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.

[EX Q]: Context: Clinical use of doxorubicin is greatly limited by its severe cardiotoxic side effects. L-carnitine is a vitamin-like substance which has been successfully used in many cardiomyopathies, however, the intracellular mechanism(s) remain unclear. The objective of this study was set to evaluate the protective effect of L-carnitine on doxorubicin-induced cardiomyocyte apoptosis, and to explore its intracellular mechanism(s).', "Primary cultured neonatal rat cardiomyocytes were treated with doxorubicin (1 M) with or without pretreatment with L-carnitine (1-30 mM). Lactate dehydrogenase assay, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling staining, and flow cytometry measurement were used to assess cytotoxicity and apoptosis. Fluorescent probes 2',7'-dichlorofluorescein diacetate and chemiluminescence assay of superoxide production were used to detect the production of reactive oxygen species. Western blotting was used to evaluate the quantity of cleaved caspase-3, cytosol cytochrome c, and Bcl-x(L) expression.", "L-carnitine inhibited doxorubicin-induced reactive oxygen species generation and NADPH oxidase activation, reduced the quantity of cleaved caspase-3 and cytosol cytochrome c, and increased Bcl-x(L) expression, resulting in protecting cardiomyocytes from doxorubicin-induced apoptosis. In addition, L-carnitine was found to increase the prostacyclin (PGI(2)) generation in cardiomyocytes. The siRNA transfection for PGI(2) synthase significantly reduced L-carnitine-induced PGI(2) and L-carnitine's protective effect. Furthermore, blockade the potential PGI(2) receptors, including PGI(2) receptors (IP receptors), and peroxisome proliferator-activated receptors alpha and delta (PPAR and PPAR), revealed that the siRNA-mediated blockage of PPAR considerably reduced the anti-apoptotic effect of L-carnitine.\Question: Does l-carnitine reduce doxorubicin-induced apoptosis through a prostacyclin-mediated pathway in neonatal rat cardiomyocytes?
[EX A]: These findings suggest that L-carnitine protects cardiomyocytes from doxorubicin-induced apoptosis in part through PGI(2) and PPAR-signaling pathways, which may potentially protect the heart from the severe toxicity of doxorubicin.

[EX Q]: Context: The current standard of care for glioblastoma (GBM) involves a combination of surgery, radiotherapy, and temozolomide chemotherapy, but this regimen fails to achieve long-term tumor control. Resistance to temozolomide is largely mediated by expression of the DNA repair enzyme MGMT; however, emerging evidence suggests that inactivation of MSH6 and other mismatch repair proteins plays an important role in temozolomide resistance. Here, we investigate endogenous MSH6 mutations in GBM, anaplastic oligodendroglial tumor tissue, and corresponding brain tumor-initiating cell lines (BTIC).', 'MSH6 sequence and MGMT promoter methylation were determined in human tumor samples and BTICs. Sensitivity to temozolomide was evaluated in vitro using BTICs in the absence and presence of O(6)-benzylguanine to deplete MGMT. The influence of MGMT and MSH6 status on in vivo sensitivity to temozolomide was evaluated using intracranial BTIC xenografts.', 'We identified 11 previously unreported mutations in MSH6 in nine different glioma samples and six paired BTIC lines from adult patients. In addition, MSH6 mutations were documented in three oligodendrogliomas and two treatment-naive gliomas, both previously unreported findings. These mutations were found to influence the sensitivity of BTICs to temozolomide both in vitro and in vivo, independent of MGMT promoter methylation status.\Question: Do novel MSH6 mutations in treatment-naive glioblastoma and anaplastic oligodendroglioma contribute to temozolomide resistance independently of MGMT promoter methylation?
[EX A]: These data demonstrate that endogenous MSH6 mutations may be present before alkylator therapy and occur in at least two histologic subtypes of adult glial neoplasms, with this report serving as the first to note these mutations in oligodendroglioma. These findings broaden our understanding of the clinical response to temozolomide in gliomas.

[EX Q]: Context: Adipose tissue (AT) content of the thigh is generally not considered to be associated with insulin resistance (IR), but it is unclear whether the distribution of AT in the thigh is a determinant of IR.', 'We investigated whether subcompartments of AT within the thigh are determinants of IR.', 'Midthigh AT, muscle composition, and insulin sensitivity were compared in 11 obese patients with type 2 diabetes mellitus (DM); 40 obese, glucose-tolerant (GT) and 15 lean, GT volunteers; and 38 obese subjects who completed a weight-loss program. Midthigh AT area measured with computed tomography was partitioned into 3 components: subcutaneous AT (SCAT), AT beneath the fascia (SFAT), and AT infiltrating muscle groups (IMAT). Muscle attenuation characteristics were determined.', 'Obese DM and obese GT subjects had lower insulin sensitivity than lean GT subjects. SCAT was greater in obesity, yet did not correlate with insulin sensitivity. SFAT was approximately 8% of total thigh AT and correlated with insulin sensitivity. IMAT was highest in obese DM, and although it accounted for only approximately 3% of thigh AT, it was a strong correlate of insulin sensitivity. Mean attenuation was highest in lean subjects and was associated with higher insulin sensitivity. Weight loss reduced the amount of thigh AT, the proportion of thigh IMAT, and the amount of low-density thigh muscle.\Question: Is thigh adipose tissue distribution associated with insulin resistance in obesity and in type 2 diabetes mellitus?
[EX A]:
SFAT and IMAT are markers of IR in obesity and DM although they are much smaller than SCAT, which does not predict IR. Muscle composition reflecting increased fat content is also associated with IR.