Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands

Methionine adenosyltransferase deficienc(MAT I/III deficiency) is an inborn error of metabolism resulting in isolated hypermethioninemia, and usually inherited as an autosomal recessive trait, although a dominant form has been reported in several families. During the last 6 years, approximately 520,000 newborns were screened in the Portuguese Newborn Screening Laboratory by MS/MS, and 21 cases of persistent hypermethioninemia were found. One case was confirmed to be a deficiency of cystathionine b-synthase and 20 cases were confirmed by MAT1A gene analysis to have an elevation of methionine due to MAT I/III deficiency, which indicates an incidence for this condition of 1/26,000. Twelve of the MAT I/III deficient newborns, belonging to 11 families, were identified in the northern region of Portugal and sent to the same treatment center, where they are under follow-up. Clinical, biochemical, and genetic characteristics of individuals from these 11 families are presented. Plasma methionine and homocysteine concentrations were found to be moderately increased in all newborns, and molecular analysis revealed that they all were heterozygous for R264H mutation. Normal growth,development, and neurological examination were observed in all cases, and cerebral MRI performed in six cases revealed myelination abnormalities in one case. Plasma methionine concentration for all 12 cases was always below 300 mM, and they are all on a normal diet for their age

Selective patterning of ZnO nanorods on silicon substrates using nanoimprint lithography

In this research, nanoimprint lithography (NIL) was used for patterning crystalline zinc oxide (ZnO) nanorods on the silicon substrate. To fabricate nano-patterned ZnO nanorods, patterning of an n-octadecyltrichlorosilane (OTS) self-assembled monolayers (SAMs) on SiO2 substrate was prepared by the polymer mask using NI. The ZnO seed layer was selectively coated only on the hydrophilic SiO2 surface, not on the hydrophobic OTS SAMs surface. The substrate patterned with the ZnO seed layer was treated with the oxygen plasma to oxidize the silicon surface. It was found that the nucleation and initial growth of the crystalline ZnO were proceeded only on the ZnO seed layer, not on the silicon oxide surface. ZnO photoluminescence spectra showed that ZnO nanorods grown from the seed layer treated with plasma showed lower intensity than those untreated with plasma at 378 nm, but higher intensity at 605 nm. It is indicated that the seed layer treated with plasma produced ZnO nanorods that had a more oxygen vacancy than those grown from seed layer untreated with plasma. Since the oxygen vacancies on ZnO nanorods serve as strong binding sites for absorption of various organic and inorganic molecules. Consequently, a nano-patterning of the crystalline ZnO nanorods grown from the seed layer treated with plasma may give the versatile applications for the electronics devices

Three-dimensionally Ordered Macroporous Structure Enabled Nanothermite Membrane of Mn2O3/Al

Mn2O3 has been selected to realize nanothermite membrane for the first time in the literature. Mn2O3/Al nanothermite has been synthesized by magnetron sputtering a layer of Al film onto three-dimensionally ordered macroporous (3DOM) Mn2O3 skeleton. The energy release is significantly enhanced owing to the unusual 3DOM structure, which ensures Al and Mn2O3 to integrate compactly in nanoscale and greatly increase effective contact area. The morphology and DSC curve of the nanothermite membrane have been investigated at various aluminizing times. At the optimized aluminizing time of 30 min, energy release reaches a maximum of 2.09 kJ∙g−1, where the Al layer thickness plays a decisive role in the total energy release. This method possesses advantages of high compatibility with MEMS and can be applied to other nanothermite systems easily, which will make great contribution to little-known nanothermite research

New variable separation approach: application to nonlinear diffusion equations

The concept of the derivative-dependent functional separable solution, as a generalization to the functional separable solution, is proposed. As an application, it is used to discuss the generalized nonlinear diffusion equations based on the generalized conditional symmetry approach. As a consequence, a complete list of canonical forms for such equations which admit the derivative-dependent functional separable solutions is obtained and some exact solutions to the resulting equations are described.Comment: 19 pages, 2 fig

