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Glioblastoma multiforme (GBM) is amongst the deadliest of human cancers, with a median survival rate of just over one year following diagnosis. Characterized by rapid proliferation and diffuse infiltration into the brain, GBM is notoriously difficult to treat, with tumor cells showing limited response to existing therapies and eventually developing resistance to these interventions. As such, there is intense interest in better understanding the molecular alterations in GBM to guide the development of more efficient targeted therapies. GBM tumors can be classified into several molecular subtypes which have distinct genetic signatures, and they show aberrant activation of numerous signal transduction pathways, particularly those connected to receptor tyrosine kinases (RTKs) which control glioma cell growth, survival, migration, invasion, and angiogenesis. There are also non-canonical modes of RTK signaling found in GBM, which involve G-protein-coupled receptors and calcium channels. This review uses The Cancer Genome Atlas (TCGA) GBM dataset in combination with a data-mining approach to summarize disease characteristics, with a focus on select molecular pathways that drive GBM pathogenesis. We also present a unique genomic survey of RTKs that are frequently altered in GBM subtypes, as well as catalog the GBM disease association scores for all RTKs. Lastly, we discuss current RTK targeted therapies and highlight emerging directions in GBM research.

Nephrin is a key structural component of the podocyte slit diaphragm, and proper expression of nephrin on the cell surface is critical to ensure integrity of the blood filtration barrier. Maintenance of nephrin within this unique cell junction has been proposed to require dynamic phosphorylation events and endocytic recycling, although the molecular mechanisms that control this interplay are poorly understood. Here, we investigated the possibility that the phosphotyrosine adaptor protein ShcA regulates nephrin turnover. Western blotting and immunostaining analysis confirmed that ShcA is expressed in podocytes. In immunoprecipitation and pulldown assays, ShcA, via its SH2 domain, was associated with several phosphorylated tyrosine residues on nephrin. Overexpression of ShcA promoted nephrin tyrosine phosphorylation and reduced nephrin signaling and cell surface expression in vitro In a rat model of reversible podocyte injury and proteinuria, phosphorylated nephrin temporally colocalized with endocytic structures coincident with upregulation of ShcA expression. In vivo biotinylation assays confirmed that nephrin expression decreased at the cell surface and correspondingly increased in the cytosol during the injury time course. Finally, immunostaining in kidney biopsy specimens demonstrated overexpression of ShcA in several human proteinuric kidney diseases compared with normal conditions. Our results suggest that increases in ShcA perturb nephrin phosphosignaling dynamics, leading to aberrant nephrin turnover and slit diaphragm disassembly., (Copyright © 2018 by the American Society of Nephrology.)

Proteins of the Src homology and collagen (Shc) family are typically involved in signal transduction events involving Ras/MAPK and PI3K/Akt pathways. In the nervous system, they function proximal to the neurotrophic factors that regulate cell survival, differentiation, and neuron-specific characteristics. The least characterized homolog, ShcD, is robustly expressed in the developing and mature nervous system, but its contributions to neural cell circuitry are largely uncharted. We now report that ShcD binds to active Ret, TrkA, and TrkB neurotrophic factor receptors predominantly via its phosphotyrosine-binding (PTB) domain. However, in contrast to the conventional Shc adaptors, ShcD suppresses distal phosphorylation of the Erk MAPK. Accordingly, genetic knock-out of mouse ShcD enhances Erk phosphorylation in the brain. In cultured cells, this capacity is tightly aligned to phosphorylation of ShcD CH1 region tyrosine motifs, which serve as docking platforms for signal transducers, such as Grb2. Erk suppression is relieved through independent mutagenesis of the PTB domain and the CH1 tyrosine residues, and successive substitution of these tyrosines breaks the interaction between ShcD and Grb2, thereby promoting TrkB-Grb2 association. Erk phosphorylation can also be restored in the presence of wild type ShcD through Grb2 overexpression. Conversely, mutation of the ShcD SH2 domain results in enhanced repression of Erk. Although the SH2 domain is a less common binding interface in Shc proteins, we demonstrate that it associates with the Ptpn11 (Shp2) phosphatase, which in turn regulates ShcD tyrosine phosphorylation. We therefore propose a model whereby ShcD competes with neurotrophic receptors for Grb2 binding and opposes activation of the MAPK cascade., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background and Purpose: Phantom limb pain (PLP) can be disabling for nearly two thirds of amputees. Hence, there is a need to find an effective and inexpensive treatment that can be self administered. Among the non-pharmacological treatment for PLP, transcutaneous electrical nerve stimulation (TENS) applied to the contralateral extremity and mirror therapy are two promising options. However, there are no studies to compare the two treatments. The purpose of this study is to evaluate and compare mirror therapy and TENS in the management of PLP in subjects with amputation., Methods: The study was an assessor blinded randomized controlled trial conducted at Physiotherapy Gymnasium of Physical Medicine and Rehabilitation Department, Christian Medical College, Vellore. Twenty-six subjects with PLP consented to participate. An initial assessment of pain using visual analogue scale (VAS) and universal pain score (UPS) was performed by a therapist blinded to the treatment given. Random allocation into Group I-mirror therapy and Group II-TENS was carried out. After 4 days of treatment, pain was re-assessed by the same therapist. The mean difference in Pre and Post values were compared among the groups. The change in pre-post score was analyzed using the paired t test., Results: Participants of Group I had significant decrease in pain [VAS ( p = 0.003) and UPS ( p = 0.001)]. Group II also showed a significant reduction in pain [VAS ( p = 0.003) and UPS ( p = 0.002)]. However, no difference was observed between the two groups [VAS ( p = 0.223 and UPS ( p = 0.956)]., Discussion: Both Mirror Therapy and TENS were found to be effective in pain reduction on a short-term basis. However, no difference between the two groups was found. Substantiation with long-term follow-up is essential to find its long-term effectiveness. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

