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Personality traits are relevant in understanding substance use disorders (SUD) and schizophrenia (SZ), but few works have also included patients with dual schizophrenia (SZ+) and personality traits. We explored personality profile in a sample of 165 male patients under treatment, using the Temperament and Character Inventory-Revised. The participants were assigned to three groups of 55 patients each, according to previous diagnosis: SUD, SZ- and SZ+ (without/with SUD). We analyzed their clinical characteristics, relating them to personality dimensions. The SUD and SZ+ groups scored higher than SZ- in Novelty/Sensation Seeking. SZ- and SZ+ presented higher Harm Avoidance and lower Persistence than the SUD group. SZ+ patients showed the lowest levels of Self-directedness, while SZ- and SZ+ had higher scores in Self-transcendence than the SUD group. Several clinical characteristics were associated with personality dimensions depending on diagnosis, and remarkably so for psychiatric symptoms in the SZ- and SZ+ groups. The three groups had a maladaptive personality profile compared to general population. Our results point to different profiles for SUD versus SZ, while both profiles appear combined in the SZ+ group, with extreme scores in some traits. Thus, considering personality endophenotypes in SZ+ could help in designing individualized interventions for this group.

El presente trabajo explora el curso clínico y las recaídas en una muestra de 223 pacientes varones, con seguimientos a los 3, 6 y 12 meses y un diseño no estudiado previamente. Éstos se distribuyeron en tres grupos: 80 con patología dual (PD; 37 con esquizofrenia y 43 con depresión mayor), 80 con trastorno por uso de sustancias (TUS) y 63 con trastorno mental severo (TMS; 32 con esquizofrenia y 31 con depresión mayor). Los grupos PD y TMS mostraron más adherencia al tratamiento que el TUS a los 6 (p = 0,035) y 12 meses (p = 0,008). Los intentos de suicidio no difirieron entre grupos a los 3 meses, pero sí a los 6 (p = 0.040) y 12 meses (p = 0.007) con una mayor tasa de intentos en los grupos PD y TUS. Los pacientes PD y TMS con depresión mayor fueron quienes sumaron mayor casuística en los intentos de suicido durante el seguimiento. El 21,8% de pacientes PD tuvieron un intento de suicidio durante el seguimiento. En todos los seguimientos, el grupo PD presentó el mayor número de consultas médicas externas al tratamiento principal, el grupo SUD mostró el menor número y el grupo TMS una posición intermedia (p

Las estrategias de afrontamiento tienen un impacto en los trastornos por uso de sustancias (TUS) y en los trastornos mentales severos (TMS), tanto a nivel de características clínicas como de adherencia al tratamiento. Sin embargo, el conocimiento en esta área es escaso, especialmente en los pacientes con patología dual (PD). El presente trabajo explora si existen diferencias en las estrategias de afrontamiento en pacientes varones adheridos a tratamiento con diagnóstico de PD (37 con esquizofrenia y 42 con depresión mayor), TUS (80) y TMS (31 con esquizofrenia y 32 con depresión mayor). Los grupos PD y SUD no diferían en los meses de abstinencia o la severidad de la adicción, y la cocaína y el alcohol eran las sustancias principales de consumo, aunque en ambos casos prevalecía el policonsumo. Todos los pacientes con TMS se hallaban estables. Los análisis de varianza, considerando la edad como covariable, indicaron diferencias entre grupos en las estrategias de autocrítica (F (2,121)=10,75; p

In common with other self-cleaving RNAs, the lead-dependent ribozyme (leadzyme) undergoes dynamic fluctuations to a chemically activated conformation. We explored the connection between conformational dynamics and self-cleavage function in the leadzyme using a combination of NMR spin-relaxation analysis of ribose groups and conformational restriction via chemical modification. The functional studies were performed with a North-methanocarbacytidine modification that prevents fluctuations to C2′-endo conformations while maintaining an intact 2′-hydroxyl nucleophile. Spin-relaxation data demonstrate that the active-site Cyt-6 undergoes conformational exchange attributed to sampling of a minor C2′-endo state with an exchange lifetime on the order of microseconds to tens of microseconds. A conformationally restricted species in which the fluctuations to the minor species are interrupted shows a drastic decrease in self-cleavage activity. Taken together, these data indicate that dynamic sampling of a minor species at the active site of this ribozyme, and likely of related naturally occurring motifs, is strongly coupled to catalytic function. The combination of NMR dynamics analysis with functional probing via conformational restriction is a general methodology for dissecting dynamics-function relationships in RNA.

There is urgent need for health systems to prevent diabetes. To date, few health systems have implemented the evidence-based Diabetes Prevention Program (DPP), and the few that have mostly partnered with community-based organizations to implement the program. Given the recent decision by the Centers for Medicare & Medicaid Services to reimburse for diabetes prevention, there is likely much interest in how such programs can be implemented within large health systems or how community partnerships can be expanded to support DPP implementation. Beginning in 2010, Montefiore Health System (MHS), a large health care system in the Bronx, NY, partnered with the Young Men's Christian Association (YMCA) of Greater New York to deliver the YMCA's DPP. Over 4 years, 1390 referrals to YMCA's DPP were made; 287 participants attended ≥3 classes, and average weight loss was 3.4%. Because of increased patient demand and internal capacity, MHS assumed responsibility for DPP implementation in May 2015. Fully integrating the program within the health system took 5–6 months, including configuring electronic health record templates/reports, hiring a coordinator, and creating clinical referral workflows/training guides. Billing workflows were designed for risk-based contracts. In the first 11 months of implementation, 1277 referrals were made, and referrals increased over time. Twenty-four class cycles were initiated, and 282 patients began attending classes. Average weight loss among 61 graduates from the Summer/Fall 2015 wave of MDPP classes was 3.8%. Additional opportunities for expansion include training allied health staff, providing patient incentives, increasing master trainer capacity, offering DPP to employees, and securing reimbursement.

Service learning holds the potential to educate for citizenship, preparing students as individuals who can respond not only to the daily challenges of an interconnected yet fragmented world but also to the emerging calls to rebuild disaster-stricken communities. Although seen by some as a cumbersome pedagogical approach, service learning can offer opportunities for students to recognize their role in society, take part in intercultural conversation, and develop into critical citizens, making it worthwhile to undertake for a citizenship oriented towards social justice. This case study illustrates such meaningful accounts from undergraduate students involved in postdisaster rehabilitation and recovery efforts.

Population dynamics is a branch of ecology that studies temporal changes in the abundance of a population of organisms over time. This paper presents a study of the factors influencing population abundance of the acanthocephalan Neoechinorhynchus brentnickoli in Dormitator latifrons, the Pacific fat sleeper, from Tres Palos Lagoon. Fish were sampled from February 2012 to February 2013. A total of 688 adult fish were examined. The mean total length of fish varied significantly from 16.10 ± 1.93 cm (September 2012) to 20.78 ± 3.82 cm (August 2012). ‘Prevalence of acanthocephalans exceeded 90% in all months, and mature individuals were present year round, indicating that recruitment of helminths occurred throughout the year. Mean abundance ranged from 32.3 (July 2012) to 89.3 helminths per fish (March 2012) and was significantly lower in the rainy season. The body size of fish was the best predictor of acanthocephalan abundance in every month; larger fish harbored more acanthocephalans than smaller o...

Purpose The purpose of this study was to identify patient and program delivery characteristics associated with engagement and weight loss in a Diabetes Prevention Program (DPP) implemented in an urban hospital system. Methods Patient and program delivery data were collected between July 2015 and December 2017. DPP eligibility was determined based on age, body mass index (BMI), and hemoglobin A1C data via the electronic health record. Engagement was measured at 3 levels: ≤3 sessions, 4 to 8 sessions, and ≥9 sessions. Weight was measured at each DPP session. Results Among the eligible patients (N = 31 524), referrals and engagement were lower in men than women, in Spanish speakers than English speakers, in younger (18-34 years) and middle-aged (35-54 years) than older adults, and in patients receiving Medicaid than other patients. Referral and engagement were higher in patients with higher BMIs and those prescribed ≥5 medications. Current smokers were less frequently engaged. Prior health care provider contact was associated with higher engagement. Overall, 28% of DPP participants achieved ≥5% weight loss; younger and middle-aged patients and those who gained weight in the prior 2 years were less likely to lose weight. Conclusion This assessment identified characteristics of patients with lower levels of referral and engagement. The DPP staff may need to increase outreach to address barriers to referral and during all points of engagement among men, younger patients, and Spanish speakers. Future research is needed to increase understanding with regard to why referrals and engagement are lower among these groups.

Coping strategies have an impact on substance use disorders (SUD), relapses, and clinical variables, but knowledge on this area is scarce. We explored the coping strategies used during treatment in patients with dual diagnosis (DD), SUD, and severe mental illness (SMI), and the relation with clinical course and relapses at one-year follow-up. A sample of 223 patients was divided into three groups depending on diagnosis: DD (N = 80; SUD with comorbid schizophrenia or major depressive disorder), SUD only (N = 80), and SMI only (N = 63; schizophrenia or major depressive disorder). MANCOVA analyses reflected differences in self-criticism and problem avoidance, with a higher use of these in the DD and SUD groups. The coping strategies used differed depending on the presence/absence of a SUD, but not depending on psychiatric diagnosis. At one-year follow-up, social support was the only strategy that predicted the presence of relapses in DD patients with schizophrenia (positively), and in SMI patients with major depressive disorder (negatively). Thus, social support was associated with relapses, but the relationship was different depending on psychiatric diagnosis. Further studies should analyze the implications of social support as a coping strategy in different mental disorders, as well as its usefulness in individualized interventions.

Personality plays an important role in individuals with Substance Use Disorder (SUD) and co-occurring Severe Mental Illness (SMI). However, the possible personality differences in SUD patients considering their co-occurring SMI remain unknown. We explored the personality in a sample of 104 male patients with SUD and SMI: 35 had co-occurring Schizophrenia (SZ +), 32 had Bipolar Disorder (BD +), and 35 had Major Depressive Disorder (MDD +). We followed the Alternative Five Factor Model and used the Zuckerman-Kuhlman Personality Questionnaire. Moreover, we examined the relationship among SUD and SMI variables, and personality. The type of co-occurring SMI modulates the Neuroticism-Anxiety, Sociability, and Impulsivity Sensation-Seeking personality traits. BD + patients were characterized by a higher Neuroticism-Anxiety than MDD +, and a higher Impulsivity Sensation-Seeking than SZ + and MDD +. Manic symptoms were positively linked to Neuroticism-Anxiety for BD +. Patients with SZ + showed a lower Sociability than BD +, and an older age of SUD onset was related to a higher sociability for SZ +. Overall, SUD treatment for BD + patients should emphasize strategies to manage negative emotions and impulsivity. Our results underline the importance of a dimensional understanding of personality among patients with SUD and co-occurring SMI, which could inform of specific approaches to improve their treatment and prognosis.

In this paper, we study the elastic properties of the entropy-stabilized oxide (Mg, Co, Ni, Cu, Zn)O using experimental and first principles techniques. Our measurements of the indentation modulus on grains with a wide range of crystallographic orientations of the entropy-stabilized oxide revealed a high degree of elastic isotropy at ambient conditions. First principles calculations predict mild elastic anisotropy for the paramagnetic structure, which decreases when the system is considered to be non-magnetic. When the antiferromagnetic state of CoO, CuO, and NiO is accounted for in the calculations, a slight increase in elastic anisotropy is observed, suggesting a coupling between magnetic ordering and the orientation dependent elastic properties. Furthermore, an examination of the local structure reveals that the isotropy is favored through local ionic distortions of Cu and Zn—due to their tendencies to form tenorite and wurtzite phases. The relationships between the elastic properties of the multicomponent oxide and those of its constituent binary oxides are reviewed. These insights open up new avenues for controlling isotropy for technological applications through tuning composition and structure in the entropy-stabilized oxide or the high-entropy compounds in general.

Nanostructured thin films were synthesized using a silica-based sol-gel method. The morphology of the films was tailored by controlling the hydrolysis and crosslinking mechanisms of the tetraethyl orthosilicate precursor. Silica nanoparticle self-assembled structures and linear silica chains were crosslinked and formed monolithic nanostructured films. The self-assembly mechanism was investigated using coarse-grained molecular dynamic simulation. Three nanostructured configurations were synthesized and studied to optimize the surface features of the films and minimize the adhesion of sand particles. Surface microscopy imaging and adhesion force measurements using atomic force microscopy with an attached silica particle on the cantilever tip were performed to correlate the adhesion force and the surface structure. The solar specular reflectance of coated solar mirror samples was measured across the solar spectrum before and after the soiling test of the samples. The mechanical properties of the thin films were evaluated using nanoindentation measurements on coated substrates. The solution-derived thin film coatings can provide anti-soiling protection of solar glass in desert environments and increase the efficiency of photovoltaic and concentrated solar power installations.

The efficiency of generating electricity from heat using concentrated solar power plants (which use mirrors or lenses to concentrate sunlight in order to drive heat engines, usually involving turbines) may be appreciably increased by operating with higher turbine inlet temperatures, but this would require improved heat exchanger materials. By operating turbines with inlet temperatures above 1,023 kelvin using closed-cycle high-pressure supercritical carbon dioxide (sCO2) recompression cycles, instead of using conventional (such as subcritical steam Rankine) cycles with inlet temperatures below 823 kelvin1–3, the relative heat-to-electricity conversion efficiency may be increased by more than 20 per cent. The resulting reduction in the cost of dispatchable electricity from concentrated solar power plants (coupled with thermal energy storage4–6) would be an important step towards direct competition with fossil-fuel-based plants and a large reduction in greenhouse gas emissions7. However, the inlet temperatures of closed-cycle high-pressure sCO2 turbine systems are limited8 by the thermomechanical performance of the compact, metal-alloy-based, printed-circuit-type heat exchangers used to transfer heat to sCO2. Here we present a robust composite of ceramic (zirconium carbide, ZrC) and the refractory metal tungsten (W) for use in printed-circuit-type heat exchangers at temperatures above 1,023 kelvin9. This composite has attractive high-temperature thermal, mechanical and chemical properties and can be processed in a cost-effective manner. We fabricated ZrC/W-based heat exchanger plates with tunable channel patterns by the shape-and-size-preserving chemical conversion of porous tungsten carbide plates. The dense ZrC/W-based composites exhibited failure strengths of over 350 megapascals at 1,073 kelvin, and thermal conductivity values two to three times greater than those of iron- or nickel-based alloys at this temperature. Corrosion resistance to sCO2 at 1,023 kelvin and 20 megapascals was achieved10 by bonding a copper layer to the composite surface and adding 50 parts per million carbon monoxide to sCO2. Techno-economic analyses indicate that ZrC/W-based heat exchangers can strongly outperform nickel-superalloy-based printed-circuit heat exchangers at lower cost. A robust ceramic/refractory metal (ZrC/W)-based composite for use in heat exchangers in concentrated solar power plants above 1,023 kelvin is described, having attractive high-temperature thermal, mechanical and chemical properties combined with cost-effective processing.

The purpose of this study was to determine the plasma pharmacokinetics (PK) and toxicity of zebularine, an oral cytidine analog with demethylating activity, in dogs. Plasma zebularine concentrations were determined by HPLC-MS/MS following an oral zebularine dose of 8 or 4 mg kg-1 . Plasma zebularine clearance was constant. Mean maximum concentration (Cmax ) was 23 ± 4.8 and 8.6 ± 1.4 µM following 8 and 4 mg kg-1 , respectively. Mean half-life was 5.7 ± 0.84 and 7.1 ± 2.1 following 8 and 4 mg kg-1 , respectively. A single 8 mg kg-1 dose was well tolerated. Daily 4 mg kg-1 treatment in three laboratory dogs resulted in grade 4 neutropenia (n = 3), grade 1 anorexia (n = 2) and grade 1 or 2 dermatologic changes (n = 2). All adverse events resolved with supportive care. A 4 mg kg-1 dose every 21 days was well tolerated. A follow-up dose escalation study is in progress with a lower starting dose.

Here bicyclo[3.1.0]hexane locked deoxycytidine (S-MCdC, N-MCdC), and deoxyadenosine analogs (S-MCdA and N-MCdA) were examined as substrates for purified preparations of human deoxynucleoside kinases: dCK, dGK, TK2, TK1, the ribonucleoside kinase UCK2, two NMP kinases (CMPK1, TMPK) and a NDP kinase. dCK can be important for the first step of phosphorylation of S-MCdC in cells, but S-MCdCMP was not a substrate for CMPK1, TMPK, or NDPK. dCK and dGK had a preference for the S-MCdA whereas N-MCdA was not a substrate for dCK, TK1, UCK2, TK2, dGK nucleoside kinases. The cell growth experiments suggested that N-MCdC and S-MCdA could be activated in cells by cellular kinases so that a triphosphate metabolite was formed. List of abbreviations: ddC, 2', 3'-didioxycytosine, Zalcitabine; 3TC, β-L-(-)-2',3'-dideoxy-3'-thiacytidine, Lamivudine; CdA, 2-cloro-2'-deoxyadenosine, Cladribine; AraA, 9-β-D-arabinofuranosyladenine; hCNT 1-3, human Concentrative Nucleoside Transporter type 1, 2 and 3; hENT 1-4, human Equilibrative Nucleoside Transporter type 1, 2, 3, and 4.

he XXI International Round Table (IRT) on Chemical Biology of Nucleic Acids was held in PoznanPoland, August 24�28, 2014. It attracted 400 scientists from 32 countries. Various aspects of chemistry and biology of nucleic acids and their components were discussed. There were 23 invited talks and 33 oral presentations covering topics ranging from chemical synthesis of nucleic acids to their application as drugs and tools. The meeting highlighted recent advances in DNA and RNA chemistry, biology, biochemistry, and biophysics and identified emerging concepts of their application in molecular medicine. Many talks presented at the meeting illustrated ways to approach biological properties to answer both general and detailed questions in chemical biology of nucleosides, nucleotides, and nucleic acids. More than 250 posters were presented. The poster session offered an opportunity for undergraduate Ph.D. students, postdoctoral fellows, and early career researchers to present their results and interact together and with senior scientists.To acknowledge outstanding scientific results of these young scientists, several "IS3NA, A. HolyIRT Poster Awards," sponsored by Gilead Sciences were distributed in honor of Professor Antoni

Non-small-cell lung cancer is the leading cause of cancer-related death worldwide. Chemotherapies such as the topoisomerase II (TopoII) inhibitor etoposide effectively reduce disease in a minority of patients with this cancer; therefore, alternative drug targets, including epigenetic enzymes, are under consideration for therapeutic intervention. A promising potential epigenetic target is the methyltransferase EZH2, which in the context of the polycomb repressive complex 2 (PRC2) is well known to tri-methylate histone H3 at lysine 27 (H3K27me3) and elicit gene silencing. Here we demonstrate that EZH2 inhibition has differential effects on the TopoII inhibitor response of non-small-cell lung cancers in vitro and in vivo. EGFR and BRG1 mutations are genetic biomarkers that predict enhanced sensitivity to TopoII inhibitor in response to EZH2 inhibition. BRG1 loss-of-function mutant tumours respond to EZH2 inhibition with increased S phase, anaphase bridging, apoptosis and TopoII inhibitor sensitivity. Conversely, EGFR and BRG1 wild-type tumours upregulate BRG1 in response to EZH2 inhibition and ultimately become more resistant to TopoII inhibitor. EGFR gain-of-function mutant tumours are also sensitive to dual EZH2 inhibition and TopoII inhibitor, because of genetic antagonism between EGFR and BRG1. These findings suggest an opportunity for precision medicine in the genetically complex disease of non-small-cell lung cancer.

