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Stress response pathways are critical for cellular homeostasis, promoting survival through adaptive changes in gene expression and metabolism. They play key roles in numerous diseases and are implicated in cancer progression and chemoresistance. However, the underlying mechanisms are only poorly understood. We have employed a multi-omics approach to monitor changes to gene expression after induction of a stress response pathway, the unfolded protein response (UPR), probing in parallel the transcriptome, the proteome, and changes to translation. Stringent filtering reveals the induction of 267 genes, many of which have not previously been implicated in stress response pathways. We experimentally demonstrate that UPR‐mediated translational control induces the expression of enzymes involved in a pathway that diverts intermediate metabolites from glycolysis to fuel mitochondrial one‐carbon metabolism. Concomitantly, the cells become resistant to the folate-based antimetabolites Methotrexate and Pemetrexed, establishing a direct link between UPR‐driven changes to gene expression and resistance to pharmacological treatment., The unfolded protein response (UPR) is a stress response pathway implicated in numerous diseases and chemotherapy resistance. Here, the authors define the UPR regulon with a multi-omics strategy, uncovering changes to mitochondrial one-carbon metabolism and concomitant resistance to folate-based therapeutics.

The objective was to investigate the proportion of men with metastatic prostate cancer in groups defined by T stage, Gleason Grade Group (GGG) and serum levels of prostate-specific antigen (PSA) and if PSA can be used to rule in metastatic prostate cancer when combined with T stage and GGG. We identified 102,076 men in Prostate Cancer data Base Sweden 4.0 who were diagnosed with prostate cancer in 2006-2016. Risk of metastases was assessed for PSA stratified on T stage and five-tiered GGG. For men who had not undergone bone imaging, we used multiple imputation to classify metastatic prostate cancer. Advanced T stage, high GGG and high PSA were related to bone metastases. For example: only 79/38 190 (0.2%) of men with T1-2 and GGG 1 had PSA above 500 ng/mL, and 29/79 (44%) of these men had metastases; whereas 1 154/7 018 (16%) of men with T3-4 and GGG 5 had PSA above 500 ng/ml and 1 088/1 154 (94%) of these men had metastases. However, no PSA cut-off could accurately identify the majority of men with metastatic prostate cancer (i.e. high sensitivity) while also correctly classifying most men without metastasis (i.e. high specificity). In conclusion, these results support the use of imaging to confirm bone metastases in men with advanced prostate cancer as no PSA level in combination with T stage and GGG could accurately rule in metastatic prostate cancer and thereby safely omit bone imaging.

To assess the impact of the 2005 modification of the Gleason classification on risk of biochemical recurrence (BCR) after radical prostatectomy (RP).In the Prostate Cancer data Base Sweden (PCBaSe), 2,574 men assessed with the original Gleason classification and 1,890 men assessed with the modified Gleason classification, diagnosed between 2003 and 2007, underwent primary RP. Histopathology was reported according to the Gleason Grading Groups (GGG): GGG1 = Gleason score (GS) 6, GGG2 = GS 7(3 + 4), GGG3 = GS 7(4 + 3), GGG4 = GS 8 and GGG5 = GS 9-10. Cumulative incidence and multivariable Cox proportional hazards regression models were used to assess difference in BCR.The cumulative incidence of BCR was lower using the modified compared to the original classification: GGG2 (16% vs. 23%), GGG3 (21% vs. 35%) and GGG4 (18% vs. 34%), respectively. Risk of BCR was lower for modified versus original classification, GGG2 Hazard ratio (HR) 0.66, (95%CI 0.49-0.88), GGG3 HR 0.57 (95%CI 0.38-0.88) and GGG4 HR 0.53 (95%CI 0.29-0.94).Due to grade migration following the 2005 Gleason modification, outcome after RP are more favourable. Consequently, outcomes from historical studies cannot directly be applied to a contemporary setting. J. Surg. Oncol. 2016;114:664-670. © 2016 Wiley Periodicals, Inc.

