Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy.

Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced CAR T/NK cell immunotherapy. Despite its promising activity, bryostatin 1 is neither evolved nor optimized for the treatment of human disease. Here we report the design, synthesis, and biological evaluation of several close-in analogs of bryostatin 1. Using a function-oriented synthesis approach, we synthesize a series of bryostatin analogs designed to maintain affinity for bryostatin's target protein kinase C (PKC) while enabling exploration of their divergent biological functions. Our late-stage diversification strategy provides efficient access to a library of bryostatin analogs, which per our design retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently increase cell surface expression of CD22, a promising CAR T cell target for the treatment of leukemias, highlighting the clinical potential of bryostatin analogs for enhancing targeted immunotherapies

Team on teams: a collaborative inquiry

Over the course of an academic year, we collaborated to adopt a new instructional design for teams in our classes. We recount the story of our collaboration, outlining our process of inquiry, reflection, and support. Our simple search for better techniques shifted as our colleagues helped us reveal hidden assumptions about our roles as teachers. Our critical reflection allowed us to increase our self-awareness, specifically considering the following: how power influences our classroom interactions, how we contribute to and reinforce elements of the system that are not in our best interest, and the evolving stages of our own development as teachers. We believe our lessons will resonate with other teachers engaged in the challenges and rewards of self-development efforts

Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson's Disease: An Observational and Case-Control Study.

Background/objectivesThe common non-coding single nucleotide polymorphism (SNP) rs3129882 in HLA-DRA is associated with risk for idiopathic Parkinson's disease (PD). The location of the SNP in the major histocompatibility complex class II (MHC-II) locus implicates regulation of antigen presentation as a potential mechanism by which immune responses link genetic susceptibility to environmental factors in conferring lifetime risk for PD.MethodsFor immunophenotyping, blood cells from 81 subjects were analyzed by qRT-PCR and flow cytometry. A case-control study was performed on a separate cohort of 962 subjects to determine association of pesticide exposure and the SNP with risk of PD.ResultsHomozygosity for G at this SNP was associated with heightened baseline expression and inducibility of MHC class II molecules in B cells and monocytes from peripheral blood of healthy controls and PD patients. In addition, exposure to a commonly used class of insecticide, pyrethroids, synergized with the risk conferred by this SNP (OR = 2.48, p = 0.007), thereby identifying a novel gene-environment interaction that promotes risk for PD via alterations in immune responses.ConclusionsIn sum, these novel findings suggest that the MHC-II locus may increase susceptibility to PD through presentation of pathogenic, immunodominant antigens and/or a shift toward a more pro-inflammatory CD4+ T cell response in response to specific environmental exposures, such as pyrethroid exposure through genetic or epigenetic mechanisms that modulate MHC-II gene expression

A low-cost, community knowledge approach to estimate maternal and jaundice-associated mortality in rural Bangladesh

Copyright © 2018 by The American Society of Tropical Medicine and Hygiene. In the absence of a civil registration system, a house-to-house survey is often used to estimate cause-specific mortality in low- and middle-income countries. However, house-to-house surveys are resource and time intensive. We applied a low-cost community knowledge approach to identify maternal deaths from any cause and jaundice-associated deaths among persons aged 3 14 years, and stillbirths and neonatal deaths in mothers with jaundice during pregnancy in five rural communities in Bangladesh. We estimated the method’s sensitivity and cost savings compared with a house-to-house survey. In the five communities with a total of 125,570 population, we identified 13 maternal deaths, 60 deaths among persons aged 3 14 years associated with jaundice, five neonatal deaths, and four stillbirths born to a mother with jaundice during pregnancy over the 3-year period before the survey using the community knowledge approach. The sensitivity of community knowledge method in identifying target deaths ranged from 80% for neonatal deaths to 100% for stillbirths and maternal deaths. The community knowledge approach required 36% of the staff time to undertake compared with the house-to-house survey. The community knowledge approach was less expensive but highly sensitive in identifying maternal and jaundice-associated mortality, as well as all-cause adult mortality in rural settings in Bangladesh. This method can be applied in rural settings of other low- and middle-income countries and, in conjunction with hospital-based hepatitis diagnoses, used to monitor the impact of programs to reduce the burden of cause-specific hepatitis mortality, a current World Health Organization priority

Barriers to green supply chain management: An emerging economy context

© 2019 Elsevier Ltd Green supply chain management is attracting increasing attention as a way to decrease the adverse environmental effects of industries worldwide. However, considering the context of an emerging economy like Bangladesh, green supply chain management is still in its inception and has not been widely embraced in the textile industry, and therefore barriers hindering its adoption in emerging economy context demand a comprehensive investigation. This research reviews the viewpoints and hurdles in adopting green supply chain management practices in the context of the Bangladeshi textile industry. A questionnaire survey of Bangladeshi textile practitioners of operations and supply chain management division, having a sample size of thirty, was undertaken to identify the barriers, and a hierarchical cluster analysis technique was used in the detailed analysis of this data. Opinions were sought from experts on the significance of the resulting clusters, considering the relative importance of the barriers. Fifteen barriers to the adoption of green supply chain management were identified in the review of the literature, with these barriers then analyzed by using the data collected from Bangladeshi textile industry practitioners. The research indicates that the most important barrier is that there is low demand from customers and financial constraint resulting from short term little financial benefit to businesses, with lack of government regulations also a commonly faced barrier in adopting green supply chain initiatives. This study will provide valuables insights to practitioners and relevant policy makers about the barriers prevailing in the emerging economies towards the adoption of green supply chain management practices, which, in turn, can guide to undertake appropriate steps for alleviating those barriers

Planning and Finance How CERs give project developers a competitive advantage under the REIPPP

The South African government has pledged to reduce its total annual GHG emissions by 34% below its business-as-usual trajectory by 2020. One of the incentive instruments the government has put in place to realise this objective is the REIPPP, a competitive bidding process whereby the lowest bidders are awarded long term power purchase agreements at the offered price in R/MWh. One way of improving a project's competitive edge is via the cross subsidising of its REIPPP bidding price with the revenue stream from the sale of CERs it can generate under the CDM. Now that the third bidding round under the REIPPP is in full swing and rounds 4, 5 and 6 have been announced, project developers are investigating all possible avenues to find a competitive edge. Cross subsidising will allow a project to bid at a price that is between 9% and 27% lower than it would be able to do without the CER revenue stream. Registering a REIPPP project under the CDM therefore becomes a must if a project wants to stand any chance in the competitive bidding process

Retreatment with anti-EGFR based therapies in metastatic colorectal cancer: impact of intervening time interval and prior anti-EGFR response.

BackgroundThis retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval.MethodsEighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival.ResultsRetreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156).ConclusionOur data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed