Preclinical Evaluation of Ureidosulfamate Carbonic Anhydrase IX/XII Inhibitors in the Treatment of Cancers

Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells/tissues. Upregulation of the CAIX/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. The elucidation of the crystal structure of the catalytic domains of CAIX/XII provided the basis for the generation of CAIX/XII selective inhibitors based on the sulfonamide, sulfamate and coumarins chemical structures. Ureido-substituted benzenesulfonamide CAIX/XII inhibitors have shown significant potential, with U-104 (SLC-0111) currently present in clinical Phase I/II. Ureido-substituted sulfamate CAIX/XII inhibitors have received less attention despite encouraging preclinical test results. In triple-negative breast cancer (TNBC), ureidosulfamates revealed a significant antitumour (FC9-398A) and antimetastatic potential (S4). In small cell lung cancer (SCLC), a cancer cell type very sensitive to a dysregulation in CAIX signaling, S4 treatment was particularly effective when combined with cisplatin with no evidence of acquired cisplatin-resistance. These successful anticancer strategies should provide a solid basis for future studies on ureido-substituted sulfamates

Hypoxia-inducible factor in thyroid carcinoma.

Intratumoural hypoxia (low oxygen tension) is associated with aggressive disease and poor prognosis. Hypoxia-inducible factor-1 is a transcription factor activated by hypoxia that regulates the expression of genes that promote tumour cell survival, progression, metastasis, and resistance to chemo/radiotherapy. In addition to hypoxia, HIF-1 can be activated by growth factor-signalling pathways such as the mitogen-activated protein kinases- (MAPK-) and phosphatidylinositol-3-OH kinases- (PI3K-) signalling cascades. Mutations in these pathways are common in thyroid carcinoma and lead to enhanced HIF-1 expression and activity. Here, we summarise current data that highlights the potential role of both hypoxia and MAPK/PI3K-induced HIF-1 signalling in thyroid carcinoma progression, metastatic characteristics, and the potential role of HIF-1 in thyroid carcinoma response to radiotherapy. Direct or indirect targeting of HIF-1 using an MAPK or PI3K inhibitor in combination with radiotherapy may be a new potential therapeutic target to improve the therapeutic response of thyroid carcinoma to radiotherapy and reduce metastatic burden

Radiation-induced neuroinflammation:a potential protective role for poly(ADP-ribose) polymerase inhibitors?

Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbor a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response (DDR) and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50%–90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation-induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DDR and subsequent neuroinflammation. PARP inhibitors (PARPi) have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least 3 compounds being evaluated in clinical trials. We propose that concomitant use of PARPi could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumor control by enhancing radiosensitivity

Evaluation of a Method of Estimating Agricultural Chemical Use

This research evaluated the validity of an economic-based measure of agricultural chemical use on specific crop types. Estimated chemical use measures, reported in a budget planning document prepared collaboratively with input from farmers, vendors, researchers, and representatives from numerous agricultural agencies, were compared to chemical use measures collected through face-to-face interviews with local farmers regarding their actual chemical application practices over the past growing season. A rural agricultural-based county in Mississippi, USA, was the study area for this project. The measures of comparison were the estimated and actual ounces of individual fungicides, herbicides, and insecticides used per acre on corn, rice, soybean, wheat, and cotton fields, and the estimated and actual total chemical load, which is the sum of all fungicides, herbicides and insecticides used on the various crops. To obtain information regarding crop type and area of cultivated land, contemporary satellite images, overlaid with property maps, were plotted and provided for the farmers to identify their crop types and delineate their crop boundaries. The crop boundaries were digitized, and a GIS database was developed containing data for crop types, amounts of cultivated land, and chemical types and quantities used. Outcomes of this research could assist in studies requiring agricultural chemical data by using estimates generated by the USDA and other agricultural agencies as an alternative to primary data collection

Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study.

BACKGROUND: Many investigators have suggested that malaria infection predisposes individuals to bacteraemia. We tested this hypothesis with mendelian randomisation studies of children with the malaria-protective phenotype of sickle-cell trait (HbAS). METHODS: This study was done in a defined area around Kilifi District Hospital, Kilifi, Kenya. We did a matched case-control study to identify risk factors for invasive bacterial disease, in which cases were children aged 3 months to 13 years who were admitted to hospital with bacteraemia between Sept 16, 1999, and July 31, 2002. We aimed to match two controls, by age, sex, location, and time of recruitment, for every case. We then did a longitudinal case-control study to assess the relation between HbAS and invasive bacterial disease as malaria incidence decreased. Cases were children aged 0-13 years who were admitted to hospital with bacteraemia between Jan 1, 1999, and Dec 31, 2007. Controls were born in the study area between Jan 1, 2006, and June 23, 2009. Finally, we modelled the annual incidence of bacteraemia against the community prevalence of malaria during 9 years with Poisson regression. RESULTS: In the matched case-control study, we recruited 292 cases-we recruited two controls for 236, and one for the remaining 56. Sickle-cell disease, HIV, leucocyte haemozoin pigment, and undernutrition were positively associated with bacteraemia and HbAS was strongly negatively associated with bacteraemia (odds ratio 0·36; 95% CI 0·20-0·65). In the longitudinal case-control study, we assessed data from 1454 cases and 10,749 controls. During the study period, the incidence of admission to hospital with malaria per 1000 child-years decreased from 28·5 to 3·45, with a reduction in protection afforded by HbAS against bacteraemia occurring in parallel (p=0·0008). The incidence of hospital admissions for bacteraemia per 1000 child-years also decreased from 2·59 to 1·45. The bacteraemia incidence rate ratio associated with malaria parasitaemia was 6·69 (95% CI 1·31-34·3) and, at a community parasite prevalence of 29% in 1999, 62% (8·2-91) of bacteraemia cases were attributable to malaria. INTERPRETATION: Malaria infection strongly predisposes individuals to bacteraemia and can account for more than half of all cases of bacteraemia in malaria-endemic areas. Interventions to control malaria will have a major additional benefit by reducing the burden of invasive bacterial disease. FUNDING: Wellcome Trust

Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomas.

