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: Most solid human tumors exist in an acidic microenvironment, due in part to inefficient vasculature and a higher intrinsic rate of glycolysis. This leads to a tumor-selective pH gradient, which can be exploited therapeutically with antitumor agents such as the camptothecins (CPTs). Previous work in this laboratory has shown that camptothecin activity is enhanced 40- to 60-fold in monolayer cell culture by reducing the extracellular pH to 6.8. Three-dimensional histoculture has been shown to be a technique that allows human tumor tissue to grow in an in vivo-like way with maintenance of tissue histology and function and drug sensitivity for long periods of time.', 'In the current study, we utilized these features of histoculture to study new analogues of camptothecin that have superior pharmacological properties.', 'We evaluated six CPT analogues in histocultures of human brain, neuroblastoma, breast, colon, and prostate tumors. Fragments were exposed to 10,11-methylenedioxy-CPT (MDC), 7-chloromethyl-MDC, SN-38, topotecan (TPT), 9-amino-CPT, 10-amino-CPT, paclitaxel, 5-fluorouracil, 4-hydroperoxycyclophosphamide and doxorubicin, and antitumor activity was assessed. For in vivo tumor outgrowth studies, fragments were treated in parallel, implanted into nude mice, and monitored for development of tumors. RESULTS. Against 15 of 16 tumor xenografts and all primary tumor samples tested, all compounds were cytotoxic at pH 7.4 (IC(50) range 13-921 microM). MDC, SN-38, TPT, and 9-amino-CPT achieved an average 5-fold increase in activity (range 3-14) at pH 6.8, while 7-chloromethyl-MDC was enhanced 8-fold (range 6-14). The most potentiated analogue was 10-amino-CPT at 27-fold (range 17-49). In contrast, the other agents were active against one or more tumor types but were not enhanced by acidic pH. Importantly, the toxicity of MDC in histoculture of D54 glioma xenografts strongly correlated with the outgrowth of treated fragments subsequently implanted in vivo.\Question: Is the activity of camptothecin analogues enhanced in histocultures of human tumors and human tumor xenografts by modulation of extracellular pH?

SOLUTION: Evaluation of anticancer drug activity in native-state histoculture supports the concept that pH modulation may be an important approach to improve the selectivity and antitumor effectiveness of camptothecin-based chemotherapy.

PROBLEM: Context: Patients with diabetes are at increased risk of ischemic events. Suv39h1 is a histone methyltransferase that catalyzes the methylation of histone 3 lysine 9, which is associated with the suppression of inflammatory genes in diabetes. However, the role of Suv39h1 in myocardial ischemia/reperfusion (I/R) injury under diabetic condition has not been evaluated.', 'To generate diabetic model, male SD rats were fed with 60% fat diet followed by intraperitoneal injection with 40mg/kg streptozotocin. Adenovirus encoding Suv39h1 gene was used for Suv39h1 overexpression. Each rat received injections of adenovirus at five myocardial sites. Three days after gene transfection, each rat was subjected to left main coronary artery occlusion and reperfusion. After 30 min ischemia and reperfusion for 4 h, the rats were euthanized for real-time PCR, Western blot, immunohistochemical staining, and morphometric analysis.', 'Delivery of Ad-Suv39h1 into the hearts of diabetic rats could markedly increase Suv39h1 expression. Up-regulation of Suv39h1 significantly reduced infarct size and tissue damage after I/R injury, which was associated with protection from apoptosis of cardiac myocytes and reduction of inflammatory response. In addition, compared with injury group, Ad-Suv39h1 led to a decreased activity of mitogen-activated protein kinase family and its down-steam transcriptional factor NF-κB.\Question: Does suv39h1 protect from myocardial ischemia-reperfusion injury in diabetic rats?

SOLUTION: Overexpression of Suv39h1 results in the de-activation of proinflammatory pathways and reduced apoptosis and myocardial injury. Therefore, Suv39h1 might represent a novel therapeutic strategy to reduce I/R injury under diabetic condition.

PROBLEM: Context: Formalin injection induces nociceptive bahaviour in phase I and II, with a quiescent phase between them. While active inhibitory mechanisms are proposed to be responsible for initiation of interphase, the exact mechanisms which lead to termination of nociceptive response in phase II are not clear yet. Phase II is a consequence of peripheral and central sensitization processes, which can lead to termination of the noxious stimuli responses; 45-60 minutes after formalin injection via possible recruitment of active inhibitory mechanisms which we have investigated in this study.', 'To test our hypothesis, in the first set of experiments, we evaluated nociceptive response after two consecutive injection of formalin (50µL, 2%), with intervals of 5 or 60 minutes. In the next set, formalin tests were carried out in companion with injection of Naloxone Hydrochloride, a non-selective antagonist of opioid receptors, pre-formalin injection and 30 and 45 minutes post formalin injection.', 'While normal nociceptive behaviour was observed in the group receiving one injection of formalin, a diminished response was observed in phases I and II of those receiving consequent injection of formalin, 60 minute after first injection. While second injection of formalin, 5 minute after first injection, had no effect. Administration of naloxone (1mg/kg) decreased nociception in phase 2A; but had no effect on delayed termination of formalin test.\Question: Is termination of Nociceptive Bahaviour at the End of Phase 2 of Formalin Test Attributable to Endogenous Inhibitory Mechanisms , but not by Opioid Receptors Activation?

SOLUTION:
The results of this study suggest the existence of an active inhibitory mechanism, other than the endogenous opioids, that is responsible for termination of nociceptive behaviour at the end of formalin test.