Cdk5 activity in the brain - multiple paths of regulation

Cyclin dependent kinase-5 (Cdk5), a family member of the cyclin-dependent kinases, plays a pivotal role in the central nervous system. During embryogenesis, Cdk5 is indispensable for brain development and, in the adult brain, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation. However, Cdk5 activity becomes deregulated in several neurological disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, which leads to neurotoxicity. Therefore, precise control over Cdk5 activity is essential for its physiological functions. This Commentary covers the various mechanisms of Cdk5 regulation, including several recently identified protein activators and inhibitors of Cdk5 that control its activity in normal and diseased brains. We also discuss the autoregulatory activity of Cdk5 and its regulation at the transcriptional, post-transcriptional and post-translational levels. We finally highlight physiological and pathological roles of Cdk5 in the brain. Specific modulation of these protein regulators is expected to provide alternative strategies for the development of effective therapeutic interventions that are triggered by deregulation of Cdk5. © 2014. Published by The Company of Biologists Ltd

Identification of LIMK2 as a therapeutic target in castration resistant prostate cancer

This study identified LIMK2 kinase as a disease-specific target in castration resistant prostate cancer (CRPC) pathogenesis, which is upregulated in response to androgen deprivation therapy, the current standard of treatment for prostate cancer. Surgical castration increases LIMK2 expression in mouse prostates due to increased hypoxia. Similarly, human clinical specimens showed highest LIMK2 levels in CRPC tissues compared to other stages, while minimal LIMK2 was observed in normal prostates. Most notably, inducible knockdown of LIMK2 fully reverses CRPC tumorigenesis in castrated mice, underscoring its potential as a clinical target for CRPC. We also identified TWIST1 as a direct substrate of LIMK2, which uncovered the molecular mechanism of LIMK2-induced malignancy. TWIST1 is strongly associated with CRPC initiation, progression and poor prognosis. LIMK2 increases TWIST1 mRNA levels upon hypoxia; and stabilizes TWIST1 by direct phosphorylation. TWIST1 also stabilizes LIMK2 by inhibiting its ubiquitylation. Phosphorylation-dead TWIST1 acts as dominant negative and fully prevents EMT and tumor formation in vivo, thereby highlighting the significance of LIMK2-TWIST1 signaling axis in CRPC. As LIMK2 null mice are viable, targeting LIMK2 should have minimal collateral toxicity, thereby improving the overall survival of CRPC patients

Contraceptive Access in the US Post-Dobbs

This Viewpoint contraceptive justice after the Dobbs v Jackson Women’s Health Organization US Supreme Court decision, which led to a decline in contraceptive access, especially in states with abortion bans

Pediatric Spasticity

Children with special health care needs (CSHCN) are increasingly prevalent in US hospitals. The pediatric hospitalist is often the primary provider of inpatient care for these patients. However, exposure to this patient population during training varies from provider to provider. No published educational curricula are specific to the inpatient care of this population. The purpose of this project is to build a multi-modal educational curriculum for providers with the overall goal of improving inpatient care for this at-risk population. This curriculum is primarily composed of a series of topic-specific learning modules. Asynchronous learning modules, utilized appropriately, can augment learning by providing individualized instruction and mastery of fundamentals. This particular resource was created to provide pediatricians with educational materials related to care of the medically complex child with spasticity. This module was distributed to our division. So far, seventeen colleagues have participated in this learning module with favorable results. Comments included good pathophysiology reminders and this was very informative and very well organized. On a 5-point Likert scale evaluation, over 90% of respondents felt that this learning module was A. relevant to my clinical practice, B. will change my clinical practice, C. increase my comfort with teaching this topic to trainees. The average pre-test score was 64% and post-test score was 82% which was statistically significant (p\u3c0.05). This module will be distributed to resident physicians within our institution this academic year. AAMC MedEdPORTAL publication ID 9282. Link to original

Dissecting yeast Hog1 MAP kinase pathway using a chemical genetic approach

AbstractUsing a chemical genetic approach, we identified four novel physiological substrates of Hog1 kinase (Krs1, Tdh3, Hsp26, and Shm2). These substrates suggest plausible mechanisms for actin reorganization, cell cycle arrest and regulation of protein synthesis observed upon osmotic stress. We further show that the human homolog of Shm2 (SHMT1) is a novel physiological substrate of p38 MAP kinase in vitro and in vivo. Down-regulation of its enzymatic activity was observed following p38-mediated phosphorylation revealing a potential cancer-modulating property of p38 MAP kinase. This screen has uncovered several novel Hog1 substrates that provide new avenues for investigation into the mechanism of osmoadaptation by this kinase

A review on determinants and barriers affecting the transition from curative care to palliative care in patients suffering from terminal cancer

The integration of palliative care into comprehensive cancer care has become increasingly recognized as an essential aspect of cancer treatment. Palliative care can improve patient outcomes, symptom management, and overall satisfaction with care. However, despite the benefits of palliative care, several barriers exist that prevent its widespread implementation, including lack of awareness and understanding of palliative care, lack of access to palliative care services, and stigma associated with palliative care. The decision to transition from curative to palliative care is complex and influenced by several factors, including patient preferences, disease stage, and prognosis, symptom burden, comorbidities, and social support. Effective communication between healthcare providers, patients, and families is essential in ensuring that patients are informed about their options and can make informed decisions about their care. This literature review aims to explore the factors that influence the decision to transition to palliative care and to identify the barriers to the implementation of palliative care in cancer patients. The review also discusses strategies to overcome these barriers and highlights the importance of integrating palliative care into cancer care from the time of cancer diagnosis.