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Mutant p53 partners in crime
Mutant p53 proteins impart changes in cellular behavior and function through interactions with proteins that alter gene expression. The milieu of intracellular proteins available to interact with mutant p53 is context specific and changes with disease, cell type, and environmental conditions. Varying conformations of mutant p53 largely dictate protein–protein interactions as different point mutations within protein-coding regions greatly alter the extent and array of gain-of-function (GOF) activities. Given such variables, how can knowledge regarding p53 missense mutations be translated into predicting or altering biologic activity for therapy? How may knowledge regarding mutant p53 functions within certain disease contexts be harnessed to blunt or ablate mutant p53 GOF for therapy? In this article, we review known proteins that interact with mutant p53 and result in the activation of genes that contribute to p53 GOF with particular emphasis on context dependency and an evolving appreciation of GOF mechanisms.
Journal Article
Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier
Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB) is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM) occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery.
Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans) in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption.
In all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1-3 weeks before decreasing to baseline by 6 weeks.
The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1-2 weeks after laser ablation and resolving by 4-6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced.
ClinicalTrials.gov NCT01851733.
Journal Article
North Korea and nuclear weapons : entering the new era of deterrence
North Korea is perilously close to developing strategic nuclear weapons capable of hitting the United States and its allies in East Asia. Since their first nuclear test in 2006, North Korea has struggled to perfect delivery systems, but Kim Jong-un's regime now appears to be close. Sung Chull Kim, Michael Cohen, and the contributors to this volume contend that the time to prevent North Korea from getting this capability is virtually over, and instead scholars and policymakers must turn their attention to how to deter North Korea. The United States, South Korea, and Japan must also come to terms with the fact their North Korea will be able to deter them with its nuclear arsenal. How will the erratic Kim Jong-un behave when North Korea does develop the capability to hit medium- and long-range targets with nuclear weapons; how will the United States, South Korea, and China respond; and what will this mean for regional stability in the short term and long term? The international group of authors in this volume address these questions and offer a timely analysis of the consequences of an operational North Korean nuclear capability for international security.
Book
Universal adaptability
The gold-standard approaches for gleaning statistically valid conclusions from data involve random sampling from the population. Collecting properly randomized data, however, can be challenging, so modern statistical methods, including propensity score reweighting, aim to enable valid inferences when random sampling is not feasible. We put forth an approach for making inferences based on available data from a source population that may differ in composition in unknown ways from an eventual target population. Whereas propensity scoring requires a separate estimation procedure for each different target population, we show how to build a single estimator, based on source data alone, that allows for efficient and accurate estimates on any downstream target data. We demonstrate, theoretically and empirically, that our target-independent approach to inference, which we dub “universal adaptability,” is competitive with target-specific approaches that rely on propensity scoring. Our approach builds on a surprising connection between the problem of inferences in unspecified target populations and the multicalibration problem, studied in the burgeoning field of algorithmic fairness. We show how the multicalibration framework can be employed to yield valid inferences from a single source population across a diverse set of target populations.
Journal Article
Orthostatic Hypotension: A Practical Approach
Orthostatic hypotension is defined as a decrease in blood pressure of 20 mm Hg or more systolic or 10 mm Hg or more diastolic within three minutes of standing from the supine position or on assuming a head-up position of at least 60 degrees during tilt table testing. Symptoms are due to inadequate physiologic compensation and organ hypoperfusion and include headache, lightheadedness, shoulder and neck pain (coat hanger syndrome), visual disturbances, dyspnea, and chest pain. Prevalence of orthostatic hypotension in the community setting is 20% in older adults and 5% in middle-aged adults. Risk factors such as diabetes mellitus increase the prevalence of orthostatic hypotension in all age groups. Orthostatic hypotension is associated with a significant increase in cardiovascular risk and falls, and up to a 50% increase in relative risk of all-cause mortality. Diagnosis is confirmed by performing a bedside simplified Schellong test, which consists of blood pressure and heart rate measurements after five minutes in the supine position and three minutes after moving to a standing position. If the patient is unable to stand safely or the clinical suspicion for orthostatic hypotension is high despite normal findings on the bedside test, head-up tilt table testing is recommended. Orthostatic hypotension is classified as neurogenic or nonneurogenic, depending on etiology and heart rate response. Treatment goals for orthostatic hypotension are reducing symptoms and improving quality of life. Initial treatment focuses on the underlying cause and adjusting potentially causative medications. Nonpharmacologic strategies include dietary modifications, compression garments, physical maneuvers, and avoiding environments that exacerbate symptoms. First-line medications include midodrine and droxidopa. Although fludrocortisone improves symptoms, it has concerning long-term effects.
Journal Article
هل تحتاج حقا إلى فريق عمل ؟
يبرز هذا الكتاب كدليل يساعد المديرين على اتخاذ قرارهم بشأن تشكيل فرق عمل فيما إذا كانت الأخيرة هي الأداة الصحيحة لتحقيق هدف ما في العمل كما أنه يوضح العقبات والتحديات المحتملة التي يمكن أن تقف في طريق تشكيل فريق يعمل بكامل قدراته وبرغم كل ما تعول عليه من أهمية تبقى فرق العمل قاصرة في بعض الحالات عن كونها أفضل الطرق فاعلية في التصدي لتحديات العمل بالإضافة إلى كونها مكلفة ويستغرق إنشاؤها الكثير من الوقت.
Book
Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses
Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly coactivated ensembles following contextual fear discrimination identified the dorsolateral septum (DLS) as a relay of the dentate gyrus–CA3 circuit. Retrograde monosynaptic tracing and electrophysiological whole-cell recordings demonstrated that DLS somatostatin-expressing interneurons (SST-INs) receive direct CA3 inputs. Longitudinal in vivo calcium imaging of DLS SST-INs in awake, behaving mice identified a stable population of footshock-responsive SST-INs during contextual conditioning whose activity tracked and predicted non-freezing epochs during subsequent recall in the training context but not in a similar, neutral context or open field. Optogenetic attenuation or stimulation of DLS SST-INs bidirectionally modulated conditioned fear responses and recruited proximal and distal subcortical targets. Together, these observations suggest a role for a potentially hard-wired DLS SST-IN subpopulation as arbiters of mobility that calibrate context-appropriate behavioral fear responses.Besnard et al. uncover functional heterogeneity of somatostatin interneurons (SST-INs) in the dorsolateral septum and reveal a role for a subpopulation of SST-INs as hippocampal relays that govern mobility to calibrate adaptive fear responses.
Journal Article