Ras proteins are small GTPases, cycling between inactive GDP-bound and active GTP-bound states. Through these switches they regulate signaling that controls cell growth and proliferation. Activating Ras mutations are associated with approximately 30% of human cancers, which are frequently resistant to standard therapies. Over the past few years, structural biology and in silico drug design, coupled with improved screening technology, led to a handful of promising inhibitors, raising the possibility of drugging Ras proteins. At the same time, the invariable emergence of drug resistance argues for the critical importance of additionally honing in on signaling pathways which are likely to be involved. Here we overview current advances in Ras structural knowledge, including the conformational dynamic of full-length Ras in solution and at the membrane, therapeutic inhibition of Ras activity by targeting its active site, allosteric sites, and Ras–effector protein-protein interfaces, Ras dimers, the K-Ras4B/calmodulin/PI3Kα trimer, and targeting Ras with siRNA. To mitigate drug resistance, we propose signaling pathways that can be co-targeted along with Ras and explain why. These include pathways leading to the expression (or activation) of YAP1 and c-Myc. We postulate that these and Ras signaling pathways, MAPK/ERK and PI3K/Akt/mTOR, act independently and in corresponding ways in cell cycle control. The structural data are instrumental in the discovery and development of Ras inhibitors for treating RAS-driven cancers. Together with the signaling blueprints through which drug resistance can evolve, this review provides a comprehensive and innovative master plan for tackling mutant Ras proteins.
BackgroundAcute coronary artery diseases have been observed to be associated with some meteorological variables. But few of the previous studies considered autocorrelated outcomes. Electrocardiography is a widely used tool in the initial diagnosis of acute cardiovascular events, and emergency electrocardiography counts were shown to be highly correlated with acute myocardial infarction in our pilot study, hence a good index of prediction for acute cardiovascular events morbidity among the elderly. To indirectly assess the impact of temperature on the number of acute cardiovascular events, we studied the association between temperature and emergency electrocardiography counts while considering autocorrelated nature of the response variables.MethodsWe collected daily emergency electrocardiography counts for elderly females and males in Shanghai from 2007 to middle 2012, and studied temperature and other effects on these data using Mixed Generalized Additive Modelling methods. Delayed temperature effect distribution was described as the weighted average of the temperatures within 3 days before the counts was recorded. Autoregressive random effects were used in the model to describe the autocorrelation of the response variables.Main ResultsTemperature effect was observed to be piecewise linearly associated with the logarithm of emergency electrocardiography counts. The optimal weights of the delayed temperature effect distribution were obtained from the model estimation. The weights of lag-1 were the maximums, significantly greater than the weights of lag-2 and lag-3 for both females and males. The model showed good fit with R2 values of 0.860 for females and 0.856 for males.ConclusionFrom the mixed generalized additive model, we infer that during cold and mild days, the number of emergency electrocardiography counts increase as temperature effect decreases, while during hot days, counts increase as temperature effect increases. Similar properties could be inferred for the occurrence of cardiovascular events.
Desmoplastic infantile astrocytoma is a rare low-grade malignant brain tumor found in infants. Its pathological diagnosis can be made on the basis of its histological characteristics and immunohistochemical staining. A case of desmoplastic infantile astrocytoma, including its clinical manifestations, pathological characteristics, differential diagnosis, treatment, and prognosis, is reported. Presurgical percutaneous decompression and subsequent resection resulted in a satisfactory therapeutic outcome.
Objectiv:
The authors devised a multiple small incisions minimally invasive technique for use in isolated nonsyndromic sagittal synostosis to achieve better esthetic effect and satisfactory reshaping of the calvarial vault. The purpose of this study is to provide clinicians with new and feasible solution.
Methods:
From April 2016 to January 2017, 5 male patients were successfully treated with minimally invasive surgery. The age ranges from 1.5 to 3.3 years. The authors designed 9 short skin linear incisions (2–3 cm long) strategically to disperse in the scalp. The patient was assessed in a series including sex, age of surgery, blood loss, blood transfusion, duration of surgery, postoperative complications, preoperative and postoperative cephalic index (CI), length of stay (LOS), esthetic outcomes, and intellectual developmental quotient (DQ).
Results:
The shortest operation time is 1.5 hours. The shortest hospital stay is 6 days. The blood loss ranged from 135 to 280 mL. No serious complications occurred during the follow-up time. Postoperative 3-dimensional CT scan showed that the extensive floating bone formed well. Preoperative CI ranged from 64.2 to 68 and postoperatively 69.4 to 74.3. Mental development was tested by children heath care practioners, significantly improving DQ from 67 to 81 preoperatively and 76 to 90 postoperatively. All children receive good esthetic results.
Conclusion:
The new technique is safe and effective. The advantages are satisfactory: calvarial fornix remodeling, less visible appearance of scars, shorter length of surgery, lower mental and financial stress, optimal age for surgery, no endoscopic adjuvant and postoperative helmet are needed.
Only through thorough understanding of the pathology of the lipoma of the conus medullaris, we could optimally excise the lipoma, untether the spinal cord, reconstruct the normal anatomy of the spinal cord, and rehabilitate neurological function.
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