Background Patient-perceived health-related quality of life has become an important outcome in health care as an indicator of treatment effectiveness and recovery for patients with substance use disorder. As no study has assessed health-related quality of life among male patients with substance use disorder and co-existing severe mental illness, we compared health-related quality of life among patients with substance use disorder and the following severe mental illness diagnosis in Barcelona, Spain: schizophrenia, bipolar disorder, major depressive disorder, and examined the associations with clinically related variables. Additionally, we compared results for health-related quality of life in patients with substance use disorder and severe mental illness, with Spanish population norms. Methods We assessed 107 substance use disorder male patients using the 36-Item Short Form Health Survey comparing results across three groups with: comorbid schizophrenia (n = 37), comorbid bipolar disorder (n = 34), and comorbid major depressive disorder (n = 36). Multiple analyses of variance were performed to explore health-related quality of life by the type of co-existing SMI and linear regression analyses examined clinical correlates for the 36-Item Short Form Health Survey dimensions for each group. Results There were differences in Physical Functioning, Vitality and the Physical Composite Scale among groups. Poorer Physical Functioning was observed for patients with comorbid schizophrenia (80.13±3.27) and major depressive disorder (81.97±3.11) compared with comorbid bipolar disorder patients (94.26±1.93). Patients with substance use disorder and schizophrenia presented lower scores in Vitality (41.6±2.80) than those with co-existing bipolar disorder (55.68±3.66) and major depressive disorder (53.63±2.92). Finally, results in the Physical Composite Scale showed lower scores for patients with comorbid schizophrenia (51.06±1.41) and major depressive disorder (51.99±1.87) than for those with bipolar disorder (60.40±2.17). Moreover, all groups had poorer health-related quality of life, especially Social Functioning, Role-Emotional and Mental Health, compared with population norms. Different clinical variables (e.g. medical disease comorbidity, severity of addiction, psychiatric symptomatology, suicide attempts, drug relapses) were related to different health-related quality of life dimensions depending on the co-existing severe mental illness. Conclusions Among male patients with substance use disorder, co-existing severe mental illness may influence some health-related quality of life dimensions and clinically related variables. Such differences may require tailored therapeutic interventions.

Nucleic Acids Research, 26 (10), ISSN:1362-4962, ISSN:0301-5610

Opiate substitution treatment and needle exchanges have reduced blood borne virus (BBV) transmission among people who inject drugs (PWID). Psychosocial interventions could further prevent BBV. A systematic review and meta-analysis examined whether psychosocial interventions (e.g. CBT, skills training) compared to control interventions reduced BBV risk behaviours among PWID. 32 and 24 randomized control trials (2000-May 2015 in MEDLINE, PsycINFO, CINAHL, Cochrane Collaboration and Clinical trials, with an update in MEDLINE to December 2016) were included in the review and meta-analysis respectively. Psychosocial interventions appear to reduce: sharing of needles/syringes compared to education/information (SMD −0.52; 95% CI −1.02 to −0.03; I2 = 10%; p = 0.04) or HIV testing/counselling (SMD −0.24; 95% CI −0.44 to −0.03; I2 = 0%; p = 0.02); sharing of other injecting paraphernalia (SMD −0.24; 95% CI −0.42 to −0.06; I2 = 0%; p

Introduction The reach of the New York State YMCA's Diabetes Prevention Program (DPP) to at-risk populations may be increased through integration with primary care settings. Although considerable effort has been made in the referral and retention of patients, little is known about the factors associated with the placement of potential participants into YMCA's DPP. Methods Among Montefiore Health System (MHS) patients referred to YMCA's DPP (n = 1,249) from July 10, 2010, through November 11, 2015, we identified demographic factors (eg, age, preferred language) and primary care practice-level factors (eg, time between referral and start of session, session season) associated with placement into a session and subsequent drop-out. We also evaluated factors associated with weight loss. Results Patients were predominantly female (71%) and aged 45 years or older (71%). Patients preferring sessions in Spanish were less often placed in sessions. Patients aged 18 to 44 years were less often placed (P = .01) and enrolled (P = .001) than patients aged 60 years or older. Sessions conducted in the summer and spring had higher enrollment than fall and winter months. Patients who started the YMCA's DPP within 2 months of their referral date were more often enrolled (54.4%) than patients who waited 4 or more months (21.6%) to start their sessions. Patients aged 45 to 59 years lost marginally less weight than those aged 60 years or older (-3.1% vs -3.8%; P = .07). Conclusion Although this evaluation gives some insight into the barriers to placement and enrollment in YMCA's DPP, challenges remain. Efforts are under way to increase referral of patients to community-based DPPs.

