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The European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (EUGEI); The Spanish sample was supported by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024) (...), Velthorst, E., Mollon, J., Murray, R.M., de Haan, L., Germeys, I.M., Glahn, D.C., Arango, C., van der Ven, E., Di Forti, M., Bernardo, M., Guloksuz, S., Delespaul, P., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Santos, J.L., Jiménez-López, E., Sanjuan, J., Aguilar, E.J., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Atbaşoğlu, C., Saka, M.C., Üçok, A., Alptekin, K., Akdede, B., Binbay, T., Altınyazar, V., Ulaş, H., Yalınçetin, B., Gümüş-Akay, G., Beyaz, B.C., Soygür, H., Cankurtaran, E.Ş., Kaymak, S.U., Maric, N.P., Mihaljevic, M.M., Petrovic, S.A., Mirjanic, T., Del-Ben, C.M., Ferraro, L., Gayer-Anderson, C., Jones, P.B., Jongsma, H.E., Kirkbride, J.B., La Cascia, C., Lasalvia, A., Tosato, S., Llorca, P.-M., Menezes, P.R., Morgan, C., Quattrone, D., Menchetti, M., Selten, J.-P., Szöke, A., Tarricone, I., Tortelli, A., McGuire, P., Valmaggia, L., Kempton, M.J., van der Gaag, M., Riecher-Rössler, A., Bressan, R.A., Barrantes-Vidal, N., Nelson, B., McGorry, P., Pantelis, C., Krebs, M.-O., Ruhrmann, S., Sachs, G., Rutten, B.P.F., van Os, J., