TASK DEFINITION: Given a passage, 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: Although evidence suggests that antiretroviral (ARV) regimens containing nonnucleoside reverse transcriptase inhibitors (NNRTIs) are superior to single-protease inhibitor (PI)-based regimens at suppressing viral load, it is unclear how much of the improved viral suppression is due to intrinsic drug potency versus higher levels of adherence to simpler regimens. We therefore examined adherence and viral suppression in NNRTI and single-PI regimens in a cohort of largely ARV-experienced participants by using objective measures of adherence.', "Participants were recruited from the Research on Access to Care in the Homeless (REACH) Cohort and were included in the study if they were on single-PI-based or NNRTI-based highly active antiretroviral therapy (HAART) regimens for at least 3 months prior to study entry. Adherence was measured by unannounced pill counts at the participant's usual place of residence. The primary outcome was suppression of HIV viral RNA to <50 copies/mL.", 'Among 109 individuals who were followed for a median of 8.7 months, the odds of virologic suppression were approximately 8 times higher (p < .01) for participants on NNRTI-based regimens (n = 53) compared with those using single-PI-based regimens (n = 56) when controlling for adherence, as well as other potential confounders in a multivariable analysis. The only other independent predictors of viral suppression in multivariable modeling were ARV adherence (p < .01), CD4 nadir (p = .02), and continuous months on current regimen prior to the start of adherence monitoring (p < .01). There was no significant difference in adherence by unannounced pill counts in participants receiving NNRTI- versus single-PI-containing regimens.

SOLUTION: Are higher rates of viral suppression with nonnucleoside reverse transcriptase inhibitors compared to single protease inhibitors explained by better adherence?

PROBLEM: Wnt proteins are important for developmental processes and certain diseases. WNT5A is a non-canonical Wnt protein that previously has been shown to play a role in the progression of malignant melanoma. High expression of WNT5A in melanoma tumors correlates to formation of distant metastasis and poor prognosis. This has partly been described by the findings that WNT5A expression in melanoma cell lines increases migration and invasion.', 'Malignant melanoma cell lines were treated with rWNT5A or WNT5A siRNA, and mRNA versus protein levels of soluble mediators were measured using RT-PCR, cytokine bead array and ELISA. The induced signaling pathways were analyzed using inhibitors, Rho-GTPase pull down assays and western blot. Ultracentrifugation and electron microscopy was used to analyze microvesicles. Gene expression microarray data obtained from primary malignant melanomas was used to verify our data.', 'We show that WNT5A signaling induces a Ca2+-dependent release of exosomes containing the immunomodulatory and pro-angiogenic proteins IL-6, VEGF and MMP2 in melanoma cells. The process was independent of the transcriptional machinery and depletion of WNT5A reduced the levels of the exosome-derived proteins. The WNT5A induced exosomal secretion was neither affected by Tetanus toxin nor Brefeldin A, but was blocked by the calcium chelator Bapta, inhibited by a dominant negative version of the small Rho-GTPase Cdc42 and was accompanied by cytoskeletal reorganization. Co-cultures of melanoma/endothelial cells showed that depletion of WNT5A in melanoma cells decreased endothelial cell branching, while stimulation of endothelial cells with isolated rWNT5A-induced melanoma exosomes increased endothelial cell branching in vitro. Finally, gene expression data analysis of primary malignant melanomas revealed a correlation between WNT5A expression and the angiogenesis marker ESAM.

SOLUTION: Does wNT5A induce release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells?

PROBLEM: Incisional biopsies, including the diagnostic core needle biopsy (CNB), routinely performed before surgical excision of breast cancer tumors are hypothesized to increase the risk of metastatic disease. In this study, we experimentally determined whether CNB of breast cancer tumors results in increased distant metastases and examine important resultant changes in the primary tumor and tumor microenvironment associated with this outcome.', 'To evaluate the effect of CNB on metastasis development, we implanted murine mammary 4T1 tumor cells in BALB/c mice and performed CNB on palpable tumors in half the mice. Subsequently, emulating the human scenario, all mice underwent complete tumor excision and were allowed to recover, with attendant metastasis development. Tumor growth, lung metastasis, circulating tumor cell (CTC) levels, variation in gene expression, composition of the tumor microenvironment, and changes in immunologic markers were compared in biopsied and non-biopsied mice.', 'Mice with biopsied tumors developed significantly more lung metastases compared to non-biopsied mice. Tumors from biopsied mice contained a higher frequency of myeloid-derived suppressor cells (MDSCs) accompanied by reduced CD4+ T cells, CD8+ T cells, and macrophages, suggesting biopsy-mediated development of an increasingly immunosuppressive tumor microenvironment. We also observed a CNB-dependent up-regulation in the expression of SOX4, Ezh2, and other key epithelial-mesenchymal transition (EMT) genes, as well as increased CTC levels among the biopsy group.

SOLUTION:
Does core needle biopsy of breast cancer tumors increase distant metastases in a mouse model?