Genome analysis of Tepidibacter sp. SWIR-1, an anaerobic endospore-forming bacterium isolated from a deep-sea hydrothermal vent.

Tepidibacter sp. SWIR-1, a putative new species isolated from deep-sea hydrothermal vent field on the Southwest Indian Ridge (SWIR), is an anaerobic, mesophilic and endospore-forming bacterium belonging to the family Peptostreptococcaceae. In this study, we present the complete genome sequence of strain SWIR-1, consists of a single circular chromosome comprising 4,122,966 nucleotides with 29.25% G + C content and a circular plasmid comprising 38,843 nucleotides with 29.46% G + C content. In total, 3861 protein coding genes, 104 tRNA genes and 46 rRNA genes were obtained. SWIR-1 genome contains numerous genes related to sporulation and germination. Compared with the other three Tepidibacter species, SWIR-1 contained more spore germination receptor proteins. In addition, SWIR-1 contained more genes involved in chemotaxis and two-component systems than other Tepidibacter species. These results indicated that SWIR-1 has developed versatile adaptability to the Southwest Indian Ridge hydrothermal vent environment. The genome of strain SWIR-1 will be helpful for further understanding adaptive strategies used by bacteria dwelling in the deep-sea hydrothermal vent environments of different oceans.

Machine learning algorithms for predicting the risk of fracture in patients with diabetes in China.

Background: Patients with diabetes are more likely to be predisposed to fractures compared to those without diabetes. In clinical practice, predicting fracture risk in diabetics is still difficult because of the limited availability and accessibility of existing fracture prediction tools in the diabetic population. The purpose of this study was to develop and validate models using machine learning (ML) algorithms to achieve high predictive power for fracture in patients with diabetes in China. Methods: In this study, the clinical data of 775 hospitalized patients with diabetes was analyzed by using Decision Tree (DT), Gradient Boosting Decision Tree (GBDT), Logistic Regression (LR), Random Forest (RF), Support Vector Machine (SVM), eXtreme Gradient Boosting (XGBoost) and Probabilistic Classification Vector Machines (PCVM) algorithms to construct risk prediction models for fractures. Moreover, the risk factors for diabetes-related fracture were identified by the feature selection algorithms. Results: The ML algorithms extracted 17 most relevant factors from raw clinical data to maximize the accuracy of the prediction results, including bone mineral density, age, sex, weight, high-density lipoprotein cholesterol, height, duration of diabetes, total cholesterol, osteocalcin, N-terminal propeptide of type I, diastolic blood pressure, and body mass index. The 7 ML models including LR, SVM, RF, DT, GBDT, XGBoost, and PCVM had f1 scores of 0.75, 0.83, 0.84, 0.85, 0.87, 0.88, and 0.97, respectively. Conclusions: This study identified 17 most relevant risk factors for diabetes-related fracture using ML algorithms. And the PCVM model proved to perform best in predicting the fracture risk in the diabetic population. This work proposes a cheap, safe, and extensible ML algorithm for the precise assessment of risk factors for diabetes-related fracture.

Up-regulation of LCN2 in the anterior cingulate cortex contributes to neural injury-induced chronic pain.

Chronic pain caused by disease or injury affects more than 30% of the general population. The molecular and cellular mechanisms underpinning the development of chronic pain remain unclear, resulting in scant effective treatments. Here, we combined electrophysiological recording, in vivo two-photon (2P) calcium imaging, fiber photometry, Western blotting, and chemogenetic methods to define a role for the secreted pro-inflammatory factor, Lipocalin-2 (LCN2), in chronic pain development in mice with spared nerve injury (SNI). We found that LCN2 expression was upregulated in the anterior cingulate cortex (ACC) at 14 days after SNI, resulting in hyperactivity of ACC glutamatergic neurons (ACCGlu) and pain sensitization. By contrast, suppressing LCN2 protein levels in the ACC with viral constructs or exogenous application of neutralizing antibodies leads to significant attenuation of chronic pain by preventing ACCGlu neuronal hyperactivity in SNI 2W mice. In addition, administering purified recombinant LCN2 protein in the ACC could induce pain sensitization by inducing ACCGlu neuronal hyperactivity in naïve mice. This study provides a mechanism by which LCN2-mediated hyperactivity of ACCGlu neurons contributes to pain sensitization, and reveals a new potential target for treating chronic pain.

