ATAMM enhancement and multiprocessor performance evaluation

ATAMM (Algorithm To Architecture Mapping Model) enhancement and multiprocessor performance evaluation is discussed. The following topics are included: the ATAMM model; ATAMM enhancement; ADM (Advanced Development Model) implementation of ATAMM; and ATAMM support tools

PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux

Cancer therapies will increasingly be utilized in combination to treat advanced malignancies so as to increase their long-term efficacy in a greater proportion of patients. In particular, much attention has focused on developing targeted therapies that inhibit the PI3K-AKT-mTOR signaling network which is dysregulated in many cancer types. In addition, there is now a growing appreciation that targeting of these pathways can impact not only on cancer cells, but also host immunity. The clinical success of cancer immunotherapies targeting T-cell immune checkpoint receptors PD-1/PD-L1 has demonstrated the importance of immunoevasion as a hallmark of cancer. In this review, we discuss how PI3K-AKT-mTOR inhibitors target cancer cell biology, attenuate immune cell effector function and modulate the tumor microenvironment. We next discuss how the immunomodulatory potential of these inhibitors can be exploited through rational combinations with immunotherapies and targeted therapies

Sequential Acquisition of T Cells and Antibodies to Nontyphoidal Salmonella in Malawian Children

Background Salmonella Typhimurium (STm) remain a prominent cause of bacteremia in sub-Saharan Africa. Complement-fixing antibodies to STm develop by 2 years of age. We hypothesized that STm-specific CD4+ T cells develop alongside this process. Methods Eighty healthy Malawian children aged 0–60 months were recruited. STm-specific CD4+ T cells producing interferon γ, tumor necrosis factor α, and interleukin 2 were quantified using intracellular cytokine staining. Antibodies to STm were measured by serum bactericidal activity (SBA) assay, and anti-STm immunoglobulin G antibodies by enzyme-linked immunosorbent assay. Results Between 2006 and 2011, STm bacteremias were detected in 449 children <5 years old. STm-specific CD4+ T cells were acquired in infancy, peaked at 14 months, and then declined. STm-specific SBA was detectable in newborns, declined in the first 8 months, and then increased to a peak at age 35 months. Acquisition of SBA correlated with acquisition of anti–STm–lipopolysaccharide (LPS) immunoglobulin G (r = 0.329 [95% confidence interval, .552–.062]; P = .01) but not anti–STm–outer membrane protein or anti–STm-flagellar protein (FliC). Conclusions Acquisition of STm-specific CD4+ T cells in early childhood is consistent with early exposure to STm or cross-reactive protein antigens priming this T-cell development. STm-specific CD4+ T cells seem insufficient to protect against invasive nontyphoidal Salmonella disease, but sequential acquisition of SBA to STm LPS is associated with a decline in its incidence

Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1

Although the ability of bioactive lipid sphingosine-1-phosphate (S1P) to positively regulate anti-apoptotic/pro-survival responses by binding to S1P1 is well known, the molecular mechanisms remain unclear. Here we demonstrate that expression of S1P1 renders CCL39 lung fibroblasts resistant to apoptosis following growth factor withdrawal. Resistance to apoptosis was associated with attenuated accumulation of pro-apoptotic BH3-only protein Bim. However, although blockade of extracellular signal-regulated kinase (ERK) activation could reverse S1P1-mediated suppression of Bim accumulation, inhibition of caspase-3 cleavage was unaffected. Instead S1P1-mediated inhibition of caspase-3 cleavage was reversed by inhibition of phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC), which had no effect on S1P1 regulation of Bim. However, S1P1 suppression of caspase-3 was associated with increased expression of anti-apoptotic protein Mcl-1, the expression of which was also reduced by inhibition of PI3K and PKC. A role for the induction of Mcl-1 in regulating endogenous S1P receptor-dependent pro-survival responses in human umbilical vein endothelial cells was confirmed using S1P receptor agonist FTY720-phosphate (FTY720P). FTY720P induced a transient accumulation of Mcl-1 that was associated with a delayed onset of caspase-3 cleavage following growth factor withdrawal, whereas Mcl-1 knockdown was sufficient to enhance caspase-3 cleavage even in the presence of FTY720P. Consistent with a pro-survival role of S1P1 in disease, analysis of tissue microarrays from ER+ breast cancer patients revealed a significant correlation between S1P1 expression and tumour cell survival. In these tumours, S1P1 expression and cancer cell survival were correlated with increased activation of ERK, but not the PI3K/PKB pathway. In summary, pro-survival/anti-apoptotic signalling from S1P1 is intimately linked to its ability to promote the accumulation of pro-survival protein Mcl-1 and downregulation of pro-apoptotic BH3-only protein Bim via distinct signalling pathways. However, the functional importance of each pathway is dependent on the specific cellular context

Evidence and perceptions of rainfall change in Malawi: Do maize cultivar choices enhance climate change adaptation in sub-Saharan Africa?

