TASK DEFINITION: In this task, you are given a passage which has a question and the context. You have to generate an answer to the question based on the information present in the context.
PROBLEM: Context: The population analysis of cardiovascular risk and non-risk genetic variation can help to identify adaptive or random demographic processes that shaped coronary incidence variation across geography.', 'In this study, 114 single nucleotide polymorphisms and 17 tandem repeat polymorphisms from Nitric Oxide Synthases (NOS) regions were analyzed in 1686 individuals from 35 populations from Europe, North Africa, and the Middle East. NOS genes encode for key enzymes on nitric oxide availability, which is involved in several cardiovascular processes. These genetic variations were used to test for selection and to infer the population structure of NOS regions. Moreover, we tested whether the variation in the incidence of coronary events and in the levels of classical risk factors in 11 of these European populations could be explained by the population structure estimates.', 'Our results supported, first, the absence of clear signs of selection for NOS genetic variants associated with cardiovascular diseases, and second, the presence of a continuous genetic pattern of variation across European and North African populations without a Mediterranean barrier for gene flow. Finally, population structure estimates from NOS regions are closely correlated with coronary event rates and classical risk parameters (explaining 39-98%) among European populations.\Question: Does population structure from NOS genes correlate with geographical differences in coronary incidence across Europe?

SOLUTION: Our results reinforce the hypothesis that genetic bases of cardiovascular diseases and associated complex phenotypes could be geographically shaped by random demographic processes.

PROBLEM: Context: Due to lack of a targeted therapy for the triple-negative breast cancer (TNBC) patients, it is important to explore this aggressive breast cancer type in more detail and to establish novel therapeutic approaches. TNBC is defined negative for the protein expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). One prominent feature of this cancer type is the frequent overexpression of major components of the urokinase-type plasminogen activator system (uPAS) including uPA, its receptor uPAR and the inhibitor PAI-1, which may be valuable as therapeutic targets.', 'Direct interactions of uPAR with interactors were demonstrated by immunoprecipitations and proximity ligation assays. For stable knockdowns of target proteins, lentiviral vectors were used and the effects were analysed by immunoblottings and using in vitro cell viability, migration and invasion assays. Immunohistochemical and statistical analyses of biomarkers and clinical parameters were conducted in a TNBC cohort (n=174).', 'Direct tumour-promoting interactions of uPAR with uPA and the insulin-like growth factor receptor 1 (IGF1R) were shown in TNBC cells and these interactions were significantly reduced (p=0.001) when uPAR was downregulated. The combined knockdown of uPAR and uPA or IGF1R additively and significantly reduced cell viability, migration and invasion of the model cell lines. In TNBC tissue, the complexes formed by uPAR with uPA or with IGF1R significantly correlated with the histological grade (p=0.0019) as well as with cathepsin B and D (p0.0001) that are implicated in cell invasion and metastasis.\Question: Does uPAR enhance malignant potential of triple-negative breast cancer by directly interacting with uPA and IGF1R?

SOLUTION: Our outcomes show that not only overexpressed biomarkers promote tumourigenesis, but rather their interactions further potentiate tumour progression. This study emphasises the potential of combined approaches targeting uPAR and its interactors with regard to an improved therapy of TNBC.

PROBLEM: Context: Peritoneal fibrosis is one of the long-term complications in peritoneal dialysis (PD) patients. Recent evidences have suggested that hydrogen sulfide (H2S) is beneficial in treating various fibrotic diseases, including pulmonary fibrosis, cirrhosis, kidney fibrosis and cardiac hypertrophy. However, no information is known about the effect of H2S on peritoneal fibrosis. In the present study, we investigated the effect of H2S on peritoneal fibrosis and explored its potential mechanisms.', 'We developed a model of peritoneal fibrosis by intraperitoneally injecting 4.25%-glucose PD fluids and lipopolysaccharide to Sprague-Dawley rats. The rats received daily intraperitoneal injections of NaHS (56 g/kg), an H2S donor. After 28 days, the peritoneal equilibration test (PET) was used to assess peritoneal function. At the end of dialysis, the rats were killed and parietal peritoneum was harvested for microscopic examination and immunohistochemistry.', 'On the 28th day, the parietal peritoneum of the PD rats markedly thickened as a result of increased depositions of type III collagen and fibronectin. Moreover, the number of ED-1-positive cells and the expressions of monocyte chemoattractant protein-1, transforming growth factor-1 (TGF-1), -smooth muscle actin and CD31 were significantly increased in the fibrotic peritoneum. Administration of NaHS markedly decreased the biomarkers of inflammation, fibrosis and angiogenesis in the peritoneum. NaHS also improved peritoneal function assessed by PET.\Question: Does hydrogen Sulfide alleviate Peritoneal Fibrosis via Attenuating Inflammation and TGF-1 Synthesis?

SOLUTION:
Exogenous H2S ameliorates the pathologic process of peritonitis via attenuating inflammatory events and TGF-1 synthesis. These results suggest that H2S may be a potential therapy against peritoneal fibrosis during chronic PD. In the future, compounds releasing H2S at controlled rate will be assessed as potential candidates to treat peritoneal fibrosis.