The ubiquitin proteasome system in neurodegenerative diseases: Culprit,accomplice or victim?

A shared hallmark for many neurodegenerative disorders is the accumulation of toxic protein species which is assumed to be the cause for these diseases. Since the ubiquitin proteasome system (UPS) is the most important pathway for selective protein degradation it is likely that it is involved in the aetiology neurodegenerative disorders. Indeed, impairment of the UPS has been reported to occur during neurodegeneration. Although accumulation of toxic protein species (amyloid β) are in turn known to impair the UPS the relationship is not necessarily causal. We provide an overview of the most recent insights in the roles the UPS plays in protein degradation and other processes. Additionally, we discuss the role of the UPS in clearance of the toxic proteins known to accumulate in the hallmarks of neurodegenerative diseases. The present paper will focus on critically reviewing the involvement of the UPS in specific neurodegenerative diseases and will discuss if UPS impairment is a cause, a consequence or both of the disease.     

Pre-MDS: CHIP,ICUS, CCUS

Our ability to perform next-generation sequencing has ushered in an explosion of understanding regarding the molecular development of myeloid malignancies. We now appreciate that with age, there is acquisition of somatic mutations within hematopoietic stem cells, termed clonal hematopoiesis of indeterminate potential (CHIP), which is a risk factor for leukemias, lymphomas, solid tumors, cardiovascular diseases and poor outcomes after stem cell transplant. By definition, patients with CHIP have     

顺铂腹腔热灌注化疗的药代动力学实验研究

目的：探讨顺铂（DDP）腹腔热灌注化疗（CHIP）的药代动力学特点。方法：家兔15只,平均分为3组。组A（CHIP组）用DDP200mg/m^2溶于41－42℃生理盐水1000ml,腹腔循环灌注60min。组B（腹腔化疗组）用DDP90mg/m^2溶于41－42℃生理盐水200ml,一次性腹腔注入。组C( 静脉用药组）用DDP90mg/m^2静脉注射。液相色谱分析24h内腹腔液和血浆DDP浓度变化。结果：组A之腹腔DDP峰值浓度和AUC（药时曲线下面积）分别为血浆峰值和AUC之10倍和2．9倍。组A与组C相比,腹腔液峰值和AUC分别为10．4倍和7．8倍,差异均有高度显著性意义（P＜0．001）,血浆峰值较低（P＜0．05）,而AUC较高（P＞0．05）。组A与组B比较,后者腹腔液峰值更高（P＜0．05）,但AUC较低（P＞0．05）。结论：CHIP腹腔DDP浓度高,血浆峰值较低,以及高温作用,有利于化疗药物在局部对肿瘤细胞发挥作用,减少肾毒性和全身副作用。     

CHIP‐associated mutant ASXL1 in blood cells promotes solid tumor progression

Clonal hematopoiesis of indeterminate potential (CHIP) is an age‐associated phenomenon characterized by clonal expansion of blood cells harboring somatic mutations in hematopoietic genes, including DNMT3A, TET2, and ASXL1. Clinical evidence suggests that CHIP is highly prevalent and associated with poor prognosis in solid‐tumor patients. However, whether blood cells with CHIP mutations play a causal role in promoting the development of solid tumors remained unclear. Using conditional knock‐in mice that express CHIP‐associated mutant Asxl1 (Asxl1‐MT), we showed that expression of Asxl1‐MT in T cells, but not in myeloid cells, promoted solid‐tumor progression in syngeneic transplantation models. We also demonstrated that Asxl1‐MT–expressing blood cells accelerated the development of spontaneous mammary tumors induced by MMTV‐PyMT. Intratumor analysis of the mammary tumors revealed the reduced T‐cell infiltration at tumor sites and programmed death receptor‐1 (PD‐1) upregulation in CD8⁺ T cells in MMTV‐PyMT/Asxl1‐MT mice. In addition, we found that Asxl1‐MT induced T‐cell dysregulation, including aberrant intrathymic T‐cell development, decreased CD4/CD8 ratio, and naïve‐memory imbalance in peripheral T cells. These results indicate that Asxl1‐MT perturbs T‐cell development and function, which contributes to creating a protumor microenvironment for solid tumors. Thus, our findings raise the possibility that ASXL1‐mutated blood cells exacerbate solid‐tumor progression in ASXL1‐CHIP carriers.     

Targeting glutamine utilization to block metabolic adaptation of tumor cells under the stress of carboxyamidotriazole-induced nutrients unavailability

Tumor cells have unique metabolic programming that is biologically distinct from that of corresponding normal cells. Resetting tumor metabolic programming is a promising strategy to ameliorate drug resistance and improve the tumor microenvironment. Here, we show that carboxyamidotriazole (CAI), an anticancer drug, can function as a metabolic modulator that decreases glucose and lipid metabolism and increases the dependency of colon cancer cells on glutamine metabolism. CAI suppressed glucose and lipid metabolism utilization, causing inhibition of mitochondrial respiratory chain complex I, thus producing reactive oxygen species (ROS). In parallel, activation of the aryl hydrocarbon receptor (AhR) increased glutamine uptake via the transporter SLC1A5, which could activate the ROS-scavenging enzyme glutathione peroxidase. As a result, combined use of inhibitors of GLS/GDH1, CAI could effectively restrict colorectal cancer (CRC) energy metabolism. These data illuminate a new antitumor mechanism of CAI, suggesting a new strategy for CRC metabolic reprogramming treatment.     

Improving Children's Access to Oral Health Services: The Oral Health Initiative

Although major improvements have been made in oral health during the 20th century, many children in minority groups, from families with low-income, and with special health care needs still do not receive the oral health services that they need. To address the problem, the Health Resources and Services Administration (HRSA), working with the Health Care Financing Administration (HCFA), has launched the Oral Health Initiative. The initiative seeks to strengthen oral health service-delivery systems, enhance collaboration among federal agencies, and provide states with the resources needed to improve the oral health of hard-to-reach children. HRSA's activities include enhancing programs, services, and training, such as expanding the number of direct-service dental programs; establishing or enhancing graduate training programs in pediatric and general dentistry and in dental public health; and funding training programs in dentistry to train dental public health leaders.     

Alternative Payment Models in Radiology: The Legislative and Regulatory Roadmap for Reform

The Medicare Access and CHIP Reauthorization Act (MACRA) replaces the sustainable growth rate with a payment system based on the Merit-Based Incentive Payment System and incentives for alternative payment model participation. It is important that radiologists understand the statutory requirements of MACRA. This includes the nature of the Merit-Based Incentive Payment System composite performance score and its impact on payments. The timeline for MACRA implementation is fairly aggressive and includes a robust effort to define episode groups, which include radiologic services. A number of organizations, including the ACR, are commenting on the structure of MACRA-directed initiatives.     

CHIP E3 ligase regulates mammalian senescence by modulating the levels of oxidized proteins

Senescence can be induced by various stressors including oxidative stress. It has been reported that CHIP (C-terminus of Hsp70-interacting protein) ligase is induced during senescence while CHIP^−/− mice exhibit accelerated aging. Here, we explore the effects of modulating CHIP expression on mammalian senescence. We demonstrate that CHIP silencing induces premature senescence that is accompanied by elevated levels of oxidized proteins. On the contrary, ectopic expression of CHIP leads to oxidized proteins levels reduction. Moreover, we reveal that CHIP^−/− mouse fibroblasts have an impaired ubiquitin proteasome system. Taken together, we propose that CHIP influences cellular senescence by modulating the oxidative load.