The edges of understanding

A culture's icons are a window onto its soul. Few would disagree that, in the culture of molecular biology that dominated much of the life sciences for the last third of the 20th century, the dominant icon was the double helix. In the present, post-modern, 'systems biology' era, however, it is, arguably, the hairball

Increasing malaria hospital admissions in Uganda between 1999 and 2009

<p>Abstract</p> <p>Background</p> <p>Some areas of Africa are witnessing a malaria transition, in part due to escalated international donor support and intervention coverage. Areas where declining malaria rates have been observed are largely characterized by relatively low baseline transmission intensity and rapid scaling of interventions. Less well described are changing patterns of malaria burden in areas of high parasite transmission and slower increases in control and treatment access.</p> <p>Methods</p> <p>Uganda is a country predominantly characterized by intense, perennial malaria transmission. Monthly pediatric admission data from five Ugandan hospitals and their catchments have been assembled retrospectively across 11 years from January 1999 to December 2009. Malaria admission rates adjusted for changes in population density within defined catchment areas were computed across three time periods that correspond to periods where intervention coverage data exist and different treatment and prevention policies were operational. Time series models were developed adjusting for variations in rainfall and hospital use to examine changes in malaria hospitalization over 132 months. The temporal changes in factors that might explain changes in disease incidence were qualitatively examined sequentially for each hospital setting and compared between hospital settings</p> <p>Results</p> <p>In four out of five sites there was a significant increase in malaria admission rates. Results from time series models indicate a significant month-to-month increase in the mean malaria admission rates at four hospitals (trend <it>P </it>< 0.001). At all hospitals malaria admissions had increased from 1999 by 47% to 350%. Observed changes in intervention coverage within the catchments of each hospital showed a change in insecticide-treated net coverage from <1% in 2000 to 33% by 2009 but accompanied by increases in access to nationally recommended drugs at only two of the five hospital areas studied.</p> <p>Conclusions</p> <p>The declining malaria disease burden in some parts of Africa is not a universal phenomena across the continent. Despite moderate increases in the coverage of measures to reduce infection and disease without significant coincidental increasing access to effective medicines to treat disease may not lead to severe disease burden reductions in high transmission areas of Africa. More data is needed from a wider range of malaria settings to provide an honest tracking progress of the impact of scaled intervention coverage in Africa.</p

Future perspectives in melanoma research: meeting report from the "Melanoma Bridge";: Napoli, December 3rd-6th 2014.

The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma