A real-world pharmacovigilance study investigating the toxicities of histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors are emerging as promising treatments for hematological malignancies, with potential applications extending to solid tumors in the future. Given their wide-ranging biological effects, there is a pressing need for a thorough understanding of the toxicities linked to HDAC inhibition. In this study, a pharmacovigilance analysis was conducted using the FDA Adverse Event Reporting System database. Suspected adverse events linked to HDAC inhibitors were detected through various statistical methodologies, including reporting odds ratio, proportional reporting ratio, information component, and Empirical Bayes Geometric Mean. Our study findings have illuminated that, among the total reported cases examined, gastrointestinal disorders accounted for 13% patients of the cohort, while lymphatic system disorders comprised 8% cases of the cohort, all of which manifested as adverse events induced by HDAC inhibitors. Importantly, the usage of HDAC inhibitors was found to be associated with incidents of atrial fibrillation, heart failure, respiratory failure, hepatic dysfunction, and acute kidney injury. Romidepsin and belinostat demonstrated more pronounced signals of adverse events compared to panobinostat and vorinostat, emphasizing the need for vigilant monitoring of adverse events in this particular population. Furthermore, atrial fibrillation (clinical priority score of 7 points) emerged as the paramount medical event warranting utmost clinical attention. Eventually, multiple adverse events were observe to emerge within the initial and second months following the initiation of treatment. Vigilant monitoring and supportive care strategies are critical in addressing the toxicities associated with HDAC inhibitors, particularly those concerning cardiotoxicity, respiratory toxicity, renal toxicity, and hepatotoxicity.

Knockdown of the VEGFB/VEGFR1 signaling suppresses pubertal mammary gland development of mice via the inhibition of PI3K/Akt pathway.

Vascular endothelial growth factor B (VEGFB) has been well demonstrated to play a crucial role in regulating vascular function by binding to the VEGF receptors (VEGFRs). However, the specific role of VEGFB and VEGFRs in pubertal mammary gland development remains unclear. In this study, we observed that blocking the VEGF receptors with Axitinib suppressed the pubertal mammary gland development. Meanwhile, the proliferation of mammary epithelial cells (HC11) was repressed by blocking the VEGF receptors with Axitinib. Additionally, knockdown of VEGFR1 rather than VEGFR2 and NRP1 elicited the inhibition of HC11 proliferation, suggesting the essential role of VEGFR1 during this process. Furthermore, Axitinib or VEGFR1 knockdown led to the inhibition of the PI3K/Akt pathway. However, the inhibition of HC11 proliferation induced by Axitinib and or VEGFR1 knockdown was eliminated by the Akt activator SC79, indicating the involvement of the PI3K/Akt pathway. Finally, the knockdown of VEGFB and VEGFR1 suppressed the pubertal development of mice mammary gland with the inhibition of the PI3K/Akt pathway. In summary, the results showed that knockdown of the VEGFB/VEGFR1 signaling suppresses pubertal mammary gland development of mice via the inhibition of the PI3K/Akt pathway, which provides a new target for the regulation of pubertal mammary gland development.

Conjugated linoleic acid (CLA) reduces HFD-induced obesity by enhancing BAT thermogenesis and iWAT browning via the CD36-AMPK pathway.

The antiobesity effect of conjugated linoleic acid (CLA) has been reported. However, the underlying mechanisms have not been fully clarified. Thus, this study aimed to investigate the effects of CLA on thermogenesis of interscapular brown adipose tissue (iBAT) and browning of inguinal subcutaneous white adipose tissue (iWAT) and explore the possible signaling pathway. The in vivo results showed that CLA enhanced the O2 consumption and heat production in HFD (high-fat diet)-fed female mice by roughly 38%. Meanwhile, CLA increased the average iBAT temperature by 2°C at the room temperature and cold exposure, respectively. Correspondingly, CLA caused 1.6- and 2.4-fold increases in the expression of UCP1 (uncoupling protein 1) of BAT and iWAT, respectively, suggesting the activated iBAT thermogenesis and iWAT browning in HFD-fed female mice. Meanwhile, CLA could promote the formation of brown and beige adipocytes in differentiated stromal vascular cells (SVCs) isolated from iBAT and iWAT (the expressions of UCP1 were promoted by about twofold changes). In possible mechanisms, CLA stimulated the expression of CD36 and the activation of the AMPK pathway in mice iBAT and iWAT as well as the differentiated SVCs. However, inhibition of CD36 and AMPK (adenosine 5'-monophosphate-activated protein kinase) abolished the promotive effects of CLA on brown and beige adipocytes formation. Hence, we showed that CLA reduced HFD-induced obesity through enhancing iBAT thermogenesis and iWAT browning via the  CD36-AMPK pathway.

Circulating leptin levels in the assessment of Crohn's disease activity and its relation to nutritional status.

Introduction: Objective: to evaluate leptin levels and its relation to nutritional status in Crohn's disease (CD). Methods: the study included 154 CD patients and healthy controls. Leptin level was determined before treatment. Nutrition levels were assessed using the Nutrition Risk Screening 2002 (NRS-2002) and Patient-Generated Subjective Global Assessment (PG-SGA). Indicators included body mass index (BMI), mid-arm circumference, the circumference of the upper-arm muscle, triceps skinfold thickness, and circumference of legs. Results: leptin levels differed between CD patients (1,025 ± 874 ng/ml) and controls (18,481,222 ng/ml). Significant differences were seen in NRS-2002, PG-SGA scores, BMI and other nutritional indicators. Negative correlations were observed between leptin and NRS-2002, PG-SGA scores, while positive correlations were observed with other nutritional indicators. The receiver operating characteristic (ROC) curve showed association between leptin and the diagnosis of CD, suggesting leptin concentration below 803.02 ng/ml as a threshold for CD. Conclusion: dysfunctional leptin regulation may relate to poor nutritional status associated with CD. The leptin level is thus an additional tool for evaluating CD patients, predicting disease activity and clinical response. Leptin may be a potential target for intervention in CD to improve nutritional status.

Introducción: Objetivo: evaluar los niveles de leptina y su relación con el estado nutricional en la enfermedad de Crohn (EC). Métodos: se incluyeron 154 pacientes con EC y controles sanos. El nivel de leptina se determinó antes del tratamiento. La situación nutricional se evaluó mediante el examen de riesgo nutricional 2002 (NRS-2002) y la Valoración Global Subjetiva Generada por el Paciente (VGS-GP). Los indicadores incluyen el índice de masa corporal (IMC), la circunferencia media del brazo, la circunferencia del músculo superior del brazo, el grosor del pliegue cutáneo del tríceps y la circunferencia de las piernas. Resultados: los niveles de leptina difirieron entre los pacientes con EC (1.025 ± 874 ng/ml) y los controles (18.481.222 ng/ml). Se observaron diferencias significativas en NRS-2002, puntajes de VGS-GP, IMC y otros indicadores nutricionales. Se observaron correlaciones negativas entre leptina y NRS-2002, puntuaciones de VGS-GP, mientras que se observaron correlaciones positivas con otros indicadores nutricionales. La curva ROC mostró asociación entre leptina y el diagnóstico de EC, sugiriendo concentraciones de leptina por debajo de 803,02 ng/ml como umbral para EC. Conclusión: puede relacionarse la alteración en la regulación de la leptina con la peor situación nutricional en enfermos con EC.La leptina puede ser un objetivo potencial para la intervención en EC a fin de mejorar el estado nutricional.

Browning of Mammary Fat Suppresses Pubertal Mammary Gland Development of Mice via Elevation of Serum Phosphatidylcholine and Inhibition of PI3K/Akt Pathway.

Mammary fat plays a profound role in the postnatal development of mammary glands. However, the specific types (white, brown, or beige) of adipocytes in mammary fat and their potential regulatory effects on modulating mammary gland development remain poorly understood. This study aimed to investigate the role of the browning of mammary fat on pubertal mammary gland development and explore the underlying mechanisms. Thus, the mammary gland development and the serum lipid profile were evaluated in mice treated with CL316243, a ß3-adrenoceptor agonist, to induce mammary fat browning. In addition, the proliferation of HC11 cells co-cultured with brown adipocytes or treated with the altered serum lipid metabolite was determined. Our results showed that the browning of mammary fat by injection of CL316243 suppressed the pubertal development of mice mammary glands, accompanied by the significant elevation of serum dioleoylphosphocholine (DOPC). In addition, the proliferation of HC11 was repressed when co-cultured with brown adipocytes or treated with DOPC. Furthermore, DOPC suppressed the activation of the PI3K/Akt pathway, while the DOPC-inhibited HC11 proliferation was reversed by SC79, an Akt activator, suggesting the involvement of the PI3K/Akt pathway in the DOPC-inhibited proliferation of HC11. Together, the browning of mammary fat suppressed the development of the pubertal mammary gland, which was associated with the elevated serum DOPC and the inhibition of the PI3K/Akt pathway.

Survival analysis and development of a prognostic nomogram for patients with hepatitis B virus-associated hepatocellular carcinoma.

Background and aims: Hepatitis B virus (HBV) is a common cause of hepatocellular carcinoma (HCC) in China, and this study aimed to identify high-risk factors for overall survival and develop a nomogram prediction model. Methods: In the present retrospective cohort study, patients with HBV-associated HCC diagnosed from January 2009 to December 2018 were enrolled. Their clinical characteristics and time-to-event information were retrieved from electronic medical records. The zero time was the date of HCC diagnosis, and the endpoint was death or liver transplantation. Multivariable COX proportional hazard regression was used to screen independent risk factors for overall survival; then a nomogram model was developed to predict the survival probability of HCC patients. Results: A total of 1723 patients were enrolled, with 82.7 % male and a median age of 54.0 years. During a median follow-up time of 41.3 months, 672 cases (39.0 %) died. Age ≥60 years (HR = 1.209), Male (HR = 1.293), ALB <35 g/L (HR = 1.491), AST ≥80 U/L (HR = 1.818); AFP 20-400 ng/mL (HR = 2.284), AFP ≥400 ng/mL (HR = 2.746); LSM 9-22 kPa (HR = 2.266), LSM ≥22 kPa (HR = 4.326); BCLC stage B/C (HR = 4.079) and BCLC stage D (HR = 16.830) were the independent high-risk factors associated with HCC survival. A prognostic nomogram with a consistency index of 0.842 (95 % CI: 0.827-0.858) was developed. The calibration curve for long-term survival rate fitted well. Conclusions: This study identified independent risk factors affecting the survival of patients with HBV-associated HCC and constructed a predictive nomogram model, which can individually predict the overall survival and has good clinical application value.

Joint Detection of Serum Vitamin D, Body Mass Index, and Tumor Necrosis Factor Alpha for the Diagnosis of Crohn's Disease.

OBJECTIVE: Vitamin D (VD) deficiency was reported to contribute to the progression of Crohn's disease (CD) and affect the prognosis of CD patients. This study investigated the role of serum VD, body mass index (BMI), and tumor necrosis factor alpha (TNF-α) in the diagnosis of Crohn's disease. METHODS: CD patients (n=76) and healthy subjects (n=76) were enrolled between May 2019 and December 2020. The serum 25-hydroxyvitamin D [25(OH)D] levels, BMI, and TNF-α levels, together with other biochemical parameters, were assessed before treatment. The diagnostic efficacy of the single and joint detection of serum 25(OH)D, BMI, and TNF-α was determined using receiver operating characteristic (ROC) curves. RESULTS: The levels of 25(OH) D, BMI, and nutritional indicators, including hemoglobin, total protein, albumin, and high-density lipoprotein cholesterol, were much lower, and the TNF-α levels were much higher in the CD patients than in the healthy subjects (P<0.05 for all). The areas under the ROC curve for the single detection of 25(OH)D, BMI, and TNF-α were 0.887, 0.896, and 0.838, respectively, with the optimal cutoff values being 20.64 ng/mL, 19.77 kg/m2, and 6.85 fmol/mL, respectively. The diagnostic efficacy of the joint detection of 25(OH)D, BMI, and TNF-α was the highest, with an area under the ROC curve of 0.988 (95%CI: 0.968-1.000). CONCLUSION: The joint detection of 25(OH)D, TNF-α, and BMI showed high sensitivity, specificity, and accuracy in CD diagnosis; thus, it would be effective for the diagnosis of CD in clinical practice.

Autoimmunity associates with severity of illness in elderly patients with drug-induced liver injury.

Background: Drug-induced liver injury (DILI) is a potentially serious adverse drug reaction. Due to the lack of definite etiology, specific clinical manifestations, and diagnostic methods, its prediction and diagnosis are challenging. Elderly individuals are deemed to be at high risk for DILI due to abnormal pharmacokinetics, aging tissue repair function, comorbidities, and taking multiple drugs. This study aimed to identify the clinical characteristics and explore the risk factors associated with the severity of illness in elderly patients with DILI. Methods: In the present study, the clinical characteristics at the time of liver biopsy of consecutive patients with biopsy-proven DILI who presented at our hospital from June 2005 to September 2022 were evaluated. Hepatic inflammation and fibrosis were assessed according to the Scheuer scoring system. The presence of autoimmunity was considered if IgG level >1.1 × ULN (1826 mg/dL), or high titer (>1:80) of ANA, or SMA. Results: In total, 441 patients were enrolled, and the median age was 63.3 years (IQR, 61.0-66.0); 122 (27.7%), 195 (44.2%), or 124 (28.1%) were classified as having minor, moderate, or severe hepatic inflammation, respectively; and 188 (42.6%), 210 (47.6%) or 43 (9.8%) patients presented minor, significant fibrosis or cirrhosis, respectively. Female sex (73.5%) and the cholestatic pattern (47.6%) were dominant in elderly DILI patients. Autoimmunity existed in 201 patients (45.6%). Comorbidities were not directly associated with the severity of DILI. PLT (OR: 0.994, 95% CI: 0.991-0.997; p < 0.001), AST (OR: 1.001, 95% CI: 1.000-1.003, p = 0.012), TBIL (OR: 1.006, 95% CI: 1.003-1.010, p < 0.001), and autoimmunity (OR: 1.831, 95% CI: 1.258-2.672, p = 0.002) were associated with the degree of hepatic inflammation. Meanwhile, PLT (OR: 0.990, 95% CI: 0.986-0.993, p < 0.001), TBIL (OR: 1.004, 95% CI: 1.000-1.007, p = 0.028), age (OR: 1.123, 95% CI: 1.067-1.183, p < 0.001), and autoimmunity (OR: 1.760, 95% CI: 1.191-2.608, p = 0.005) were associated with the stage of hepatic fibrosis. Conclusion: This study revealed that the presence of autoimmunity represents a more serious illness state of DILI, deserving more intensive monitoring and progressive treatment.

Overexpression of POU3F2 promotes radioresistance in triple-negative breast cancer via Akt pathway activation.

PURPOSE: POU3F2 is associated with malignant behaviors and poor prognosis in cancer. However, the function and mechanism of POU3F2 in breast cancer remain to be elucidated. Our study aimed to explore the role of POU3F2 in triple-negative breast cancer and radiotherapy. METHODS: POU3F2 expression was examined by RT-PCR and Western blot. The proliferation of cancer cells was measured by MTT assay. Migration of cancer cells was determined by Transwell assay and wound healing assay. To determine which protein interacts with POU3F2, Co-IP was performed. Survival analysis was performed based on the online database GEPIA. DNA damage after radiation was examined by Comet Assay. Radiosensitivity was evaluated with clonogenic survival assays. A tumor xenograft model was established with MDA-MB-231 breast cancer cells in BALB/c nude mice to explore the effect of POU3F2 in vivo. RESULTS: We found that the expression of POU3F2 was significantly elevated in breast cancer cells, especially in TNBC, and higher POU3F2 expression was related to poor prognosis of patients with breast cancer. Functional assays revealed that POU3F2 promoted proliferation, migration, and invasion of triple-negative breast cancer (TNBC) cells in vitro and in vivo. In addition, the knockdown of POU3F2 decreased the radioresistance of TNBC cells in vitro. Furthermore, POU3F2 could enhance the activation of the Akt pathway by interacting with ARNT2, thereby promoting proliferation and radioresistance in TNBC cells. CONCLUSIONS: Our results provide evidence that high expression of POU3F2 promotes radioresistance in triple-negative breast cancer via Akt pathway activation by interacting with ARNT2.

