Given a passage with a context and an answer, construct a question on the basis of the information present in the passage. Construct the question in such a way that (i) it is unambiguous, (ii) it is answerable from the passage, (iii) its answer is unique (iv) it answer uses text phrases from the passage. Avoid creating questions that (i) can't be answered correctly without actually understanding the passage and (ii) uses the same words or phrases given in the passage.

Q: Context: Chronic HIV/HCV co-infection carries increased risk of cirrhosis, hepatocellular carcinoma, and death. Due to anti-inflammatory properties, HMG co-A inhibitors (statins) may be useful adjunctive therapy to reduce liver disease progression.', 'Clinical information was extracted from the Veterans Affairs HIV and HCV Clinical Case Registries (1999 - 2010). HIV-related variables included combination anti-retroviral therapy (cART) era of diagnosis, CD4 cell count, and percent time with undetectable HIV viral load. Metabolic variables included diabetes, low-HDL, and hypertension. Statin use was measured as percent time with active prescription (time-updated throughout the follow-up period). Cox proportional hazards analysis was used to determine risk factors for cirrhosis (ICD-9 or APRI>2) overall and in groups stratified by alanine aminotransferase (ALT) level above and below 40\u200aIU/L.', 'The cohort included 5985\u200aHIV/HCV co-infected veterans. The majority was black race, and the mean age at index date was 45 years. Statin use was significantly protective of cirrhosis for patients with ALT ≤40\u200aIU/L; for every 30% increase in time on statin, there was a 32% decreased risk of developing cirrhosis (HR 0.68, 95% CI 0.47 -0.98). Diabetes and low-HDL were significantly associated with cirrhosis in patients with ALT > 40\u200aIU/L (HR 1.15, p\u200a<\u200a0.04 and HR 1.3, p\u200a<\u200a0.0001).
Answer: Statin drug use is beneficial in mitigating the risk of liver disease progression for HIV/HCV co-infected patients without advanced liver disease. Low-HDL and diabetes in co-infected patients with abnormal ALT have greater risk of cirrhosis development.

A: Do statin drugs decrease progression to cirrhosis in HIV/HCV co-infected individuals?
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Q: Context: Perturbation of the endoplasmic reticulum (ER) homeostasis has emerged as one of the prominent features of obesity and diabetes. This occurs when the adaptive unfolded protein response (UPR) fails to restore ER function in key metabolic tissues. We previously reported increased inflammation and impaired heat shock response (HSR) in obese human subjects that were restored by physical exercise. Here, we investigated the status of ER stress chaperone; glucose-regulated protein 78 (GRP78) and its downstream UPR pathways in human obese, and their modulation by a supervised 3-month physical exercise.', "Subcutaneous adipose tissue (SAT) and blood samples were collected from non-diabetic adult human lean (n=40) and obese (n=40, at baseline and after 3months of physical exercise). Transcriptomic profiling was used as a primary screen to identify differentially expressed genes and it was carried out on SAT samples using the UPR RT(2) Profiler PCR Array. Conventional RT-PCR, immunohistochemistry, immunofluorescence, Western blot and ELISA were used to validate the transcriptomic data. Correlation analyses with the physical, clinical and biochemical outcomes were performed using Pearson's rank correlation coefficient.", 'Levels of GRP78 and its three downstream UPR arms; activating transcription factor-6 (ATF6), inositol-requiring enzyme-1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) were increased in obese subjects. More interestingly, higher levels of circulating GRP78 protein were found in obese compared to lean subjects which correlated negatively with maximum oxygen uptake (VO2 Max) but positively with high-sensitivity C-reactive protein (hsCRP) and obesity indicators such as BMI, percentage body fat (PBF) and waist circumference. GRP78 increased secretion in obese was further confirmed in vitro using 3T3-L1 preadipocyte cells under ER stress. Finally, we showed that physical exercise significantly attenuated the expression and release of GRP78 with a concomitant reduction in the phosphorylation of IRE1α and eukaryotic initiation factor-2α (eIF2α).
Answer: Our results suggest that physical exercise alleviates ER stress in human obese through attenuation of GRP78 signaling network.

A: Does physical exercise alleviate ER stress in obese humans through reduction in the expression and release of GRP78 chaperone?
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Q: Context: Treatment resistance and metastasis are the major causes of death among patients with colorectal cancer (CRC). Approximately 20% of surgically treated patients ultimately develop metastases during the follow-up period. Currently, the TNM system is the only available prognostic test. Therefore, the identification of new markers for CRC remains important. Thrombomodulin (TM), a glycoprotein, is involved in angiogenesis and has been linked to many malignant diseases. However, the function of TM in CRC remains unclear.', 'A total of 170 patients with CRC participated in this study. TM expression was analyzed via immunohistochemistry. Univariate (Kaplan-Meier) analysis was used to analyze patient outcomes, including overall survival (OS) and disease-free survival (DFS). TM expression was manipulated using shRNA or an overexpression system. Transwell migration assays, wound healing migration assays, and the xCELLigence biosensor system were used to detect cell proliferative and migratory capacities.', "TM expression in the tumor tissues significantly and positively correlated with the DFS and OS of non-metastatic patients with CRC (ps = 0.036 and 0.0218, respectively). Suppression of TM expression increased the proliferation and migration of DLD-1 cells. TM overexpression reduced the cells' proliferative and migratory capacities. Cyclooxygenase (COX)-2 expression was up-regulated following TM silencing. Furthermore, the association between the migration of colon cancer cells and the levels of TM and epithelial-to-mesenchymal transition (EMT) markers (fibronectin, vimentin and ezrin) was confirmed in HT29 and DLD-1 cells.
Answer: Our study demonstrates that patients with non-metastatic CRC display low TM expression in their tumors and exhibit reduced DFS and OS. The enhanced expression of mesenchymal markers and COX-2 may be involved in the mechanisms that underlie recurrence in patients with cancer displaying low TM expression.

A:
Does thrombomodulin influence the Survival of Patients with Non-Metastatic Colorectal Cancer through Epithelial-To-Mesenchymal Transition ( EMT )?
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