High-dose versus standard-dose radiotherapy in concurrent chemoradiotherapy for inoperable esophageal cancer: A systematic review and meta-analysis.

PURPOSE: The aim of this study was to evaluate the effectiveness and safety of high-dose (HD-RT) versus standard-dose radiotherapy (SD-RT) in concurrent chemoradiotherapy (CCRT) for inoperable esophageal cancer (EC) patients. METHODS: A systematic search of the literature was conducted by screening PubMed, Web of Science, EMBASE and Cochrane Library databases before October 7, 2022 to collect controlled clinical studies of high-dose (≥60 Gy) and standard-dose (50-50.4 Gy) radiation in CCRT for EC. For statistical analysis, a fixed-effects model was used to synthesize HR and OR if there was no significant heterogeneity among studies; otherwise, a random-effects model was employed. RESULTS: There were ten studies with 4625 patients included in the study, 3667 of whom (79.3%) were esophageal squamous cell carcinoma (ESCC). The HD-RT group had no significant benefits in overall survival (OS) (HR = 0.88, 95% confidence interval [CI] = 0.74-1.05, P = 0.16) and progression-free survival (HR = 0.84, 95%CI = 0.67-1.04, P = 0.12) in total EC patients, compared with SD-RT group. However, in ESCC subgroup analysis, compared with SD-RT group, a better OS was observed in the HD-RT group (HR = 0.78, 95%CI = 0.70-0.88, P < 0.0001). CONCLUSION: Compared with the radiation dose of 50-50.4 Gy, the increase of radiation dose (≥60 Gy) did not achieve benefits in survival for inoperable EC patients receiving CCRT. However, in patients with ESCC, high dose (≥60 Gy) of radiation probably improved OS.

Hologenome analysis reveals independent evolution to chemosymbiosis by deep-sea bivalves.

BACKGROUND: Bivalves have independently evolved a variety of symbiotic relationships with chemosynthetic bacteria. These relationships range from endo- to extracellular interactions, making them ideal for studies on symbiosis-related evolution. It is still unclear whether there are universal patterns to symbiosis across bivalves. Here, we investigate the hologenome of an extracellular symbiotic thyasirid clam that represents the early stages of symbiosis evolution. RESULTS: We present a hologenome of Conchocele bisecta (Bivalvia: Thyasiridae) collected from deep-sea hydrothermal vents with extracellular symbionts, along with related ultrastructural evidence and expression data. Based on ultrastructural and sequencing evidence, only one dominant Thioglobaceae bacteria was densely aggregated in the large bacterial chambers of C. bisecta, and the bacterial genome shows nutritional complementarity and immune interactions with the host. Overall, gene family expansions may contribute to the symbiosis-related phenotypic variations in different bivalves. For instance, convergent expansions of gaseous substrate transport families in the endosymbiotic bivalves are absent in C. bisecta. Compared to endosymbiotic relatives, the thyasirid genome exhibits large-scale expansion in phagocytosis, which may facilitate symbiont digestion and account for extracellular symbiotic phenotypes. We also reveal that distinct immune system evolution, including expansion in lipopolysaccharide scavenging and contraction of IAP (inhibitor of apoptosis protein), may contribute to the different manners of bacterial virulence resistance in C. bisecta. CONCLUSIONS: Thus, bivalves employ different pathways to adapt to the long-term co-existence with their bacterial symbionts, further highlighting the contribution of stochastic evolution to the independent gain of a symbiotic lifestyle in the lineage.

Copper oxides activate peroxymonosulfate for degradation of methylene blue via radical and nonradical pathways: surface structure and mechanism.

