Variation in clinical presentation of childhood group A streptococcal pharyngitis in four countries

Funding Information: This study was supported by USAID. The Croatian and Latvian site was funded by the Department of Child and Adolescent Health and Development, World Health Organization, Geneva.We conducted a cross-sectional study from September 2001 to August 2003 during which children between 2 and 12 years of age presenting with complaint of sore throat were recruited from urban pediatric clinics in Brazil, Croatia, Egypt and Latvia. The objective of the study was to compare clinical signs and symptoms of children presenting to urban pediatric clinics with sore throat in and between countries and to identify common clinical criteria predicting group A beta hemolytic streptococcal (GAS) pharyngitis. Using a single standard protocol in all four sites, clinical data were recorded and throat swabs obtained for standard GAS culture in 2040 children. Signs and symptoms were tested for statistical association with GAS positive/negative pharyngitis, and were compared using X2 tests, ANOVA and Odds Ratios. Clinical signs of GAS pharyngitis in children presenting to clinics varied significantly between countries, and there were few signs or symptom that could statistically be associated with GAS pharyngitis in all four countries, though several were useful in two or three countries. Our results indicate that the clinical manifestations of pharyngitis in clinics may vary by region. It is therefore critical that clinical decision rules for management of pharyngitis should have local validation.publishersversionPeer reviewe

Lung Adenocarcinoma of Never Smokers and Smokers Harbor Differential Regions of Genetic Alteration and Exhibit Different Levels of Genomic Instability

Recent evidence suggests that the observed clinical distinctions between lung tumors in smokers and never smokers (NS) extend beyond specific gene mutations, such as EGFR, EML4-ALK, and KRAS, some of which have been translated into targeted therapies. However, the molecular alterations identified thus far cannot explain all of the clinical and biological disparities observed in lung tumors of NS and smokers. To this end, we performed an unbiased genome-wide, comparative study to identify novel genomic aberrations that differ between smokers and NS

BORIS, a paralogue of the transcription factor, CTCF, is aberrantly expressed in breast tumours

BORIS (for brother of the regulator of imprinted sites), a paralogue of the transcription factor, CTCF, is a novel member of the cancer-testis antigen family. The aims of the present study were as follows: (1) to investigate BORIS expression in breast cells and tumours using immunohistochemical staining, western and real-time RT–PCR analyses and (2) assess potential correlation between BORIS levels in tumours with clinical/pathological parameters. BORIS was detected in all 18 inspected breast cell lines, but not in a primary normal breast cell culture. In 70.7% (41 of 58 cases) BORIS was observed in breast tumours. High levels of BORIS correlated with high levels of progesterone receptor (PR) and oestrogen receptor (ER). The link between BORIS and PR/ER was further confirmed by the ability of BORIS to activate the promoters of the PR and ER genes in the reporter assays. Detection of BORIS in a high proportion of breast cancer patients implies potential practical applications of BORIS as a molecular biomarker of breast cancer. This may be important for diagnosis of the condition and for the therapeutic use of BORIS. The ability of BORIS to activate promoters of the RP and ER genes points towards possible involvement of BORIS in the establishment, progression and maintenance of breast tumours

The landscape of somatic copy-number alteration across human cancers

available in PMC 2010 August 18.A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κΒ pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P50CA90578)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, R01CA109038))National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, R01CA109467)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P01CA085859)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P01CA 098101)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, K08CA122833

Evidence for a retroviral insertion in TRPM1 as the cause of congenital stationary night blindness and leopard complex spotting in the horse

Leopard complex spotting is a group of white spotting patterns in horses caused by an incompletely dominant gene (LP) where homozygotes (LP/LP) are also affected with congenital stationary night blindness. Previous studies implicated Transient Receptor Potential Cation Channel, Subfamily M, Member 1 (TRPM1) as the best candidate gene for both CSNB and LP. RNA-Seq data pinpointed a 1378 bp insertion in intron 1 of TRPM1 as the potential cause. This insertion, a long terminal repeat (LTR) of an endogenous retrovirus, was completely associated with LP, testing 511 horses (χ²=1022.00, p<<0.0005), and CSNB, testing 43 horses (χ2=43, p<<0.0005). The LTR was shown to disrupt TRPM1 transcription by premature poly-adenylation. Furthermore, while deleterious transposable element insertions should be quickly selected against the identification of this insertion in three ancient DNA samples suggests it has been maintained in the horse gene pool for at least 17,000 years. This study represents the first description of an LTR insertion being associated with both a pigmentation phenotype and an eye disorder.Rebecca R. Bellone … David L. Adelson, Sim Lin Lim … et al

Evaluation of the WHO clinical decision rule for streptococcal pharyngitis

Aims: To prospectively assess the WHO clinical decision rule (CDR) for group A beta haemolytic streptococcal (GABHS) pharyngitis in three countries. Methods: A prospective, observational cohort study in urban outpatient clinics in Rio de Janeiro, Cairo, and Zagreb. There were 2225 children aged 2–12 years with cough, rhinorrhoea, red or sore throat; 1810 of these with sore throat were included in the analysis. Results: The proportion of children presenting with sore throat and found to have GABHS pharyngitis ranged from 24.6% (Brazil) to 42.0% (Croatia). WHO CDR sensitivity was low for all sites in both age groups. In children age 5 or older, sensitivity ranged from 3.8% in Egypt to 10.8% in Brazil. In children under 5, sensitivity was low (0.0–4.6%) Specificity was high in both age groups in all countries (93.8–97.4%). Conclusions: In these populations, the current WHO CDR has high specificity, but low sensitivity; it did not detect up to 96.0% of children who have laboratory confirmed GABHS pharyngitis. A CDR with higher sensitivity should be developed for use in regions where rheumatic fever and rheumatic heart disease are still major health problems

Integrated Genomic Analysis of Nodular Tissue in Macronodular Adrenocortical Hyperplasia: Progression of Tumorigenesis in a Disorder Associated with Multiple Benign Lesions

Integrated transcriptomic and genomic data for AIMAH provides supporting evidence that larger adrenal nodules accumulate an increased number of genetic, and consequently, transcript abnormalities

FAS and NF-kappa B signalling modulate dependence of lung cancers on mutant EGFR

Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs), but the magnitude of tumour regression is variable and transient(1,2). This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-kappa B pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-kappa B through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of I kappa B (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-kappa B enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-kappa B inhibitor I kappa B predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-kappa B as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence