Translation suppression promotes stress granule formation and cell survival in response to cold shock

Cells respond to different types of stress by inhibition of protein synthesis and subsequent assembly of stress granules (SGs), cytoplasmic aggregates that contain stalled translation preinitiation complexes. Global translation is regulated through the translation initiation factor eukaryotic initiation factor 2a (eIF2a) and the mTOR pathway. Here we identify cold shock as a novel trigger of SG assembly in yeast and mammals. Whereas cold shock-induced SGs take hours to form, they dissolve within minutes when cells are returned to optimal growth temperatures. Cold shock causes eIF2a phosphorylation through the kinase PERK in mammalian cells, yet this pathway is not alone responsible for translation arrest and SG formation. In addition, cold shock leads to reduced mitochondrial function, energy depletion, concomitant activation of AMP-activated protein kinase (AMPK), and inhibition of mTOR signaling. Compound C, a pharmacological inhibitor of AMPK, prevents the formation of SGs and strongly reduces cellular survival in a translation-dependent manner. Our results demonstrate that cells actively suppress protein synthesis by parallel pathways, which induce SG formation and ensure cellular survival during hypothermia.

Long-term graft survival in patients with flexible open-loop anterior chamber intraocular lenses

Purpose. To evaluate the long-term graft survival in patients with flexible open-loop anterior chamber intraocular lenses (AC IOL). Methods. We retrospectively reviewed the records of patients with aphakic/pseudophakic bullous keratopathy who underwent penetrating keratoplasty and flexible open-loop AC IOL implantation in our institution from 1983 to 1988. Results. 79 eyes from 77 patients were included in the study. Mean follow-up was 50 months (range 1 to 123 months). At last follow-up 61 eyes (77.2%) had clear grafts. Among them, the visual acuity was = 20/40 in 14 eyes (23.0%), 20/50-20/100 in 22 eyes (36.1%), 20/200-20/400 in 9 eyes (14.8%) and = CF in 16 (26.2%). Increment of glaucoma medications and/or glaucoma surgery was the most frequent complication (37 eyes, 46,8%). Cystoid macular edema was newly diagnosed in 10 eyes (12.7%). Conclusions. Flexible, open-loop anterior chamber lens are a viable option in the treatment of patients with aphakic or pseudophakic bullous keratopathy undergoing penetrating keratoplasty.

Long-term graft survival in patients with flexible open-loop anterior- chamber intraocular lenses

Purpose. To evaluate the long-term graft survival and complications of flexible, open-loop anterior-chamber intraocular lenses in patients with penetrating keratoplasty for pseudophakic or aphakic bullous keratopathy. Methods. We reviewed charts of all consecutive patients who underwent penetrating keratoplasty for pseudophakic or aphakic bullous keratopathy combined with implantation of a flexible, open-loop, anterior-chamber intraocular lens at our institution between 1983 and 1988. One-hundred one eyes of 99 patients were evaluated. Graft-survival rates were calculated by using the Kaplan-Meier actuarial method. Results. Mean follow-up was 49.8 months (range. 1-144). The probability of graft survival at 1, 2, 4, 6, and 8 years was 93, 87, 78, 65, and 65%, respectively. A total of 25 (24.8%) grafts failed. Progressive corneal edema without signs of rejection was the most common finding in patients with failed grafts (10 eyes, 40%). The most frequent complication observed was newly diagnosed or worsening of preexisting glaucoma (46 eyes, 45.5%). Conclusions. Our long-term results support flexible, open-loop anterior-chamber intraocular lenses as a reasonable option, at the time of penetrating keratoplasty, in patients with pseudophakic and aphakic bullous keratopathy.

US Credit Unions: Survival, Consolidation and Growth

This study uses hazard function estimations and time-series and cross-sectional growth regressions to examine the impact of exit through merger and acquisition (M&A) or failure, and internally-generated growth, on the firm-size distribution within the US credit union sector. Consolidation through M&A was the principal cause of a reduction in the number of credit unions, but impact on concentration was small. Divergence between the average internally-generated growth of smaller and larger credit unions was the principal driver of the rise in concentration.

Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer

Secretory factors that drive cancer progression are attractive immunotherapeutic targets. We used a whole-genome data-mining approach on multiple cohorts of breast tumours annotated for clinical outcomes to discover such factors. We identified Serine protease inhibitor Kazal-type 1 (SPINK1) to be associated with poor survival in estrogen receptor-positive (ER+) cases. Immunohistochemistry showed that SPINK1 was absent in normal breast, present in early and advanced tumours, and its expression correlated with poor survival in ER+ tumours. In ER- cases, the prognostic effect did not reach statistical significance. Forced expression and/or exposure to recombinant SPINK1 induced invasiveness without affecting cell proliferation. However, down-regulation of SPINK1 resulted in cell death. Further, SPINK1 overexpressing cells were resistant to drug-induced apoptosis due to reduced caspase-3 levels and high expression of Bcl2 and phospho-Bcl2 proteins. Intriguingly, these anti-apoptotic effects of SPINK1 were abrogated by mutations of its protease inhibition domain. Thus, SPINK1 affects multiple aggressive properties in breast cancer: survival, invasiveness and chemoresistance. Because SPINK1 effects are abrogated by neutralizing antibodies, we suggest that SPINK1 is a viable potential therapeutic target in breast cancer.

ProP Is Required for the Survival of Desiccated Salmonella enterica Serovar Typimurium Cells on a Stainless Steel Surface

Consumers trust commercial food production to be safe, and it is important to strive to improve food safety at every level. Several outbreaks of food-borne disease have been caused by Salmonella strains associated with dried food. Currently we do not know the mechanisms used by Salmonella enterica serovar Typhimurium to survive in desiccated environments. The aim of this study was to discover the responses of S. Typhimurium ST4/74 at the transcriptional level to desiccation on a stainless steel surface and to subsequent rehydration. Bacterial cells were dried onto the same steel surfaces used during the production of dry foods, and RNA was recovered for transcriptomic analysis. Subsequently, dried cells were rehydrated and were again used for transcriptomic analysis. A total of 266 genes were differentially expressed under desiccation stress compared with a static broth culture. The osmoprotectant transporters proP, proU, and osmU (STM1491 to STM1494) were highly upregulated by drying. Deletion of any one of these transport systems resulted in a reduction in the long-term viability of S. Typhimurium on a stainless steel food contact surface. The proP gene was critical for survival; proP deletion mutants could not survive desiccation for long periods and were undetectable after 4 weeks. Following rehydration, 138 genes were differentially expressed, with upregulation observed for genes such as proP, proU, and the phosphate transport genes (pstACS). In time, this knowledge should prove valuable for understanding the underlying mechanisms involved in pathogen survival and should lead to improved methods for control to ensure the safety of intermediate-and low-moisture foods. © 2013, American Society for Microbiology.

Alpha emitter radium-223 and survival in metastatic prostate cancer

Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases.

Effects of modified low-density lipoproteins on human retinal pericyte survival

According to a current paradigm cardiovascular diseases can be initiated by exposure of vascular cells to qualitatively modified low-density lipoproteins (LDL). Capillary leakage, an early feature of diabetic retinopathy, results in the exposure of retinal pericytes to modified LDL, including glycated (G-LDL) and heavily oxidized glycated LDL (HOG-LDL). We demonstrate here that modified LDL inhibits the proliferation and survival of cultured human retinal pericytes. Modified LDL also induced DNA fragmentation in bovine retinal pericytes. Overall, HOG-LDL produced a significantly higher extent of cytotoxicity and apoptosis in retinal pericytes. These results indicate that exposure of pericytes to HOG-LDL could be implicated in the development of diabetic retinopathy.

The effect of socioeconomic deprivation on corneal graft survival in the United Kingdom

Objective: To investigate the effect of socioeconomic deprivation on cornea graft survival in the United Kingdom.