Getting farmers to adopt new cultivars with greater tolerance for coping with climatic extremes and variability is considered as one way of adapting agricultural production to climate change. However, for successful adaptation to occur, an accurate recognition and understanding of the climate signal by key stakeholders (farmers, seed suppliers and agricultural extension services) is an essential precursor. This paper presents evidence based on fieldwork with smallholder maize producers and national seed network stakeholders in Malawi from 2010 to 2011, assessing understandings of rainfall changes and decision-making about maize cultivar choices. Our findings show that preferences for short-season maize cultivars are increasing based on perceptions that season lengths are growing shorter due to climate change and the assumption that growing shorter-season crops represents a good strategy for adapting to drought. However, meteorological records for the two study areas present no evidence for shortening seasons (or any significant change to rainfall characteristics), suggesting that short-season cultivars may not be the most suitable adaptation option for these areas. This demonstrates the dangers of oversimplified climate information in guiding changes in farmer decision-making about cultivar choice

WHO 2010 Guidelines for Prevention of Mother-to-Child HIV Transmission in Zimbabwe: Modeling Clinical Outcomes in Infants and Mothers

The Zimbabwean national prevention of mother-to-child HIV transmission (PMTCT) program provided primarily single-dose nevirapine (sdNVP) from 2002-2009 and is currently replacing sdNVP with more effective antiretroviral (ARV) regimens.Published HIV and PMTCT models, with local trial and programmatic data, were used to simulate a cohort of HIV-infected, pregnant/breastfeeding women in Zimbabwe (mean age 24.0 years, mean CD4 451 cells/µL). We compared five PMTCT regimens at a fixed level of PMTCT medication uptake: 1) no antenatal ARVs (comparator); 2) sdNVP; 3) WHO 2010 guidelines using "Option A" (zidovudine during pregnancy/infant NVP during breastfeeding for women without advanced HIV disease; lifelong 3-drug antiretroviral therapy (ART) for women with advanced disease); 4) WHO "Option B" (ART during pregnancy/breastfeeding without advanced disease; lifelong ART with advanced disease); and 5) "Option B+:" lifelong ART for all pregnant/breastfeeding, HIV-infected women. Pediatric (4-6 week and 18-month infection risk, 2-year survival) and maternal (2- and 5-year survival, life expectancy from delivery) outcomes were projected.Eighteen-month pediatric infection risks ranged from 25.8% (no antenatal ARVs) to 10.9% (Options B/B+). Although maternal short-term outcomes (2- and 5-year survival) varied only slightly by regimen, maternal life expectancy was reduced after receipt of sdNVP (13.8 years) or Option B (13.9 years) compared to no antenatal ARVs (14.0 years), Option A (14.0 years), or Option B+ (14.5 years).Replacement of sdNVP with currently recommended regimens for PMTCT (WHO Options A, B, or B+) is necessary to reduce infant HIV infection risk in Zimbabwe. The planned transition to Option A may also improve both pediatric and maternal outcomes

Prevention of mother-to-child transmission of HIV in Zambia: implementing efficacious ARV regimens in primary health centers

<p>Abstract</p> <p>Background</p> <p>Safety and effectiveness of efficacious antiretroviral (ARV) regimens beyond single-dose nevirapine (sdNVP) for prevention of mother-to-child transmission (PMTCT) have been demonstrated in well-controlled clinical studies or in secondary- and tertiary-level facilities in developing countries. This paper reports on implementation of and factors associated with efficacious ARV regimens among HIV-positive pregnant women attending antenatal clinics in primary health centers (PHCs) in Zambia.</p> <p>Methods</p> <p>Blood sample taken for CD4 cell count, availability of CD4 count results, type of ARV prophylaxis for mothers, and additional PMTCT service data were collected for HIV-positive pregnant women and newborns who attended 60 PHCs between April 2007 and March 2008.</p> <p>Results</p> <p>Of 14,815 HIV-positive pregnant women registered in the 60 PHCs, 2,528 (17.1%) had their CD4 cells counted; of those, 1,680 (66.5%) had CD4 count results available at PHCs; of those, 796 (47.4%) had CD4 count ≤ 350 cells/mm³and thus were eligible for combination antiretroviral treatment (cART); and of those, 581 (73.0%) were initiated on cART. The proportion of HIV-positive pregnant women whose blood sample was collected for CD4 cell count was positively associated with (1) blood-draw for CD4 count occurring on the same day as determination of HIV-positive status; (2) CD4 results sent back to the health facilities within seven days; (3) facilities <it>without </it>providers trained to offer ART; and (4) urban location of PHC. Initiation of cART among HIV-positive pregnant women was associated with the PHC's capacity to provide care and antiretroviral treatment services. Overall, of the 14,815 HIV-positive pregnant women registered, 10,015 were initiated on any type of ARV regimen: 581 on cART, 3,041 on short course double ARV regimen, and 6,393 on sdNVP.</p> <p>Conclusion</p> <p>Efficacious ARV regimens beyond sdNVP can be implemented in resource-constrained PHCs. The majority (73.0%) of women identified eligible for ART were initiated on cART; however, a minority (11.3%) of HIV-positive pregnant women were assessed for CD4 count and had their test results available. Factors associated with implementation of more efficacious ARV regimens include timing of blood-draw for CD4 count and capacity to initiate cART onsite where PMTCT services were being offered.</p