Lessons from a BACE1 inhibitor trial: off-site but not off base

Alzheimer's disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-β peptide (Aβ). The rate-limiting step in the production of Aβ is the processing of Aβ precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Aβ within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of β-galactoside α-2,6-sialyltransferase I (STGal6 I). In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future

Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5′-untranslated region: Implications in Alzheimer’s disease

In addition to the devastating symptoms of dementia, Alzheimer’s disease (AD) is characterized by accumulation of the processing products of the amyloid-β (Aβ) peptide precursor protein (APP). APP’s non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~ 20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3′-untranslated region (UTR) sequence. By contrast, we report a novel activity of miR-346: specifically, that it targets the APP mRNA 5′-UTR to upregulate APP translation and Aβ production. This upregulation is reduced but not eliminated by knockdown of argonaute 2. The target site for miR-346 overlaps with active sites for an iron-responsive element (IRE) and an interleukin-1 (IL-1) acute box element. IREs interact with iron response protein1 (IRP1), an iron-dependent translational repressor. In primary human brain cultures, miR-346 activity required chelation of Fe. In addition, miR-346 levels are altered in late-Braak stage AD. Thus, miR-346 plays a role in upregulation of APP in the CNS and participates in maintaining APP regulation of Fe, which is disrupted in late stages of AD. Further work will be necessary to integrate other metals, and IL-1 into the Fe-miR-346 activity network. We, thus, propose a “FeAR” (Fe, APP, RNA) nexus in the APP 5′-UTR that includes an overlapping miR-346-binding site and the APP IRE. When a “healthy FeAR” exists, activities of miR-346 and IRP/Fe interact to maintain APP homeostasis. Disruption of an element that targets the FeAR nexus would lead to pathogenic disruption of APP translation and protein production

The Heat Kernel on AdS_3 and its Applications

We derive the heat kernel for arbitrary tensor fields on S^3 and (Euclidean) AdS_3 using a group theoretic approach. We use these results to also obtain the heat kernel on certain quotients of these spaces. In particular, we give a simple, explicit expression for the one loop determinant for a field of arbitrary spin s in thermal AdS_3. We apply this to the calculation of the one loop partition function of N=1 supergravity on AdS_3. We find that the answer factorizes into left- and right-moving super Virasoro characters built on the SL(2, C) invariant vacuum, as argued by Maloney and Witten on general grounds.Comment: 46 pages, LaTeX, v2: Reference adde

Expanding Access to Parasite-based Malaria Diagnosis through Retail Drug shops in Tanzania: Evidence from a Randomized Trial and Implications for Treatment.

Tanzania has seen a reduction in the fraction of fevers caused by malaria, likely due in part to scale-up of control measures. While national guidelines require parasite-based diagnosis prior to treatment, it is estimated that more than half of suspected malaria treatment-seeking in Tanzania initiates in the private retail sector, where diagnosis by malaria rapid diagnostic test (RDT) or microscopy is illegal. This pilot study investigated whether the introduction of RDTs into Accredited Drug Dispensing Outlets (ADDOs) under realistic market conditions would improve case management practices.\ud Dispensers from ADDOs in two intervention districts in Tanzania were trained to stock and perform RDTs and monitored quarterly. Each district was assigned a different recommended retail price to evaluate the need for a subsidy. Malaria RDT and artemisinin-based combination therapy (ACT) uptake and availability were measured pre-intervention and 1 year post-intervention through structured surveys of ADDO owners and exiting customers in both intervention districts and one contiguous control district. Descriptive analysis and logistic regression were used to compare the three districts and identify predictive variables for testing. A total of 310 dispensers from 262 ADDOs were trained to stock and perform RDTs. RDT availability in intervention ADDOs increased from 1% (n = 172) to 73% (n = 163) during the study; ACT medicines were available in 75% of 260 pre-intervention and 68% of 254 post-intervention ADDOs. Pre-treatment testing performed within the ADDO increased from 0 to 65% of suspected malaria patients who visited a shop (95% CI 60.8-69.6%) with no difference between intervention districts. Overall parasite-based diagnosis increased from 19 to 74% in intervention districts and from 3 to 18% in the control district. Prior knowledge of RDT availability (aOR = 1.9, p = 0.03) and RDT experience (aOR = 1.9, p = 0.01) were predictors for testing. Adherence data indicated that 75% of malaria positives received ACT, while 3% of negatives received ACT. Trained and supervised ADDO dispensers in rural Tanzania performed and sold RDTs under real market conditions to two-thirds of suspected malaria patients during this one-year pilot. These results support the hypothesis that introducing RDTs into regulated private retail sector settings can improve malaria testing and treatment practices without an RDT subsidy. Trial registration ISRCTN ISRCTN14115509

Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators

SummaryAlthough androgen receptor (AR)-mediated signaling is central to prostate cancer, the ability to modulate AR signaling states is limited. Here we establish a chemical genomic approach for discovery and target prediction of modulators of cancer phenotypes, as exemplified by AR signaling. We first identify AR activation inhibitors, including a group of structurally related compounds comprising celastrol, gedunin, and derivatives. To develop an in silico approach for target pathway identification, we apply a gene expression-based analysis that classifies HSP90 inhibitors as having similar activity to celastrol and gedunin. Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy

Seasonal malaria chemoprevention packaged with malnutrition prevention in northern Nigeria: A pragmatic trial (SMAMP study) with nested case-control.

