Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT

Activation of the phosphatidylinositol-3-kinase (PI3K)/AKT survival pathway is a mechanism of cytotoxic drug resistance in ovarian cancer, and inhibitors of this pathway can sensitize to cytotoxic drugs. The HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) depletes some proteins involved in PI3K/AKT signaling, e.g., ERBB2, epidermal growth factor receptor (EGFR), and phosphorylated AKT (p-AKT). 17-AAG and paclitaxel were combined (at a fixed 1:1 ratio of their IC(50)) in four ovarian cancer cell lines that differ in expression of p-AKT, EGFR, and ERBB2. The EGFR-overexpressing A431 and KB epidermoid cell lines were also included. Combination indices (CI) were calculated using the median-effect equation and interpreted in the context of 17-AAG-mediated inhibition of PI3K signaling. Synergy was observed in IGROV-1- and ERBB2-overexpressing SKOV-3 ovarian cancer cells that express a high level of constitutively activated p-AKT [CI at fraction unaffected (fu)(0.5) = 0.50 and 0.53, respectively]. Slight synergy was observed in A431 cells (moderate p-AKT/overexpressed EGFR; CI at fu(0.5) = 0.76) and antagonism in CH1 (moderate p-AKT), HX62 cells (low p-AKT), and KB cells (low p-AKT/overexpressed EGFR; CI at fu(50) = 3.0, 3.5, and 2.0, respectively). The observed effects correlated with changes in the rate of apoptosis induction. 17-AAG induced a decrease in HSP90 client proteins (e.g., C-RAF, ERBB2, and p-AKT) or in downstream markers of their activity (e.g., phosphorylated extracellular signal-regulated kinase or p-AKT) in SKOV-3, IGROV-1, and CH1 cells at IC(50) concentrations. A non-growth-inhibitory concentration (6 nmol/L) reduced the phosphorylation of AKT (but not extracellular signal-regulated kinase) and sensitized SKOV-3 cells to paclitaxel. In conclusion, 17-AAG may sensitize a subset of ovarian cancer to paclitaxel, particularly those tumors in which resistance is driven by ERBB2 and/or p-AKT.     

Striatal D2 receptors regulate dendritic morphology of medium spiny neurons via Kir2 channels

Structural plasticity in the adult brain is essential for adaptive behaviors and is thought to contribute to a variety of neurological and psychiatric disorders. Medium spiny neurons of the striatum show a high degree of structural plasticity that is modulated by dopamine through unknown signaling mechanisms. Here, we demonstrate that overexpression of dopamine D2 receptors in medium spiny neurons increases their membrane excitability and decreases the complexity and length of their dendritic arbors. These changes can be reversed in the adult animal after restoring D2 receptors to wild-type levels, demonstrating a remarkable degree of structural plasticity in the adult striatum. Increased excitability and decreased dendritic arborization are associated with downregulation of inward rectifier potassium channels (Kir2.1/2.3). Downregulation of Kir2 function is critical for the neurophysiological and morphological changes in vivo because virally mediated expression of a dominant-negative Kir2 channel is sufficient to recapitulate the changes in D2 transgenic mice. These findings may have important implications for the understanding of basal ganglia disorders, and more specifically schizophrenia, in which excessive activation of striatal D2 receptors has long been hypothesized to be of pathophysiologic significance.     

Prevalence of thyroid disorders is not different in type 2 diabetes mellitus compared to nondiabetics in South India

International Journal of Diabetes in Developing Countries - Studies on thyroid disorders in type 2 diabetes mellitus (DM) are fewer than those in type 1 diabetes, but data from different parts of...     

Large solitary ovarian metastasis from colorectal cancer diagnosed by endoscopic ultrasound

A case is presented of rectal carcinoma in which during staging by endoscopic ultrasound （EUS） a second large extra recta l mass was seen not otherwise visualized on computer tomograghy （CT） that was a solitary ovarian metastasis. The surgeon was alerted to the EUS finding prior to the planned laparoscopic colectomy. On retrospective review of the CT pelvis after surgery, the radiologist could still not diagnose the ovarian lesion separated from the primary rectal tumor due to their close proximity. However, on EUS we were able to clearly see on real-time imaging that there was a distinct peri-rectal mass apart from the primary rectal tumor.     

Urokinase-a very popular cardiovascular agent

Urokinase (UK) [EC 3.4.99.26] is a serine protease that activates plasminogen to plasmin, which in turn degrades fibrin clots. Hence, UK finds its value as an important anti-thromboembolic drug. Plasmin has diverse physiological roles apart from its fibrinolytic role in the regulation of blood clotting. It has been implicated in complement activation, cell migration, wound healing, and generation of localized extracellular proteolysis during tissue remodelling, pro-hormone conversion, carcinogenesis and neoplasia. Among the plasminogen activators, UK provides a superior alternative for the simple reasons of its being more potent as compared to tissue-plasminogen activator and non-antigenic by virtue of its human origin unlike streptokinase. Based on these observations, UK is a very popular cardiovascular agent. Hence, UK, as one of the most potent plasminogen activators is attracting a great deal of attention. We will summarize recent patents related to the occurrence, mechanism of action, structure and function, physico-chemical properties, in vitro production, cloning and expression, purification and applications of UK.     

Clinical and mutation profile of multicentric osteolysis nodulosis and arthropathy

​Multicentric osteolysis nodulosis and arthropathy (MONA) is an infrequently described autosomal recessive skeletal dysplasia characterized by progressive osteolysis and arthropathy. Inactivating mutations in MMP2, encoding matrix metalloproteinase‐2, are known to cause this disorder. Fifteen families with mutations in MMP2 have been reported in literature. In this study we screened thirteen individuals from eleven families for MMP2 mutations and identified eight mutations (five novel and three known variants). We characterize the clinical, radiographic and molecular findings in all individuals with molecularly proven MONA from the present cohort and previous reports, and provide a comprehensive review of the MMP2 related disorders. © 2015 Wiley Periodicals, Inc.

     

Patients undergoing intragastric balloon achieve approximately 50% of their target weight loss in the first month postoperatively: an MBSAQIP analysis

BackgroundIntragastric balloon (IGB) placement can provide a mean percent total weight loss (%TWL) of 10.2% at 6-month follow-up.ObjectivesWe aimed to evaluate 30-day outcomes and safety of patients undergoing IGB placement.SettingMetabolic and Bariatric Surgery Accreditation and Quality Improvement Program.MethodsThe 2016 to 2017 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program was queried for adult patients who underwent primary IGB placement. Demographic characteristics and preoperative risk factors were collected. Postoperative outcomes included %TWL, percent excess weight loss, and complications rates and causes. Subset analysis was done for outcomes comparison between surgeons or gastroenterologists performing the procedure. Statistical analysis was performed using SPSS 25.0.ResultsA total of 1221 patients were included. The majority was female (81.9%), Caucasian (81.2%), with a mean age of 48 ± 11.3 years and a mean preoperative body mass index of 34.9 ± 11.2 kg/m². Of patients, 98.8% were discharged within 24 hours of the procedure. Two patients were admitted to the intensive care unit, and 7.2% received postoperative treatment for dehydration. Reoperation and readmission rates were 1.1% and 7.2%, respectively, mainly due to nausea, vomiting, and poor nutritional status (n = 22). The intervention rate was 6.2%. Patients in this cohort achieved a mean %TWL of 6.2% (standard deviation, 5.52%) and mean TWL of 6.8 kg within 30 days postoperatively (n = 147; 24–30 d).ConclusionsOur data show patients met approximately 50% of their target weight loss 30 days after IGB placement. Nausea, vomiting, and poor nutrition status were the most common complications within 30 days of the procedure. Long-term follow-up is necessary to determine if these patients are able to sustain their weight loss and for how long.     

Cardiovascular Implications in the Treatment of Obstructive Sleep Apnea

Epidemiological studies provide strong evidence that obstructive sleep apnea (OSA) is associated with cardiovascular complications such as systemic hypertension, congestive heart failure, and atrial fibrillation. Successful OSA treatment with continuous positive airway pressure (CPAP) has resulted in coincident reductions in systemic hypertension, improvements in left ventricular systolic function, and reductions in sympathetic nervous activity. These data suggest that successful treatment of OSA may reduce cardiovascular morbidity in such patients. Although CPAP is the more successful treatment for OSA when used properly and consistently, its clinical success is often limited by poor patient and partner acceptance, which leads to suboptimal compliance. Oral appliances or upper airway surgeries are considered a second line of treatment for patients with mild to moderate OSA who do not comply with or refuse long-term CPAP treatment. Oral devices such as mandibular repositioning appliances were recently shown to improve arterial hypertension in OSA patients. Electrical stimulation of the hypoglossal nerve is a new investigational therapy for patients with moderate to severe OSA. This new treatment option, if proven effective, may provide cardiovascular benefits secondary to treating OSA.     

Pediatric endocrine hypertension

Endocrine causes of hypertension are rare in children and screening for endocrine hypertension in children should be carried out only after ruling out renal and renovascular causes. Excess levels and/or action of mineralocorticoids associated with low renin levels lead to childhood hypertension and this can be caused by various conditions which are discussed in detail in the article. Childhood pheochromocytomas are being increasingly diagnosed because of the improved application of genetic testing for familial syndromes associated with pheochromocytomas. Adolescents with polycystic ovarian syndrome (PCOS) can also have hypertension associated with their obese phenotype.