Background Electronic prescription was traditionally used in our country by primary health centres but it has also been progressively introduced into hospitals. This has had an economic impact on some products, such as those used in artificial home nutrition. Purpose To assess the economic impact arising from electronic prescription of diet products at a specialty hospital. To establish effective measures to compensate for the economic impact resulting from the transfer of responsibilities from primary health care to hospital care. Material and methods Retrospective observational study of the increase in spending and number of prescriptions for diet products in outpatient clinics and on hospital discharge. The period from November 2014 to October 2015 was compared with an equivalent period from the previous year. These data were then correlated with percentage of implementations of the electronic prescription module. Prescription details, number of prescriptions and costs were retrieved from the Microstrategy assistance application. The data were broken down by medical service, prescriber and product. Results After analysing the data, an increase in home prescriptions for diet products was found: the number of prescriptions rose by 45.24%, which caused a total increase in costs of 55.14%. These data are explained by a higher degree of implementation of the electronic prescription module (88% in 2014 vs 98.28% in 2015), as well as greater flexibility in computer based procedures for visa issuance. The endocrinology department was responsible for 66.9% of diet product spending. We observed a greater increase in prescription of complete formulae for diabetics (99.08%); polymeric, normoproteic, normocaloric, fibre-free formulae (538.46%), and hypercaloric, fibre-rich formulae (149.36%). A project was developed to incorporate the pharmacist into the visa circuit, in order to ensure efficient management of diet products in compliance with national legislation. To accomplish this goal, the unit of clinical management of pharmacy undertakes the management of visa approval for diet products. Conclusion Prescribing via electronic prescription has involved an increase in spending on artificial home diet at our centre. Incorporating a hospital pharmacist into the visa circuit might optimise usage of dietary therapeutic products, thereby ensuring compliance with safety and efficacy criteria, as well as appropriateness of treatment and patient follow-up. No conflict of interest

Background Iron deficiency (ID) is an important comorbidity associated with chronic heart failure. This often leads to worsening functional class, quality of life and poor prognosis. Diagnosis and prompt treatment of ID are essential. Purpose The aim of this study was to analyse compliance with a new protocol for intravenous ferric carboxymaltose (FCM) in the heart failure unit and the short term safety and analytical profile of intravenous FCM. Material and methods A review was conducted by a multidisciplinary team (MT). After review, the MT decided to implement a new protocol using FCM in a definite group of patients. Absolute ID was defined as ferritin Results 62 patients were analysed in this retrospective observational study. Mean age was 65.2±12.9 years, and patients were predominantly men (70%). Relevant laboratory parameters before and after treatment with intravenous FCM were requested and analysed according to the protocol. Haematological and iron status parameters: haemoglobin (13.04 vs 13.78 mg/dL), haematocrit (38.5 vs 41.6), blood iron level (67.85 vs 109.11 mg/dL), ferritin (79.65 vs 424.62 mg/dL) and TSAT (17.23% vs 33.64%) improved significantly (p Conclusion In our study, this therapy safely and effectively corrected deficient iron stores in the short term. Studies that analysed the effects of intravenous iron treatment in patients with heart failure have demonstrated improved quality of life and functional capacity. The intravenous FCM protocol had an acceptable degree of compliance but the importance of diagnosis and monitoring patients must be stressed as the long term effects of intravenous iron therapy are not yet well defined. No conflict of interest

The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2–5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined. Fil: Garcia, Lia C.. Instituto Nacional de Tecnología Industrial; Argentina Fil: Gandolfi Donadío, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina Fil: Mann, Ella. Ben Gurion University of The Negev; Israel Fil: Kolusheva, Sofiya. Ben Gurion University of The Negev; Israel Fil: Kedei, Noemi. National Cancer Institute. Bethesda; Estados Unidos Fil: Lewin, Nancy E.. National Cancer Institute. Bethesda; Estados Unidos Fil: Hill, Collin S.. National Cancer Institute. Bethesda; Estados Unidos Fil: Kelsey, Jessica S.. National Cancer Institute. Bethesda; Estados Unidos Fil: Yang, Jing. National Cancer Institute. Bethesda; Estados Unidos Fil: Esch, Timothy E.. National Cancer Institute. Bethesda; Estados Unidos Fil: Santos, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina Fil: Peach, Megan L.. National Institutes of Health; Estados Unidos Fil: Kelley, James A.. National Institutes of Health; Estados Unidos Fil: Blumberg, Peter M.. National Cancer Institute. Bethesda; Estados Unidos Fil: Jelinek, Raz. Ben Gurion University of The Negev; Israel Fil: Marquez, Victor E.. National Institutes of Health; Estados Unidos Fil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentina

Leukemia stem cells (LSC) are resistant to conventional chemotherapy and persistent LSC after chemotherapy are supposed to be a major cause of relapse. However, information on genetic or epigenetic regulation of stem cell properties is still limited and LSC-targeted drugs have scarcely been identified. Epigenetic regulators are associated with many cellular processes including maintenance of stem cells. Of note are polycomb group proteins, because they potentially control stemness, and can be pharmacologically targeted by a selective inhibitor (DZNep). Therefore, we investigated the therapeutic potential of EZH2 inhibition in mixed lineage leukemia (MLL) fusion leukemia. Intriguingly, EZH2 inhibition by DZNep or shRNA not only suppressed MLL fusion leukemia proliferation but also reduced leukemia initiating cells (LIC) frequency. Expression analysis suggested that p16 upregulation was responsible for LICs reduction. Knockdown of p16 canceled the survival advantage of mice treated with DZNep. Chromatin immunoprecipitation assays demonstrated that EZH2 was highly enriched around the transcription-start-site of p16, together with H3K27 methylation marks in MLL/ENL and Hoxa9/Meis1 transduced cells but not in E2A/HLF transduced cells. Although high expression of Hoxa9 in MLL fusion leukemia is supposed to be responsible for the recruitment of EZH2, our data also suggest that there may be some other mechanisms independent of Hoxa9 activation to suppress p16 expression, because expression levels of Hoxa9 and p16 were not inversely related between MLL/ENL and Hoxa9/Meis1 transduced cells. In summary, our findings show that EZH2 is a potential therapeutic target of MLL fusion leukemia stem cells.