Identification of Potent EGFR Inhibitors from TCM Database@Taiwan

Overexpression of epidermal growth factor receptor (EGFR) has been associated with cancer. Targeted inhibition of the EGFR pathway has been shown to limit proliferation of cancerous cells. Hence, we employed Traditional Chinese Medicine Database (TCM Database@Taiwan) (http://tcm.cmu.edu.tw) to identify potential EGFR inhibitor. Multiple Linear Regression (MLR), Support Vector Machine (SVM), Comparative Molecular Field Analysis (CoMFA), and Comparative Molecular Similarities Indices Analysis (CoMSIA) models were generated using a training set of EGFR ligands of known inhibitory activities. The top four TCM candidates based on DockScore were 2-O-caffeoyl tartaric acid, Emitine, Rosmaricine, and 2-O-feruloyl tartaric acid, and all had higher binding affinities than the control Iressa®. The TCM candidates had interactions with Asp855, Lys716, and Lys728, all which are residues of the protein kinase binding site. Validated MLR (r² = 0.7858) and SVM (r² = 0.8754) models predicted good bioactivity for the TCM candidates. In addition, the TCM candidates contoured well to the 3D-Quantitative Structure-Activity Relationship (3D-QSAR) map derived from the CoMFA (q² = 0.721, r² = 0.986) and CoMSIA (q² = 0.662, r² = 0.988) models. The steric field, hydrophobic field, and H-bond of the 3D-QSAR map were well matched by each TCM candidate. Molecular docking indicated that all TCM candidates formed H-bonds within the EGFR protein kinase domain. Based on the different structures, H-bonds were formed at either Asp855 or Lys716/Lys728. The compounds remained stable throughout molecular dynamics (MD) simulation. Based on the results of this study, 2-O-caffeoyl tartaric acid, Emitine, Rosmaricine, and 2-O-feruloyl tartaric acid are suggested to be potential EGFR inhibitors.National Science Council of Taiwan (NSC 99-2221-E-039-013-)Committee on Chinese Medicine and Pharmacy (CCMP100-RD-030)China Medical University (CMU98-TCM)China Medical University (CMU99-TCM)China Medical University (CMU99-S-02)China Medical University (CMU99-ASIA-25)China Medical University (CMU99-ASIA-26)China Medical University (CMU99-ASIA-27)China Medical University (CMU99-ASIA-28)Asia UniversityTaiwan Department of Health. Clinical Trial and Research Center of Excellence (DOH100-TD-B-111-004)Taiwan Department of Health. Cancer Research Center of Excellence (DOH100-TD-C-111-005

Adjusting a cancer mortality-prediction model for disease status-related eligibility criteria

<p>Abstract</p> <p>Background</p> <p>Volunteering participants in disease studies tend to be healthier than the general population partially due to specific enrollment criteria. Using modeling to accurately predict outcomes of cohort studies enrolling volunteers requires adjusting for the bias introduced in this way. Here we propose a new method to account for the effect of a specific form of healthy volunteer bias resulting from imposing disease status-related eligibility criteria, on disease-specific mortality, by explicitly modeling the length of the time interval between the moment when the subject becomes ineligible for the study, and the outcome.</p> <p>Methods</p> <p>Using survival time data from 1190 newly diagnosed lung cancer patients at MD Anderson Cancer Center, we model the time from clinical lung cancer diagnosis to death using an exponential distribution to approximate the length of this interval for a study where lung cancer death serves as the outcome. Incorporating this interval into our previously developed lung cancer risk model, we adjust for the effect of disease status-related eligibility criteria in predicting the number of lung cancer deaths in the control arm of CARET. The effect of the adjustment using the MD Anderson-derived approximation is compared to that based on SEER data.</p> <p>Results</p> <p>Using the adjustment developed in conjunction with our existing lung cancer model, we are able to accurately predict the number of lung cancer deaths observed in the control arm of CARET.</p> <p>Conclusions</p> <p>The resulting adjustment was accurate in predicting the lower rates of disease observed in the early years while still maintaining reasonable prediction ability in the later years of the trial. This method could be used to adjust for, or predict the duration and relative effect of any possible biases related to disease-specific eligibility criteria in modeling studies of volunteer-based cohorts.</p

Who died as a result of the tsunami? – Risk factors of mortality among internally displaced persons in Sri Lanka: a retrospective cohort analysis

BACKGROUND: Describing adverse health effects and identifying vulnerable populations during and after a disaster are important aspects of any disaster relief operation. This study aimed to describe the mortality and related risk factors which affected the displaced population over a period of two and a half months after the 2004 Indian Ocean tsunami in an eastern coastal district of Sri Lanka. METHODS: A cross-sectional household survey was conducted in 13 evacuation camps for internally displaced persons (IDP). Information on all pre-tsunami family members was collected from householders, and all deaths which occurred during the recall period (77 to 80 days starting from the day of the tsunami) were recorded. The distribution of mortality and associated risk factors were analysed. Logistic regression modelling using the generalized estimating equations method was applied in multivariate analysis. RESULTS: Overall mortality rate out of 3,533 individuals from 859 households was 12.9% (446 deaths and 11 missing persons). The majority of the deaths occurred during and immediately after the disaster. A higher mortality was observed among females (17.5% vs. 8.2% for males, p < 0.001), children and the elderly (31.8%, 23.7% and 15.3% for children aged less than 5 years, children aged 5 to 9 years and adults over 50 years, respectively, compared with 7.4% for adults aged 20 to 29 years, p < 0.001). Other risk factors, such as being indoors at the time of the tsunami (13.8% vs. 5.9% outdoors, p < 0.001), the house destruction level (4.6%, 5.5% and 14.2% in increasing order of destruction, p < 0.001) and fishing as an occupation (15.4% vs. 11.2% for other occupations, p < 0.001) were also significantly associated with increased mortality. These correlations remained significant after adjusting for the confounding effects by multivariate analysis. CONCLUSION: A significantly high mortality was observed in women and children among the displaced population in the eastern coastal district of Sri Lanka who were examined by us. Reconstruction activities should take into consideration these changes in population structure

