Citations

The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-β. Chromatin IP assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-α protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.

Purpose:Today, data surrounding most of our lives are collected and stored. Data scientists are beginning to explore applications that could harness this information and make sense of it.Materials and Methods:In this review, the topic of Big Data is explored, and applications in modern health care are considered.Results:Big Data is a concept that has evolved from the modern trend of “scientism.” One of the primary goals of data scientists is to develop ways to discover new knowledge from the vast quantities of increasingly available information.Conclusions:Current and future opportunities and challenges with respect to radiology are provided with emphasis on cardiothoracic imaging.

Objective: Activation encompasses energy and activity and is a central feature of bipolar disorder. However, the impact of activation on treatment response of bipolar depression requires further exploration. The aims of this study were to assess the association of decreased activation and sustained remission in bipolar depression and test for factors that could affect this association. Methods: We assessed participants with Diagnostic and Statistical Manual of Mental Disorders (4th ed) bipolar depression ( n = 303) included in a comparative effectiveness study of lithium- and quetiapine-based treatments (the Bipolar CHOICE study). Activation was evaluated using items from the Bipolar Inventory of Symptoms Scale. The selection of these items was based on a dimension of energy and interest symptoms associated with poorer treatment response in major depression. Results: Decreased activation was associated with lower remission rates in the raw analyses and in a logistic regression model adjusted for baseline severity and subsyndromal manic symptoms (odds ratio = 0.899; p = 0.015). The manic features also predicted lower remission (odds ratio = 0.934; p < 0.001). Remission rates were similar in the two treatment groups. Conclusion: Decreased activation and subsyndromal manic symptoms predict lower remission rates in bipolar depression. Patients with these features may require specific treatment approaches, but new studies are necessary to identify treatments that could improve outcomes in this population.

OBJECTIVE Intensive treatment (INT) of type 1 diabetes reduces the incidence of cardiovascular disease (CVD) events compared with conventional treatment (CONV), but it also results in more weight gain. Our objective was to examine whether excessive weight gain from INT of type 1 diabetes is independently associated with subsequent CVD events. RESEARCH DESIGN AND METHODS Quartiles (Q) of weight gain in 1,213 participants aged 18 years and older at enrollment in the Diabetes Control and Complications Trial (DCCT) were determined within randomized treatment groups (INT vs. CONV) using change in BMI from baseline to the closeout DCCT visits. Effects of this weight gain on CVD risk factors and outcomes during an additional 20 years of observational follow-up were then determined. RESULTS The Q4 INT group experienced greater proportional weight gain (median change in BMI, 6.08 kg/m2), increases in CVD risk factors, and need for medications for hypertension and lipids compared with the Q1–3 INT and comparable CONV groups. Over a mean of 26 years of follow-up, the numbers of major and total CVD events were not statistically different in Q4 compared with Q1–3 of either the INT or CONV group. By year 14, however, the incident CVD event curve became significantly higher in the Q4 INT group than in the Q1–3 INT groups (P = 0.024) and was similar to that for the CONV group. CONCLUSIONS For the first 13 years after DCCT, INT for type 1 diabetes reduced macrovascular events compared with CONV, even when excessive weight gain occurred. After this, total CVD events significantly increased in the Q4 INT group, becoming equivalent to those in the CONV group. Longer follow-up is needed to determine whether this trend continues and results in more major CVD events.

101 Background: Socioeconomic status (SES) influences healthcare outcomes, but the influence of SES on cancer cachexia is unknown. We identify components of SES associated with pre-treatment cachexia in patients with non-small cell lung cancer (NSCLC) and assess their prognostic significance on survival. Methods: A prospectively maintained institutional tumor registry identified 1,365 patients with NSCLC consecutively treated at a tertiary care health system from 1/1/06 to 12/31/13. Insurance status was abstracted from the registry. Educational attainment and household income were estimated from census data using location of primary residence. Cancer cachexia was defined retrospectively using the international consensus definition. Multivariable regression analysis was used to identify prognostic factors of pre-treatment cancer cachexia and survival. Results: Cachexia was present at the time of NSCLC diagnosis in 30% of all patients including 17% of patients with stage I disease. Patients with Medicaid or no insurance were more likely to have pre-treatment cachexia compared to those with private insurance (Odds Ratio [OR] 1.9, 95% Confidence Interval [CI] 1.2-3.1; OR 2.1, 95% CI 1.2-3.4, respectively). Attainment of a high school diploma was inversely associated with pre-treatment cachexia (OR: 0.1, 95% CI 0.02-0.2). On multivariable analysis, comorbidity, histology, tumor grade, and disease stage were prognostic of survival among cachectic patients; however, insurance status, educational attainment, and household income were not. Conclusions: Lower SES is associated with pre-treatment cachexia in patients with NSCLC, but pre-treatment cachexia is detrimental to survival regardless of SES. Together, these findings suggest early intervention for patients with cancer cachexia may improve outcomes.

AbstractObjective:The aim of the study was to determine the association between self-reported vasomotor symptoms (VMS) and obstructive sleep apnea (OSA) risk.Methods:The STOP-BANG to evaluate OSA and Menopause Rating Scale (MRS) were administered to 2,935 women seen in the Women's Health Clinic at Mayo Clinic in Rochester, MN, between May 2015 and December 2016. Of these, 1,691 women were included in the analysis. Total MRS and VMS ratings were compared using logistic regression, with age, smoking, and body mass index (BMI) included as covariates between women at intermediate/high risk versus low risk for OSA.Results:Total MRS scores were significantly higher in women with intermediate/high-risk OSA scores versus those with low-risk scores [mean (SD): 16.8 (8.0) vs 12.9 (7.0),P < 0.001]. Women at intermediate/high OSA risk were older, had more education, self-reported hypertension, BMI >35 kg/m2, and were less likely to be married or employed. Self-reported severe/very severe VMS were significantly associated with intermediate/high risk versus low risk for OSA (26.6% vs 15.0%;P < 0.001). After adjusting for age, BMI, smoking status, and self-reported hypertension, the odds of having intermediate/high risk for OSA were 1.87 times higher for those with severe/very severe VMS compared with those with none/mild/moderate VMS (95% CI, 1.29-2.71,P < 0.001). This association persisted upon subgroup analysis based on BMI <25 kg/m2(odds ratio 2.15; 95% CI, 1.12-4.16,P= 0.022).Conclusions:Self-reported severe/very severe VMS were associated with intermediate/high risk for OSA in midlife women, even in women with BMI <25 kg/m2. Given the limitations of the STOP-BANG tool, OSA risk may, however, have been overestimated.

Significance Obesity is a major public health problem affecting physical and emotional well-being. Although lifestyle-based programs can help with weight loss, avoiding weight regain is nearly impossible because of persistent hormonal adaptations. Here, in mouse models, we explored a more effective strategy using viral gene transfer of butyrylcholinesterase (BChE) to control the appetite-mediating hormone acyl-ghrelin. We found that a single injection of BChE vector led to a lifetime high enzyme expression and lower circulating acyl-ghrelin. This same treatment suppressed postdieting hyperphagia, corrected metabolic lesions, and lowered weight regain. This outcome confirms the impact of the BChE-ghrelin axis on body weight and indicates that BChE gene transfer could be a successful strategy for long-term control of obesity and the “metabolic syndrome.”

Abstract Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479–90. ©2017 AACR.