We propose LongQC as an easy and automated quality control tool for genomic datasets generated by third generation sequencing (TGS) technologies such as Oxford Nanopore technologies (ONT) and SMRT ...sequencing from Pacific Bioscience (PacBio). Key statistics were optimized for long read data, and LongQC covers all major TGS platforms. LongQC processes and visualizes those statistics automatically and quickly.
Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder marked by hamartoma growth in multiple organ systems. We performed mutational analyses on 325 individuals with definite ...tuberous sclerosis complex diagnostic status. We identified mutations in 72% (199/257) of de novo and 77% (53/68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in two previous large studies. We showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. We also observed results consistent with two similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. On performing meta-analyses of our data and the other two largest studies in the literature, we found significant correlations for several features that individual studies did not have sufficient power to conclude. Male patients showed more frequent neurologic and eye symptoms, renal cysts, and ungual fibromas. Correlating genotypes with phenotypes should facilitate the disease management of tuberous sclerosis complex.
The extent of cellular heterogeneity in breast cancer could have potential impact on diagnosis and long-term outcome. However, pathology evaluation is limited to biomarker immunohistochemical ...staining and morphology of the bulk cancer. Inter-cellular heterogeneity of biomarkers is not usually assessed. As an initial evaluation of the extent of breast cancer cellular heterogeneity, we conducted quantitative and spatial imaging of Estrogen Receptor (ER), Progesterone Receptor (PR), Epidermal Growth Factor Receptor-2 (HER2), Ki67, TP53, CDKN1A (P21/WAF1), CDKN2A (P16INK4A), CD8 and CD20 of a tissue microarray (TMA) representing subtypes defined by St. Gallen surrogate classification.
Quantitative, single cell-based imaging was conducted using an Immunofluorescence protein multiplexing platform (MxIF) to study protein co-expression signatures and their spatial localization patterns. The range of MxIF intensity values of each protein marker was compared to the respective IHC score for the TMA core. Extent of heterogeneity in spatial neighborhoods was analyzed using co-occurrence matrix and Diversity Index measures.
On the 101 cores from 59 cases studied, diverse expression levels and distributions were observed in MxIF measures of ER and PR among the hormonal receptor-positive tumor cores. As expected, Luminal A-like cancers exhibit higher proportions of cell groups that co-express ER and PR, while Luminal B-like (HER2-negative) cancers were composed of ER+, PR- groups. Proliferating cells defined by Ki67 positivity were mainly found in groups with PR-negative cells. Triple-Negative Breast Cancer (TNBC) exhibited the highest proliferative fraction and incidence of abnormal P53 and P16 expression. Among the tumors exhibiting P53 overexpression by immunohistochemistry, a group of TNBC was found with much higher MxIF-measured P53 signal intensity compared to HER2+, Luminal B-like and other TNBC cases. Densities of CD8 and CD20 cells were highest in HER2+ cancers. Spatial analysis demonstrated variability in heterogeneity in cellular neighborhoods in the cancer and the tumor microenvironment.
Protein marker multiplexing and quantitative image analysis demonstrated marked heterogeneity in protein co-expression signatures and cellular arrangement within each breast cancer subtype. These refined descriptors of biomarker expressions and spatial patterns could be valuable in the development of more informative tools to guide diagnosis and treatment.
To describe the prevalence of epiretinal membrane (ERM) and its risk factors in an Indian population and compare the findings with other populations.
The Singapore Indian Eye Study is a ...population-based survey of 3400 Asian Indians aged between 40 and 80 years. A comprehensive ophthalmic examination, standardized interviews, and laboratory blood tests were performed. Digital retinal fundus photographs were assessed for the presence of ERM following the definitions used in the Blue Mountains Eye Study (BMES). ERM was classified into a less severe form termed "cellophane macular reflex" (CMR) and a more severe form termed "preretinal macular fibrosis" (PMF) and also as primary and secondary (if it was associated with retinal pathology or cataract surgery).
A total of 3328 persons (mean age 57.8 ± SD 10.1 years, and 50.2% male) provided data in this study. The age-standardized prevalence of ERM was 7.6% (95% confidence interval CI, 6.8-8.6), CMR 4.1% (95% CI, 3.5-4.9), and PMF 3.5% (95% CI, 2.9-4.2). Older age (odds ratio OR, 1.09; 95% CI, 1.07-1.11, per year increase), increasing myopic refraction (OR, 1.14; 95% CI, 1.07-1.22, per diopter decrease), and narrower retinal arteriolar diameter (OR, 1.02; 95% CI, 1.00-1.03, per μm decrease) were significantly associated with primary ERM.
The age-standardized prevalence of ERM in the Indian population in Singapore was 7.6%. This is similar to Malays in Singapore (8.0%) and higher than the prevalence in whites in Australia (4.7%). Significant factors associated with primary ERM were older age, myopia, and narrower retinal arteriolar diameter.
Functional hypothalamic amenorrhea is common among female athletes and may be difficult to treat. Restoration of menses (ROM) is crucial to prevent deleterious effects to skeletal and reproductive ...health.
To determine the natural history of menstrual disturbances in female college athletes managed with nonpharmacologic therapies including increased dietary intake and/or decreased exercise expenditure and to identify factors associated with ROM.
A 5-yr retrospective study of college athletes at a major Division I university.
373 female athletes' charts were reviewed. For athletes with menstrual disturbances, morphometric variables were noted. Months to ROM were recorded for each athlete.
