Phosphomannomutase 2 (PMM2) variants leading to hyperinsulinism-polycystic kidney disease are associated with early-onset inflammatory bowel disease and gastric antral foveolar hyperplasia

Phosphomannomutase 2 (PMM2) deficiency causes Congenital Disorder of Glycosylation (PMM2-CDG), but does not have a recognised association with Inflammatory Bowel Disease (IBD). A distinct clinical syndrome of hyperinsulinism and autosomal recessive polycystic kidney disease (HIPKD) arises in the context of a specific variant in the PMM2 promotor, either in homozygosity, or compound heterozygous with a deleterious PMM2 variant. Here, we describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6, and 10 years of age. In each case, intestinal inflammation coincided with the unusual finding of gastric antral foveolar hyperplasia. IBD disease was of variable severity at onset but well controlled with conventional and first-line biologic treatment approaches. The organ-level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A). Analysis of published transcriptomic data suggests that IBD most likely arises due to an impact on epithelial cellular function. We identify a specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology

Inhibition of Dihydrotestosterone Synthesis in Prostate Cancer by Combined Frontdoor and Backdoor Pathway Blockade

Androgen deprivation therapy (ADT) is palliative and prostate cancer (CaP) recurs as lethal castration-recurrent/resistant CaP (CRPC). One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α,17β-diol (DIOL) to dihydrotestosterone (DHT). The goal was to determine whether inhibition of 3α-oxidoreductase activity decreased conversion of DIOL to DHT. Protein sequence analysis showed that the four 3α-oxidoreductases have identical catalytic amino acid residues. Mass spectrometry data showed combined treatment using catalytically inactive 3α-oxidoreductase mutants and the 5α-reductase inhibitor, dutasteride, decreased DHT levels in CaP cells better than dutasteride alone. Combined blockade of frontdoor and backdoor pathways of DHT synthesis provides a therapeutic strategy to inhibit CRPC development and growth

Intake of dietary antioxidants is inversely associated with biomarkers of oxidative stress among men with prostate cancer

Abstract Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer-related mortality among men in the USA. Growing evidence suggests that oxidative stress is involved in the development and progression of prostate cancer. In this study, the association between antioxidants from diet and supplements and biomarkers of oxidative stress in blood ( n 278), urine ( n 298) and prostate tissue ( n 55) were determined among men from the North Carolina-Louisiana Prostate Cancer Project. The association between antioxidant intake and oxidative stress biomarkers in blood and urine was determined using linear regression, adjusting for age, race, prostate cancer aggressiveness and smoking status. Greater antioxidant intake was found to be associated with lower urinary 8-isoprostane concentrations, with a 10 % increase in antioxidant intake corresponding to an unadjusted 1·1 % decrease in urinary 8-isoprostane levels (95 % CI −1·7, −0·3 %; P value<0·01) and an adjusted 0·6 % decrease (95 % CI −1·4, 0·2 %; P value=0·16). In benign prostate tissue, thioredoxin 1 was inversely associated with antioxidant intake ( P =0·02). No significant associations were found for other blood or urinary biomarkers or for malignant prostate tissue. These results indicate that antioxidant intake may be associated with less oxidative stress among men diagnosed with prostate cancer

Thioredoxin 1 in Prostate Tissue Is Associated with Gleason Score, Erythrocyte Antioxidant Enzyme Activity, and Dietary Antioxidants

Background. Prostate cancer is the most common noncutaneous cancer and second leading cause of cancer-related mortality in men in the US. Growing evidence suggests that oxidative stress is involved in prostate cancer. Methods. In this study, thioredoxin 1 (Trx 1), an enzyme and subcellular indicator of redox status, was measured in prostate biopsy tissue from 55 men from the North Carolina-Louisiana Prostate Cancer Project. A pathologist blindly scored levels of Trx 1. The association between Trx 1 and the Gleason score, erythrocyte antioxidant enzyme activity, and dietary antioxidant intake was determined using Fisher’s exact test. Results. Trx 1 levels in benign prostate tissue in men with incident prostate cancer were positively associated with the Gleason score (P=0.01) and inversely associated with dietary antioxidant intake (P=0.03). In prostate cancer tissue, Trx 1 levels were associated with erythrocyte glutathione peroxidase activity (P=0.01). No association was found for other erythrocyte enzymes. Greater Gleason score of malignant tissue corresponds to a greater difference in Trx 1 levels between malignant and benign tissue (P=0.04). Conclusion. These results suggest that the redox status of prostate tissue is associated with prostate cancer grade and both endogenous and exogenous antioxidants

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Paneth cell dysfunction and the intestinal microbiome in XIAP deficiency

New data suggest how epithelial dysfunction and intestinal dysbiosis contribute to inflammatory bowel disease in patients and in models of XIAP deficiency (see the related Research Articles by Strigli et al. and Wahilda et al.)

SOIL SALINITY MAPPING USING MULTITEMPORAL LANDSAT DATA

Soil salinity is one of the most important problems affecting many areas of the world. Saline soils present in agricultural areas reduce the annual yields of most crops. This research deals with the soil salinity mapping of Seyhan plate of Adana district in Turkey from the years 2009 to 2010, using remote sensing technology. In the analysis, multitemporal data acquired from LANDSAT 7-ETM&amp;lt;sup&amp;gt;+&amp;lt;/sup&amp;gt; satellite in four different dates (19 April 2009, 12 October 2009, 21 March 2010, 31 October 2010) are used. As a first step, preprocessing of Landsat images is applied. Several salinity indices such as NDSI (Normalized Difference Salinity Index), BI (Brightness Index) and SI (Salinity Index) are used besides some vegetation indices such as NDVI (Normalized Difference Vegetation Index), RVI (Ratio Vegetation Index), SAVI (Soil Adjusted Vegetation Index) and EVI (Enhamced Vegetation Index) for the soil salinity mapping of the study area. The field’s electrical conductivity (EC) measurements done in 2009 and 2010, are used as a ground truth data for the correlation analysis with the original band values and different index image bands values. In the correlation analysis, two regression models, the simple linear regression (SLR) and multiple linear regression (MLR) are considered. According to the highest correlation obtained, the 21st March, 2010 dataset is chosen for production of the soil salinity map in the area. Finally, the efficiency of the remote sensing technology in the soil salinity mapping is outlined.</jats:p

SOIL SALINITY MAPPING USING MULTITEMPORAL LANDSAT DATA

Soil salinity is one of the most important problems affecting many areas of the world. Saline soils present in agricultural areas reduce the annual yields of most crops. This research deals with the soil salinity mapping of Seyhan plate of Adana district in Turkey from the years 2009 to 2010, using remote sensing technology. In the analysis, multitemporal data acquired from LANDSAT 7-ETM+ satellite in four different dates (19 April 2009, 12 October 2009, 21 March 2010, 31 October 2010) are used. As a first step, preprocessing of Landsat images is applied. Several salinity indices such as NDSI (Normalized Difference Salinity Index), BI (Brightness Index) and SI (Salinity Index) are used besides some vegetation indices such as NDVI (Normalized Difference Vegetation Index), RVI (Ratio Vegetation Index), SAVI (Soil Adjusted Vegetation Index) and EVI (Enhamced Vegetation Index) for the soil salinity mapping of the study area. The field’s electrical conductivity (EC) measurements done in 2009 and 2010, are used as a ground truth data for the correlation analysis with the original band values and different index image bands values. In the correlation analysis, two regression models, the simple linear regression (SLR) and multiple linear regression (MLR) are considered. According to the highest correlation obtained, the 21st March, 2010 dataset is chosen for production of the soil salinity map in the area. Finally, the efficiency of the remote sensing technology in the soil salinity mapping is outlined

Abstract A10: CaMKK2 regulates cellular proliferation and androgen receptor activity during prostate cancer progression

Abstract Mounting evidence suggests that the androgen receptor (AR) plays a critical role in prostate cancer (PCa) progression. However, the molecular mechanisms by which the AR regulates cell proliferation in androgen-dependent and castration-resistant PCa are incompletely understood. We report here that calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) expression increases during progression of human PCa and becomes nuclear or perinuclear in advanced disease. In a mouse model of PCa (transgenic adenocarcinoma of mouse prostate, TRAMP), CaMKK2 expression increases with progression and is predominantly nuclear. CaMKK2 expression is markedly higher in the AR-expressing, tumorigenic cell line LNCaP compared to cell lines which are AR-nonexpressing and/or nontumorigenic. Silencing of CaMKK2 expression by RNA interference (RNAi) reduces cell proliferation in LNCaP cells but not in AR-non-expressing PC3 cells. In LNCaP cells, dihydrotestosterone (DHT) induces CaMKK2 mRNA and protein expression while androgen withdrawal suppresses CaMKK2 expression. RNAi of CaMKK2 reduces expression of the AR target, prostate specific antigen (PSA) and the cell cycle regulators cyclin D1 and phospho-pRB. Our results suggest that in PCa progression, CaMKK2 is transcriptionally induced by the AR to maintain AR activity, AR-dependent cell cycle control and continued cell proliferation. Citation Format: Loukia G. Karacosta, Barbara A. Foster, Azabdaftari Gissou, David M. Feliciano, Arthur M. Edelman. CaMKK2 regulates cellular proliferation and androgen receptor activity during prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A10.</jats:p