Prioritization of zoonotic diseases in Kenya, 2015

INTRODUCTION:Zoonotic diseases have varying public health burden and socio-economic impact across time and geographical settings making their prioritization for prevention and control important at the national level. We conducted systematic prioritization of zoonotic diseases and developed a ranked list of these diseases that would guide allocation of resources to enhance their surveillance, prevention, and control. METHODS:A group of 36 medical, veterinary, and wildlife experts in zoonoses from government, research institutions and universities in Kenya prioritized 36 diseases using a semi-quantitative One Health Zoonotic Disease Prioritization tool developed by Centers for Disease Control and Prevention with slight adaptations. The tool comprises five steps: listing of zoonotic diseases to be prioritized, development of ranking criteria, weighting criteria by pairwise comparison through analytical hierarchical process, scoring each zoonotic disease based on the criteria, and aggregation of scores. RESULTS:In order of importance, the participants identified severity of illness in humans, epidemic/pandemic potential in humans, socio-economic burden, prevalence/incidence and availability of interventions (weighted scores assigned to each criteria were 0.23, 0.22, 0.21, 0.17 and 0.17 respectively), as the criteria to define the relative importance of the diseases. The top five priority diseases in descending order of ranking were anthrax, trypanosomiasis, rabies, brucellosis and Rift Valley fever. CONCLUSION:Although less prominently mentioned, neglected zoonotic diseases ranked highly compared to those with epidemic potential suggesting these endemic diseases cause substantial public health burden. The list of priority zoonotic disease is crucial for the targeted allocation of resources and informing disease prevention and control programs for zoonoses in Kenya

Src activation by β-adrenoreceptors is a key switch for tumor metastasis

Norepinephrine (NE) can modulate multiple cellular functions important for cancer progression; however, how this single extracellular signal regulates such a broad array of cellular processes is unknown. Here, we identify Src as a key regulator of phosphoproteomic signaling networks activated in response to beta-adrenergic signaling in cancer cells. These results also identify a new mechanism of Src phosphorylation that mediates beta-adrenergic/PKA regulation of downstream networks, thereby enhancing tumor cell migration, invasion and growth. In human ovarian cancer samples, high tumoral NE levels were correlated with high pSrcY419 levels. Moreover, among cancer patients, the use of beta blockers was significantly associated with reduced cancer-related mortality. Collectively, these data provide a pivotal molecular target for disrupting neural signaling in the tumor microenvironment

2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity

Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2′-O-Methyl (2′-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2′-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types

Assessment of age-related changes in pediatric gastrointestinal solubility

PurposeCompound solubility serves as a surrogate indicator of oral biopharmaceutical performance. Between infancy and adulthood, marked compositional changes in gastrointestinal (GI) fluids occur. This study serves to assess how developmental changes in GI fluid composition affects compound solubility.MethodsSolubility assessments were conducted in vitro using biorelevant media reflective of age-specific pediatric cohorts (i.e., neonates and infants). Previously published adult media (i.e., FaSSGF, FeSSGF, FaSSIF.v2, and FeSSIF.v2) were employed as references for pediatric media development. Investigations assessing age-specific changes in GI fluid parameters (i.e., pepsin, bile acids, pH, osmolality, etc.) were collected from the literature and served to define the composition of neonatal and infant media. Solubility assessments at 37°C were conducted for seven BCS Class II compounds within the developed pediatric and reference adult media.ResultsFor six of the seven compounds investigated, solubility fell outside an 80–125% range from adult values in at least one of the developed pediatric media. This result indicates a potential for age-related alterations in oral drug performance, especially for compounds whose absorption is delimited by solubility (i.e., BCS Class II).ConclusionDevelopmental changes in GI fluid composition can result in relevant discrepancies in luminal compound solubility between children and adults.<br/

India -- 1960-61 -- OPV Production, International -- letter, 1961-08-09

Letter from Gharpure, P. V. to Sabin, Albert B. dated 1961-08-09.Sabin Collection Fair Use Policy</a

India -- 1962-73 -- OPV Production, International -- letter, 1963-03-30

Letter from Gharpure, P. V. to Sabin, Albert B. dated 1963-03-30.Sabin Collection Fair Use Policy</a

India -- 1960-61 -- OPV Production, International -- letter, 1960-09-22

Letter from Gharpure, P. V. to Sabin, Albert B. dated 1960-09-22.Sabin Collection Fair Use Policy</a

July-December -- 1966 -- Correspondence, Miscellaneous -- letter, 1966-08-26

Letter from Gharpure, P. V. to Sabin, Albert B. dated 1966-08-26.Sabin Collection Fair Use Policy</a

India -- 1962-73 -- OPV Production, International -- letter, 1963-05-09

Letter from Gharpure, P. V. to Sabin, Albert B. dated 1963-05-09.Sabin Collection Fair Use Policy</a

India -- 1962-73 -- OPV Production, International -- letter, 1962-03-01

Letter from Gharpure, P. V. to Sabin, Albert B. dated 1962-03-01.Sabin Collection Fair Use Policy</a