Polyethylene (PE) wear and osteolysis is a recognised problem with non-cross linked PE liners and first generation modular cup designs. Wear particles induce osteolysis leading to aseptic loosening. We retrospectively compared the linear PE wear and implant survival and revision rates of the Reflection Cup and the Duraloc 300. After a mean clinical follow-up of 13 years (range 11-15 years), the 2D linear PE wear-rate of the Reflection liner (n = 68) was 0.23 mm/year, with a mean total wear of 3.14 mm (1.04-7.36), SD 1.45. The wear-rate of the Duraloc 300 cups (n = 32) was 0.14 mm/year, with a mean total wear of 1.84 mm (0.55-4.63), SD 1.07. The difference in PE wear-rate as well as mean total wear was highly significant (p = 0.0001). There was a positive correlation between wear-rate and both Oxford Hip Score and Harris Hip Score (p = 0.02). Large acetabular cup size (>54 mm), HA coating on the stem and age

OBJECTIVE To assess the efficacy and safety of switching from sitagliptin to liraglutide in metformin-treated adults with type 2 diabetes. RESEARCH DESIGN AND METHODS In an open-label trial, participants randomized to receive either liraglutide (1.2 or 1.8 mg/day) or sitagliptin (100 mg/day), each added to metformin, continued treatment for 52 weeks. In a 26-week extension, sitagliptin-treated participants were randomly allocated to receive instead liraglutide at either 1.2 or 1.8 mg/day, while participants originally randomized to receive liraglutide continued unchanged. RESULTS Although 52 weeks of sitagliptin changed glycosylated hemoglobin (HbA1c) by −0.9% from baseline, additional decreases occurred after switching to liraglutide (1.2 mg/day, −0.2%, P = 0.006; 1.8 mg/day, −0.5%, P = 0.0001). Conversion to liraglutide was associated with reductions in fasting plasma glucose (FPG) (1.2 mg/day, −0.8 mmol/L, P = 0.0004; 1.8 mg/day, −1.4 mmol/L, P < 0.0001) and body weight (1.2 mg/day, −1.6 kg; 1.8 mg/day, −2.5 kg; both P < 0.0001) and with an increased proportion of patients reaching HbA1c

A case of primary adenocarcinoma in appendiceal diverticulosis is reported. Such a case has never been mentioned before in the literature. It was not possible to diagnose the case preoperatively. This emphasizes the importance of histological examination of all appendiceal samples.

INTRODUCTION: As the only femoral stem, the Exeter stem has shown acceptable results with Boneloc cement, but no long-term results have been published. The aim of this study was to evaluate the 20-year performance of Boneloccemented primary Exeter hip arthroplasty. MATERIAL AND METHODS: From March 1992 to June 1994, a total of 200 consecutive Boneloc-cemented primary hip arthroplasties were performed in 183 patients aged 26-90 years, mean 71 years. At follow-up after 18-20 years, the primary endpoint was prosthetic survival assessed by the Kaplan-Meier analysis. Secondary endpoints were clinical and radiographic follow-up examination. RESULTS: After a mean 18.4 (17.6-19.6)-year period, 27 patients/32 hips had been revised. At endpoint revision for any reason the 20-year cumulative overall survival was 73% (95% confidence interval (CI): 49-89%); at endpoint revision for aseptic loosening the 20-year cumulative survival was 84% (95% CI: 68-96%) for the stem and 76% (95% CI: 6192%) for the cup. Cementing technique, implant size and metal backing of the cup were not associated with revision rates. A total of 23 patients/24 hips had clinical/radiographic examination, and 10 patients/12 hips were assessed by telephone. According to patient reported evaluation, all were very satisfied or satisfied. Radiographs showed loosening of two cups and possible loosening of two stems. CONCLUSION: This study provides the first long-term results on Boneloc-cemented primary hip arthroplasty. The Exeter prosthesis, especially the stem, maintains the previously published acceptable survival and results despite the documented inferior quality of the cement.