A one-step hydrothermal method for preparation of copper oxides with different valences using ascorbic acid as a reducing reagent was developed for environmental remediation. The results suggested that the notable degradation performance of CuO0 may be attributable to the abundant active sites, such as Cu or Cu-O, and was not significantly related to the Cu valence state. In contrast to direct degradation of pollutants by traditional superoxide radicals (O2•-), O2•- played an important role in the reduction of high-valence Cu ions (Cu(III)). In addition, a series of radical quenching, electron paramagnetic resonance (EPR), and electrochemical experiments validated the existence of direct electron transfer between methylene blue (MB) and PMS mediated by CuO0 and surface-bound radicals. The results suggested that the CuO0/PMS system may be less susceptible to diverse ions and natural organic matter other than dihydrogen phosphate anions. The mechanism of MB degradation under alkaline conditions was different from that under acidic conditions in that it was not reliant on radicals or charge transfer but direct oxidation by PMS. This study provides new insights into the heterogeneous processes involved in PMS activation by the copper oxides. Furthermore, this paper devotes to providing theoretical basis on pollutant removal via PMS activated by copper oxides and developing low-cost and high-efficiency catalysts.

Anti-programmed death ligand 1 immunotherapy in patients with limited-stage small cell lung cancer: a real-world exploratory study.

The aim of this study was to investigate the safety and efficacy of anti-programmed death ligand 1 (PD-L1) immunotherapy plus chemoradiotherapy for patients with limited-stage small cell lung cancer (LS-SCLC) in clinical practice. Patients with LS-SCLC treated with anti-PD-L1 (atezolizumab/durvalumab) plus chemoradiotherapy (CRT) as the initial treatment at three general hospitals between March 2020 and December 2021 were retrospectively analysed. 1:2 propensity score matching for controls that receive CRT only was performed. Clinical data (age, sex, history of cancer treatment, adverse events, etc.) were collected to evaluate toxicity, progression-free survival (PFS) and objective response rate (ORR). Researchers used univariate Chi-squared analyses to determine if anti-PD-L1 immunotherapy had a significant association with toxicity or ORR. Kaplan-Meier survival analysis, and the log-rank test were used to compare survival curves between the two groups. In the anti-PD-L1 plus CRT and CRT groups, 15 and 30 patients were analyzed; median follow-up was 16.39 months and 16.64 months, respectively. Incidence of toxicity between the two groups was similar and there were no new safety signals. Anti-PD-L1 immunotherapy significantly improved PFS (P = 0.02). The median PFS was not reached in the anti-PD-L1 plus CRT group versus 8.18 months [95% confidence interval (CI), 6.14-10.22 months] in the CRT group. The ORR were 93.33% and 76.67%, respectively (P = 0.34). This study supports adding anti-PD-L1 immunotherapy (atezolizumab/durvalumab) to CRT as an initial treatment option in patients with LS-SCLC for its favorable safety profile and efficacy.

Direct degradation of methylene blue by unactivated peroxymonosulfate: reaction parameters, kinetics, and mechanism.

Advanced oxidation processes (AOPs) are efficient methods for water purification. However, there are few studies on using peroxymonosulfate (PMS) to remove pollutants directly. In this study, about 76% of methylene blue (MB) was removed by PMS directly within 180 min through a non-radical pathway, verified by scavenging tests, electron paramagnetic resonance and kinetic calculations. Additionally, the effects of PMS dosage, MB concentration, temperature, initial pH and competitive anions were determined. High PMS dosage, temperature and pH promoted MB degradation (from 76 to 98%) while MB concentration showed no effect on MB removal. Besides, MB degradation followed pseudo-first-order kinetic with rate constants of 0.0082 to 0.3912 min-1. The second-order rate constant for PMS reaction with MB was 0.08 M-1 s-1 at pH 3-6, but increased dramatically to 4.68 M-1 s-1 at pH 10.50. Chlorine could be catalysed by PMS at high concentration Cl- and degradation efficiency reached 98% within 90 min. High concentration of bicarbonate accelerated MB removal due to the high pH value while humic acid showed a marginal effect on MB degradation. Furthermore, TOC removal rate of MB in the presence of chloride reached 45%, whereas PMS alone caused almost no mineralisation. This study provides new insights into pollutant removal and an additional strategy for water purification.

