dynamic process of G/P partitioning in local atmospheric transport studies. Moreover, the influence of ϕ0 should be incorporated into future investigations examining the dynamic process of G/P partitioning.

Development and validation of an ensemble machine-learning model for predicting early mortality among patients with bone metastases of hepatocellular carcinoma.

Purpose: Using an ensemble machine learning technique that incorporates the results of multiple machine learning algorithms, the study's objective is to build a reliable model to predict the early mortality among hepatocellular carcinoma (HCC) patients with bone metastases. Methods: We extracted a cohort of 124,770 patients with a diagnosis of hepatocellular carcinoma from the Surveillance, Epidemiology, and End Results (SEER) program and enrolled a cohort of 1897 patients who were diagnosed as having bone metastases. Patients with a survival time of 3 months or less were considered to have had early death. To compare patients with and without early mortality, subgroup analysis was used. Patients were randomly divided into two groups: a training cohort (n = 1509, 80%) and an internal testing cohort (n = 388, 20%). In the training cohort, five machine learning techniques were employed to train and optimize models for predicting early mortality, and an ensemble machine learning technique was used to generate risk probability in a way of soft voting, and it was able to combine the results from the multiply machine learning algorithms. The study employed both internal and external validations, and the key performance indicators included the area under the receiver operating characteristic curve (AUROC), Brier score, and calibration curve. Patients from two tertiary hospitals were chosen as the external testing cohorts (n = 98). Feature importance and reclassification were both operated in the study. Results: The early mortality was 55.5% (1052/1897). Eleven clinical characteristics were included as input features of machine learning models: sex (p = 0.019), marital status (p = 0.004), tumor stage (p = 0.025), node stage (p = 0.001), fibrosis score (p = 0.040), AFP level (p = 0.032), tumor size (p = 0.001), lung metastases (p < 0.001), cancer-directed surgery (p < 0.001), radiation (p < 0.001), and chemotherapy (p < 0.001). Application of the ensemble model in the internal testing population yielded an AUROC of 0.779 (95% confidence interval [CI]: 0.727-0.820), which was the largest AUROC among all models. Additionally, the ensemble model (0.191) outperformed the other five machine learning models in terms of Brier score. In terms of decision curves, the ensemble model also showed favorable clinical usefulness. External validation showed similar results; with an AUROC of 0.764 and Brier score of 0.195, the prediction performance was further improved after revision of the model. Feature importance demonstrated that the top three most crucial features were chemotherapy, radiation, and lung metastases based on the ensemble model. Reclassification of patients revealed a substantial difference in the two risk groups' actual probabilities of early mortality (74.38% vs. 31.35%, p < 0.001). Patients in the high-risk group had significantly shorter survival time than patients in the low-risk group (p < 0.001), according to the Kaplan-Meier survival curve. Conclusions: The ensemble machine learning model exhibits promising prediction performance for early mortality among HCC patients with bone metastases. With the aid of routinely accessible clinical characteristics, this model can be a trustworthy prognostic tool to predict the early death of those patients and facilitate clinical decision-making.

A machine learning-Based model to predict early death among bone metastatic breast cancer patients: A large cohort of 16,189 patients.

Purpose: This study aims to develop a prediction model to categorize the risk of early death among breast cancer patients with bone metastases using machine learning models. Methods: This study examined 16,189 bone metastatic breast cancer patients between 2010 and 2019 from a large oncological database in the United States. The patients were divided into two groups at random in a 90:10 ratio. The majority of patients (n = 14,582, 90%) were served as the training group to train and optimize prediction models, whereas patients in the validation group (n = 1,607, 10%) were utilized to validate the prediction models. Four models were introduced in the study: the logistic regression model, gradient boosting tree model, decision tree model, and random forest model. Results: Early death accounted for 17.4% of all included patients. Multivariate analysis demonstrated that older age; a separated, divorced, or widowed marital status; nonmetropolitan counties; brain metastasis; liver metastasis; lung metastasis; and histologic type of unspecified neoplasms were significantly associated with more early death, whereas a lower grade, a positive estrogen receptor (ER) status, cancer-directed surgery, radiation, and chemotherapy were significantly the protective factors. For the purpose of developing prediction models, the 12 variables were used. Among all the four models, the gradient boosting tree had the greatest AUC [0.829, 95% confident interval (CI): 0.802-0.856], and the random forest (0.828, 95% CI: 0.801-0.855) and logistic regression (0.819, 95% CI: 0.791-0.847) models came in second and third, respectively. The discrimination slopes for the three models were 0.258, 0.223, and 0.240, respectively, and the corresponding accuracy rates were 0.801, 0.770, and 0.762, respectively. The Brier score of gradient boosting tree was the lowest (0.109), followed by the random forest (0.111) and logistic regression (0.112) models. Risk stratification showed that patients in the high-risk group (46.31%) had a greater six-fold chance of early death than those in the low-risk group (7.50%). Conclusion: The gradient boosting tree model demonstrates promising performance with favorable discrimination and calibration in the study, and this model can stratify the risk probability of early death among bone metastatic breast cancer patients.

A novel nomogram to stratify quality of life among advanced cancer patients with spinal metastatic disease after examining demographics, dietary habits, therapeutic interventions, and mental health status.

BACKGROUND: It would be very helpful to stratify patients and direct patient selection if risk factors for quality of life were identified in a particular population. Nonetheless, it is still challenging to forecast the health-related quality of life among individuals with spinal metastases. The goal of this study was to stratify patient's populations for whom the assessment of quality of life should be encouraged by developing and validating a nomogram to predict the quality of life among advanced cancer patients with spine metastases. METHODS: This study prospectively analyzed 208 advanced cancer patients with spine metastases, and collected their general characteristics, food preferences, addictions, comorbidities, therapeutic strategies, and mental health status. The functional assessment of cancer therapy-general (FACT-G) and hospital anxiety and depression scale (HADS) were used to assess quality of life and mental health, respectively. The complete cohort of patients was randomly divided into two groups: a training set and a validation set. Patients from the training set were conducted to train and develop a nomogram, while patients in the validation set were performed to internally validate the nomogram. The nomogram contained significant variables discovered using the least absolute shrinkage and selection operator (LASSO) approach in conjunction with 10-fold cross-validation. The nomogram's predictive ability was assessed utilizing discrimination, calibration, and clinical usefulness. Internal validation was also completed using the bootstrap method after applying 500 iterations of procedures. A web calculator was also developed to promote clinical practice. RESULTS: Advance cancer patients with spinal metastases had an extremely low quality of life, as indicated by the average FACT-G score of just 60.32 ± 20.41. According to the LASSO and 10-fold cross-validation, Eastern Cooperative Oncology Group (ECOG) score, having an uncompleted life goal, preference for eating vegetables, chemotherapy, anxiety status, and depression status were selected as nomogram predictors. In the training set, the area under the receiver operating characteristic curve (AUROC) was 0.90 (95% CI: 0.84-0.96), while in the validation set, it was 0.85 (95% CI: 0.78-0.93). They were 0.50 (95% CI: 0.41-0.58) and 0.44 (95% CI: 0.33-0.56), respectively, for the discrimination slopes. The nomogram had favorable capacity to calibrate and was clinically useful, according to the calibration curve and decision curve analysis. When compared to patients in the low-risk group, patients in the high-risk group were above four times more likely to experience a poor quality of life (82.18% vs. 21.50%, P < 0.001). In comparison to patients in the low-risk group, patients in the high-risk group also exhibited significant higher levels of anxiety and depression. The webpage for the web calculator was https://starshiny.shinyapps.io/DynNomapp-lys/ . CONCLUSIONS: This study suggests a nomogram that can be applied as a practical clinical tool to forecast and categorize the quality of life among patients with spine metastases. Additionally, patients with poor quality of life experience more severe anxiety and depression. Effective interventions should be carried out as soon as possible, especially for patients in the high-risk group, to improve their quality of life and mental health condition.

Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment.