To explore the feasibility of developing ligands targeted to the atypical C1 domains of protein kinase C ζ and ι, we have prepared diacylglycerol lactones substituted with hydrophilic groups on their side chains, which potentially could interact with the arginine residues that distinguish the atypical C1 domains of PKCζ and PKCι from typical C1 domains, and we have measured their binding to mutated versions of the C1b domain of PKCδ that incorporate one or more of these arginine residues. The most selective of the diacylglycerol lactones showed only a 10-fold reduction in binding affinity with the triple arginine mutant (N7R/S10R/L20R) compared to the wild-type, whereas phorbol 12,13-dibutyrate showed a 6000-fold loss of affinity. Molecular modeling confirms that these ligands are indeed able to interact with the arginine residues. Our results show that dramatic changes in selectivity can be obtained through appropriate substitution of diacylglycerol lactones.

The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS.

RESUMEN: Objetivo. Evaluar la actividad antiproliferativa y genotóxica de una fracción con actividad citotóxica obtenida de la esponja marina del Caribe colombiano Topsentia ophiraphidites (Fracción T4). Materiales y métodos. La fracción T4 de la esponja marina Topsentia ophiraphidites fue obtenida en el laboratorio de Productos Naturales Marinos de la Universidad de Antioquia. La actividad antiproliferativa se evaluó mediante ensayos de eficiencia de clonación, función de acumulación y cinética proliferativa por intercambio de cromátidas hermanas (ICH); la actividad genotóxica se evaluó mediante electroforesis en gel de células individuales (Ensayo cometa) e intercambio de cromátidas hermanas (ICH). Todas las pruebas fueron realizadas sobre las líneas celulares Jurkat y CHO. Resultados. La fracción T4 afectó el ciclo celular de las células CHO y mostró daño genotóxica crónico en las células Jurkat. Conclusiones. Se recomienda la evaluación de la fracción T4 en otras líneas celulares derivadas de tumor con el fin de determinar un posible efecto diferencial, además de evaluar otras actividades de tipo antimicrobiano, antimalárico, entre otros. ABSTRACT: Objective. To evaluate the antiproliferative and genotoxic activity of a fraction (T4 fraction) of the Colombian Caribbean marine sponge Topsentia ophiraphidites, with cytotoxic activity. Materials and methods. T4 fraction from the marine sponge Topsentia ophiraphidites was provided by the group of marine natural products from Universidad de Antioquia. The antiproliferative activity was evaluated by cloning efficiency tests, accumulation function, and proliferative kinetics by sister chromatid exchange (SCE), genotoxic activity was evaluated by SCE and gel electrophoresis of individual cells (Comet assay). All tests were performed on Jurkat and CHO cell lines. Results. The T4 fraction affected the cell cycle of CHO cells and presented chronic genotoxic damage in Jurkat cells. Conclusions. It is recommended to evaluate the T4 fraction in other derived tumor cell lines, in order to observe a possible differential effect, and to evaluate antimicrobial and antimalarial activities among others. COL0015043

ORNL collaborated with Faurecia Interior Systems to investigate the feasibility of developing a thermomagnetic preventive maintenance program for nickel tooling used in powder slush molding. It was found that thermal treatments at temperatures greater than 500°C can anneal strain hardening in nickel tooling and a range of temperatures and times for effective thermal annealing were identified. It was also observed that magnetic fields applied during thermal annealing do not alter the kinetics of strain hardening annealing. The results obtained in this investigation provide a foundation for establishing a preventive maintenance program for nickel tooling.

This work is part of a wider research named BIOTECH that intends to assure the quality of linguistic modeling activity for automatic systems, making it possible to automate the management of words and natural language. Words are considered part of the complex articulation of language expressions. BIOTECH aims to take it as a tool to evaluate and track linguistic and verbal communication distorsion in patients with Autistic Spectrum Disorder. The main contribution of this paper is to discuss the validity of fractals when used to model linguistic reasoning, and the relevance of considering not only statistics but also epistemology-related metrics. Furthermore, a set of metrics is introduced as a first approach to evaluate epistemological quality as well as statistical representativeness. The metrics are applied in a small dataset to evaluate a fractal model proposed for vowels in Spanish.