Upfront brain radiotherapy improves intracranial progression-free survival but not overall survival in lung adenocarcinoma patients with brain metastases: a retrospective, single-institutional analysis from China.

Aims: The optimal timing of brain radiotherapy (BRT) for lung adenocarcinoma patients with brain metastases (BM) remains controversial. In this retrospective study, we performed a retrospective review to investigate the differential benefit of upfront versus deferred BRT for lung adenocarcinoma patients with BM. Methods: A total of 354 lung adenocarcinoma patients with BM treated in the Affiliated Cancer Hospital of Shandong University met the inclusion criteria for the study. Patients were divided into two groups: upfront BRT and deferred BRT. Intracranial progression-free survival (PFS) and overall survival (OS) were measured from the date of brain metastases. Subgroup analyses according to gene mutation status were also performed. Results: Among the entire cohort, the median intracranial PFS with upfront BRT (16.3 months) was longer than that with deferred BRT (11.3 months, p=0.001). However, the median OS did not differ significantly between patients who received upfront BRT and deferred BRT (27.6 and 31.5 months, respectively, p=0.813). Subgroup analyses indicated that upfront BRT yielded a significantly longer intracranial PFS than deferred BRT (p=0.003) for patients without EGFR (19 or 21) mutation. In both subgroups, the median OS showed no significant difference between upfront BRT and deferred BRT. Conclusion: This single-institutional retrospective study showed that in lung adenocarcinoma patients with brain metastases, upfront BRT was associated with a significantly longer intracranial PFS but not improvement in OS compared with deferred BRT. Considering the neurocognitive toxicities of BRT previously reported in the literature, deferred BRT might be considered as an acceptable therapeutic option for the treatment of patients with lung adenocarcinoma and BM.

Heart rate-corrected QT interval: A novel diagnostic biomarker for diabetic peripheral neuropathy.

AIMS/INTRODUCTION: To explore the relationship between heart rate-corrected QT (QTc) interval and diabetic peripheral neuropathy (DPN), and whether QTc interval has diagnostic utility for DPN beyond nerve conduction velocity. MATERIALS AND METHODS: A total of 965 patients with diabetes, including 473 patients with DPN and 492 patients without DPN, underwent standard 12-lead electrocardiography and detailed assessments of peripheral neuropathy. RESULTS: Patients with DPN had longer QTc intervals than those without. Among participants, from the first to fourth quartile of QTc interval, the proportion of patients with DPN appreciably increased and the nerve conduction velocity obviously decreased (P for trend <0.001). The univariate and multivariate analyses showed that prolonged QTc interval was closely associated with increased risk of DPN (univariable odds ratio 1.112, 95% confidence interval 1.097-1.127, P < 0.001; multivariable odds ratio 1.118, 95% confidence interval 1.099-1.137, P < 0.001). Receiver operating characteristic analysis for the diagnosis of DPN showed a greater area under the curve for QTc interval of 0.894 than the median nerve motor conduction velocity of 0.691, median nerve sensory conduction velocity of 0.664 and peroneal nerve motor conduction velocity of 0.692. The optimal cut-off point of QTc interval for DPN was 428.5 ms with sensitivity of 0.715 and specificity of 0.920 (P < 0.001). The combination of QTc interval and nerve conduction testing increased the area under the curve for the diagnosis of DPN (from 0.736 to 0.916; P < 0.001). CONCLUSIONS: QTc interval with 428.5 ms has more reliable diagnostic utility for DPN than nerve conduction velocity, and prolonged QTc interval is closely associated with an increased risk of DPN.

The Value of Anlotinib in the Treatment of Intractable Brain Edema: Two Case Reports.

