Recent advances in the targeting of epigenetic regulators in b-cell non-hodgkin lymphoma

In the last 10 years, major advances have been made in the diagnosis and development of selective therapies for several blood cancers, including B-cell non-Hodgkin lymphoma (B-NHL), a heterogeneous group of malignancies arising from the mature B lymphocyte compartment. However, most of these entities remain incurable and current treatments are associated with variable efficacy, several adverse events, and frequent relapses. Thus, new diagnostic paradigms and novel therapeutic options are required to improve the prognosis of patients with B-NHL. With the recent deciphering of the mutational landscapes of B-cell disorders by high-throughput sequencing, it came out that different epigenetic deregulations might drive and/or promote B lymphomagenesis. Consistently, over the last decade, numerous epigenetic drugs (or epidrugs) have emerged in the clinical management of B-NHL patients. In this review, we will present an overview of the most relevant epidrugs tested and/or used so far for the treatment of different subtypes of B-NHL, from first-generation epigenetic therapies like histone acetyl transferases (HDACs) or DNA-methyl transferases (DNMTs) inhibitors to new agents showing selectivity for proteins that are mutated, translocated, and/or overexpressed in these diseases, including EZH2, BET, and PRMT. We will dissect the mechanisms of action of these epigenetic inhibitors, as well as the molecular processes underlying their lack of efficacy in refractory patients. This review will also provide a summary of the latest strategies being employed in preclinical and clinical settings, and will point out the most promising lines of investigation in the field

Logopenic and nonfluent variants of primary progressive aphasia are differentiated by acoustic measures of speech production

Differentiation of logopenic (lvPPA) and nonfluent/agrammatic (nfvPPA) variants of Primary Progressive Aphasia is important yet remains challenging since it hinges on expert based evaluation of speech and language production. In this study acoustic measures of speech in conjunction with voxel-based morphometry were used to determine the success of the measures as an adjunct to diagnosis and to explore the neural basis of apraxia of speech in nfvPPA. Forty-one patients (21 lvPPA, 20 nfvPPA) were recruited from a consecutive sample with suspected frontotemporal dementia. Patients were diagnosed using the current gold-standard of expert perceptual judgment, based on presence/absence of particular speech features during speaking tasks. Seventeen healthy age-matched adults served as controls. MRI scans were available for 11 control and 37 PPA cases; 23 of the PPA cases underwent amyloid ligand PET imaging. Measures, corresponding to perceptual features of apraxia of speech, were periods of silence during reading and relative vowel duration and intensity in polysyllable word repetition. Discriminant function analyses revealed that a measure of relative vowel duration differentiated nfvPPA cases from both control and lvPPA cases (r2 = 0.47) with 88% agreement with expert judgment of presence of apraxia of speech in nfvPPA cases. VBM analysis showed that relative vowel duration covaried with grey matter intensity in areas critical for speech motor planning and programming: precentral gyrus, supplementary motor area and inferior frontal gyrus bilaterally, only affected in the nfvPPA group. This bilateral involvement of frontal speech networks in nfvPPA potentially affects access to compensatory mechanisms involving right hemisphere homologues. Measures of silences during reading also discriminated the PPA and control groups, but did not increase predictive accuracy. Findings suggest that a measure of relative vowel duration from of a polysyllable word repetition task may be sufficient for detecting most cases of apraxia of speech and distinguishing between nfvPPA and lvPPA

Genetic Associations in the Vitamin D Receptor and Colorectal Cancer in African Americans and Caucasians

Low vitamin D levels are associated with an increased incidence of colorectal cancer (CRC) and higher mortality from the disease. In the US, African Americans (AAs) have the highest CRC incidence and mortality and the lowest levels of vitamin D. Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been previously associated with CRC, but few studies have included AAs. We studied 795 AA CRC cases and 985 AA controls from Chicago and North Carolina as well as 1324 Caucasian cases and 990 Caucasian controls from Chicago and Spain. We genotyped 54 tagSNPs in VDR (46586959 to 46521297 Mb) and tested for association adjusting for West African ancestry, age, gender, and multiple testing. Untyped markers were imputed using MACH1.0. We analyzed associations by gender and anatomic location in the whole study group as well as by vitamin D intake in the North Carolina AA group. In the joint analysis, none of the SNPs tested was significantly associated with CRC. For four previously tested restriction fragment length polymorphisms, only one (referred to as ApaI), tagged by the SNP rs79628898, had a nominally significant p-value in AAs; none of these polymorphisms were associated with CRC in Caucasians. In the North Carolina AAs, for whom we had vitamin D intake data, we found a significant association between an intronic SNP rs11574041 and vitamin D intake, which is evidence for a VDR gene-environment interaction in AAs. In summary, using a systematic tagSNP approach, we have not found evidence for significant associations between VDR and CRC in AAs or Caucasians

