A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer

BACKGROUND: Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy. METHODOLOGY: This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day –7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate. MAIN FINDINGS: 16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1–2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5(m)C content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively. CONCLUSIONS: Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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The embryo as moral work object: PGD/IVF staff views and experiences

Copyright @ 2008 the authors. This article is available in accordance with the Creative Commons Deed, Attribution 2.5, see http://creativecommons.org/licenses/by-nc-nd/2.5/deed.en_CA.We report on one aspect of a study that explored the views and experiences of practitioners and scientists on social, ethical and clinical dilemmas encountered when working in the field of preimplantation genetic diagnosis (PGD) for serious genetic disorders. The study produced an ethnography based on observation, interviews and ethics discussion groups with staff from two PGD/IVF Units in the UK. We focus here on staff perceptions of work with embryos that entails disposing of ‘affected’ or ‘spare’ embryos or using them for research. A variety of views were expressed on the ‘embryo question’ in contrast to polarised media debates. We argue that the prevailing policy acceptance of destroying affected embryos, and allowing research on embryos up to 14 days leaves some staff with rarely reported, ambivalent feelings. Staff views are under-researched in this area and we focus on how they may reconcile their personal moral views with the ethical framework in their field. Staff construct embryos in a variety of ways as ‘moral work objects’. This allows them to shift attention between micro-level and overarching institutional work goals, building on Casper's concept of ‘work objects’ and focusing on negotiation of the social order in a morally contested field.The Wellcome Trust Biomedical Ethics Programme, who funded the projects‘Facilitating choice, framing choice: the experience of staff working in pre-implantation genetic diagnosis’ (no: 074935), and ‘Ethical Frameworks for Embryo Donation:the views and practices of IVF/PGD staff’ (no: 081414)

Neural crest-derived tumor neuroblastoma and melanoma share 1p13.2 as susceptibility locus that shows a long-range interaction with the SLC16A1 gene

Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10−8). We also detected a suggestive (P < 10−7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10−4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC development, underlying both tumors. In vitro and in silico analyses indicated that the rs2153977-T protective allele, located in an NB and CMM enhancer, decreased expression of SLC16A1 via long-range loop formation and altered a T-box protein binding site. Upon depletion of SLC16A1, we observed a decrease of cellular proliferation and invasion in both NB and CMM cell lines, suggesting its role as oncogene. This is the largest study to date examining pleiotropy across two NC cell-derived tumors identifying 1p13.2 as common susceptibility locus for NB and CMM risk. We demonstrate that combining genome-wide association studies results across cancers with same origins can identify new loci common to neuroblastoma and melanoma arising from tissues which originate from neural crest cells. Our results also show 1p13.2 confer risk to neuroblastoma and melanoma by regulating SLC16A1

Executive dysfunction screening and intelectual coefficient measurement in children with attention deficit hyperactivity disorder Tamizaje de la disfunción ejecutiva y medición del coeficiente intelectual en niños con trastorno por déficit de atención-hiperactividad

OBJECTIVE: To perform a complete Intelligence quotient (IQ) measurement (verbal, performance, and total) and subsequently, to compare executive function (EF) measurements in subgroups of children with attention deficit-hyperactivity disorder (ADHD) with a control group. METHOD: We studied a group of children from 7-12 years of age from public elementary schools. Children were selected by means of Diagnostic and Statistical Manual of Mental Disorders-IV-Revised (DSM-IV-R) parent and teacher questionnaires for ADHD. EFs were screened by Weschler Intelligence Scale for Children (WISC-R) performance intelligence quotient (IQ) determination of the following sub-tests: picture completion; block designs, and object assembly tests. Simultaneously, total (T-), performance (P-), and verbal (V-) IQs were measured for each patient. RESULTS: We studied 26 control subjects, and 35 children with ADHD. Numbers of children in each ADHD sub-type group were as follows: 15 in the combined group (-C), 13 in the inattentive group (-I), and 7 in hyperactivity group (-H). We found significant lower EF scores in picture arrangement (F=3.76, df 3,57, p=0.01), block design (F=4.55, df 3,57, p<0.01), and object assembly (F=4.52, df 3,57, p<0.01). Post-hoc analysis showed that differences were located among ADHD-C, ADHD-I, and ADHD-H groups when compared with controls. We found significantly lower cognitive scores in the ADHD-I group as follows: P-IQ (F=3.57, df 3,57, p=0.02), and T-IQ (F=2.90, df 3,57, p=0.04). CONCLUSION: Our results showed that screening of EF alteration in children with ADHD is easy and rapid by means of certain P-IQ determination sub-scales of the WISC test; moreover, complementary IQ determination can be measured simultaneously. Overall, children with ADHD exhibited an EF alteration. ADHD-I children demonstrated lower P-IQ, and T-IQ scores than control children.<br>OBJETIVO: Realizar una medición global de cociente intelectual (CI) (verbal, ejecutivo y total) y comparar las funciones ejecutivas (FE) en los subgrupos de niños con trastorno por déficit de atención-hiperactividad (TDAH) con un grupo control. MÉTODO: Se estudiaron niños de 7-12 años, provenientes de escuelas oficiales primarias. Se les aplicó el cuestionario de criterios diagnósticos de TDAH del DSM-IV-R para padres y maestros. Las FE se tamizaron mediante las sub-escalas de: ordenación de dibujos, diseño con cubos y composición de objetos del WISC-R. En forma paralela se midieron los CI Verbal (-V), Ejecutivo (-E), Total (-T) de cada paciente. RESULTADOS: Se estudiaron 26 niños control y 35 con TDAH. La distribución de niños con TDAH en los diferentes subtipos clínicos fue la siguiente: 15 niños con TDAH combinado (-C), 13 con inatención (-I) y 7 con hiperactividad-impulsividad (-H). Se encontraron calificaciones menores en las sub-escalas de: ordenación de dibujos (F=3,76, gl 3,57, p=0,01), diseño con cubos (F=4,55, gl 3,57, p<0,01) y en la composición de objetos (F=4,52, gl 3,57, p<0,01). El análisis post-hoc mostró que las diferencias se produjeron entre los grupos de TDAH-I, TDAH-H y TDAH-C en relación al de control. Encontramos calificaciones menores en el CI del grupo de TDAH-I en la siguiente forma: CI-E (F=3,57, gl 3,57, p=0,02) y CI-T (F=2,90, gl 3,57 p=0,04). CONCLUSIÓN: Nuestros resultados muestran que las alteraciones de las FE pueden ser fácilmente tamizadas por WISC-R, además de medir simultáneamente el CI. Se encontró que los niños con TDAH de los 3 tipos muestran una disfunción de las FE. También se encontró que los niños con TDAH-I muestran menores puntajes del CI-E y CI-T que los controles