Introduction: Duodenal perforation is one of the common pathologies in patients presenting in emergency with acute abdominal pain in an emergency ward and requires prompt surgery as life saving and curative intervention. The present study was conducted to determine whether the minimal access approach by laparoscopy was equally feasible as the open method., Aim: To compare laparoscopic vs. open management duodenal perforation in all aspects., Inclusion Criteria: patients presenting to the emergency ward with acute pain in the abdomen with clinical signs of peritonitis and air under the diaphragm on X-ray abdomen standing were selected. Exclusion criteria were: patient age < 15 years and > 70 years, presentation > 2 days, shock with systolic blood pressure < 90 mm Hg which did not improve after hydration with 2000 ml of Ringer lactate solution, respiratory distress, history of cardiac disorder or respiratory disorders such as ischemic heart disease, arrhythmias, chronic obstructive pulmonary disease or asthma, bleeding and clotting disorders, pregnancy in females, previous upper abdominal surgery, and intra-operatively patients having perforation other than duodenal perforation. After excluding patients fitting the above criteria, two groups - test and control - were formed., Results: We found that complications both early and late were significantly fewer in patients treated by laparoscopy. Thus laparoscopy was both feasible and had comparable mortality and leakage rate., Conclusions: Laparoscopic management of perforated duodenal ulcer is feasible, effective and decreases morbidity and overall treatment time and cost if performed in properly selected patients.

Purpose: We report the anesthetic management for a scheduled Cesarean section of a 29-yr-old female who previously had a repair of her dissecting thoracic aortic aneurysm during the 14th week of her pregnancy., Clinical Features: A 29-yr-old female with a history of hypertension and previously diagnosed aortic dissection secondary to suspected Marfan's syndrome, presented to our institution for the first time after she became pregnant. A transesophageal echocardiogram revealed a dissecting aortic aneurysm greater than 8 cm in diameter beginning distal to the left subclavian artery and extending into the descending thoracic aorta. The patient was counseled in great detail about the risk of rupture with continuing pregnancy. She refused termination and chose elective repair of the aneurysm, with continuation of the pregnancy. Partial repair of the thoracic aneurysm was undertaken when the pregnancy was 13(5/7) weeks by ultrasound dates. She was subsequently maintained on labetolol and hydralazine for blood pressure control. A decision was made to proceed with a Cesarean section at 32 weeks. After placement of a radial artery catheter and two large peripheral iv catheters, she received a of 7 and 7 at one and five minutes was delivered., Conclusions: Aortic dissection in pregnancy may have catastrophic results. Undoubtedly, it presents unique challenges for anesthetic and obstetrical management. With appropriate care and surgical correction of the dissecting aneurysm early in pregnancy, a successful outcome for the pregnancy was possible.

Cell death by apoptosis is now known to be an important mechanism of cell population control in organ development and in normal tissue homeostasis. Inappropriate apoptosis also contributes to the pathogenesis of a number of diseases involving the heart and lungs. Knowledge of the regulation of apoptosis in these organs is therefore of fundamental importance. A growing body of evidence suggests that the renin-angiotensin system (RAS), traditionally viewed as an endocrine system in the regulation of blood pressure, also functions as a regulator of apoptosis in a variety of cell types through both paracrine and autocrine mechanisms that are likely independent of the endocrine RAS. Much of the evidence in support of this premise comes from investigations of cardiac myocytes, endothelial cells and epithelial cells of the lung, both in culture and in situ within human pathological specimens and animal models of heart, vascular and pulmonary disease. Evidence from each of these areas is reviewed and discussed in relation to diseases of the heart, vascular system and lungs.