instruction:
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.
question:
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-naïve 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-naïve glioblastoma and anaplastic oligodendroglioma contribute to temozolomide resistance independently of MGMT promoter methylation?
answer:
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.


question:
Context: To investigate the effects of interval aerobic training combined with strength-endurance exercise (IASE) and caloric restriction (CR) on body composition, glycaemic and lipid profile and inflammatory markers.', 'Thirty-two Zucker diabetic fatty rats were randomised into 4 groups (sedentary\xa0+\xa0CR; sedentary\xa0+\xa0adlibitum; IASE\xa0+\xa0CR; and IASE\xa0+\xa0adlibitum). Training groups conducted an IASE programme in the same session, 5 days/week for 2 months. Body weight, fat and muscle mass and body water were measured using a body composition analyser. Plasma total, LDL and HDL cholesterol, phospholipids, triglycerides, insulin, adiponectin, tumour necrosis factor alpha, interleukin 1 and 10 were measured. Blood fasting and postprandial glucose were assessed. Body weight was lower in the CR compared to the adlibitum groups (p\xa0<\xa00.001). Fat mass was lower in the CR compared to the adlibitum (p\xa0<\xa00.05) and in the IASE compared to the sedentary groups (p\xa0<\xa00.001), but IASE increased lean mass (p\xa0<\xa00.001). Triglycerides were lower in the CR compared to the adlibitum groups (p\xa0<\xa00.001) whereas total and LDL-cholesterol and fasting glucose were reduced only in the IASE groups (all, p\xa0<\xa00.001). Phospholipids decreased in the CR compared to the adlibitum (p\xa0<\xa00.05) and the IASE compared to the sedentary groups (p\xa0<\xa00.001). The area under the curve after oral glucose tolerance test, insulin and homoeostatic model assessment were lower in the IASE and the CR compared to the sedentary and adlibitum groups, respectively (all, p\xa0<\xa00.001). Adiponectin was lower in the CR groups (p\xa0<\xa00.001).\Question: Does interval aerobic training combined with strength-endurance exercise improve metabolic markers beyond caloric restriction in Zucker rats?
answer:
Overall, IASE as well as CR were both useful interventions, especially when combined. However, IASE showed greater improvements on body composition, inflammatory and glycaemic profile than CR did.


question:
Context: Smoking is an important risk factor for cardiovascular disease. Sympathetic responses to cigarette smoking may be implicated in the link between smoking and cardiovascular disease. We tested the hypothesis that the sympathetic neural responses to smoking are age dependent.', 'We examined the effects of cigarette smoking and sham smoking on muscle sympathetic nerve activity, blood pressure and heart rate in 14 normotensive middle-aged (49 +/- 4 years) and 12 young (29 +/- 4 years) habitual smokers matched for body mass index (25 +/- 2 kg/m2 in both groups).', 'Sham smoking had no significant effect on sympathetic drive, blood pressure or heart rate in either group. Cigarette smoking increased heart rate in both middle-aged subjects and young subjects. In comparison to younger subjects, middle-aged smokers showed similar smoking-related increases in systolic blood pressure (SBP) [10 +/- 3 versus 12 +/- 2 mmHg, respectively, not significant (NS)]. Smoking decreased sympathetic nerve activity by 28 +/- 12% of baseline values (P < 0.01) in young subjects. However, muscle sympathetic nerve activity did not change significantly after smoking in middle-aged subjects (5 +/- 8%, NS), despite the increased blood pressures, which would be expected to inhibit sympathetic activity. By contrast, in young subjects, the heart rate increase (22 +/- 2 bpm) was greater than that seen in middle-aged subjects (13 +/- 2 bpm, P < 0.01).\Question: Are sympathetic neural responses to smoking age dependent?
answer:

The autonomic responses to smoking are age dependent. While blood pressure increases are similar in both groups, young subjects respond to smoking by marked increases in heart rate and suppression of central sympathetic outflow. In middle-aged subjects, the heart rate increase is less marked, but sympathetic vasoconstrictor activity is not suppressed.