Cancer-associated fibroblasts induce growth and radioresistance of breast cancer cells through paracrine IL-6.

In breast cancer, the most numerous stromal cells are cancer-associated fibroblasts (CAFs), which are associated with disease progression and chemoresistance. However, few studies have explored the function of CAFs in breast cancer cell radiosensitivity. Here, CAF-derived conditioned media was observed to induce breast cancer cell growth and radioresistance. CAFs secrete interleukin 6 (IL-6) which activates signal transducer and activator of transcription 3 (STAT3) signaling pathway, thus promoting the growth and radioresistance of breast cancer cells. Treatment with an inhibitor of STAT3 or an IL-6 neutralizing antibody blocked the growth and radioresistance induced by CAFs. In in vivo mouse models, tocilizumab (an IL-6 receptor monoclonal antibody) abrogated CAF-induced growth and radioresistance. Moreover, in breast cancer, a poor response to radiotherapy was associated with IL-6 and p-STAT3 expression. These results indicated that IL-6 mediates cross-talk between breast cancer cells and CAFs in the tumor microenvironment. Our results identified the IL-6/STAT3 signaling pathway as an important therapeutic target in breast cancer radiotherapy.

Knockdown of VEGFB/VEGFR1 Signaling Promotes White Adipose Tissue Browning and Skeletal Muscle Development.

It has been demonstrated that vascular endothelial growth factor B (VEGFB) and vascular endothelial growth factor receptor 1 (VEGFR1) play a vital role in regulating vascular biological function. However, the role of VEGFB and VEGFR1 in regulating fat deposition and skeletal muscle growth remains unclear. Therefore, this study was conducted to investigate the effects of VEGFB and VEGFR1 on fat deposition and skeletal muscle growth in mice. Our results showed that knockdown of VEGFB decreased body weight and iWAT index, stimulated the browning of mice iWAT with increased expression of UCP1, decreased the diameters of adipocytes, and elevated energy expenditure. In contrast, knockdown of VEGFB increased gastrocnemius (GAS) muscle index with increased proliferation of GAS muscle by expression of PCNA and Cyclin D1. Meanwhile, knockdown of endothelial VEGFR1 induced the browning of iWAT with increased expression of UCP1 and decreased diameters of adipocytes. By contrast, knockdown of endothelial VEGFR1 inhibited GAS muscle differentiation with decreased expression of MyoD. In conclusion, these results suggested that the loss of VEGFB/VEGFR1 signaling is associated with enhanced browning of inguinal white adipose tissue and skeletal muscle development. These results provided new insights into the regulation of skeletal muscle growth and regeneration, as well as fat deposition, suggesting the potential application of VEGFB/VEGFR1 as an intervention for the restriction of muscle diseases and obesity and related metabolic disorders.

VEGFB Promotes Myoblasts Proliferation and Differentiation through VEGFR1-PI3K/Akt Signaling Pathway.

It has been demonstrated that vascular endothelial growth factor B (VEGFB) plays a vital role in regulating vascular biological function. However, the role of VEGFB in regulating skeletal muscle cell proliferation and differentiation remains unclear. Thus, this study aimed to investigate the effects of VEGFB on C2C12 myoblast proliferation and differentiation and to explore the underlying mechanism. For proliferation, VEGFB significantly promoted the proliferation of C2C12 myoblasts with the upregulating expression of cyclin D1 and PCNA. Meanwhile, VEGFB enhanced vascular endothelial growth factor receptor 1 (VEGFR1) expression and activated the PI3K/Akt signaling pathway in a VEGFR1-dependent manner. In addition, the knockdown of VEGFR1 and inhibition of PI3K/Akt totally abolished the promotion of C2C12 proliferation induced by VEGFB, suggesting that VEGFB promoted C2C12 myoblast proliferation through the VEGFR1-PI3K/Akt signaling pathway. Regarding differentiation, VEGFB significantly stimulated the differentiation of C2C12 myoblasts via VEGFR, with elevated expressions of MyoG and MyHC. Furthermore, the knockdown of VEGFR1 rather than NRP1 eliminated the VEGFB-stimulated C2C12 differentiation. Moreover, VEGFB activated the PI3K/Akt/mTOR signaling pathway in a VEGFR1-dependent manner. However, the inhibition of PI3K/Akt/mTOR blocked the promotion of C2C12 myoblasts differentiation induced by VEGFB, indicating the involvement of the PI3K/Akt pathway. To conclude, these findings showed that VEGFB promoted C2C12 myoblast proliferation and differentiation via the VEGFR1-PI3K/Akt signaling pathway, providing new insights into the regulation of skeletal muscle development.

