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Hurst Hopkins posted an update 6 months, 3 weeks ago
C-terminus of HSC70-interacting protein (CHIP) encoded by the gene STUB1 is a co-chaperone and E3 ligase that acts as a key regulator of cellular protein homeostasis. Mutations in STUB1 cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16) with widespread neurodegeneration manifesting as spastic-ataxic gait disorder, dementia and epilepsy. CHIP-/- mice display severe cerebellar atrophy, show high perinatal lethality and impaired heat stress tolerance. To decipher the pathomechanism underlying SCAR16, we investigated the heat shock response (HSR) in primary fibroblasts of three SCAR16 patients. We found impaired HSR induction and recovery compared to healthy controls. HSPA1A/B transcript levels (coding for HSP70) were reduced upon heat shock but HSP70 remained higher upon recovery in patient- compared to control-fibroblasts. As SCAR16 primarily affects the central nervous system we next investigated the HSR in cortical neurons (CNs) derived from induced pluripotent stem cells of SCAR16 patients. We found CNs of patients and controls to be surprisingly resistant to heat stress with high basal levels of HSP70 compared to fibroblasts. ALC-0159 datasheet Although heat stress resulted in strong transcript level increases of many HSPs, this did not translate into higher HSP70 protein levels upon heat shock, independent of STUB1 mutations. Furthermore, STUB1(-/-) neurons generated by CRISPR/Cas9-mediated genome editing from an isogenic healthy control line showed a similar HSR to patients. Proteomic analysis of CNs showed dysfunctional protein (re)folding and higher basal oxidative stress levels in patients. Our results question the role of impaired HSR in SCAR16 neuropathology and highlight the need for careful selection of proper cell types for modeling human diseases.
Treatment of older patients with acute myeloid leukemia (AML) is still controversial. To facilitate treatment decisions, the “fitness criteria” proposed by Ferrara et al. (Leukemia, 2013), including age>75years, performance status and comorbidities, were verified retrospectively in 699 patients with AML (419 de-novo, 280 secondary AML), diagnosed at 8 Hematological Centers (REL).
Patients were categorized in FIT to intensive chemotherapy (i-T) (292, 42.5%), UNFIT to i-T (289, 42.1%), or unfit even to non-intensive therapy (non i-T) (FRAIL) (105, 15.3%). Biological characteristics and treatment actually received by patients were recorded.
“Fitness criteria” were easily applicable in 98.1% of patients. Overall concordance between “fitness criteria” and treatment actually received by patients was high (79.4%), 76% in FIT, 82.7% in UNFIT and 80% in FRAIL patients. Fitness independently predicted survival (median survival 10.9, 4.2 and 1.8months in FIT, UNFIT and FRAIL patients, respectively; p=0.000), as confirmed also by multivariate analysis. In FRAIL patients, survival with any treatment was no better than with BSC, in UNFIT non i-T was as effective as i-T and better than BSC, and in FIT patients i-T was better than non i-T or BSC. In addition, a non-adverse risk AML, an ECOG PS <2, and receiving any treatment other than BSC had a favorable effect on survival (p<0.001).
These simple “fitness criteria” applied at the time of diagnosis could facilitate, together with AML biologic risk evaluation, the choice of the most appropriate treatment intensity in older AML patients.
These simple “fitness criteria” applied at the time of diagnosis could facilitate, together with AML biologic risk evaluation, the choice of the most appropriate treatment intensity in older AML patients.Lumbar interbody fusion (LIF) is an effective and popular surgical procedure for the management of various spinal pathologies, especially degenerative diseases. Currently, LIF can be performed with posterior, transforaminal, anterior, and lateral approaches by open surgery or minimally invasive surgery (MIS). Each technique has its own advantages and disadvantages. In general, posterior LIF is a well-established procedure with good fusion rates and low complication rates but is limited by the possibility of iatrogenic injury to the neural structures and paraspinal muscles. Transforaminal LIF is frequently performed using an MIS technique and has an advantage of reducing these iatrogenic injuries. Anterior LIF (ALIF) can restore the disk height and sagittal alignment but has inherent approach-related challenges such as visceral and vascular complications. Lateral LIF and oblique LIF are performed using an MIS technique and have shown postoperative outcomes similar to ALIF; however, these approaches carry a risk of injury to psoas, lumbar plexus, and vascular structures. Herein, we provide a detailed description of the surgical procedures of each LIF technique. We shall then consider the pearls and pitfalls, as well as propose surgical indications and contraindications based on the available evidence in the literatures.MTORC1 activity is critical for tissue regeneration in multiple organs and contexts. In this issue of Developmental Cell, Miao et al. describe upstream regulators of mTORC1 activity which promote paligenosis, a process where mature cells de-differentiate to acquire stem cell activity in the face of injury.Recently revised public health guidelines acknowledge the health benefits of regular intermittent bouts of vigorous intensity incidental physical activity done as part of daily living, such as carrying shopping bags, walking uphill, and stair climbing. Despite this recognition and the advantages such lifestyle physical activity has over continuous vigorous intensity structured exercise, a scoping review we conducted revealed that current research in this area is, at best, rudimentary. Key gaps include the absence of an empirically-derived dose specification (e.g., minimum duration of lifestyle physical activity required to achieve absolute or relative vigorous intensity), lack of acceptable measurement standards, limited understanding of acute and chronic (adaptive) effects of intermittent vigorous bouts on health, and paucity of essential information necessary to develop feasible and scalable interventions (e.g., acceptability of this kind of physical activity by the public). To encourage collaboration and research agenda alignment among groups interested in this field, we propose a research framework to further understanding of vigorous intermittent lifestyle physical activity (VILPA).
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