Design: Retrospective cohort study.

Participants: All the recipients (n = 13?644) undergoing their first penetrating keratoplasty (PK) registered on the United Kingdom Transplant Registry between April 1999 and March 2011 were included.

Methods: Data of patients' demographic details, indications, graft size, corneal vascularization, surgical complication, rejection episodes, and postoperative medication were collected at the time of surgery and 1, 2, and 5 years postoperatively. Patients with endophthalmitis were excluded from the study. Patients' home postcodes were used to determine the socioeconomic status using a well-validated deprivation index in the United Kingdom: A Classification of Residential Neighborhoods (ACORN). Kaplan–Meier survival and Cox proportional hazards regression were used to evaluate the influence of ACORN categories on 5-year graft survival, and the Bonferroni method was used to adjust for multiple comparisons.

Main Outcome Measures: Patients' socioeconomic deprivation status and corneal graft failure.

Results: A total of 13?644 patients received their first PK during the study periods. A total of 1685 patients (13.36%) were lost to follow-up, leaving 11?821 patients (86.64%) for analysis. A total of 138 of the 11?821 patients (1.17%) developed endophthalmitis. The risk of graft failure within 5 years for the patients classified as hard-pressed was 1.3 times that of the least deprived (hazard ratio, 1.3; 95% confidence interval, 1.1–1.5; P = 0.003) after adjusting for confounding factors and indications. There were no statistically significant differences between the causes of graft failure and the level of deprivation (P = 0.14).

Conclusions: Patients classified as hard-pressed had an increased risk of graft failure within 5 years compared with the least deprived patients.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article

The cemented custom femoral stem--a 10 year review

We report a series of 706 patients (759 hip implants) with an average follow up of 10.5 years (range, 10-11 years) following total hip replacement (THR) using a cemented custom-made femoral stem and a cemented HDP acetabular component. The fate of every implant is known. One hundred and seventy-four patients (23%) were deceased at the time of their 10-year review all died with a functioning THR in situ. Four hundred and sixty-two patients (61%) were subsequently reviewed. One hundred and twenty three patients (16%) were assessed by telephone review, as they were too ill or unwilling to attend. Kaplan-Meier survival analysis (all components) demonstrated a median survival at 10 years of 96.05% or 95% Confidence Intervals (CI) for median survival of (94.41% to 97.22%). Revision surgery occurred in 30 cases (3.9%). Seventeen had full revisions (2.2%) and 13 (1.7%) socket revisions only. Twenty-one out of 30 revisions were for infection or dislocation. There were 2 cases (0.3%) of revision for aseptic loosening of the stem. The 10-year results of the custom femoral titanium stem are encouraging and compare well with other cemented systems.

Effects of sintering temperature on morphology and mechanical characteristics of 3D printed porous titanium used as dental implant

Porous titanium samples were manufactured using the 3D printing and sintering method in order to determine the effects of final sintering temperature on morphology and mechanical properties. Cylindrical samples were printed and split into groups according to a final sintering temperature (FST). Irregular geometry samples were also printed and split into groups according to their FST. The cylindrical samples were used to determine part shrinkage, in compressive tests to provide stress-strain data, in microCT scans to provide internal morphology data and for optical microscopy to determine surface morphology. All of the samples were used in microhardness testing to establish the hardness. Below 1100 C FST, shrinkage was in the region of 20% but increased to approximately 30% by a FST of 1300 C. Porosity varied from a maximum of approximately 65% at the surface to the region of 30% internally. Between 97 and 99% of the internal porosity is interconnected. Average pore size varied between 24 µm at the surface and 19 µm internally. Sample hardness increased to in excess of 300 HV0.05 with increasing FST while samples with an FST of below 1250 C produced an elastic-brittle stress/strain curve and samples above this displayed elastic-plastic behaviour. Yield strength increased significantly through the range of sintering temperatures while the Young's modulus remained fairly consistent. © 2013 Elsevier B.V.