The LAC Score Indicates Significant Fibrosis in Patients With Chronic Drug-Induced Liver Injury: A Large Biopsy-Based Study.

Currently, there are no satisfactory noninvasive methods for the diagnosis of fibrosis in patients with chronic drug-induced liver injury (DILI). Our goal was to develop an algorithm to improve the diagnostic accuracy of significant fibrosis in this population. In the present study, we retrospectively investigated the biochemical and pathological characteristics of consecutive patients with biopsy-proven chronic DILI, who presented at our hospital from January 2013 to December 2017. A noninvasive algorithm was developed by using multivariate logistic regression, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) to diagnose significant fibrosis in the training cohort, and the algorithm was subsequently validated in the validation cohort. Totally, 1,130 patients were enrolled and randomly assigned into a training cohort (n = 848) and a validation cohort (n = 282). Based on the multivariate analysis, LSM, CHE, and APRI were independently associated with significant fibrosis. A novel algorithm, LAC, was identified with the AUROC of 0.81, which was significantly higher than LSM (AUROC 0.78), CHE (AUROC 0.73), and APRI (AUROC 0.68), alone. The best cutoff value of LAC in the training cohort was 5.4. When the LAC score was used to diagnose advanced fibrosis and cirrhosis stages, the optimal cutoff values were 6.2 and 6.7, respectively, and the AUROC values were 0.84 and 0.90 in the training cohort and 0.81 and 0.83 in the validation cohort. This study proved that the LAC score can contribute to the accurate assessment of high-risk disease progression and the establishment of optimal treatment strategies for patients with chronic DILI.

Switching from entecavir to tenofovir alafenamide for chronic hepatitis B patients with low-level viraemia.

BACKGROUND AND AIMS: About 20% of patients receiving nucleos(t)ide analogues treatment experienced low-level viraemia (LLV), which is associated with progression of liver fibrosis and high risk of hepatocellular carcinoma. We aimed to evaluate the effectiveness and safety of switching from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in ETV-treated patients with LLV. METHODS: In this prospective study, ETV-treated patients with LLV, presented to our hospital from December 2018 to October 2019, were enrolled. Switching to TAF or continuing ETV was given. The primary effectiveness endpoint was complete virological response (CVR) at 24 weeks, and the safety endpoint was the first occurrence of any clinical adverse event during the treatment. RESULTS: Totally, 211 patients were recruited and propensity score matching (PSM) generated 75 patients in either TAF or ETV group. After PSM, baseline characteristics were balanced in two groups. After 24-week treatment, the CVR and ALT normalization in TAF group were 62.7% and 47.6%, which were higher than 9.3% and 10.5% in ETV group (OR 16.4, 95% CI 6.6-40.0, P < .001) respectively. Subgroup analysis showed that switching to TAF achieved favours CVR regardless of the status of sex, age, CHB family history, HBV DNA, HBeAg and cirrhosis, whereas alcohol consumption and diabetes mellitus might compromise the CVR of switching to TAF. Both therapies were well tolerated and had satisfying renal safety. CONCLUSIONS: For ETV-treated patients with LLV, switching to TAF is safe enough and superior compared with continuing ETV monotherapy regarding both virological and biochemical benefits.

Tumor-suppressive microRNA-145 induces growth arrest by targeting SENP1 in human prostate cancer cells.