About 20-30 percent of patients with cancer, such as non-small cell lung cancer, breast cancer, melanoma and renal cell carcinoma, will develop brain metastases (BM). Primary and secondary brain tumors are often accompanied by peritumoral edema. Due to the limited intracranial space, peritumoral edema will further increase the intracranial pressure and aggravate clinical symptoms. Radiotherapy, as a basic component of the treatment of intracranial tumors, induces blood vessel damage and aggravates brain edema. The combination of edema caused by the tumor itself and radiotherapy is collectively referred to as intractable brain edema. Edema can increase intracranial pressure and cause associated neurologic symptoms, which seriously affects the quality of life of patients. Steroids, specifically dexamethasone, have become the gold standard for the management of tumor-associated edema. However, steroids can lead to variety of adverse effects, including moon face, high blood pressure, high blood sugar, increased risk of infection, bone thinning (osteoporosis), and fractures, especially with prolonged use. The investigation of other types of drugs is urgently needed to address this problem.Compared to other anti-angiogenic agents, anlotinib acts on vascular endothelial growth factor receptors (VEGFR1, VEGFR2/KDR, and VEGFR3), fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3 and FGFR4), platelet derived growth factor receptor (PDGFR) and stem cell factor receptor (c-kit) simultaneously. However, according to the literature retrieval, there are no studies on anlotinib for the treatment of intractable brain edema. We describe here two cases of brain edema and review the literature available and hope to discover new agents that are safer and more effective.

Effect of sodium-glucose co-transporter-2 inhibitors on the levels of serum asprosin in patients with newly diagnosed type 2 diabetes mellitus.

BACKGROUND: Asprosin, a novel adipokine that raises glucose levels and stimulates appetite, has been proved to be pathologically increased in populations predisposed to type 2 diabetes mellitus (T2DM), obesity, and cardiovascular diseases. The mechanisms of sodium-glucose co-transporter-2 (SGLT2) inhibitors for hypoglycemic effect and cardiovascular protection have not been fully clarified. Therefore, we conducted this study to assess change in the levels of serum asprosin after treatment with SGLT2 inhibitors in patients with newly diagnosed T2DM. METHODS: This study was a randomized, double-blind, placebo-controlled trial. A total of 29 participants with newly diagnosed T2DM with body mass index (BMI) ≥ 23.0 kg/m2 and haemoglobin A1c (HbA1c) levels of 58-85 mmol/mol (7.5-10%) were randomized to SGLT2 inhibitors dapagliflozin 10 mg/d (n = 19) or placebo (n = 10) treatment for 24 weeks. We analyzed asprosin concentrations by an enzyme-linked immunosorbent assay. Besides, body weight, BMI, HbA1c, fasting plasma glucose (FPG), and lipid levels were measured at baseline and 24 weeks. RESULTS: At 24 weeks, participants with SGLT2 inhibitors treatment exhibited lower levels of serum asprosin (22.87 vs 45.06 ng/ml in the placebo group; P < 0.001) after adjusting for baseline values. The levels of body weight, BMI, HbA1c, FPG, and triglyceride (TG) were decreased, while high density lipoprotein-cholesterol (HDL-C) was increased after SGLT2 inhibitors dapagliflozin treatment compared with placebo (P < 0.05 for all). Low density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) levels were unchanged in the SGLT2 inhibitors group and placebo group. No statistical correlation was found between the levels of serum asprosin and body weight, BMI, HbA1c, FPG, and lipid levels during the SGLT2 inhibitor dapagliflozin treatment. CONCLUSIONS: These findings indicated that SGLT2 inhibitors can lower serum asprosin levels and improve glucolipid and weight in patients with newly diagnosed T2DM, which may benefit the cardiovascular system. Trial registration CTR20131268; Registered 20 March 2014 CTR20150102; Registered 03 March 2015. http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml .

Whole Brain Radiation Therapy Plus Focal Radiation Boost May Generate Better Survival Benefit for Brain Metastases From Non-small Cell Lung Cancer.

BACKGROUND: Owing to improved systemic therapies, the survival of patients with non-small cell lung cancer (NSCLC) was prolonged, and the risk of brain metastases was consequently increased. This study aims to compare different radiotherapy for brain metastases in patients with NSCLC. MATERIALS AND METHODS: The patients with NSCLC who were treated with whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) for brain metastases at three medical centers between January 2012 and December 2017 were retrospectively analyzed. RESULTS: Of the 684 eligible patients, 217 received WBRT plus focal radiation boost (WBRT+boost), 324 received WBRT, and 143 received SRS. Patients with WBRT+boost lived longer than those with WBRT (median overall survival (OS), 22.2 vs 13.7 months, P < 0.001) or SRS (22.2 vs 17.3 months, P = 0.011). In subgroup analyses, the survival advantage of WBRT+boost was more obvious among patients with 1 to 3 brain metastases or who received targeted therapy than did SRS. From pair-wise comparisons of intracranial progression-free survival (iPFS), WBRT+boost was also superior to WBRT (12.9 vs 10.6 months, P = 0.028) and SRS (12.9 vs 9.1 months, P = 0.001). CONCLUSIONS: Patients who were treated with WBRT+boost experienced significantly longer OS and iPFS than those with WBRT or SRS alone. WBRT+boost should be a preferred strategy for brain metastases in NSCLC patients.

Whole brain radiation therapy plus focal boost may be a suitable strategy for brain metastases in SCLC patients: a multi-center study.

BACKGROUND: The treatment for brain metastases in small cell lung cancer (SCLC) is still controversial. The purpose of this study was to compare different brain radiotherapy treatments on SCLC patients with brain metastases. METHODS: In this multi-center retrospective study, SCLC patients who had undergone whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) for brain metastases from January 2012 to December 2018 were retrospectively screened. RESULTS: A total of 263 eligible SCLC patients were included in this study, among whom, 73 were women and 190 were men. According to accepted brain radiotherapy, the remaining patients were divided into WBRT plus focal radiation boost (WBRT+boost), WBRT, and SRS groups. In pairwise comparisons of the overall survival (OS), WBRT+boost group led to longer survival than did WBRT both in all patients (17.9 vs 8.7 months; P < 0.001) and 140 matched patients (17.9 vs 11.7 months; P = 0.045). There were no significant differences in OS between WBRT+boost and SRS groups in all patients (17.9 vs 14.5 months; P = 0.432). Among 74 matched patients between WBRT+boost and SRS groups, however, patients who received WBRT+boost led to a longer survival than did SRS alone (21.8 vs 12.9 months; P = 0.040). In pairwise comparison of the intracranial progression-free survival time (iPFS), WBRT+boost group also showed survival advantages over WBRT (10.8 vs 6.5 months; P = 0.005) and SRS groups (10.8 vs 7.5 months; P = 0.032). CONCLUSION: Due to the SCLC-derived multiple brain metastases and better survival time, focal radiation boost combined with adjuvant WBRT may be a preferred strategy for SCLC patients with brain metastases.

Dosimetric evaluation of four whole brain radiation therapy approaches with hippocampus and inner ear avoidance and simultaneous integrated boost for limited brain metastases.

AIMS: To perform a dosimetric evaluation of four different simultaneous integrated boost whole brain radiotherapy modalities with hippocampus and inner ear avoidance in the treatment of limited brain metastases. METHODS: Computed tomography/magnetic resonance imaging data of 10 patients with limited (1-5) brain metastases were used to replan step-and-shoot intensity-modulated radiotherapy (sIMRT), dynamic intensity-modulated radiation therapy (dIMRT), volumetric-modulated arc therapy (VMAT), and helical tomotherapy (Tomo). The prescribed doses of 40-50 Gy in 10 fractions and 30 Gy in 10 fractions were simultaneously delivered to the metastatic lesions and the whole-brain volume, respectively. The hippocampal dose met the RTOG 0933 criteria for hippocampal avoidance (Dmax ≤17 Gy, D100% ≤10 Gy). The inner ear dose was restrained to Dmean ≤15 Gy. Target coverage (TC), homogeneity index (HI), conformity index (CI), maximum dose (Dmax), minimum dose (Dmin) and dose to organs at risk (OARs) were compared. RESULTS: All plans met the indicated dose restrictions. The mean percentage of planning target volume of metastases (PTVmets) coverage ranged from 97.1 to 99.4%. For planning target volume of brain (PTVbrain), Tomo provided the lowest average D2% (37.5 ± 2.8 Gy), the highest average D98% (25.2 ± 2.0 Gy), and the best TC (92.6% ± 2.1%) and CI (0.79 ± 0.06). The two fixed gantry IMRT modalities (step and shot, dynamic) provided similar PTVbrain dose homogeneity (both 0.76). Significant differences across the four approaches were observed for the maximum and minimum doses to the hippocampus and the maximum doses to the eyes, lens and optic nerves. CONCLUSION: All four radiotherapy modalities produced acceptable treatment plans with good avoidance of the hippocampus and inner ear. Tomo obtained satisfactory PTVbrain coverage and the best homogeneity index. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03414944 . Registered 29 January 2018.

Combination therapy with F5/35 fiber chimeric conditionally replicative adenoviruses expressing IL-24 enhances the antitumor effect of temozolomide against melanoma.

BACKGROUND: Temozolomide (TMZ) is widely used to treat melanoma; however, response rates to TMZ are low because of rapid and frequent resistance. Conditionally, replicative adenoviruses (CRAds) are an effective and promising approach. The receptor for adenovirus is coxsackie-adenovirus receptor (CAR), which is poorly expressed in most cells. However, CD46, which is the receptor of species B adenoviruses (Ads), is highly expressed in many cells. METHODS: We constructed CRAd F5/35-ZD55-IL-24, which uses the viral receptors CAR and CD46 for entry into cells. We investigated the antitumor effect of F5/35-ZD55-IL-24 in combination with TMZ to treat melanoma in vitro and in vivo. RESULTS: The \results indicated that F5/35-ZD55-IL-24 in combination with TMZ produced additive or synergistic antitumor and pro-apoptotic effects in melanoma cells. The combination of F5/35-ZD55-IL-24 and TMZ significantly inhibited the growth of melanoma in vivo. In addition, the antitumor effect of F5/35-ZD55-IL-24 was superior to that of ZD55-IL-24 and ZD55-IL-24 combined with TMZ. CONCLUSIONS: The use of F5/35-ZD55-IL-24 in conjunction with TMZ is a promising approach for anti-melanoma therapy. Our results indicated that F5/35-ZD55-IL-24 in combination with TMZ produced additive or synergistic antitumor effect and pro-apoptotic effect in melanoma cells highly expressed CD46. The combination of F5/35-ZD55-IL-24 and TMZ significantly inhibited the growth of melanoma in vivo. We also found the antitumor effect of F5/35-ZD55-IL-24 was superior to ZD55-IL-24, the combination of F5/35-ZD55-IL-24 and TMZ had a more significant antitumor effect than ZD55-IL-24 combining with TMZ.

1α,25(OH)2-Vitamin D3 Inhibits C2C12 Cell Differentiation by Activating c-Src and ERK1/2.

BACKGROUND: The steroid hormone 1α,25(OH)2-vitamin D3 (1,25-D3) induced some biological responses through activation of MAPK cascades in various cell types. It seems that 1,25-D3 plays different roles at different stages of proliferating, differentiating, and differentiated C2C12 cells. We wanted to detect the effect of 1,25-D3 on myogenic differentiation and the role of ERK1/2 in differentiating stage induced by 2% horse serum with 1,25-D3. METHODS: In this study, cells were induced to differentiate with 2% horse serum until the 7th day (with addition of 1,25-D3 every two days). The protein level of MHC (myosin heavy chain) and phosphorylation level of Src and ERK1/2 were determined with western blot. U0126 (MEK inhibitor) and PP2 (Src specific inhibitor) were used to confirm the relationship between 1,25-D3, MHC, Src, and ERK1/2. RESULTS: 1,25-D3 inhibited differentiation of C2C12 cells and fusion of myotubes by phosphorylating and activating Src and ERK1/2. Phosphorylation of ERK1/2 was inhibited, not only by U0126 but also by PP2 (a Src specific inhibitor) which led to the promotion of differentiation of C2C12 cells; however, U0126 did not inhibit Src phosphorylation. CONCLUSIONS: These results suggested that 1,25-D3 possibly inhibited C2C12 differentiation through Src and ERK1/2, and Src played an upstream role in this signaling pathway.

A novel fiber chimeric conditionally replicative adenovirus-Ad5/F35 for tumor therapy.