Fatty Acid Desaturase-1 (FADS1) or delta 5 desaturase (D5D) is a rate-limiting enzyme involved in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), i.e., arachidonic acid (ARA) and eicosapentaenoic (EPA). These LC-PUFAs and their metabolites play essential and broad roles in cancer cell proliferation, metastasis, and tumor microenvironment. However, the role of FADS1 in cancers remains incompletely understood. Utilizing The Cancer Genome Atlas (TCGA) database, we explored the role of FADS1 across different cancer types using multiple bioinformatics and statistical tools. Moreover, we studied the impact of a FADS1 inhibitor (D5D-IN-326) on proliferation of multiple cancer cell lines. We identified that FADS1 gene is a predictor for cancer survival in multiple cancer types. Compared to normal tissue, the mRNA expression of FADS1 is significantly increased in primary tumors while even higher in metastatic and recurrent tumors. Mechanistically, pathway analysis demonstrated that FADS1 is associated with cholesterol biosynthesis and cell cycle control genes. Interestingly, FADS1 expression is higher when TP53 is mutated. Tumors with increased FADS1 expression also demonstrated an increased signatures of fibroblasts and macrophages infiltration among most cancer types. Our in vitro assays showed that D5D-IN-326 significantly inhibited cell proliferation of kidney, colon, breast, and lung cancer cell lines in a dose-dependent manner. Lastly, single nucleotide polymorphisms (SNPs) which are well-established expression quantitative trait loci (eQTLs) for FADS1 in normal human tissues are also significantly correlated with FADS1 expression in tumors of multiple tissue types, potentially serving as a marker to stratify cancer patients with high/low FADS1 expression in their tumor tissue. Our study suggests that FADS1 plays multiple roles in cancer biology and is potentially a novel target for precision cancer treatment.

Shuganning injection, a traditional Chinese patent medicine, induces ferroptosis and suppresses tumor growth in triple-negative breast cancer cells.

BACKGROUND: Triple-negative breast cancer (TNBC), lacking targeted therapies currently, is susceptible to ferroptosis, a recently defined form of cell death. PURPOSE: To evaluate the anticancer activity of Shuganning injection (SGNI), a traditional Chinese patent medicine, on TNBC cells; To elucidate the mechanism of SGNI induced ferroptosis. METHODS: The anticancer activity of SGNI was examined via in vitro cell proliferation assays and in vivo xenograft growth assay. Ferroptosis was determined by flow-cytometric analysis of lipid ROS, labile iron pool measurement, and propidium iodide exclusion assay. The dependency on heme oxygenase 1 (HO-1) of SGNI induced ferroptosis was confirmed by genetic knockdown and pharmacological inhibition of the protein. RESULTS: SGNI selectively inhibited the proliferation of TNBC cells compared to non-TNBC breast cancer cells and normal cells. The cell death induced by SGNI in TNBC cells showed distinct morphology from apoptosis and could not be rescued by the pan-caspase inhibitor Z-VAD(OMe)-FMK. On the other hand, SGNI induced cell death was blocked by the lipid ROS scavengers ferrostatin-1 and liproxstatin-1, the acyl-CoA synthetase long chain family member 4 inhibitor rosiglitazone, and the iron chelators 1,10-phenanthroline and deferoxamine. These data indicated that SGNI induced a ferroptotic cell death of TNBC cells. Mechanistically, SGNI induced ferroptosis was dependent on HO-1, which promotes intracellular labile iron pool accumulation, and was alleviated by HO-1 knockdown and inhibition by tin protoporphyrin IX. In line with the in vitro data, SGNI significantly inhibited the xenograft growth of TNBC cell line MD-MB-231 in nude mice. CONCLUSION: Collectively, our study elaborates on a promising regimen for TNBC treatment through induction of ferroptosis by SGNI, a traditional Chinese patent medicine currently available in the clinic, which merits further investigation.

Autophagy inhibitors increase the susceptibility of KRAS-mutant human colorectal cancer cells to a combined treatment of 2-deoxy-D-glucose and lovastatin.