Prostate cancer (PCa) prevails as the most commonly diagnosed malignancy in men and the third leading cause of cancer-related deaths in developed countries. One of the distinct characteristics of prostate cancer is overexpression of the small ubiquitin-like modifier (SUMO)-specific protease 1 (SENP1), and the upregulation of SENP1 contributes to the malignant progression and cell proliferation of PCa. Previous studies have shown that the expression of microRNA-145 (miRNA-145) was extensively deregulated in PCa cell lines and primary clinical prostate cancer samples. Independent target prediction methods have indicated that the 3'-untranslated region of SENP1 mRNA is a potential target of miR-145. Here we found that low expression of miR-145 was correlated with high expression of SENP1 in PCa cell line PC-3. The transient introduction of miR-145 caused cell cycle arrest in PC-3 cells, and the opposite effect was observed when miR-145 inhibitor was transfected. Further studies revealed that the SENP1 3'-untranslated region was a regulative target of miR-145 in vitro. MicroRNA-145 also suppressed tumor formation in vivo in nude mice. Taken together, miR-145 plays an important role in tumorigenesis of PCa through interfering SENP1.

Balloon dilation versus Amplatz dilation during ultrasound-guided percutaneous nephrolithotomy for staghorn stones.

BACKGROUND: Amplatz dilation and balloon dilation are different methods in creating the accesses during percutaneous nephrolithotomy (PCNL). The aim of this study was to review the surgical experiences of managing staghorn calculi by Amplatz dilation and balloon dilation for 3 years. METHODS: We retrospectively analyzed clinical data from 125 patients (129 kidneys) with staghorn kidney stones who underwent PCNL from January 2010 to December 2012, of whom 60 patients underwent Amplatz dilation (AD group) and 65 underwent balloon dilation (BD group) during PCNL. RESULTS: The AD and BD groups were similar in age, male-female ratio, stone burden, stone type, hydronephrosis, and proportion of patients who had undergone extracorporeal lithotripsy. However, these two groups showed significant differences in terms of duration of percutaneous access (15.1 ± 3.6) minutes vs. (10.0 ± 3.3) minutes, one-attempt success rate of dilation via a single access 88.9% (72/81) vs. 97.8% (91/93), hemoglobin drop after surgery (3.5 ± 0.9) g/dl vs. (1.7 ± 0.9) g/dl, number of cases requiring intraoperative and postoperative blood transfusion 27.9% (n = 17) vs. 13.2% (n = 9), changes of central venous pressure before and after surgery (2.3 ± 1.2) cmH2O vs. (1.2 ± 0.7) cmH2O, number of patients who experienced postoperative fever >37.5°C 21 (34.4%) vs. 13 (19.1%) (all P < 0.05). No injury of adjacent organs, including pleura, liver, spleen, or bowel, was noted in patients. CONCLUSIONS: During ultrasound-guided PCNL for staghorn stones, balloon dilation and Amplatz dilation are all effective and safe. Compared with Amplatz dilation, balloon dilation is a better choice, as it has a higher access creation success rate, shorter access creation time less blood loss, and lower proportions of circulatory overload and postoperative fever.

Ultrasound-guided minimally invasive percutaneous nephrolithotomy in flank position for management of complex renal calculi.

OBJECTIVES: To evaluate the safety and efficacy of performing ultrasound-guided minimally invasive percutaneous nephrolithotomy (MPCNL) in the flank position for the management of complex renal calculi. Percutaneous nephrolithotomy is usually performed with the patient in the prone position under fluoroscopic guidance; however, this position, and guidance method have some limitations. METHODS: From January 2007 to December 2009, 93 patients (101 kidneys) with complex renal calculi underwent ultrasound-guided MPCNL in the flank position. RESULTS: The mean age of the patients was 45.3 years (range 29-71). The calculi-free rate in the patients who underwent a single procedure was 78.2% (79 of 101 kidneys). The average operative duration was 82.6 minutes (range 45-190). Although the perioperative blood loss was not significantly different between single-tract and double-tract MPCNL (P = .087, F = 2.981), the calculi-free rate was significantly greater in the patients who underwent double-tract MPCNL than in those who underwent single-tract MPCNL (P = .027, chi-square = 4.873). Perioperative blood transfusions were not required in any patient. Similarly, ureteral calculi due to percutaneous nephrolithotomy were not observed. Secondary renal hemorrhage occurred in 3 patients who had undergone single-tract MPCNL and 1 underwent nephrectomy. CONCLUSIONS: The results of our study have shown that ultrasound-guided MPCNL with the patient in the flank position is safe and effective for treating complex renal calculi, without the side effects of radiation to the patient and surgeon. Double-tract MPCNL is suitable for complex renal calculi and, in some cases, is required to increase the calculi-free rate. The insertion of twin ureteral catheters before lithotripsy might be helpful in avoiding residual ureteral calculi after percutaneous nephrolithotomy.