Fifty-one female athletes (19.7%) had menstrual disturbances (14.7% oligomenorrheic, 5.0% amenorrheic). In all, 17.6% of oligo-/amenorrheic athletes experienced ROM with nonpharmacologic therapy. Mean time to ROM among all athletes with menstrual disturbances was 15.6 ± 2.6 mo. Total absolute (5.3 ± 1.1 kg vs. 1.3 ± 1.1 kg, p < .05) and percentage (9.3% ± 1.9% vs. 2.3% ± 1.9%, p < .05) weight gain and increase in body-mass index (BMI; 1.9 ± 0.4 kg/m2 vs. 0.5 ± 0.4 kg/m2, p < .05) emerged as the primary differentiating characteristics between athletes with ROM and those without ROM. Percent weight gain was identified as a significant positive predictor of ROM, OR (95% CI) = 1.25 (1.01, 1.56), p < .05.
Nonpharmacologic intervention in college athletes with menstrual disturbances can restore regular menstrual cycles, although ROM may take more than 1 yr. Weight gain or an increase in BMI may be important predictors of ROM.
Purpose: To sensitize non–small cell lung cancer (NSCLC) to radiotherapy by tumor-specific delivery of tumor necrosis factor–related apoptosis-inducing ligand ( TRAIL ) gene.
Experimental Design: The ...TRAIL was delivered to human NSCLC cell lines and normal human bronchial epithelial cells by the replication-defective
adenoviral vector Ad/TRAIL-F/RGD using a tumor-specific human telomerase reverse transcriptase promoter. Cancer growth was
studied using 2,3-bis2-methoxy-4-nitro-5-sulfophenyl-2H-tetrazolium-5-carboxanilide inner salt and clonogenic assays. Activation
of the apoptosis pathway was analyzed in a Western blot and sub-G 1 DNA accumulation. A xenograft mouse lung cancer model was treated by intratumoral injections of Ad/TRAIL-F/RGD and local
radiotherapy; the other groups received one of these treatments alone or a control agent. Apoptosis and TRAIL expression in
tumors were also analyzed.
Results: Ad/TRAIL-F/RGD specifically targets human NSCLC cells without significant effect in normal human bronchial epithelial cells.
The combination of Ad/TRAIL-F/RGD and radiotherapy significantly improved cell-killing effect in all NSCLC cell lines tested
( P < 0.05). Expression of TRAIL showed a dose-dependent relationship with Ad/TRAIL-F/RGD, and radiation seemed to increase TRAIL expression. Activation of the apoptosis by TRAIL and radiation was shown by activation of caspase-9, caspase-8, caspase-3,
and poly(ADP-ribose) polymerase and increased DNA sub-G 1 accumulation. The combination of TRAIL and radiotherapy significantly increased apoptosis in vivo, inhibited tumor growth, and prolonged mean survival in mice bearing human NSCLC to 43.7 days compared with 23.7 days (TRAIL
only) and 16.5 days (radiotherapy only; P < 0.05).
Conclusions: The combination of Ad/TRAIL-F/RGD and radiotherapy significantly improved therapeutic efficacy in suppressing NSCLC tumor
growth and prolonging survival. Ad/TRAIL-F/RGD may improve the therapeutic ratio of radiotherapy in NSCLC.
This study used National Health and Nutrition Examination Survey III to study the relationship between blood lead concentration and all cause, all cancer and lung cancer mortality in adults.
Public ...use National Health and Nutrition Examination Survey (NHANES III) data were used. NHANES III uses stratified, multistage probabilistic methods to sample nationally representative samples. Household adult, laboratory and mortality data were merged. Sample persons who were available to be examined in aMobile Examination Center (MEC) were included in this study. Specialized survey analysis software was used.
A total of 3,482 sample participants with complete information for all variables were included in this analysis. For all cause death, the odds ratios (S.E.) for statistically significant variables were body mass index, 1.03 (1.01- 1.06); age 1.01 (1.01-1.01); blood lead concentration, 1.05 (1.01-1.08); poverty income ratio, 0.823 (0.76-0 .89); and drinking hard liquor, 1.01 (1.00-1.02). For all cancer mortality, the odds ratios (S.E.) of the statistically significant variables were: age, 1.01 (1.01-1.01); blood lead concentration, 1.07 (1.04-1.12), black race, using non-Hispanic white as reference, 1.69 (1.12-2.56); and smoking, 1.02 (1.01-1.04). For lung cancer mortality, the odds ratios (S.E.) of the statistically significant variables were: age, 1.01 (1.01-1.01); blood lead concentration, 1.09 (1.05-1.13); Mexican Americans, using non-Hispanic white as reference, 0.33 (0.129-0.850); other races, 1.80 (0.53-6.18); and smoking, 1.03 (1.02-1.05).
Blood lead concentration correlated with all cause, all cancer, and lung cancer mortality in adults.
This study analyzed Surveillance, Epidemiology and End Results (SEER) data to assess if socio- economic factors (SEFs) impact on endometrial cancer survival.
Endometrial cancer patients treated from ...2004-2007 were included in this study. SEER cause specific survival (CSS) data were used as end points. The areas under the receiver operating characteristic (ROC) curve were computed for predictors. Time to event data were analyzed with Kaplan-Meier method. Univariate and multivariate analyses were used to identify independent risk factors.
This study included 64,710 patients. The mean follow up time (S.D.) was 28.2 (20.8) months. SEER staging (ROC area of 0.81) was the best pretreatment predictor of CSS. Histology, grade, race/ethnicity and county level family income were also significant pretreatment predictors. African American race and low income neighborhoods decreased the CSS by 20% and 3% respectively at 5 years.
This study has found significant endometrial survival disparities due to SEFs. Future studies should focus on eliminating socio-economic barriers to good outcomes.
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