RAS-driven colorectal cancer relies on glucose metabolism to support uncontrolled growth. However, monotherapy with glycolysis inhibitors like 2-deoxy-D-glucose causes limited effectiveness. Recent studies suggest that anti-tumor effects of glycolysis inhibition could be improved by combination treatment with inhibitors of oxidative phosphorylation. In this study we investigated the effect of a combination of 2-deoxy-D-glucose with lovastatin (a known inhibitor of mevalonate pathway and oxidative phosphorylation) on growth of KRAS-mutant human colorectal cancer cell lines HCT116 and LoVo. A combination of lovastatin (>3.75 µM) and 2-deoxy-D-glucose (>1.25 mM) synergistically reduced cell viability, arrested cells in the G2/M phase, and induced apoptosis. The combined treatment also reduced cellular oxygen consumption and extracellular acidification rate, resulting in decreased production of ATP and lower steady-state ATP levels. Energy depletion markedly activated AMPK, inhibited mTOR and RAS signaling pathways, eventually inducing autophagy, the cellular pro-survival process under metabolic stress, whereas inhibition of autophagy by chloroquine (6.25 µM) enhanced the cytotoxic effect of the combination of lovastatin and 2-deoxy-D-glucose. These in vitro experiment results were reproduced in a nude mouse xenograft model of HCT116 cells. Our findings suggest that concurrently targeting glycolysis, oxidative phosphorylation, and autophagy may be a promising regimen for the management of RAS-driven colorectal cancers.

NEOVASCULAR COMPLICATIONS FROM CYTOMEGALOVIRUS NECROTIZING RETINOPATHY IN PATIENTS AFTER HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION.

PURPOSE: To report the incidence and clinical features of neovascular complications from cytomegalovirus (CMV) necrotizing retinopathy in patients after haploidentical hematopoietic stem cell transplantation. METHODS: Thirty-nine patients (58 eyes) of CMV necrotizing retinopathy after haploidentical hematopoietic stem cell transplantation in our institute between January 2018 and June 2020 were retrospectively reviewed, and cases that developed neovascular complications during follow-up were identified and described. RESULTS: Two (2 eyes) cases that developed neovascular glaucoma from CMV necrotizing retinopathy were identified. Both of them manifested as granular peripheral retinitis, panretinal occlusive vasculitis, and some degree of intraocular inflammation, which were consistent with chronic retinal necrosis. Insidious progression of isolated immune-mediated occlusive vasculitis that could only be observed on fundus fluorescein angiography without active retinitis or intraocular inflammation was recognized to be the cause in one of two cases. CONCLUSION: Neovascular glaucoma developed in 5.1%/cases and 3.4%/eyes complicated by CMV chronic retinal necrosis and vasculitis in patients after haploidentical hematopoietic stem cell transplantation, which warrants the needs for long-term follow-up. Immune-mediated CMV vasculitis could be an isolated manifestation in patients with a minimal immune deviation and may only be found on fundus fluorescein angiography, which emphasizes the importance of fundus fluorescein angiography on a regular basis during follow-up.

Continuous High-Dose (6 mg) vs. Low-Dose (3 mg) Intravitreal Ganciclovir for Cytomegalovirus Retinitis After Haploidentical Hematopoietic Stem Cell Transplantation: A Randomized Controlled Study.

Purpose: To evaluate the safety and efficacy of continuous high-dose (6 mg) intravitreal ganciclovir injections (IVG) for cytomegalovirus (CMV) retinitis (CMVR) after haploidentical hematopoietic stem cell transplantation (Haplo-HSCT), and to explore factors that may influence the treatment procedure. Design: Prospective, randomized, single-blinded, positive-controlled, interventional, comparative study. Methods: A total of 22 patients with CMVR (32 eyes) were randomized to either high-dose group (IVG 6 mg weekly) or low-dose group (IVG 3 mg given twice weekly for 2 weeks as induction phase and weekly thereafter as maintenance phase). Patients who were recorded any positive CMV DNAemia or other active CMV diseases and needed systemic anti-CMV treatment during the study period were excluded. The vision outcome, variables of the treatment procedure, and incidence of complication and CMVR recurrence were analyzed and compared. Logistic regression was applied to determine the factors that may have an impact on the treatment process at baseline. Results: Compared to the low-dose group, the high-dose group resulted in a median of two less intravitreal injections (4 vs. 6 times, respectively, P = 0.016), while the rate of vision stability or improvement (81.2 vs. 87.5%), the incidence of complication (6.2 vs. 18.8%), and CMVR recurrence (12.5% vs. 6.2%) were similar (all P > 0.05). No drug-related toxicity was observed. Initial aqueous CMV-DNA load (OR: 6.872, 95% CI: 1.335-35.377, P = 0.021) and extension of lesion (OR: 0.942, 95% CI: 0.897 to .991, P = 0.020), but not dosing regimen (P = 0.162), were predictors of the treatment duration. Conclusions: Continuous high-dose regimen was well tolerated and resulted in less intravitreal injections, with similar vision outcomes and safety profiles. The clinical course of CMVR after Haplo-HSCT was determined by its own nature at baseline and could not be modified by treatment protocols under consistent immune background.

