BackgroundThe mechanistic (or mammalian) target of rapamycin (mTOR), a Ser/Thr kinase, associates with different subunits forming two functionally distinct complexes, mTORC1 and mTORC2, regulating a diverse set of cellular functions in response to growth factors, cellular energy levels, and nutrients. The mechanisms regulating mTORC1 activity are well characterized; regulation of mTORC2 activity, however, remains obscure. While studies conducted in Dictyostelium suggest a possible role of Ras protein as a potential upstream regulator of mTORC2, definitive studies delineating the underlying molecular mechanisms, particularly in mammalian cells, are still lacking.MethodsProtein levels were measured by Western blotting and kinase activity of mTORC2 was analyzed by in vitro kinase assay. In situ Proximity ligation assay (PLA) and co-immunoprecipitation assay was performed to detect protein-protein interaction. Protein localization was investigated by immunofluorescence and subcellular fractionation while cellular function of mTORC2 was assessed by assaying extent of cell migration and invasion.ResultsHere, we present experimental evidence in support of the role of Ras activation as an upstream regulatory switch governing mTORC2 signaling in mammalian cancer cells. We report that active Ras through its interaction with mSIN1 accounts for mTORC2 activation, while disruption of this interaction by genetic means or via peptide-based competitive hindrance, impedes mTORC2 signaling.ConclusionsOur study defines the regulatory role played by Ras during mTORC2 signaling in mammalian cells and highlights the importance of Ras-mSIN1 interaction in the assembly of functionally intact mTORC2.
Renal transplant patients on immunosuppression are at risk for malignancy. One form of malignancy that commonly affects this population is Kaposi-sarcoma. Kaposi-sarcoma is a human herpesvirus-8 (HHV-8)-driven process classically associated with skin lesions in immunocompromised patients. The pulmonary system may be involved in disseminated disease. In this case, a renal transplant patient was re-admitted with acute hypoxic respiratory failure and hemoptysis of an unclear etiology. Following a broad workup, HHV-8 PCR and a lymph node biopsy confirmed pulmonary Kaposi-sarcoma. Workup for multicentric Castleman disease was negative. The patient was treated with liposomal doxorubicin, ganciclovir, and prednisone. Her immunosuppression was changed to sirolimus and she is scheduled to complete six cycles of liposomal doxorubicin.
ObjectiveDue to a progressive decline in beta-cell function, a considerable number of patients with type 2 diabetes mellitus (T2D) ultimately require multiple daily injections of large doses of insulin for glycemic control. Majority of studies have reported only short-term benefits of continuous subcutaneous insulin infusion (CSII) using an insulin pump in T2D. Our five-year follow-up data of CSII in T2D is one of the few studies showing persistent benefit in glucose control in this population.Research design and methodsWe did a chart review of patients treated with an insulin pump for five years. Inclusion criteria were: type 2 diabetes, 18–75 years of age, glycosylated hemoglobin (HbA1c) more than 6.5% (48 mmol/mol) on multiple doses of insulin (MDI > four injections per day) or more than 100 units of insulin/day, wide glycemic excursions, and intractable hypoglycemia. We identified a total of 13 patients. The primary endpoint was change in HbA1c from baseline to five years. We also reviewed the difference in weight, basal insulin requirements, hypoglycemia, and patient satisfaction questionnaire at one year. Exclusion criteria were: type 1 diabetes (T1D) and pregnancy.ResultsThe HbA1c at five years was found to be 7.72% (61 mmol/mol) compared to a baseline of 8.89% (74 mmol/mol), p-value 0.0076. We did not find any increased risk of severe hypoglycemia, weight gain, and insulin requirement.ConclusionsThe beneficial effect of insulin pump persisted for five years of follow-up, suggesting it as a valuable treatment option for difficult to treat T2D.
e17509 Background: HNC patients are at risk for weight loss which can cause treatment interruptions, and poorer outcomes. There is no consensus on optimal timing of PEG tube placement in HNC patients undergoing concurrent ChemoTherapy (CT) and RadioTherapy (RT). The aim of this study is to determine if pPEG tube would decrease weight loss (WL) in HNC patients. We also analyzed correlation between WL and CT interruptions (CTI), RT interruptions (RTI), and intravenous fluid requirements (IVFr). Methods: This is a prospective study. A total of 16 HNC patients undergoing concurrent CT, RT were included. Before treatment initiation, a PEG tube placement was recommended as a mode of nutrition. 13 patients chose to get pPEG tube and 3 refused. We collected data on weight at 0 and 2 months, CTI, RTI, and IVFr. CTI included missed as well as reduced chemotherapy doses. RTI included missed radiations. Statistical tests used - t-test, Levene’s test for equality of variances and point biserial correlation. Results: Median age - 63 years; Gender: 14 Male/2 Female; Tumor location - Oral cavity - 31.3%; Oropharynx - 43.7%; Larynx - 25%; Nasopharynx and Hypopharynx- 0%. Stages were - II (6.2%), III (37.5%) and IV (56.3%). 2 patients were non-smoker and 4 were Human Papilloma Virus positive. Mean WL(lb) in pPEG (n = 11) vs non-PEG (n = 3) group was 10.3 vs 20.3 (p = 0.045, one-tailed t-test). Average percentage of WL: PEG vs non-PEG - 5.8 vs 8.2; RTI vs not - 8.9 vs 5.3; CTI vs not - 6.9 vs 5.8; IVFr vs not - 6.8 vs 4.5 ( > 7.5% WL over 3 months is significant (ADA/ASPEN)). CTI, RTI and IVFr were positively correlated to WL (correlation coefficient: 0.16; 0.32; 0.17 respectively). CTI and RTI in pPEG group were 23.1% and 38.5% respectively. CTI and RTI in non-PEG group were 33.3% and 66.7% respectively. 2 patients in pPEG group had average weight gain of 2.75 lb. Only 3 patients had PEG tube related complications - infections and clogging. Conclusions: pPEG tube decreases weight loss in locally advanced HNC patients. Patients with higher weight loss had more chemoradiation interruptions and IVFr. HNC patients undergoing concurrent CT, RT should be encouraged to maintain weight and get a PEG tube.
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