TASK DEFINITION: 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.
PROBLEM: Context: Resistance to cisplatin-centered chemotherapy is a major cause of treatment failure in human ovarian cancer. Whereas PTEN, a tumor suppressor gene product, is believed to promote apoptosis primarily via inactivation of the PI3K/Akt cell survival pathway, recent evidence suggests that PTEN may function independently of this pathway. Activation of p53 is a key determinant of sensitivity to cisplatin-induced apoptosis. Whether PTEN can facilitate cisplatin sensitivity, and this involves the activation of p53, remains unclear. In this study, we determined whether and how PTEN over-expression sensitizes ovarian cancer cells to CDDP-induced apoptosis.', 'Using pairs of chemosensitive and chemoresistant ovarian cancer cell lines (OV20028 vs. C13* and A2780-s vs. A2780-cp) as an in vitro model, we have examined the influence of PTEN over-expression in regulation of cisplatin-induced apoptosis. Apoptosis was assessed morphologically by Hoechst staining and confirmed by the detection of cleaved products of caspase-3 and PARP by Western blot. Over-expression of PTEN by PTEN cDNA transfection up-regulates p53 content and increases the sensitivity of chemoresistant cells to cisplatin-induced apoptosis without detectable changes in the levels of phosphorylated Akt and FKHR as well as FasL mRNA abundance as determined by Western blot and RT-PCR, respectively. PTEN-mediated chemosensitization was attenuated by p53 down-regulation by siRNA in C13*, a chemoresistant wild-type p53 cell. Moreover, PTEN over-expression failed to sensitize the chemoresistant p53 mutant ovarian cancer cell line A2780-cp to cisplatin-induced apoptosis, unless wild-type p53 was reconstituted by adenoviral p53 infection.
Answer: Taken together, these data suggest that PTEN over-expression may represent a novel therapeutic approach for chemoresistant human ovarian cancer and that this may involve a p53-mediated apoptotic cascade independent of the PI3K/Akt pathway.

SOLUTION: Does over-expression of PTEN sensitize human ovarian cancer cells to cisplatin-induced apoptosis in a p53-dependent manner?

PROBLEM: Context: Surfactant protein (SP) D shares target cells with the proinflammatory cytokine TNF-alpha, an important autocrine stimulator of dendritic cells and macrophages in the airways.', 'We sought to study the mechanisms by which TNF-alpha and SP-D can affect cellular components of the pulmonary innate immune system.', 'Cytokine and SP-D protein and mRNA expression was assessed by means of ELISA, Western blotting, and real-time PCR, respectively, by using in vivo models of allergic airway sensitization. Macrophage and dendritic cell phenotypes were analyzed by means of FACS analysis. Maturation of bone marrow-derived dendritic cells was investigated in vitro.', 'TNF-alpha, elicited either by allergen exposure or pulmonary overexpression, induced SP-D, IL-13, and mononuclear cell influx in the lung. Recombinant IL-13 by itself was also capable of enhancing SP-D in vivo and in vitro, and the SP-D response to allergen challenge was impaired in IL-13-deficient mice. Allergen-induced increase of SP-D in the airways coincided with resolution of TNF-alpha release and cell influx. SP-D-deficient mice had constitutively high numbers of alveolar mononuclear cells expressing TNF-alpha, MHC class II, CD86, and CD11b, characteristics of proinflammatory, myeloid dendritic cells. Recombinant SP-D significantly suppressed all of these molecules in bone marrow-derived dendritic cell cultures.
Answer: TNF-alpha can contribute to enhanced SP-D production in the lung indirectly through inducing IL-13. SP-D, on the other hand, can antagonize the proinflammatory effects of TNF-alpha on macrophages and dendritic cells, at least partly, by inhibiting production of this cytokine.

SOLUTION: Does surfactant protein D inhibit TNF-alpha production by macrophages and dendritic cells in mice?

PROBLEM: Context: Overweight/obesity is known to increase the risk of developing renal cell carcinoma (RCC). However, data on the prognostic impact of overweight in RCC is still conflicting. We assessed whether different body mass index (BMI) levels at the time of surgery had an effect on the long-term prognosis of RCC patients.', "We evaluated 771 patients, with complete information about their BMI, who had undergone renal surgery for RCC between 1990 and 2005 at the authors' institution; the mean follow-up was 5.48 years.", 'Underweight, normal weight, pre-obesity, and obesity were diagnosed in 4 (0.5%), 239 (31%), 356 (46.2%), and 172 (22.3%) RCC patients, respectively. Overweight (BMI >25) was significantly associated with younger age (P = 0.004) and positive nodal status (P = 0.04) but not with tumor stage, grade, visceral metastasis, gender, histological subtype, or tumor-related symptoms. Overweight patients had a significantly lower risk of cancer-related death; their median 5-year tumor-specific survival rate was 80% as opposed to 72% for patients with a BMI below 25 (P = 0.003). Interestingly, subgroup analysis revealed that the positive association between overweight and survival was even more pronounced in organ-confined (P < 0.001) RCC, but no correlation was observed in advanced disease (P = 0.23).
Answer: We were able to identify overweight as an independent prognostic marker of improved tumor-specific survival in patients with organ-confined RCC. Basic research is required to resolve the dilemma of why, if a higher BMI predisposes to RCC, it concurrently prolongs survival after patients have undergone (partial) nephrectomy.

SOLUTION:
Is overweight associated with improved cancer-specific survival in patients with organ-confined renal cell carcinoma?