High expression of HOXA5 is associated with poor prognosis in acute myeloid leukemia.

BACKGROUND: HOXA5 is considered as an oncogene in many tumors. This study in- vestigated the HOXA5 expression in Chinese acute myeloid leukemia (AML) patients and evaluated the predictive significance of HOXA5 with a single-center retrospective study. METHODS: We investigated the expression pattern and prognostic value of HOXA5 in patients with AML through by using a series of databases and various datasets, including the ONCOMINE, TCGA, and STRING datasets. The bone marrow samples of 53 newly diagnosed AML patients (non-M3 subtype) and 19 benign individuals were collected in our center. HOXA5 mRNA expression levels were detected by real-time qPCR, HOXA5 protein expression levels were detected by Western Blot. Clinical data was obtained from inpatient medical records. RESULTS: Two microarrays in Oncomine showed that the expression level of HOXA5 was significantly upregulated in AML. Our data revealed that AML patients had higher HOXA5 mRNA and protein expression levels than the controls (P < 0.001). The blast percentage in bone marrow of HOXA5 high-expression group was higher that of HOXA5 low-expression group (P < 0.05). Higher expression level of HOXA5 revealed a worse OS in AML (P < 0.05). CONCLUSION: Our findings suggested that HOXA5 might have the potential ability to act as a diagnostic biomarker and potential therapeutic target for AML.

Efficacy of shoulder arthroscopic surgery for the treatment of rotator cuff injury: A protocol of systematic review and meta-analysis.

BACKGROUND: This study will investigate the efficacy and safety of shoulder arthroscopic surgery (SAS) for patients with rotator cuff injury (RCI). METHODS: We will systematically search for randomized controlled trials in the electronic databases of PUBMED, EMBASE, Cochrane Library, CINAHL, PsycINFO, Web of Science, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All above databases will be searched from their beginning to March 1, 2020 without language restrictions. Two reviewers will independently scan retrieved records, evaluate study quality and extract data. If possible, we will synthesize the data and conduct a meta-analysis by RevMan 5.3 software. RESULTS: This systematic review will summarize the most recent evidence to explore the efficacy and safety of SAS for patients with RCI. CONCLUSION: The findings of this study will help to provide a genuine understanding of perspective from a scientific basis on the efficacy and safety of SAS for patients with RCI. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020170009.

Unusual presentation of congenital radioulnar synostosis with osteoporosis, fragility fracture and nonunion: A case report and review of literature.

BACKGROUND: Congenital radioulnar synostosis (CRUS) is a rare deformity of the upper extremity. It is characterized by loss of rotation of the involved forearm and functional limitations in daily activities. No studies on CRUS with osteoporosis have been reported to date, and osteoporosis is usually recognized as an important dimension of genetic disorder in children. We discuss the possible relationship among this disorder, osteoporosis and fracture nonunion, investigate the strict surgical indications and recommended treatments. CASE SUMMARY: A 14-year-old male patient with bilateral CRUS with osteoporosis, fragility fracture and nonunion of fractures in ulna and radius presented our institution for further treatment, complaining of limitation in rotation. The bone mineral density of the hip and lumbar spine was 0.687 g/cm2 and 0.705 g/cm2, respectively, and the Z-score for both was -2.1, which revealed osteoporosis and a high risk of fracture. Tow serum bone turnover markers indicated an imbalance of bone metabolism. Reoperation for ulna fracture with autogenous bone grafting and a postoperative physiotherapy program were adopted rather than the separation of pathological synostosis. Radiological examination, observational posture assessment and limb function scale were evaluated before and 1 year after surgery. At 1 year, the fracture nonunion had almost recovered, forearm movement function on the fracture side was restored, and function on the healthy side was significantly improved compared with that before rehabilitation. CONCLUSION: Surgical indications for CRUS vary from person to person. Surgery should not be the first choice of treatment, and physiotherapy is not inferior to surgical treatment.