Anaplastic (ATC) and certain follicular thyroid-carcinomas (FTCs) are radioresistant. The Phosphatidylinositide 3-kinase (PI3K) pathway is commonly hyperactivated in thyroid-carcinomas. PI3K can modify the PI3K-related kinases (PIKKs) in response to radiation: How PIKKs interact with PI3K and contribute to radioresistance in thyroid-carcinomas is unknown. Further uncertainties exist in how these interactions function under the radioresistant hypoxic microenvironment. Under normoxia/anoxia, ATC (8505c) and FTC (FTC-133) cells were irradiated, with PI3K-inhibition (via GDC-0941 and PTEN-reconstitution into PTEN-null FTC-133s) and effects on PIKK-activation, DNA-damage, clonogenic-survival and cell cycle, assessed. FTC-xenografts were treated with 5 × 2 Gy, ± 50 mg/kg GDC-0941 (twice-daily; orally) for 14 days and PIKK-activation and tumour-growth assessed. PIKK-expression was additionally assessed in 12 human papillary thyroid-carcinomas, 13 FTCs and 12 ATCs. GDC-0941 inhibited radiation-induced activation of Ataxia-telangiectasia mutated (ATM), ATM-and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Inhibition of ATM and DNA-PKcs was PI3K-dependent, since activation was reduced in PTEN-reconstituted FTC-133s. Inhibition of PIKK-activation was greater under anoxia: Consequently, whilst DNA-damage was increased and prolonged under both normoxia and anoxia, PI3K-inhibition only reduced clonogenic-survival under anoxia. GDC-0941 abrogated radiation-induced cell cycle arrest, an effect most likely linked to the marked inhibition of ATR-activation. Importantly, GDC-0941 inhibited radiation-induced PIKK-activation in FTC-xenografts leading to a significant increase in time taken for tumours to triple in size: 26.5 ± 5 days (radiation-alone) versus 31.5 ± 5 days (dual-treatment). PIKKs were highly expressed across human thyroid-carcinoma classifications, with ATM scoring consistently lower. Interestingly, some loss of ATM and DNA-PKcs was observed. These data provide new insight into the mechanisms of hypoxia-associated radioresistance in thyroid-carcinoma

CD4 intragenic SNPs associate with HIV-2 plasma viral load and CD4 count in a community-based study from Guinea-Bissau, West Africa.

OBJECTIVES: The human genetics of HIV-2 infection and disease progression is understudied. Therefore, we studied the effect of variation in 2 genes that encode products critical to HIV pathogenesis and disease progression: CD4 and CD209. DESIGN: This cross-sectional study consisted of 143 HIV-2, 30 HIV-1 + HIV-2 and 29 HIV-1-infected subjects and 194 uninfected controls recruited from rural Guinea-Bissau. METHODS: We genotyped 14 CD4 and 4 CD209 single nucleotide polymorphisms (SNPs) that were tested for association with HIV infection, HIV-2 plasma viral load (high vs. low), and CD4 T-cell count (high vs. low). RESULTS: The most significant association was between a CD4 haplotype rs11575097-rs10849523 and high viral load [odds ratio (OR): = 2.37, 95% confidence interval (CI): 1.35 to 4.19, P = 0.001, corrected for multiple testing], suggesting increased genetic susceptibility to HIV-2 disease progression for individuals carrying the high-risk haplotype. Significant associations were also observed at a CD4 SNP (rs2255301) with HIV-2 infection (OR: = 2.36, 95% CI: 1.19 to 4.65, P = 0.01) and any HIV infection (OR: = 2.50, 95% CI: 1.34 to 4.69, P = 0.004). CONCLUSIONS: Our results support a role of CD4 polymorphisms in HIV-2 infection, in agreement with recent data showing that CD4 gene variants increase risk to HIV-1 in Kenyan female sex workers. These findings indicate at least some commonality in HIV-1 and HIV-2 susceptibility

Religious faith and psychosocial adaptation among stroke patients in Kuwait: A mixed method study

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2012 Springer Science+Business Media.Religious faith is central to life for Muslim patients in Kuwait, so it may influence adaptation and rehabilitation. This study explored quantitative associations among religious faith, self-efficacy, and life satisfaction in 40 female stroke patients and explored the influence of religion within stroke rehabilitation through qualitative interviews with 12 health professionals. The quantitative measure of religious faith did not relate to life satisfaction or self-efficacy in stroke patients. However, the health professionals described religious coping as influencing adaptation post-stroke. Fatalistic beliefs were thought to have mixed influences on rehabilitation. Measuring religious faith among Muslims through a standardized scale is debated. The qualitative accounts suggest that religious beliefs need to be acknowledged in stroke rehabilitation in Kuwait