Validation of the Burden Index of Caregivers (BIC), a multidimensional short care burden scale from Japan

BACKGROUND: We constructed a concise multidimensional care burden scale that reflects circumstances unique to Japan, with a focus on intractable neurological diseases. We surveyed 646 family caregivers of patients with intractable neurological diseases or stroke using 28 preliminary care burden scale items obtained from qualitative research. The results were used to finalize the feeling of care burden scale (BIC: burden index of caregivers), and verify its reliability and validity. METHODS: The survey was conducted among caregivers providing home health care to patients with intractable neurological diseases (PD [Parkinson's disease], SCD [spinocerebellar degeneration], MSA [multiple system atrophy], and ALS [amyotrophic lateral sclerosis]) or CVA (cerebrovascular accident) using a mailed, self-administered questionnaire between November, 2003 and May, 2004. RESULTS: Response rates for neurological and CVA caregivers were 50% and 67%, respectively, or 646 in total (PD, 279; SCD, 78; MSA, 39; ALS, 30; and CVA, 220). Item and exploratory factor analyses led to a reduction to 11 items, comprising 10 items from the 5 domains of time-dependent burden, emotional burden, existential burden, physical burden, and service-related burden; and 1 item on total burden. Examination of validity showed a moderate correlation between each domain of the BIC and the SF-8 (Health related quality of life scale, Short Form-8), while the correlation coefficient of the overall BIC and CES-D was 0.62. Correlation between the BIC and ZBI, a preexisting care burden scale, was high (r = 0.84), while that with the time spent on providing care was 0.47. The ICC (Intraclass correlation coefficient) by test-retest reliability was 0.83, and 0.68 to 0.80 by individual domain. CONCLUSION: These results show that the BIC, a new care burden scale comprising 11 items, is highly reliable and valid

Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

© 2017 The Author(s). Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis

Purine Nucleoside Phosphorylase mediated molecular chemotherapy and conventional chemotherapy: A tangible union against chemoresistant cancer

Background Late stage Ovarian Cancer is essentially incurable primarily due to late diagnosis and its inherent heterogeneity. Single agent treatments are inadequate and generally lead to severe side effects at therapeutic doses. It is crucial to develop clinically relevant novel combination regimens involving synergistic modalities that target a wider repertoire of cells and lead to lowered individual doses. Stemming from this premise, this is the first report of two- and three-way synergies between Adenovirus-mediated Purine Nucleoside Phosphorylase based gene directed enzyme prodrug therapy (PNP-GDEPT), docetaxel and/or carboplatin in multidrug-resistant ovarian cancer cells. Methods The effects of PNP-GDEPT on different cellular processes were determined using Shotgun Proteomics analyses. The in vitro cell growth inhibition in differentially treated drug resistant human ovarian cancer cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The involvement of apoptosis and implicated proteins in effects of different treatments was established using flow cytometry based detection of M30 (an early marker of apoptosis), cell cycle analyses and finally western blot based analyses. Results Efficacy of the trimodal treatment was significantly greater than that achieved with bimodal- or individual treatments with potential for 10-50 fold dose reduction compared to that required for individual treatments. Of note was the marked enhancement in apoptosis that specifically accompanied the combinations that included PNP-GDEPT and accordingly correlated with a shift in the expression of anti- and pro-apoptotic proteins. PNP-GDEPT mediated enhancement of apoptosis was reinforced by cell cycle analyses. Proteomic analyses of PNP-GDEPT treated cells indicated a dowregulation of proteins involved in oncogenesis or cancer drug resistance in treated cells with accompanying upregulation of apoptotic- and tumour- suppressor proteins. Conclusion Inclusion of PNP-GDEPT in regular chemotherapy regimens can lead to significant enhancement of the cancer cell susceptibility to the combined treatment. Overall, these data will underpin the development of regimens that can benefit patients with late stage ovarian cancer leading to significantly improved efficacy and increased quality of life