Is hip fracture surgery safe for patients on antiplatelet drugs and is it necessary to delay surgery? A systematic review and meta-analysis.

BACKGROUND: Hip fractures are common and account for a large proportion of orthopedic surgical admissions in elderly patients. However, determining the timing for surgery has been controversial for patients who develop hip fractures while on antiplatelet treatment. METHODS: Computerized databases for studies published from the inception date to January 2020, including the Cochrane Library, PubMed (Medline), EMBASE, Web of ScienceTM, ClinicalTrials, ClinicalKey, and Google Scholar, were searched using the keywords "Hip AND Fracture", "Antiplatelet", "Antithrombocyte", "Platelet aggregation inhibitors", "Aspirin", "Plavix", and "Clopidogrel". RESULTS: In total, 2328 initial articles were identified. Twenty-four studies with 5423 participants were ultimately included in our analysis. Early surgery was associated with an increased transfusion rate in the antiplatelet group compared to the non-antiplatelet group (OR = 1.21; 95% CI, 1.01 to 1.44; p = 0.03). Early surgery for hip fracture patients on antiplatelet therapy was associated with a greater decrease in hemoglobin compared to delayed surgery (WMD = 0.75; 95% CI, 0.50 to 1.00; p < 0.001). However, early surgery appeared to decrease the length of hospitalization (WMD = - 6.05; 95% CI, - 7.06 to - 5.04; p < 0.001) and mortality (OR = 0.43; 95% CI, 0.23 to 0.79; p = 0.006). CONCLUSION: It is unnecessary to delay surgery to restore platelet function when patients with hip fractures receive antiplatelet therapy. Furthermore, early surgery can significantly reduce mortality and hospital stay, which is conducive to patient recovery. Future randomized trials should determine whether the results are sustained over time.

Kanglaite injection plus platinum-based chemotherapy for stage III/IV non-small cell lung cancer: A meta-analysis of 27 RCTs.

BACKGROUND: Kanglaite injection (KLT) is a broad-spectrum anti-tumor drug, which is extracted from the seeds of the Chinese medicinal herb Coix lacryma-jobi, and has been widely used for the treatment of advanced lung cancer. PURPOSE: To evaluate the combined effects of Kanglaite injection plus platinum-based chemotherapy (PBC) on patients with stage III/IV non-small cell lung cancer (NSCLC). STUDY DESIGN: A systematic review and meta-analysis of randomized clinical trials (RCTs). MATERIALS AND METHODS: Twelve databases were searched from their inceptions until July 05, 2019. All the RCTs comparing the efficacy and safety of Kanglaite injection plus PBC versus PBC alone were selected. Analyses were performed using Review Manager 5.3, Comprehensive Meta-Analysis 3.0 and Trial Sequential Analysis (TSA). Disease control rate (DCR) was defined as the primary endpoint, objective response rate (ORR), survival rate, quality of life (QOL), cellular immunity function, and toxicities were defined as the secondary endpoints. RESULTS: Twenty-seven RCTs recruiting 2,243 patients with stage III/IV NSCLC were included. The results showed that, compared with PBC alone, Kanglaite injection plus PBC improved DCR (RR = 1.20, 95% CI 1.15-1.26, p < 0.00001), ORR (RR = 1.45, 95% CI 1.31-1.60, p < 0.00001), 1-year survival rate (RR = 1.20, 95% CI 1.02-1.43, p = 0.03), QOL (RR = 1.32, 95% CI 1.25-1.40, p < 0.00001), CD4+T cells (WMD = 4.86, 95% CI 4.00-5.73, p < 0.00001), CD4+/CD8+ ratio (WMD = 0.19, 95% CI 0.07-0.31, p < 0.002), and reduced severe toxicities by 59% (RR = 0.41, 95% CI 0.33-0.51, p < 0.00001). Most results were robust and the quality of evidence was from moderate to low. CONCLUSIONS: Kanglaite injection in combination with PBC showed significantly higher efficacy than PBC alone in the treatment of stage III/IV NSCLC. Moreover, the combination therapy can improve cellular immunity and attenuate the severe toxicities caused by chemotherapy. However, high-quality RCTs are warranted to further assess the effects of the combined therapy.

lncRNA THAP9-AS1 Promotes Pancreatic Ductal Adenocarcinoma Growth and Leads to a Poor Clinical Outcome via Sponging miR-484 and Interacting with YAP.

PURPOSE: Long noncoding RNAs (lncRNA) have been observed in various cancer types. Our bioinformatic analysis of existing databases demonstrated overexpression of lncRNA THAP9-AS1 in pancreatic ductal adenocarcinoma (PDAC). We aimed to investigate the roles and mechanisms of THAP9-AS1 in PDAC. EXPERIMENTAL DESIGN: The overexpression of THAP9-AS1 in samples of patients with pancreatic cancer was characterized and was associated with clinical outcomes. The nonprotein coding property of the THAP9-AS1 was verified. Various in vitro and in vivo experiments were performed to investigate the interaction between THAP9-AS1 and YAP signaling. RESULTS: We demonstrated that lncRNA THAP9-AS1 is overexpressed in PDAC in multiple patient sample sets, which is significantly associated with poor outcome of patients with PDAC. THAP9-AS1 promotes PDAC cells growth both in vitro and in vivo. THAP9-AS1 exerts its effects via enhancing YAP signaling. Ectopic YAP expression overcame the effects of THAP9-AS1 knockdown. Inversely, YAP knockdown diminished the effects of THAP9-AS1 overexpression. THAP9-AS1 acts as a competing endogenous RNA for miR-484, leading to YAP upregulation. Moreover, THAP9-AS1 binds to YAP protein and inhibits the phosphorylation-mediated inactivation of YAP by LATS1. Reciprocally, YAP/TEAD1 complex promotes THAP9-AS1 transcription to form a feed-forward circuit. Importantly, THAP9-AS1 level positively correlates with YAP expression in PDAC tissues. YAP overexpression also predicts a poor outcome in patients with PDAC. CONCLUSIONS: Our findings indicate that THAP9-AS1 plays an important role in PDAC growth via enhancing YAP signaling, which in turn also modulates THAP9-AS1 transcription. THAP9-AS1/YAP axis may serve as a potential biomarker and therapeutic target for PDAC treatment.

Regulation of lactate production through p53/ß-enolase axis contributes to statin-associated muscle symptoms.

BACKGROUND: Statin-associated muscle symptoms (SAMS) are the major adverse effects of the class of widely used lipid-lowering agents, and the underlying mechanism remains elusive. In this study, we investigated the potential contribution and molecular mechanism of increased lactate production to SAMS in mice. METHODS: C57BL/6 J mice were administrated with lovastatin and exercise capacity and blood and muscle lactate levels were measured. A variety of metabolic and molecular experiments were carried out on skeletal muscle cell lines A-204 and C2C12 to confirm the in vivo findings, and to delineate the molecular pathway regulating lactate production by statins. FINDINGS: Blood lactate levels of mice treated with lovastatin increased 23% compared to the control group, which was reproduced in type II predominant glycolytic muscles, accompanied with a 23.1% decrease of maximum swim duration time. The in vitro evidence revealed that statins increased the expression of muscle specific glycolytic enzyme ß-enolase through promoting the degradation of basal p53 proteins, resulting in increased of lactate production. Co-administered with dichloroacetate (DCA), a reagent effective in treating lactic acidosis, reverted the elevated lactate levels and the decreased exercise capacity. INTERPRETATION: Elevated lactate production by statins through the p53/ß-enolase axis contributes to SAMS. FUND: This work was supported by grants from the Science and Technology Development Fund (FDCT) of Macau (Project codes: 034/2015/A1 and 0013/2019/A1).

MicroRNA-15a-5p Regulates the Development of Osteoarthritis by Targeting PTHrP in Chondrocytes.

BACKGROUND AND AIMS: A growing body of research has demonstrated that the degeneration of chondrocytes is the primary cause of osteoarthritis (OA). Parathyroid hormone-related protein (PTHrP) can alleviate the degeneration of chondrocytes via promotion of chondrocyte proliferation and inhibition of terminal differentiation, but the underlying mechanism remains unknown. This study aimed to identify the microRNAs (miRNAs) that may target PTHrP and regulate the proliferation and terminal differentiation of chondrocytes. METHODS: Bioinformatic analysis was used to predict which miRNAs target PTHrP. We collected human knee cartilage specimens to acquire the primary chondrocytes, which we then used to test the expression and function of the targeted miRNAs. To explore the effects of miR-15a-5p on the putative binding sites, specific mimics or inhibitors were transfected into the chondrocytes. Furthermore, a dual-luciferase reporter gene assay and chondrocyte degeneration-related factors were used to verify the possible mechanism. RESULTS: The expression of PTHrP was upregulated in the OA chondrocytes, whilst miR-15a-5p was downregulated in the OA chondrocytes. A negative correlation was observed between PTHrP and miR-15a-5p. The knockdown of miR-15a-5p promoted the growth of chondrocytes and inhibited calcium deposition, whilst overexpression of miR-15a-5p reversed this trend. The effect of miR-15a-5p overexpression was neutralised by PTHrP. Dual-luciferase reporter assays revealed that PTHrP can be used as a novel targeting molecule for miR-15a-5p. CONCLUSIONS: miR-15a-5p promotes the degeneration of chondrocytes by targeting PTHrP and, in addition to helping us understand the development of OA, may be a potential biomarker of OA.

Integrative omics analysis of p53-dependent regulation of metabolism.

Accumulated evidence in the last decade implies that regulation of metabolism by p53 represents a reviving mechanism vital to prevent tumorigenesis. To gain a more in-depth understanding of metabolic regulation by baseline levels of p53, we employed both metabolomics and transcriptomics analysis with human colon cancer cell-line HCT116 depleted of p53. Metabolomics analyses with UPLC/quadrupole time-of-flight mass spectrometry identified 283 significantly changed metabolites including 138 important metabolites. Transcriptomics analysis with microarray revealed 1317 differentially expressed genes. By integrated analysis of both omics data, we found nucleotides metabolism and sulfur-related metabolism are of great importance. Our study provided a pilot comprehensive view of the metabolism regulated by p53 and suggests several potential p53 targets in metabolism for further study.

APTM, a Thiophene Heterocyclic Compound, Inhibits Human Colon Cancer HCT116 Cell Proliferation Through p53-Dependent Induction of Apoptosis.

To evaluate the in vitro anticancer activity and to investigate the mechanism of action of a thiophene heterocyclic compound, [3-Amino-5-[(2,6-dimethylphenyl)amino]-4-(phenylsulfonyl)-2-thienyl](4-fluorophenyl)methanone (APTM) against human colon cancer HCT116 cells. Sulforhodamine B assay and colony formation assay for cell proliferation assay; propidium iodide (PI) staining for cell cycle profile analysis; Hoechst staining; annexin V-FITC/PI double staining and Western blotting for apoptosis assay. APTM inhibits the growth of HCT116 cells dose and time dependently. The growth inhibitory effect of APTM on HCT116 cells was associated with induction of apoptosis but not cell cycle arrest. Also, the isogenic cell depletion of p53 was resistant to APTM-induced apoptosis and thus grows relatively better than the wild-type cells. The anticancer effect of APTM resulted from p53-dependent induction of apoptosis. Also, APTM is a promising lead compound for the treatment of human colon cancer.