[Treatment of ureteral obstruction by holmium: YAG laser endoureterotomy: a report of 18 cases].

OBJECTIVE: To investigate the clinical value and safety of holmium: YAG laser endoureterotomy in the treatment of ureteral obstruction. METHODS: Holmium: YAG laser endoureterotomy, with the laser optic fiber 550 microm in diameter and the output power of 3.5 Watt, via ureteroscopy, was performed on 18 patients ureteral obstruction, 8 males and 10 females, aged 52.1 (34-67), 11 with the stricture in the upper segment (complete obstruction in 4 cases), 5 in the middle segment, and 2 in lower segment; and 6 cases complicated with ureteral calculus. Postoperatively, an orthopedic ureteral stent (a 6-Fr double-J ureteral stent with a movable 5 cm length 9-Fr orthopedic cannula) was remained indwelling for 3-6 months. Follow-up was conducted for 10.7 (2-14) months. RESULTS: The operative duration was 32 (25-70) minutes. One patient underwent failed endoureterotomy and was turned to percutaneous nephroscopy. Success was achieved in 16 patients. The glomerular filtration rate (GFR) of these affected kidneys increased from 16.4+/-6.9 ml/min ante-operatively to 24.9+/-8.2 ml/min (P<0.01) postoperatively. One kidney was resected because of non-function, with GFR of 2 ml/min and intractable pyelitis. No recurrence of ureteral stricture was observed. CONCLUSION: Holmium: YAG laser endoureterotomy with insertion of orthopedic ureteral stent is an efficient and safe treatment for ureteral strictures with minimal invasion, less complications and easy recovery. This operation should be performed with a thorough preparation and severely restricted indication.

MSCs guide neurite directional extension and promote oligodendrogenesis in NSCs.

Previous studies have shown that mesenchymal stem cells (MSCs) enhance repair following injury or degenerative diseases in the central nervous system, but the underlying mechanisms remain unclear. The present study investigated the functional relationship between MSCs and neural stem cells (NSCs) using co-culture systems. Results demonstrated that MSCs promoted outgrowth and guided directional extension of NSC-derived neurites. The majority of neurites were oriented parallel along the MSC axis. Stripe assay results indicated that cell adhesion molecule and extracellular matrix, such as N-cadherin, fibronectin, and laminin, contributed to this effect. Furthermore, Western blot analysis revealed that phosphorylation of cAMP response element-binding protein (CREB) increased during this process. In addition, MSCs promoted differentiation of NSCs into oligodendrocytes via secreted soluble factors. The oligodendrocytes were distributed along the MSC surface in a regular pattern. This study demonstrated that MSC transplantation could be a potential strategy for treating central nervous system injuries.

[Optimization of extracting method and inhibitory action of recombinant human endostatin in bladder cancer].

OBJECTIVE: To explore the optimal method for protein expression in rhES (recombinant human endostatin) and study the anti-tumor activities of rhES in solid tumor and established cell line. METHODS: Different IPTG concentrations, the timing of adding IPTG into the culture medium and the different time of expression were employed to explore the optimized conditions of protein expression. Activity examination: (1) animal experiment: nude mice bearing subcutaneous cancer in treated group and controlled group were observed. (2) cellular experiment: the inhibitory effect of rhES in T-24 established cell line were observed by MTT assay and cancer cell growth curve. RESULTS: The expression of rhES protein was 58.65%. Of all the E. coli body proteins, the protein purity after purification was 96.22%. Activity examination indicated that rhES could inhibit the growth of solid tumor and the established cell line. In animal experiment, the tumor inhibition rate was 66.8%. Cell experiment: the 50% inhibitory concentration (IC(50)) was 22 microg/ml. The cell population decreased 58.75% than the control group at Day 7 in the tumor cell growth curve. CONCLUSION: A high expression and activity of rhES protein can be obtained by the optimized expression conditions. rhES can inhibit the cellular growth in both solid tumor and established cell line of bladder cancer.