Use of integrative epigenetic and cytogenetic analyses to identify novel tumor-suppressor genes in malignant melanoma

The objective of this study was to identify novel tumor-suppressor genes in melanoma, using an integrative genomic approach. Data from: (i) earlier reports of DNA loss and gain in malignant melanoma accompanied by comparative genomic hybridization high-definition array data of the entire human genome; (ii) microarray expression data from melanoma-derived cell lines identifying genes with significantly increased expression due to methylation using a pharmacologic demethylating strategy; and (iii) publicly available RNA expression microarray data of primary tumors and benign nevi were integrated using statistical tools to define a population of candidate tumor-suppressor genes. Twenty-seven genes were identified in areas of deletion that demonstrated diminished expression in primary melanomas relative to benign nevi and were significantly increased in expression by 5-Aza treatment. Seven genes of these 27 genes demonstrated methylation and deletion in a validation cohort of 14 separate primary tumors. These were: CHRDL1, SFRP1, TMEM47, LPL, RARRES1, PLCXD1, and KOX15. All of these genes demonstrated growth-suppressive properties with transfection into melanoma-derived cell lines. Seven putative tumor-suppressor genes in malignant melanoma were identified using a novel integrative technique.     

Intercountry prevalences and practices of betel-quid use in south, southeast and eastern Asia regions and associated oral preneoplastic disorders: an international collaborative study by Asian betel-quid consortium of south and east Asia

Health risks stemming from betel-quid (BQ) chewing are frequently overlooked by people. Updated epidemiological data on the increased BQ use among Asian populations using comparable data collection methods have not been widely available. To investigate the prevalence, patterns of practice and associated types of oral preneoplastic disorders, an intercountry Asian Betel-quid Consortium study (the ABC study) was conducted for Taiwan, Mainland China, Malaysia, Indonesia, Nepal and Sri Lanka. A random sample of 8,922 subjects was recruited, and the data were analyzed using survey-data modules adjusted for the complex survey design. Chewing rates among men (10.7-43.6%) were significantly higher than women (1.8-34.9%) in Taiwan, Mainland China, Nepal and Sri Lanka, while women's rates (29.5-46.8%) were higher than that for men (9.8-12.0%) in Malaysia and Indonesia. An emerging, higher proportion of new-users were identified for Hunan in Mainland China (11.1-24.7%), where Hunan chewers have the unique practice of using the dried husk of areca fruit rather than the solid nut universally used by others. Men in the Eastern and South Asian study communities were deemed likely to combine chewing with smoking and drinking (5.6-13.6%). Indonesian women who chewed BQ exhibited the highest prevalence of oral lichen planus, oral submucous fibrosis and oral leukoplakia (9.1-17.3%). Lower schooling, alcohol drinking and tobacco smoking were identified as being associated with BQ chewing. In conclusion, the ABC study reveals the significant cultural and demographic differences contributing to practice patterns of BQ usage and the great health risks that such practices pose in the Asian region.     

Acute respiratory and systemic toxicity of pulmonary exposure to rutile Fe-doped TiO(2) nanorods

Nanomaterials are extensively used in medicines, industry and daily life, but little is known about their possible health effects. Titanium dioxide (TiO₂) nonmaterial-based photocatalysis is useful in the complete mineralization of organic pollutants in waste water and air. While the Fe-doping of TiO₂ enhances their photocatalytic activity, their potential pathophysiologic effects are unknown. Here, rutile Fe-doped (9%) pure titanium dioxide (TiO₂) nanorods were prepared and characterized. Subsequently, we assessed the acute (24 h) pulmonary and extrapulmonary effects of intratracheal (i.t.) instillation of these nanorods (1 and 5 mg/kg) in Wistar rats. In the bronchoalveolar lavage, the treatment induced a significant and dose-dependent increase of neutrophils, an increase of interleukin-6 (IL-6, at 5 mg/kg), and caused a dose-dependent-decrease of superoxide dismutase (SOD) activity. The lung sections of rats exposed to rutile Fe–TiO₂ nanorods showed infiltration of inflammatory cells in dose-dependent manner. Similarly, the heart rate, systolic blood pressure, plasma IL-6, and leukocyte and platelet numbers were increased at 5 mg/kg. The plasma SOD and reduced glutathaione activities were dose-dependently decreased after exposure to the nanorods. Histopathologically, the liver showed mild inflammatory cells infiltration of few portal tracts, but the kidneys and heart were unaffected. In plasma, the levels of lactate dehydrogenase and hepatic enzymes, i.e., alanine aminotranferease and aspartate aminotransferase were increased significantly. The in vitro exposure of human lung cancer cells NCI-H460-Luc2 and human hepatoma cells HepG2 to FeTiO₂ (6.25–100 μg/ml) dose-dependently reduced cellular viability. Also, the In vitro direct addition of these nanorods (0.1–1 μg/ml) to untreated rat blood, significantly and dose-dependently induced platelet aggregation. In conclusion, exposure to rutile Fe–TiO₂ promotes pulmonary and systemic inflammation and oxidative stress. It affects the liver, enhances thrombotic potential, heart rate and systolic blood pressure. Moreover, the rutile Fe–TiO₂ elicited direct toxicity on NCI-H460-Luc2 and HepG2 cells.     

Heterogeneity in the definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents: a review of the literature

Aim

There is no consensus about what constitutes a dose-limiting toxicity (DLT) in phase I cancer clinical trials. We aimed to evaluate how DLTs are defined in phase I trials of molecularly targeted agents (MTA).

Methods

We retrieved all phase I trials testing monotherapy with an MTA published over the last decade. In each trial, all items used to define DLTs were recorded.

Results

Reports of 155 phase I trials evaluating 111 different MTAs were reviewed. The most frequent determinant of whether a toxicity was regarded as a DLT was severity, usually assessed using the NCI CTCAE classification. However, for any given toxicity, there was substantial variability in the degree of severity required for a toxicity to be considered a DLT. Specifications about minimum duration of toxicity, degree of reversibility, the need to delay treatment and to reduce dose-intensity because of toxicity were infrequently incorporated in the definition of DLT. The definition of DLT varied with administration schedule. Discrepancies between the initial and the final definition of DLT were reported in 25% of trials.

Conclusions

While our results do not support a standardisation of the definition of DLT, the inclusion of following specifications in its definition when relevant would reduce the heterogeneity observed across trials: (1) DLT assessment period, (2) absolute severity according to NCI CTCAE classification as well as severity relative to baseline status, (3) minimum duration of toxicity, (4) reversibility of toxicity within a certain period of time, and (5) necessity to delay treatment or to reduce dose-intensity.     

Quantum chemical-based drug�Creceptor interaction of tetrahydroimidobenzodiazepinones (HIV-1-NNRTIs) with receptor (HIV-1-NNRTI-binding pocket)

The chemical forces responsible for interaction of drug (HIV-1-NNRTI) with receptor (HIV-1-NNRTI-binding pocket) have been studied by evaluating log P and SASA for the measurement of hydrophobic interaction; energy of protonation (ΔE) for the measurement of most favorable hydrogen bond acceptor site; bond length and bond strain for the measurement of strength of hydrogen bond formed between drug and receptor; ΔE _nm ^‡ = ∣E _n ^‡ − E _m ^‡∣ for the measurement of polar interaction. The molecular modeling and geometry optimization of the compounds (drugs) and receptor amino acids (Val, Met, and Tyr) have been done using MOPAC-2002 associated with CAChe software. Softness Calculator has been used to evaluate effective atomic softness (E _n ^‡ and E _m ^‡). The results indicate that there is strong and effective hydrophobic interaction between hydrophobic substituent at site-6 of the drug and Val-Y187 of the receptor; hydrophobic substituent at site-5 and Met-Y184. Similarly, hydrogen bonds are formed between N-atom (site-6) of the drug and H-atom of the phenolic group of the Tyr-Y188; between phenolic group of the Tyr-181 and H-atom (site-1) of the drug. Polar interaction (charge transfer) occurs between –C=O/S (site-2) of the drug and –CONH– of Asn-Y182-Tyr-Y183.     

Imaging characteristics of extrapulmonary tuberculosis lesions on dual time point imaging (DTPI) of FDG PET/CT

Introduction: This study aimed to evaluate the diagnostic value of dual time point imaging (DTPI) of 18F‐fluorodeoxyglucose (FDG) positron emission tomography/CT (PET/CT) for detecting the infective lesions in patients with extrapulmonary tuberculosis (EPTB). Methods: Eleven patients were consecutively recruited and evaluated. After the intravenous injection of 369 ± 153 MBq of FDG, all patients underwent FDG PET/CT imaging at two different time points: early scan at 57 ± 23 min and delayed scan at 136 ± 42 min. The maximum standardized uptake values (SUVmax) were recorded for both time points (early scan: SUVmax1 and delayed scan: SUVmax2). Results: In total, 30 lesions were detected. The SUVmax2 in 22 of the lesions in confirmed EPTB patients were significantly higher than the SUVmax1 (7.9 ± 3.2 vs. 6.8 ± 2.5; P = 0.001). The SUVmax for another eight non‐EPTB lesions also showed a significant increasing pattern of change (6.2 ± 2.6 vs. 6.5 ± 2.8; P = 0.044). However, there was insignificant difference between the mean percentage difference of SUVmax (%ΔSUVmax) of EPTB and non‐EPTB lesions (P = 0.06). Conclusion: Our study demonstrates that early whole body PET/CT imaging may be sufficient for the detection of the EPTB lesions and DTPI of PET/CT may also not be a useful technique in differentiating between EPTB and non‐EPTB lesions. However, our findings are based on a limited number of patients, and therefore, further investigations in larger series of patients are warranted.     

UBQLN2 mutations are rare in French and French-Canadian amyotrophic lateral sclerosis

Mutations in the UBQLN2 gene, which encodes a member of the ubiquitin-like protein family (ubiquilin-2), have been recently identified in patients with dominant X-linked amyotrophic lateral sclerosis (ALS) and ALS with dementia. We report here the sequencing of the UBQLN2 gene in 590 ALS patients of French and French-Canadian ancestry. We identified two novel missense mutations (p.S155N and p.P189T) in two individuals with sporadic ALS. Bioinformatic analysis predicts that these missense mutations affect the normal protein's function. Importantly, these findings further highlight the importance of the proline residues located in the conserved domains of the ubiquilin-2 protein, suggesting that mutations affecting these residues are particularly relevant to the development of ALS. Our findings further support a causative role of the UBQLN2 gene in the pathogenesis of ALS and suggest that UBQLN2 mutations are rare in the French and French-Canadian population.