Introduction: The fastest growing segment of the population is those over age 80, in whom there is the highest incidence of stroke. Few clinical trials, however, have targeted this population, and management of risk factors is complicated by higher rates of side effects and polypharmacy. We aimed to characterize whether the risk factors for stroke are different in those age >80 versus Methods: The study sample derives from the Northern Manhattan Study (n=3298), a prospective cohort study among an urban dwelling multi-ethnic population. At enrollment risk factors were assessed by self-report, physical examination, and laboratory data. Leisure-time physical activity (LTPA) was assessed by validated questionnaire and categorized as none versus any. Participants are followed annually for incident stroke which is adjudicated by study neurologists after review of all records and imaging. We fit Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association of cardiovascular disease risk factors (LTPA, reported alcohol use, fasting HDL-C and LDL-C, history of diabetes, hypertension, heart disease, and tobacco use) with risk of stroke. Multi-variable models also included two-way interaction terms between the primary exposures and age ( Results: The mean age was 69 years and 562 (17%) were age ≥80 years. Physical inactivity was common (41%) and did not differ by age. Subjects were followed for a median of 14 years, and there were 391 total strokes. We found a statistically significant interaction of age ≥80 on the risk of stroke with physical inactivity (p=0.02), diabetes (p=0.04), hypertension (p=0.005), and LDL-C (p=0.03). In stratified models no LTPA versus any (adjusted HR 1.61, 95%CI 1.06-2.43) was associated with an increased risk of stroke among those age ≥80 but not in those younger; LDL-C, hypertension and diabetes were mainly associated with risk of stroke in those below age 80. Conclusion: Lack of leisure-time physical activity is a potentially modifiable stroke risk factor and was more notable than hypertension, diabetes or dyslipidemia among those older than age 80. Improving activity may reduce the risk of stroke in this segment of the population.

Purpose: A deregulated epigenome contributes to the transformed phenotype of mantle cell lymphoma (MCL). This involves activity of the polycomb repressive complex (PRC) 2, containing three core proteins, EZH2, SUZ12, and EED, in which the SET domain of EZH2 mediates the histone methyltransferase activity. We determined the effects of 3-deazaneplanocin A (DZNep), an S-adenosylhomocysteine hydrolase inhibitor, and/or pan-histone deacetylase inhibitor panobinostat (PS) on cultured and primary MCL cells. Experimental Design: Following treatment with DZNep and/or PS, apoptosis and the levels and activity of EZH2 and PRC2 proteins in cultured and primary MCL cells were determined. Results: Treatment with DZNep depleted EZH2, SUZ12, and 3MeK27H3 in the cultured human MCL cells. DZNep also increased expression of p21, p27, and FBXO32, whereas it depleted Cyclin D1 and Cyclin E1 levels in MCL cells. In addition, DZNep treatment induced cell-cycle arrest and apoptosis in cultured and primary MCL cells. Furthermore, as compared with treatment with each agent alone, cotreatment with DZNep and PS caused greater depletion of EZH2, SUZ12, 3MeK27H3, and Cyclin D1 levels, whereas it induced greater expression of FBXO32, p16, p21, and p27. Combined treatment with DZNep and PS synergistically induced apoptosis of cultured and primary MCL cells while relatively sparing normal CD34 + cells. Cotreatment with DZNep and PS also caused significantly greater inhibition of tumor growth of JeKo-1 xenografts in NOD/SCID mice. Conclusions: These preclinical in vitro and in vivo findings show that cotreatment with DZNep and PS is an active combined epigenetic therapy worthy of further in vivo testing against MCL. Clin Cancer Res; 18(22); 6227–38. ©2012 AACR.

Summary We investigated the transcriptional and epigenetic repression of miR-29 by MYC , HDAC3 , and EZH2 in mantle cell lymphoma and other MYC -associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies.

Polycomb group genes (PcGs) are epigenetic effectors, essential for stem cell self-renewal and pluripotency. Two main Polycomb repressive complexes (PRC1, PRC2) mediate gene silencing through histone post-translational modifications. PcGs have been the focus of investigation in cancer research. Many cancer types show an over-expression of PcGs, predicting poor prognosis, metastasis and chemoresistance. Genetic polymorphisms of EZH2 (a PRC2 component) are significantly associated to lung cancer risk. Recently, 3-Deazaneplanocin A (DZNeP) was identified as an efficient inhibitor of PRC2 activity. DZNeP impairs cancer stem cell self-renewal and tumorigenicity. Despite the well-established role of PcGs in cancer stem cell biology, few studies dissected the clinical significance of these genes. In this paper, we explore PcGs as predictive and prognostic factors in oncology, with particular emphasis on what they can add to current biomarkers. We also propose a model for the rational development of DZNeP-based anticancer regimens and suggest the therapeutic applications of this drug.

Enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 that catalyzes the trimethylation of histone H3 on Lys 27, and represses gene transcription. EZH2 enhances cancer-cell proliferation and regulates stem cell maintenance and differentiation. Here, we demonstrate that EZH2 is highly expressed in medulloblastoma, a highly malignant brain tumor of childhood, and this altered expression is correlated with genomic gain of chromosome 7 in a subset of medulloblastoma. Inhibition of EZH2 by RNAi suppresses medulloblastoma tumor cell growth. We show that 3-deazaneplanocin A, a chemical inhibitor of EZH2, can suppress medulloblastoma cell growth partially by inducing apoptosis. Suppression of EZH2 expression diminishes the ability of tumor cells to form spheres in culture and strongly represses the ability of known oncogenes to transform neural stem cells. These findings establish a role of EZH2 in medulloblastoma and identify EZH2 as a potential therapeutic target especially in high-risk tumors.