Significant progress has been made in the diagnosis and treatment of cancer; however, significant challenges remain. Conditionally replicating adenoviruses (CRAds), which not only kill cancer cells, but also serve as vectors to express therapeutic genes, are a novel and effective method to treat cancer. However, most adenoviruses are Ad5, which infect cells through the coxsackie and adenovirus receptor (CAR). The transduction efficacy of Ad5 is restricted because of the absent or low expression of CAR on several cancer cells. Ad serotype 35 has a different tropism pattern to Ad5. Ad35 attaches to cells via a non-CAR receptor, CD46, which is expressed widely on most tumor cells. Thus, chimeric adenoviral vectors consisting of the knob and shaft of Ad35 combined with Ad5 have been constructed. The chimeric fiber adenoviral vectors can transduce CAR-positive and CAR-negative cell lines. In this review, we explore the application of the novel fiber chimeric conditionally replicative adenovirus-Ad5/F35 in tumor therapy in terms of safety, mechanism, transduction efficacy, and antitumor effect.

Mobile phone use and glioma risk: A systematic review and meta-analysis.

OBJECTIVE: Many studies have previously investigated the potential association between mobile phone use and the risk of glioma. However, results from these individual studies are inconclusive and controversial. The objective of our study was to investigate the potential association between mobile phone use and subsequent glioma risk using meta-analysis. METHODS: We performed a systematic search of the Science Citation Index Embase and PubMed databases for studies reporting relevant data on mobile phone use and glioma in 1980-2016. The data were extracted and measured in terms of the odds ratio (OR) and 95% confidence interval (CI) using the random effects model. Subgroup analyses were also carried out. This meta-analysis eventually included 11 studies comprising a total 6028 cases and 11488 controls. RESULTS: There was a significant positive association between long-term mobile phone use (minimum, 10 years) and glioma (OR = 1.44, 95% CI = 1.08-1.91). And there was a significant positive association between long-term ipsilateral mobile phone use and the risk of glioma (OR = 1.46, 95% CI = 1.12-1.92). Long-term mobile phone use was associated with 2.22 times greater odds of low-grade glioma occurrence (OR = 2.22, 95% CI = 1.69-2.92). Mobile phone use of any duration was not associated with the odds of high-grade glioma (OR = 0.81, 95% CI = 0.72-0.92). Contralateral mobile phone use was not associated with glioma regardless of the duration of use. Similarly, this association was not observed when the analysis was limited to high-grade glioma. CONCLUSIONS: Our results suggest that long-term mobile phone use may be associated with an increased risk of glioma. There was also an association between mobile phone use and low-grade glioma in the regular use or long-term use subgroups. However, current evidence is of poor quality and limited quantity. It is therefore necessary to conduct large sample, high quality research or better characterization of any potential association between long-term ipsilateral mobile phone use and glioma risk.

Curcumin induces apoptosis through mitochondrial pathway and caspases activation in human melanoma cells.

Melanoma is the most malignant skin cancer and is highly resistant to chemotherapy and radiotherapy. Curcumin is a component of turmeric, the yellow spice derived from the rhizome of Curcuma longa. It has been demonstrated to modulate multiple cell signaling pathways, including apoptosis, proliferation, angiogenesis and inflammation. In this study, we studied the signaling pathways involved in melanoma cell death after treatment with curcumin using western blotting. Colorimetric assays (MTT) assessed cell viability. Flow cytometry and DNA laddering evaluated cell apoptosis. Fluorescent microscopy was used to evaluate of Hoechst 33342 staining of nuclei. The result demonstrated that curcumin could induce apoptosis and inhibit proliferation in melanoma cells. Curcumin stimulated the expression of pro-apoptotic Bax, and inhibited the activation of anti-apoptotic Mcl-1 and Bcl-2. During curcumin treatment, caspase-8 and Caspase-3 were cleaved in time and dose-dependent manners. Curcumin treatment also altered the expressions of apoptosis associated proteins NF-κB, p38 and p53. Curcumin induced DNA double strand breaks, which were indicated by phosphorylated H2AX. Our data suggested that curcumin could be used as a novel and effective approach for the treatment of melanoma.