Genetic aberrations in oral or head and neck squamous cell carcinoma (SCCHN): 1. Carcinogen metabolism, DNA repair and cell cycle control

The ability to metabolise carcinogens or pro-carcinogens, repair DNA damage, and control cell signalling and the cell cycle are fundamental to homeostasis. Oral squamous cell carcinoma (oral cancer) and many squamous cell carcinomas of the head and neck (SCCHN) may, under appropriate exposure to mutagens, arise if these mechanisms are defective. SCCHN arise as a consequence of multiple molecular events induced by the effects of various carcinogens from habits such as tobacco use, influenced by environmental factors, possibly viruses in some instances, against a background of heritable resistance or susceptibility. Consequent genetic damage affects many chromosomes and genes, and it is the accumulation of these changes that appears to lead to carcinoma in some instances, sometimes via a clinically evident pre-malignant, or potentially malignant, lesion. Although lifestyle factors play a prominent role in aetiology, some patients appear susceptible because of an inherited trait in their ability or inability to metabolise carcinogens or pro-carcinogens, possibly along with an impaired ability to repair the DNA damage. This is the first of a series of three papers reviewing the advances in the understanding of this area of research since our last review [Scully C, Field JK. Genetic aberrations in squamous cell carcinoma of the head and neck (SCCHN), with reference to oral carcinoma (Review). Int J Oncol 1977;10:5-21] and discusses mainly oral carcinoma in the context of SCCHN.     

Left Ventricular Mechanical Assist Devices and Cardiac Device Interactions: An Observational Case Series

Background: Nonpulsatile left ventricular assist devices (LVADs) are increasingly used for treatment of refractory heart failure. A majority of such patients have implanted cardiac devices, namely implantable cardioverter-defibrillators (ICDs) or cardiac resynchronization therapy-pacemaker (CRT-P) or cardiac resynchronization therapy-defibrillator (CRT-D) devices. However, potential interactions between LVADs and cardiac devices in this category of patients remain unknown.
Methods: We reviewed case records and device logs of 15 patients with ICDs or CRT-P or CRT-D devices who subsequently had implantation of a VentrAssist LVAD (Ventracor Ltd., Chatswood, Australia) as destination therapy or bridge to heart transplantation. Pacemaker and ICD lead parameters before and after LVAD implant were compared. In addition, ventricular tachyarrhythmia event logs and potential electromagnetic interference reports were evaluated.
Results: Right ventricular (RV) sensing decreased in the first 6 months post-LVAD. Mean R-wave amplitude preimplant was 10.9 ± 5.25 mV compared with 7.2 ± 3.4 mV during follow-up (P = 0.02). RV impedance also decreased from 642 ± 240 ohms at baseline to 580 ± 212 ohms at follow-up (P = 0.007). There was a significant increase in RV stimulation threshold following implantation of the LVAD from 0.8 ± 0.6 V at baseline to 1.4 ± 1.0 V in the first 6 months postimplant (P = 0.01). A marked increase in ventricular tachyarrhythmia burden was observed in three patients. One patient displayed electromagnetic interference between the LVAD and defibrillator, resulting in inappropriate defibrillation therapy.
Conclusions: LVADs have a definite impact on cardiac devices in respect with alteration of lead parameters, ventricular tachyarrhythmias, and electromagnetic interference.     

Early Glucose Abnormalities in Cystic Fibrosis Are Preceded by Poor Weight Gain

OBJECTIVE

Progressive β-cell loss causes catabolism in cystic fibrosis. Existing diagnostic criteria for diabetes were based on microvascular complications rather than on cystic fibrosis–specific outcomes. We aimed to relate glycemic status in cystic fibrosis to weight and lung function changes.

RESEARCH DESIGN AND METHODS

We determined peak blood glucose (BG_max) during oral glucose tolerance tests (OGTTs) with samples every 30 min for 33 consecutive children (aged 10.2–18 years). Twenty-five also agreed to undergo continuous glucose monitoring (CGM) (Medtronic). Outcome measures were change in weight standard deviation score (wtSDS), percent forced expiratory volume in 1 s (%FEV1), and percent forced vital capacity (%FVC) in the year preceding the OGTT.

RESULTS

Declining wtSDS and %FVC were associated with higher BG_max (both P = 0.02) and with CGM time >7.8 mmol/l (P = 0.006 and P = 0.02, respectively) but not with BG_{120 min}. A decline in %FEV1 was related to CGM time >7.8 mmol/l (P = 0.02). Using receiver operating characteristic (ROC) analysis to determine optimal glycemic cutoffs, CGM time above 7.8 mmol/l ≥4.5% detected declining wtSDS with 89% sensitivity and 86% specificity (area under the ROC curve 0.89, P = 0.003). BG_max ≥8.2 mmol/l gave 87% sensitivity and 70% specificity (0.76, P = 0.02). BG_{120 min} did not detect declining wtSDS (0.59, P = 0.41). After exclusion of two patients with BG_{120 min} ≥11.1 mmol/l, the decline in wtSDS was worse if BG_max was ≥8.2 mmol/l (−0.3 ± 0.4 vs. 0.0 ± 0.4 for BG_max <8.2 mmol/l, P = 0.04) or if CGM time above 7.8 mmol/l was ≥4.5% (−0.3 ± 0.4 vs. 0.1 ± 0.2 for time <4.5%, P = 0.01).

CONCLUSIONS

BG_max ≥8.2 mmol/l on an OGTT and CGM time above 7.8 mmol/l ≥4.5% are associated with declining wtSDS and lung function in the preceding 12 months.Progressive β-cell loss causes catabolism and weight loss in cystic fibrosis (1,2). Weight is a prognostic indicator (3), and prevention of weight decline is a major clinical objective in children and adolescents with cystic fibrosis. Median life expectancy of patients with cystic fibrosis has risen progressively over recent decades but remains drastically shorter (∼36 years) than that of the general population (4). The presence of cystic fibrosis–related diabetes (CFRD) is associated with an increase in early mortality of up to sixfold (5). CFRD is usually diagnosed by the North American Cystic Fibrosis Foundation criteria (6) or World Health Organization (WHO) criteria for diabetes (7). These criteria were designed to identify patients at risk of microvascular complications in type 2 diabetes (8) and were not designed with cystic fibrosis–specific outcomes in mind. Microvascular complications occur in cystic fibrosis (9); however, catabolic decline in weight and deteriorating lung function may be more relevant outcomes. Poor weight gain is associated with worsening lung function (10,11), and both are associated with early mortality (12,13). Weight and lung function declines have been shown to precede the diagnosis of CFRD by standard criteria (2), but the earliest glycemic abnormality associated with clinical decline has not been determined. Glycemic status can be assessed in detail using an oral glucose tolerance test (OGTT) with 30-min samples and, more recently, continuous interstitial fluid glucose monitoring (CGM). We aimed to determine the relationship between glycemic status and the change in weight standard deviation score (wtSDS) and the change in lung function over the preceding year.     

Microdissection and chromosome painting of plant B chromosomes

Plant chromosome microdissection techniques together with different isolation and amplification methods of microisolated DNA are described. Such isolated DNA was used to 'chromosome paint' B chromosomes of the dicot Brachycome dichromosomatica and the monocot Secale cereale. It is demonstrated that the specific painting of the described chromosomes was possible because of enrichment for chromosome-specific repetitive sequences, rather than the chromosome specific low- and single-copy sequences which are responsible for the painting of mammalian chromosomes. The feasibility of 'chromosome painting' of standard chromosomes in plant species with relatively small or large genomes is discussed.     

Creative Movement Therapy Benefits Children with Autism

Thirty-eight children with autism were given movement therapy in small groups led by a trained movement therapist. After two months of biweekly sessions, the movement therapy versus the control (N = 38) children spent less time wandering, more time showing on-task behavior, less time showing negative responses to being touched, and less time resisting the teacher.     

Cancer diagnosis in first-degree relatives and non-small cell lung cancer risk: Results from a multi-centre case–control study in Europe

Because aggregation of cancers at different sites can occur in families, cancer could be considered as a broad phenotype with shared genetic factors. Here, we report results from a multi-centre case–control study of non-small cell lung cancer (NSCLC), with particular emphasis on a history of cancer in first-degree relatives and the risk of lung cancer. From 2002 to 2006, 733 NSCLC patients treated surgically were recruited in 8 European countries and matched to 1312 controls, by centre, sex and age. We used multivariate conditional logistic regression models to test the association between a history of cancer in first-degree relatives and risk of NSCLC. A family history of lung cancer was associated with an odds ratio (OR) for early-onset (54 years or younger) NSCLC of 4.72 (95% confidence interval [CI] = 1.02–21.90). A family history of gastric cancer was associated with an OR for NSCLC of 1.82 (95% CI = 1.08–3.06) and for late-onset (55 years or older) NSCLC of 2.92 (95% CI = 1.10–7.75). Our findings provide further evidence of a familial predisposition to lung cancer and support the hypothesis that family history is a significant risk factor for the disease. Because of the inherent potential for bias in familial case–control study design, cautious interpretation is warranted.     

Predictors of the use of complementary and alternative medicine (CAM) by women at high risk for breast cancer

BackgroundFew data exist regarding the use of complementary and alternative medicine (CAM) by unaffected women at high risk of breast cancer.MethodsSelf-reported CAM use by women from multiple-case breast cancer families was obtained by questionnaire. Factors associated with CAM use were assessed using multiple logistic regression.ResultsOf 892 women, 55% (n = 489) used CAM, 6% (n = 53) specifically to prevent cancer. CAM use was independently associated with tertiary education level (OR 2.56, 95% CI 1.83–3.58, p < 0.001), greater physical activity (OR 1.05 per hour of physical activity/week, 95% CI 1.00–1.10, p = 0.049), greater anxiety (OR 1.92, 95% CI 1.16–3.16, p = 0.01), not currently smoking (OR 0.64, 95% CI 0.42–0.97, p = 0.037) and lower perceived BC risk (OR 0.82 per 20 percentage points, 95% CI 0.72–0.94, p = 0.005).ConclusionsThe majority of high-risk women use CAM, but mostly for reasons other than cancer prevention. Most predictors of CAM use are consistent with the limited literature for women at high risk for cancer.     

Cytoglobin, the newest member of the globin family, functions as a tumor suppressor gene

Cytoglobin (CYGB) is a recently discovered vertebrate globin distantly related to myoglobin with unknown function. CYGB is assigned to chromosomal region 17q25, which is frequently lost in multiple malignancies. Previous studies failed to detect evidence for mutations in the CYGB gene. Recent studies provided preliminary evidence for increased methylation of the gene in lung cancer. Our study was aimed at investigating the role of CYGB as a tumor suppressor gene. By nested methylation-specific DNA sequencing analysis of lung and breast cancer cell lines and bronchial and mammary epithelial cell lines, we identified that methylation of a 110-bp CpG-rich segment of the CYGB promoter was correlated with gene silencing. We specifically targeted this sequence and developed a quantitative methylation-specific PCR assay, suitable for high-throughput analysis. We showed that the tumor specificity of CYGB methylation in discriminating patients with and without lung cancer, using biopsies and sputum samples. We further showed the tumor specificity of this assay with multiple other epithelial and hematologic malignancies. To show tumor suppressor activity of CYGB, we performed the following: (a) RNA interference-mediated knockdown of CYGB gene on colony formation in a CYGB expression-positive lung cancer cell line, resulting in increased colony formation; (b) enforced gene expression in CYGB expression-negative lung and breast cancer cell lines, reducing colony formation; and (c) identification of potential proximate targets down-stream of the CYGB genes. Our data constitute the first direct functional evidence for CYGB, the newest member of the globin family, as a tumor suppressor gene.