TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD). Truncation mutants lacking the PRD domain do not induce spontaneous SGs and are not recruited to arsenite-induced SGs, whereas the PRD forms aggregates that are recruited to SGs in low-level-expressing cells but prevent SG assembly in high-level-expressing cells. The PRD of TIA-1 exhibits many characteristics of prions: concentration-dependent aggregation that is inhibited by the molecular chaperone heat shock protein (HSP)70; resistance to protease digestion; sequestration of HSP27, HSP40, and HSP70; and induction of HSP70, a feedback regulator of PRD disaggregation. Substitution of the PRD with the aggregation domain of a yeast prion, SUP35-NM, reconstitutes SG assembly, confirming that a prion domain can mediate the assembly of SGs. Mouse embryomic fibroblasts (MEFs) lacking TIA-1 exhibit impaired ability to form SGs, although they exhibit normal phosphorylation of eukaryotic initiation factor (eIF)2alpha in response to arsenite. Our results reveal that prion-like aggregation of TIA-1 regulates SG formation downstream of eIF2alpha phosphorylation in response to stress.
Americans have end-stage renal disease, and most are treated with hemodialysis. 1 A major challenge in caring for patients undergoing hemodialysis is maintaining a functioning vascular access, which is essential for performing the dialysis procedure. The effect of vascular access dysfunction is substantial-it is a leading reason for hospitalization among patients with end-stage renal disease and has associated annual costs in the United States that exceed $1 billion. 2,3 For editorial comment see p 2205.Author Affiliations and Members of the Dialysis Access Consortium Study Group are listed at the end of this article.
Treatment of selected patients with AL amyloidosis by using high-dose melphalan and stem-cell transplantation resulted in hematologic remission, improved 5-year survival, and reversal of amyloid-related disease in a substantial proportion.
The amyloidoses are a group of disorders in which soluble proteins aggregate and deposit extracellularly in tissues as insoluble fibrils, causing progressive organ dysfunction. The kidney is one of the most frequent sites of amyloid deposition in AL, AA, and several of the hereditary amyloidoses. Amyloid fibril formation begins with the misfolding of an amyloidogenic precursor protein. The misfolded variants self-aggregate in a highly ordered manner, generating protofilaments that interact to form fibrils. The fibrils have a characteristic appearance by electron microscopy and generate birefringence under polarized light when stained with Congo red dye. Advances in elucidating the mechanisms of amyloid fibril formation, tissue deposition, and tissue injury have led to new and more aggressive treatment approaches for these disorders. This article reviews the pathogenesis, diagnosis, clinical manifestations, and treatment of the amyloidoses, focusing heavily on the renal aspects of each of these areas.
TIA-1 and TIAR are two closely related RNA recognition motif (RRM) proteins which possess three RRMtype RNA binding domains (RRMs 1, 2, and 3). Although both proteins have been implicated as effectors of apoptotic cell death, the specific functions of TIA-1 and TIAR are not known. We have performed in vitro selection/amplification from pools of random RNA sequences to identify RNAs to which TIA-1 and TIAR bind with high affinity. Both proteins selected RNAs containing one or several short stretches of uridylate residues suggesting that the two proteins have similar RNA binding specificities. Replacement of the uridylate stretch with an equal number of cytidine residues eliminates the protein-RNA interaction. Mutational analysis indicates that, for both TIA-1 and TIAR, it is the second RNA binding domain (RRM 2) which mediates the specific binding to uridylate-rich RNAs. Although RRM 2 is both necessary and sufficient for this interaction, the affinity for the selected RNA (as determined by filter binding assays) does increase when the second domain of TIAR is expressed together with the first and third domainsAlthough RRM 3 (of either TIA-1 or TIAR) does not interact with the uridylate-rich sequences selected by the full-length proteins, it is a bona fide RNA binding domain capable of affinity-precipitating a population of cellular RNAs ranging in size from 0.5 to 5 kilobases. In contrast, RRM 1 does not affinity-precipitate cellular RNA. The inability of RRM 1 to interact with RNA may be due to the presence of negatively charged amino acids within the RNP 1 octamer.RNA-binding proteins are involved in a variety of fundamental cellular processes including RNA splicing, polyadenylation, RNA transport, and translation. Specific RNA sequences with which these proteins interact have been identified in some cases, but for the majority of RNA-binding proteins, the RNA targets are unknown. TIA-1 and TIAR are two closely related members of the RNA recognition motif (RRM) 1 family of RNAbinding proteins (1, 2). The RRM (also known as the RNP motif, the RNP consensus sequence, the RNP-80, and the consensus sequence RNA-binding domain) consists of 80 -90 amino acids containing two stretches of 8 and 6 highly conserved residues called RNP 1 and RNP 2, respectively (3-5). TIA-1 and TIAR both possess three amino-terminal RRM domains and a glutamine-rich carboxyl terminus. The RRM domains of TIA-1 and TIAR are very similar with 79% amino acid identity between the first domains, 89% amino acid identity between the second domains, and 91% amino acid identity between the third domains. The carboxyl termini of the two proteins, in contrast, are only 51% identical in amino acid sequence (2). Several observations suggest that TIA-1 and TIAR are involved in signaling apoptotic cell death. The introduction of purified TIA-1 or TIAR into the cytoplasm of thymocytes permeabilized with digitonin results in fragmentation of genomic DNA into nucleosome-sized oligomers (1, 2). TIAR is translocated from the nucleus to the cytoplasm in respon...
Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stemcell transplantation (HDM/SCT), the greatest benefit is seen in those patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT at a single referral center and compared outcomes for patients with and without CR. Treatmentrelated mortality was 11.4% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event-free survival (EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after HDM/SCT and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with HDM/SCT resulted in a high organ response rate and long OS, even for those patients who did not achieve CR. (Blood. 2011;118(16):4346-4352) IntroductionImmunoglobulin light chain (AL) amyloidosis is the most common form of systemic amyloidosis, with an incidence of 5-12 persons per million per year. 1 In AL amyloidosis, clonal bone marrow plasma cells produce monoclonal light chains that misfold and deposit in tissues and organs as amyloid fibrils, resulting in progressive system and organ failure, and ultimately in death. Untreated patients with this disease have a dismal outcome, with a median survival of 10-14 months from diagnosis. 2 Moreover, fewer than 5% of patients survived for Ͼ 10 years before the introduction of high-dose melphalan and stem cell transplantation (HDM/ SCT). 3 Oral melphalan and prednisone (MP) modestly increases the median survival to 16-18 months and rarely induces hematologic complete responses (CRs) or reversal of organ dysfunction. 2,4,5 The introduction of HDM/SCT in the 1990s appears to have markedly improved these results. 6 Single and multicenter studies show CR rates of 16%-67%, organ responses in 25%-45% of patients, and a median overall survival (OS) of ϳ 5 years. [7][8][9][10][11][12][13][14][15][16] A case-control study demonstrated the benefit of this procedure for patients younger than 70 years compared with nontransplant regimens, most of them alkylator-based oral chemotherapy. 17 A major issue in HDM/SCT for AL amyloidosis is the potential for high treatment-related mortality (TRM) because of underlying organ dysfunction in this disease. Some early multicenter series reported TRM as high as 40%, but recent reports from experienced single centers have reported a TRM rate in the range of 10%-15% as a result of improved selection of patients and better peritransplantation management. [17][18][19] In previous reports, we and others have shown that patients who achieve CR after HDM/SCT have ...
Globally, the number of patients undergoing maintenance dialysis is increasing, yet throughout the world there is significant variability in the practice of initiating dialysis. Factors such as availability of resources, reasons for starting dialysis, timing of dialysis initiation, patient education and preparedness, dialysis modality and access, as well as varied "country-specific" factors significantly affect patient experiences and outcomes. As the burden of end-stage kidney disease (ESKD) has increased globally, there has also been a growing recognition of the importance of patient involvement in determining the goals of care and decisions regarding treatment. In January 2018, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference focused on dialysis initiation, including modality choice, access, and prescription. Here we present a summary of the conference discussions, including identified knowledge gaps, areas of controversy, and priorities for research. A major novel theme represented during the conference was the need to move away from a "one-size-fits-all" approach to dialysis and provide more individualized care that incorporates patient goals and preferences while still maintaining best practices for quality and safety. Identifying and including patient-centered goals that can be validated as quality indicators in the context of diverse health care systems to achieve equity of outcomes will require alignment of goals and incentives between patients, providers, regulators, and payers that will vary across health care jurisdictions.
Background In general populations, healthy lifestyle is associated with fewer adverse outcomes. We estimated the degree to which adherence to a healthy lifestyle decreases the risk of renal and cardiovascular events among adults with chronic kidney disease (CKD). Study Design Prospective cohort. Setting & Participants 3006 adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Predictors Four lifestyle factors (regular physical activity, body mass index [BMI] 20–<25 kg/m2, nonsmoking, and “healthy diet”), individually and in combination. Outcomes CKD progression (50% decrease in estimated glomerular filtration rate or end-stage renal disease), atherosclerotic events (myocardial infarction, stroke, or peripheral arterial disease), and all-cause mortality. Measurements Multivariable-adjusted Cox proportional hazards. Results During median follow-up of 4 years, we observed 726 CKD progression events, 353 atherosclerotic events, and 437 deaths. BMI ≥ 25 kg/m2 and nonsmoking were associated with reduced risk of CKD progression (HRs of 0.75 [95% CI, 0.58–0.97] and 0.61 [95% CI, 0.45–0.82] for BMIs of 25–<30 and ≥30, respectively, vs. 20–<25 kg/m2; HR for nonsmoking of 0.68 [95% CI, 0.55–0.84] compared to current smoker reference group) and reduced risk of atherosclerotic events (HRs of 0.67 [95% CI, 0.46–0.96] for BMI 25–<30 vs. 20–<25 kg/m2 and 0.55 [95% CI, 0.40–0.75] vs. current smoker). Factors associated with reduced all-cause mortality were regular physical activity (HR, 0.64 [95% CI, 0.52–0.79] vs. inactive), BMI ≥30 kg/m2 (HR, 0.64 [95% CI, 0.43–0.96] vs. 20–<25 kg/m2) and nonsmoking (HR, 0.45 [95% CI, 0.34–0.60] vs. current smoker). BMI <20 kg/m2 was associated with increased all-cause mortality risk (HR, 2.11 [95% CI, 1.13–3.93] vs. 20–25 kg/m2). Adherence to all four lifestyle factors was associated with 68% lower risk of all-cause mortality compared to adherence to no lifestyle factors (HR, 0.32; 95% CI, 0.11–0.89). Limitations Lifestyle factors were only measured once. Conclusions Regular physical activity, nonsmoking, and BMI ≥25 kg/m2 were associated with lower risk of adverse outcomes in this cohort of individuals with CKD.
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