Root hydrotropism is controlled via a cortex-specific growth mechanism

Plants can acclimate by using tropisms to link the direction of growth to environmental conditions. Hydrotropism allows roots to forage for water, a process known to depend on abscisic acid (ABA) but whose molecular and cellular basis remains unclear. Here, we show that hydrotropism still occurs in roots after laser ablation removed the meristem and root cap. Additionally, targeted expression studies reveal that hydrotropism depends on the ABA signalling kinase, SnRK2.2, and the hydrotropism-specific MIZ1, both acting specifically in elongation zone cortical cells. Conversely, hydrotropism, but not gravitropism, is inhibited by preventing differential cell-length increases in the cortex, but not in other cell types. We conclude that root tropic responses to gravity and water are driven by distinct tissue-based mechanisms. In addition, unlike its role in root gravitropism, the elongation zone performs a dual function during a hydrotropic response, both sensing a water potential gradient and subsequently undergoing differential growth

Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase) are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category) and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium.</p> <p>Methods</p> <p>CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in <it>ADH1C</it>, <it>APC</it>, <it>CCDN1</it>, <it>IL6</it>, <it>IL8</it>, <it>IRS1</it>, <it>MTHFR</it>, <it>PPARG</it>, <it>VDR </it>and <it>ARL11</it>, and 18 selected variants in the mucin gene family.</p> <p>Results</p> <p>None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a <it>P</it>-value < 0.05 in EPICOLON stage 1 [rs698 in <it>ADH1C </it>(OR = 1.63, 95% CI = 1.06-2.50, <it>P</it>-value = 0.02, recessive), rs1800795 in <it>IL6 </it>(OR = 1.62, 95% CI = 1.10-2.37, <it>P</it>-value = 0.01, recessive), rs3803185 in <it>ARL11 </it>(OR = 1.58, 95% CI = 1.17-2.15, <it>P</it>-value = 0.007, codominant), and rs2102302 in <it>GALNTL2 </it>(OR = 1.20, 95% CI = 1.00-1.44, <it>P</it>-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, <it>P</it>-value = 0.01, recessive). In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1.12, 95% CI = 1.00-1.25, <it>P</it>-value = 0.04, log-additive 0, 1, 2 alleles) and borderline significant for rs698 and rs2102302. The rs3803185 variant was not significantly associated with CRC risk in an external cohort (MCC-Spain), but it still showed some borderline significance in the pooled analysis of both cohorts (OR = 1.08, 95% CI = 0.98-1.18, <it>P</it>-value = 0.09, log-additive 0, 1, 2 alleles).</p> <p>Conclusions</p> <p><it>ARL11</it>, <it>ADH1C</it>, <it>GALNTL2 </it>and <it>IL6 </it>genetic variants may have an effect on CRC risk. Further validation and meta-analyses should be undertaken in larger CRC studies.</p

Impact of diabetes on the predictive value of heart failure biomarkers

Altres ajuts: This study was funded by the Redes Temáticas de Investigación Cooperativa en Salud (RETICS); Red Cardiovascular (RD12/0042/0047) as part of the Plan Nacional de I+D+I.Patients with diabetes mellitus (DM) have an increased risk of developing heart failure (HF). Further, DM is associated with poor prognosis in patients with HF. Our aim was to determine whether DM has any impact on the predictive value of a multi-biomarker panel in patients with HF. We included 1069 consecutive ambulatory HF patients in the study: age 66.2 ± 12.8 years, 33.5 ± 13.3 left ventricular ejection fraction, 36% diabetic patients. We measured serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), ST2, galectin-3, high-sensitivity C reactive protein (hs-CRP), cystatin-C, soluble transferrin receptor (sTfR), and neprilysin and followed patients for 4.9 ± 2.8 years. Primary endpoints were all-cause and cardiovascular death. During follow-up, 534 patients died; 283 died of cardiovascular causes. Diabetic subjects had higher mortality (57.7 vs. 45.6%, p < 0.001). NTproBNP (p = 0.07), hs-TnT (p < 0.001), galectin-3 (p < 0.001), and cystatin-C (p = 0.001) concentrations were higher in diabetic patients, whereas sTfR levels were lower (p = 0.005). There were no interactions between DM and NTproBNP, hs-TnT, galectin-3, hs-CRP, cystatin-C, sTfR, and neprilysin relative to risk prediction for all-cause or cardiovascular death. By contrast, ST2 significantly interacted with DM for all-cause (p = 0.02) and cardiovascular (p = 0.03) death. In diabetic patients, HRs for ST2 were 1.27 (95% CI 1.16-1.40, p < 0.001) and 1.23 (95% CI 1.09-1.39, p = 0.001) for all-cause and cardiovascular death, respectively. In nondiabetic patients, HRs for ST2 were 1.53 (95% CI 1.35-1.73, p < 0.001) and 1.64 (95% CI 1.31-2.05, p < 0.001) for all-cause and cardiovascular death, respectively. The multivariable Cox regression analysis showed that hs-TnT and ST2 were the only markers that were independently associated with both all-cause and cardiovascular mortality in patients with HF and diabetes. Moreover, in these patients, the combination of these two markers significantly increased discrimination as assessed by the area under the curve. Biomarkers used in the general population to predict the clinical course of heart failure are also useful in patients with diabetes. In these patients, among all the biomarkers analysed only hs-TnT and ST2 were independently associated with both all-cause and cardiovascular mortality

Descriptive analysis of childbirth healthcare costs in an area with high levels of immigration in Spain

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to estimate the cost of childbirth in a teaching hospital in Barcelona, Spain, including the costs of prenatal care, delivery and postnatal care (3 months). Costs were assessed by taking into account maternal origin and delivery type.</p> <p>Methods</p> <p>We performed a cross-sectional study of all deliveries in a teaching hospital to mothers living in its catchment area between October 2006 and September 2007. A process cost analysis based on a full cost accounting system was performed. The main information sources were the primary care program for sexual and reproductive health, and hospital care and costs records. Partial and total costs were compared according to maternal origin and delivery type. A regression model was fit to explain the total cost of the childbirth process as a function of maternal age and origin, prenatal care, delivery type, maternal and neonatal severity, and multiple delivery.</p> <p>Results</p> <p>The average cost of childbirth was 4,328€, with an average of 18.28 contacts between the mother or the newborn and the healthcare facilities. The delivery itself accounted for more than 75% of the overall cost: maternal admission accounted for 57% and neonatal admission for 20%. Prenatal care represented 18% of the overall cost and 75% of overall acts. The average overall cost was 5,815€ for cesarean sections, 4,064€ for vaginal instrumented deliveries and 3,682€ for vaginal non-instrumented deliveries (p < 0.001). The regression model explained 45.5% of the cost variability. The incremental cost of a delivery through cesarean section was 955€ (an increase of 31.9%) compared with an increase of 193€ (6.4%) for an instrumented vaginal delivery. The incremental cost of admitting the newborn to hospital ranged from 420€ (14.0%) to 1,951€ (65.2%) depending on the newborn's severity. Age, origin and prenatal care were not statistically significant or economically relevant.</p> <p>Conclusions</p> <p>Neither immigration nor prenatal care were associated with a substantial difference in costs. The most important predictors of cost were delivery type and neonatal severity. Given the impact of cesarean sections on the overall cost of childbirth, attempts should be made to take into account its higher cost in the decision of performing a cesarean section.</p

Responsiveness of the EQ-5D in breast cancer patients in their first year after treatment

<p>Abstract</p> <p>Background/aim</p> <p>The EQ-5D is a generic health-related quality of life (HRQoL) measure that is used for the purpose of economic evaluations of health interventions. Therefore, it has to be responsive to meaningful changes in health in the patient population under investigation. The aim of this study was to investigate the responsiveness of the EQ-5D in breast cancer patients in their first year after treatment.</p> <p>Methods</p> <p>The subscale global health of the disease-specific HRQoL measure EORTC QLQ-C30 was used as a reference instrument to determine meaningful changes in health and identify subgroups of patients: patients reporting a moderate-large deterioration, small deterioration, a small improvement, moderate-large improvement, or no change in health status. Responsiveness was evaluated by calculating standardized response means (SRMs) in the five subgroups of patients and performing analysis of variance procedures. The two HRQoL measures were filled out two weeks and one year after finalizing curative treatment for breast cancer (n = 192).</p> <p>Results</p> <p>The EQ-5D was able to capture both improvements and deteriorations in HRQoL. SRMs of the EQ VAS and EQ-5D Index were close to zero in the subgroup reporting no change and increased and decreased adequately in the subgroups reporting small and moderate changes. Additional analysis of variance procedures showed that the EQ-5D was able to differentiate between subgroups of patients with no change and moderate-large deterioration or improvement in health.</p> <p>Conclusion</p> <p>The EQ-5D seems an appropriate measure for the purpose of economic evaluations of health intervention in breast cancer patients after treatment.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN74071417.</p

Relative Roles of Grey Squirrels, Supplementary Feeding, and Habitat in Shaping Urban Bird Assemblages

Non-native species are frequently considered to influence urban assemblages. The grey squirrel Sciurus carolinensis is one such species that is widespread in the UK and is starting to spread across Europe; it predates birds’ nests and can compete with birds for supplementary food. Using distance sampling across the urbanisation intensity gradient in Sheffield (UK) we test whether urban grey squirrels influence avian species richness and density through nest predation and competition for supplementary food sources. We also assess how urban bird assemblages respond to supplementary feeding. We find that grey squirrels slightly reduced the abundance of breeding bird species most sensitive to squirrel nest predation by reducing the beneficial impact of woodland cover. There was no evidence that grey squirrel presence altered relationships between supplementary feeding and avian assemblage structure. This may be because, somewhat surprisingly, supplementary feeding was not associated with the richness or density of wintering bird assemblages. These associations were positive during the summer, supporting advocacy to feed birds during the breeding season and not just winter, but explanatory capacity was limited. The amount of green space and its quality, assessed as canopy cover, had a stronger influence on avian species richness and population size than the presence of grey squirrels and supplementary feeding stations. Urban bird populations are thus more likely to benefit from investment in improving the availability of high quality habitats than controlling squirrel populations or increased investment in supplementary feeding

Quality of life among Latina breast cancer patients: a systematic review of the literature

Introduction The Latino population is the most rapidly growing ethnic minority in the United States and Latinas have higher rates of advanced breast cancer and more rigorous treatments than White women. However, the literature lacks reviews on quality of life among this population of breast cancer patients. Methods A systematic review of the breast cancer quality of life (QOL) literature was conducted among studies that provided a comparison of mental, physical, social, or sexual QOL between Latinas and other racial/ethnic groups. Of the 375 studies reviewed, 20 quantitative studies and two qualitative studies met criteria for inclusion. Results Latinas were more likely to report poor mental, physical, and social QOL, relative to non-Latinas. Only four studies assessed sexual QOL, making it difficult to draw any conclusions. Of these four QOL domains, the largest disparity was found in the area of mental health in which Latinas reported poorer QOL compared to non-Latina Whites and Blacks. Discussion/conclusions Most quantitative studies revealed either that Latinas consistently evidenced significantly lower QOL than non-Latinas on all measures (6 studies) or reported mixed findings in which Latinas generally demonstrated significantly worse QOL on most, but not all, measures (12 studies) included in the study. Explanatory mechanisms including socio-demographic, treatment-related, and culturally-relevant factors are discussed. Implications for research design, measurement, and clinical work are also included. Implications for cancer survivors Although not entirely consistent, data suggest that Latina breast cancer survivors on average experience worse QOL than non-Latina Whites. Understanding ethnic differences in QOL among breast cancer survivors can inform interventions targeted at improving health status for Latinas