Transient Receptor Potential C 1/4/5 Is a Determinant of MTI-101 Induced Calcium Influx and Cell Death in Multiple Myeloma.

Multiple myeloma (MM) is a currently incurable hematologic cancer. Patients that initially respond to therapeutic intervention eventually relapse with drug resistant disease. Thus, novel treatment strategies are critically needed to improve patient outcomes. Our group has developed a novel cyclic peptide referred to as MTI-101 for the treatment of MM. We previously reported that acquired resistance to HYD-1, the linear form of MTI-101, correlated with the repression of genes involved in store operated Ca2+ entry (SOCE): PLCß, SERCA, ITPR3, and TRPC1 expression. In this study, we sought to determine the role of TRPC1 heteromers in mediating MTI-101 induced cationic flux. Our data indicate that, consistent with the activation of TRPC heteromers, MTI-101 treatment induced Ca2+ and Na+ influx. However, replacing extracellular Na+ with NMDG did not reduce MTI-101-induced cell death. In contrast, decreasing extracellular Ca2+ reduced both MTI-101-induced Ca2+ influx as well as cell death. The causative role of TRPC heteromers was established by suppressing STIM1, TRPC1, TRPC4, or TRPC5 function both pharmacologically and by siRNA, resulting in a reduction in MTI-101-induced Ca2+ influx. Mechanistically, MTI-101 treatment induces trafficking of TRPC1 to the membrane and co-immunoprecipitation studies indicate that MTI-101 treatment induces a TRPC1-STIM1 complex. Moreover, treatment with calpeptin inhibited MTI-101-induced Ca2+ influx and cell death, indicating a role of calpain in the mechanism of MTI-101-induced cytotoxicity. Finally, components of the SOCE pathway were found to be poor prognostic indicators among MM patients, suggesting that this pathway is attractive for the treatment of MM.

The Role of TRPC1 in Modulating Cancer Progression.

Calcium ions (Ca2+) play an important role as second messengers in regulating a plethora of physiological and pathological processes, including the progression of cancer. Several selective and non-selective Ca2+-permeable ion channels are implicated in mediating Ca2+ signaling in cancer cells. In this review, we are focusing on TRPC1, a member of the TRP protein superfamily and a potential modulator of store-operated Ca2+ entry (SOCE) pathways. While TRPC1 is ubiquitously expressed in most tissues, its dysregulated activity may contribute to the hallmarks of various types of cancers, including breast cancer, pancreatic cancer, glioblastoma multiforme, lung cancer, hepatic cancer, multiple myeloma, and thyroid cancer. A range of pharmacological and genetic tools have been developed to address the functional role of TRPC1 in cancer. Interestingly, the unique role of TRPC1 has elevated this channel as a promising target for modulation both in terms of pharmacological inhibition leading to suppression of tumor growth and metastasis, as well as for agonistic strategies eliciting Ca2+overload and cell death in aggressive metastatic tumor cells.

Perioperative risk factors for postoperative respiratory failure.

The study aimed to identify the risk factors for respiratory failure after surgery. Postoperative respiratory failure (PRF) was defined as prolonged intubation after surgery or reintubation after unsuccessful extubation. We conducted a retrospective analysis of the following risk factors: age, obesity as reflected by body mass index (BMI), gender, patient admitted to hospital (in-patient status) vs. outpatient surgery, smoking, hypertension, chronic obstructive pulmonary disease (COPD), diabetes, abnormal liver function, anaemia, respiratory infection, physical condition as reflected by ASA class, case type (elective or emergency), anaesthesia type, and surgical duration. The incidence of PRF was found to be 2.4%. Independent risk factors were older age, inpatient status, hypertension, COPD, elective procedure, surgical duration >2 hours, and ASA class ≥3. The study concludes that PRF results in significant postoperative complications. Minimising these risks is essential in improving PRF and subsequently surgical outcomes.

Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers.

Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead-like-2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down-regulated during experimentally induced Epithelial-Mesenchymal Transition (EMT). Here, we utilize GRHL2 re-expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK-sensitivity. GRHL2 enhanced the expression of ICAM-1, augmenting NK-target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti-correlated with EMT. We identified two novel GRHL2-interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal-epithelial transition, NK-sensitization and ICAM-1 expression were promoted by GRHL2-KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing.

Independent risk factors for surgical site infection after cesarean delivery in a rural tertiary care medical center.

BACKGROUND: We aimed to determine the incidence of surgical site infection (SSI) after cesarean delivery (CD) and identify the risk factors in a rural population. METHODS: We identified 218 SSI patients by International Classification of Disease codes and matched them with 3131 parturients (control) from the electronic record database in a time-matched retrospective quality assurance analysis. RESULTS AND DISCUSSION: The incidence of SSI after CD was 7.0 %. Risk factors included higher body mass index (BMI) [40.30 ± 10.60 kg/m2 SSI (95 % CI 38.73-41.87) vs 34.05 ± 8.24 kg/m2 control (95 % CI 33.75-34.35, P < 0.001)], years of education [13.28 ± 2.44 years SSI (95 % CI 12.9-13.66) vs 14.07 ± 2.81 years control (95 % CI 13.96-14.18, P < 0.001)], number of prior births [2 (1-9) SSI vs 1 (1-11) control (P < 0.001)], tobacco use (OR 1.49; 95 % CI 1.06-2.09, P = 0.03), prior diagnosis of hypertension (OR 1.80; 95 % CI 1.34-2.42, P < 0.001), gestational diabetes (OR 1.59; 95 % CI 1.18-2.13, P = 0.003), and an emergency/STAT CD (OR 1.6; 95 % CI 1.1-2.3, P = 0.01). CONCLUSIONS: Risk factors for SSI after CD included higher BMI, less years of education, higher prior births, tobacco use, prior diagnosis of hypertension, gestational diabetes, and emergency/STAT CD. The presence of ruptured membranes was protective against SSI.

Acute intraoperative neurogenic myocardial stunning during intracranial endoscopic fenestration and shunt revision in a pediatric patient.

Neurogenic stunned myocardium (NSM) is syndrome of myocardial dysfunction following an acute neurological insult. We report a case of NSM that occurred intraoperatively in a pediatric patient undergoing endoscopic fenestration and shunt revision. Accidental outflow occlusion of irrigation fluid and ventricular distension resulted in an acute increase in heart rate and arterial blood pressure. Subsequently, the patient developed stunned myocardium with global myocardial hypokinesia and pulmonary edema. She was promptly treated intraoperatively then admitted to the pediatric intensive care unit with resolution of her symptoms within 12 h. She was later discharged to home on the fourth postoperative day. In the current endoscopic era, this report highlights the possibility of intraoperative NSM and neurogenic pulmonary edema in the pediatric population. Early detection and treatment with a team approach help to achieve optimal control of this life-threatening condition and improve the outcome.