Integrating seasonal malaria chemoprevention (SMC), recommended by the WHO since 2012 to prevent malaria infection, with nutrition interventions may improve health outcomes and operational efficiencies. This study assessed the effects of co-packaging interventions on distribution coverage, nutrition, and clinical malaria outcomes in northern Nigeria. From August to November 2014, community volunteers delivered sulfadoxine-pyrimethamine and amodiaquine (SP-AQ) door-to-door each month to approximately 7,000 children aged 6-24 months in seven wards of Madobi, Kano State, Nigeria. In three of the wards children additionally received a lipid-based nutrient supplement (LNS-medium quantity), Plumpy Doz. Coverage, adherence, and anthropometric outcomes were assessed through baseline, midline, and endline household surveys. A facility-based case-control study was also conducted to estimate impact on clinical malaria outcomes. Coverage of SP-AQ was similar between arms at 89% (n = 2,409 child-months [88-90%]) in the SP-AQ only arm and 90% (n = 1,947 child-months [88-92%]) in the SP-AQ plus LNS arm (p = 0.52). Coverage of LNS was 83% (n = 2,409 child-months [81-84%]). Whilst there were marked changes in anthropometric status between baseline, midline and endline, these were largely accounted for by socioeconomic status and must be interpreted with care due to possible measurement issues, especially length-based indices. Overall nutritional status of our most robust measure, weight-for-age, does appear to have improved by endline, but was similar in the two study arms, suggesting no additional benefit of the LNS. While the odds of clinical malaria among those who received the intended intervention were lower in each study arm compared to children who did not receive interventions (SP-AQ only OR = 0.23 [0.09-0.6]; SP-AQ plus LNS OR = 0.22 [0.09-0.55]), LNS was not shown to have an additional impact. Coverage of SMC was high regardless of integrating LNS delivery into the SMC campaign. Supplementation with LNS did not appear to impact nutritional outcomes, but appeared to enhance the impact of SP-AQ on clinical odds of malaria. These results indicate that combining nutritional interventions with seasonal malaria chemoprevention in high-risk areas can be done successfully, warranting further exploration with other products or dosing. Trial Registration: ISRCTN 11413895

North American Climate in CMIP5 Experiments: Part III: Assessment of Twenty-First-Century Projections

In part III of a three-part study on North American climate in phase 5 of the Coupled Model Intercomparison Project (CMIP5) models, the authors examine projections of twenty-first-century climate in the representative concentration pathway 8.5 (RCP8.5) emission experiments. This paper summarizes and synthesizes results from several coordinated studies by the authors. Aspects of North American climate change that are examined include changes in continental-scale temperature and the hydrologic cycle, extremes events, and storm tracks, as well as regional manifestations of these climate variables. The authors also examine changes in the eastern North Pacific and North Atlantic tropical cyclone activity and North American intraseasonal to decadal variability, including changes in teleconnections to other regions of the globe. Projected changes are generally consistent with those previously published for CMIP3, although CMIP5 model projections differ importantly from those of CMIP3 in some aspects, including CMIP5 model agreement on increased central California precipitation. The paper also highlights uncertainties and limitations based on current results as priorities for further research. Although many projected changes in North American climate are consistent across CMIP5 models, substantial intermodel disagreement exists in other aspects. Areas of disagreement include projections of changes in snow water equivalent on a regional basis, summer Arctic sea ice extent, the magnitude and sign of regional precipitation changes, extreme heat events across the northern United States, and Atlantic and east Pacific tropical cyclone activity

Rituximab retherapy in patients with relapsed aggressive B cell and mantle cell lymphoma

Neither effective salvage regimens nor the outcome and response to retherapy with rituximab containing chemotherapy have been defined for rituximab pre-treated patients with relapsing aggressive lymphoma. We report here a single-centre retrospective outcome analysis of second-line immunochemotherapy with rituximab. In 28 patients with relapsed or refractory diffuse large B cell lymphomas, first-line immunochemotherapy had induced objective responses in 18 patients. Nine of 28 patients responded to rituximab containing salvage therapy, leading to a median overall survival of 243 days after start of second immunochemotherapy. Long-term disease free survivors (1,260 and 949 days) were restricted to the group of twelve patients that had received allogeneic stem cell transplantation as consolidation therapy. In 21 patients with relapsed mantle cell lymphomas (MCL), 19 patients had reached remissions with first-line therapy. Of those, 16 patients experienced responses to salvage therapy with a median overall survival of 226 days. Noteworthy, none of patients with initial non-responding disease reached a remission with second immunochemotherapy. Seven patients with MCL stayed free from progression after high-dose therapy with autologous or allogeneic stem cell transplantation in two and five cases, respectively. In summary, responses to repeated immunotherapy with rituximab were observed in approximately one third and two thirds of initially responding patients with aggressive B cell lymphoma and mantle cell lymphoma, respectively, but not in primarily refractory disease. Lasting remissions were achieved only by high-dose chemotherapy with stem cell transplantation