Integrative analysis of DNA copy number and gene expression in metastatic oral squamous cell carcinoma identifies genes associated with poor survival

<p>Abstract</p> <p>Background</p> <p>Lymphotropism in oral squamous cell carcinoma (OSCC) is one of the most important prognostic factors of 5-year survival. In an effort to identify genes that may be responsible for the initiation of OSCC lymphotropism, we examined DNA copy number gains and losses and corresponding gene expression changes from tumor cells in metastatic lymph nodes of patients with OSCC.</p> <p>Results</p> <p>We performed integrative analysis of DNA copy number alterations (CNA) and corresponding mRNA expression from OSCC cells isolated from metastatic lymph nodes of 20 patients using Affymetrix 250 K Nsp I SNP and U133 Plus 2.0 arrays, respectively. Overall, genome CNA accounted for expression changes in 31% of the transcripts studied. Genome region 11q13.2-11q13.3 shows the highest correlation between DNA CNA and expression. With a false discovery rate < 1%, 530 transcripts (461 genes) demonstrated a correlation between CNA and expression. Among these, we found two subsets that were significantly associated with OSCC (n = 122) when compared to controls, and with survival (n = 27), as tested using an independent dataset with genome-wide expression profiles for 148 primary OSCC and 45 normal oral mucosa. We fit Cox models to calculate a principal component analysis-derived risk-score for these two gene sets ('122-' or '27-transcript PC'). The models combining the 122- or 27-transcript PC with stage outperformed the model using stage alone in terms of the Area Under the Curve (AUC = 0.82 or 0.86 vs. 0.72, with <it>p </it>= 0.044 or 0.011, respectively).</p> <p>Conclusions</p> <p>Genes exhibiting CNA-correlated expression may have biological impact on carcinogenesis and cancer progression in OSCC. Determination of copy number-associated transcripts associated with clinical outcomes in tumor cells with an aggressive phenotype (i.e., cells metastasized to the lymph nodes) can help prioritize candidate transcripts from high-throughput data for further studies.</p

Urinary porphyrin excretion in normal children and adolescentes

Background—Urinary porphyrins are diagnostic of various metabolic disorders and xenobiotic exposures, but comprehensive normative data for urinary porphyrin concentrations in children are currently unavailable. Methods—Subjects were participants in a prospective, randomized, controlled clinical trial of dental materials safety, 8 to 12 y at inception, who were followed longitudinally for 7 y after baseline with an extensive battery of neurobehavioral, neurological, renal function and urinary porphyrin assessments. Porphyrins were quantified by HPLC. Linear regression analyses were used to measure associations of porphyrin levels with age and gender. Results—Mean concentrations, 95% confidence intervals, and 10th 50th, and 90th percentiles for all 5 typically excreted urinary porphyrins are presented by year of age and by gender. Unadjusted urinary concentrations (μg/l) of all 5 porphyrins remained relatively constant throughout the age range of 8–18 y for both males and females. In contrast, creatinine-adjusted urinary porphyrin concentrations (μg/g) declined significantly throughout this age range in both genders. Boys had significantly higher pentacarboxyl- and copro- porphyrin levels compared with girls both before and after creatinine adjustment. Conclusions—Normative longitudinal data provided herein may facilitate the clinical assessment of pediatric metabolic disorders and may be of particular relevance in evaluating porphyrin changes as a biological indicator of disease or xenobiotic exposures among children and adolescents.info:eu-repo/semantics/publishedVersio

Biomarkers of kidney integrity in children and adolescents with dental amalgam mercury exposure: findings from the casa pia children’s amalgam trial.

Mercury is toxic to the kidney, and dental amalgam is a source of mercury exposure. Few studies have evaluated the effects of dental amalgam on kidney function in a longitudinal context in children. Here, we evaluated urinary concentrations of glutathione S-transferases (GSTs) α and π as biomarkers of renal proximal and distal tubular integrity, respectively, and albumin as a biomarker of glomerular integrity in children and adolescents 8-18 years of age over a 7 year course of dental amalgam treatment. Five hundred seven children, 8-12 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral and renal effects of dental amalgam in children. Subjects were randomized to either dental amalgam or resin composite treatments. Urinary GSTs α and π, albumin and creatinine concentrations were measured at baseline and annually on all subjects. Results were evaluated using linear regression analysis. GST-α concentrations were similar between treatment groups and in each sex and race (white vs nonwhite) group in each follow-up year. GST-π levels tended upward over the course of follow-up by 4- to 6-fold. This increase was seen in all groups irrespective of treatment, race or gender. Females had GST-π levels approximately twice those of males at all ages. Albumin concentrations were constant throughout the follow-up period and did not differ by treatment, although females had 39% higher albumin levels than males. Additionally, we found no significant effects of amalgam treatment on the proportion of children with microalbuminuria (>30 mg/g creatinine). These findings are relevant within the context of children’s health risk assessment as relates to the safety of mercury exposure from dental amalgam on kidney function. These data also provide normative values for sensitive indices of renal functional integrity that may serve in the evaluation of children and adolescents with renal disorders.info:eu-repo/semantics/publishedVersio

Beyond change scores: Employing an improved statistical approach to analyze the impact of entry fitness on physical performance during British Army basic training in men and women

AbstractThe aim was to use a robust statistical approach to examine whether physical fitness at entry influences performance changes between men and women undertaking British Army basic training (BT). Performance of 2 km run, seated medicine ball throw (MBT) and isometric mid‐thigh pull (MTP) were assessed at entry and completion of Standard Entry (SE), Junior Entry‐Short (JE‐Short), and Junior Entry‐Long (JE‐Long) training for 2350 (272 women) recruits. Performance change was analyzed with entry performance as a covariate (ANCOVA), with an additional interaction term allowing different slopes for courses and genders (p &lt; 0.05). Overall, BT courses saw average improvements in 2 km run performance (SE: −6.8% [−0.62 min], JE‐Short: −4.6% [−0.43 min], JE‐Long: −7.7% [−0.70 min]; all p &lt; 0.001) and MBT (1.0–8.8% [0.04–0.34 m]; all p &lt; 0.05) and MTP (4.5–26.9% [6.5–28.8 kg]; all p &lt; 0.001). Regression models indicate an expected form of “regression to the mean” whereby test performance change was negatively associated with entry fitness in each course (those with low baseline fitness exhibit larger training improvements; all interaction effects: p &lt; 0.001, &gt; 0.006), particularly for women. However, when matched for entry fitness, men displayed considerable improvements in all tests, relative to women. Training courses were effective in developing recruit physical fitness, whereby the level of improvement is, in large part, dependent on entry fitness. Factors including age, physical maturity, course length, and physical training, could also contribute to the variability in training response between genders and should be considered when analyzing and/or developing physical fitness in these cohorts for future success of military job‐task performance

Zicam-Induced Damage to Mouse and Human Nasal Tissue

Intranasal medications are used to treat various nasal disorders. However, their effects on olfaction remain unknown. Zicam (zinc gluconate; Matrixx Initiatives, Inc), a homeopathic substance marketed to alleviate cold symptoms, has been implicated in olfactory dysfunction. Here, we investigated Zicam and several common intranasal agents for their effects on olfactory function. Zicam was the only substance that showed significant cytotoxicity in both mouse and human nasal tissue. Specifically, Zicam-treated mice had disrupted sensitivity of olfactory sensory neurons to odorant stimulation and were unable to detect novel odorants in behavioral testing. These findings were long-term as no recovery of function was observed after two months. Finally, human nasal explants treated with Zicam displayed significantly elevated extracellular lactate dehydrogenase levels compared to saline-treated controls, suggesting severe necrosis that was confirmed on histology. Our results demonstrate that Zicam use could irreversibly damage mouse and human nasal tissue and may lead to significant smell dysfunction

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Perceived Discrimination and Social Networks Among Older African Americans and Caribbean Blacks

The relationship between perceived discrimination and depressive symptoms among older black American populations is poorly understood. Although a small number of studies have examined the relationship between stress and social support, few have examined the association between perceived discrimination, social networks, and depressive symptoms among a representative sample of older racial and ethnic groups. This study examines (a) the relationship between sociodemographic factors, perceived discrimination and depressive symptoms and (b) social networks as a potential moderator in the perceived discrimination and depressive symptom relationship between 2 groups of older black Americans. This was a cross-sectional study using data from the National Survey of American Life with a sample of older African Americans (N = 837) and Caribbean blacks (N = 271). Depressive symptoms were assessed using the 12-item Center for Epidemiological Studies Depression scale. Linear regression analyses were used to predict depressive symptoms. The relationship between perceived discrimination and depressive symptoms was significant in both groups. Social networks contributed as a protective factor for depressive symptoms for both groups. However, there was no significant moderation effect. Results suggest that regardless of ethnic affiliation, the experience of perceived discrimination is similar in both groups and is a risk factor for depressive symptoms. Future research is needed in this area to better understand the associations between sociodemographic factors, perceived discrimination, social networks, and their impact on depressive symptoms

Association of Socio-Demographic Factors and Parental Education With Depressive Symptoms Among Older African Americans and Caribbean Blacks

OBJECTIVE: The purpose of this study was to examine ethnic variation in the relationship between individual socio-demographic factors, parental educational level, and late-life depressive symptoms in older African Americans and Caribbean Blacks. METHOD: This cross-sectional study used data from the National Survey of American Life. A subsample of older African Americans (N = 837) and Caribbean Blacks (N = 271) was analyzed using multiple regression analysis. RESULTS: Findings suggest differences in predictors of depressive symptoms for the two ethnic groups. Among older African Americans, lower educational attainment and lower income were predictive risk factors for higher depressive symptoms. Findings among older Caribbean Blacks suggest that nativity and income were significantly associated with depressive symptoms. This study did not find support for any association between parental education and late-life depressive symptoms. CONCLUSION: This study adds new information by considering ethnic variation in an examination of depressive symptoms in older Black Americans. The results contribute to the growing awareness of the older Caribbean Black population in the United States

Risk interval analysis of emergency room visits following colonoscopy in patients with inflammatory bowel disease.

Background and aimsPrior studies suggest that colonoscopy may exacerbate inflammatory bowel disease (IBD) symptoms. Thus, our study aimed to determine risk of emergency room (ER) visits associated with colonoscopy among IBD patients and evaluate potential modifiers of this risk.MethodsThe study population included IBD patients in the Multi-Payer Claims Database who were >20 years old and had a colonoscopy from 2007-2010. We used a self-controlled risk interval design and mixed-effects Poisson regression models to calculate risk ratios (RR) and 95% confidence intervals (CI) comparing the incidence of ER visits in the 1-4 weeks following colonoscopy (risk interval) to the incidence of ER visits in the 7-10 weeks after colonoscopy (control interval). We also conducted stratified analyses by patient characteristics, bowel preparation type, and medication.ResultsThere were 212,205 IBD patients with at least 1 colonoscopy from 2007-2010, and 3,699 had an ER visit during the risk and/or control interval. The risk of an ER visit was higher in the 4-week risk interval following colonoscopy compared to the control interval (RR = 1.24; 95% CI: 1.17-1.32). The effect was strongest in those ConclusionsOur results suggest that there is an increased risk of ER visits following colonoscopy among IBD patients, but that immunomodulators and mild bowel preparation agents may mitigate this risk

A Noninferiority Trial of a Problem-Solving Intervention for Hospice Caregivers: In Person versus Videophone

Article discussing in person versus videophone and a noninferiority trial of a problem-solving intervention for hospice caregivers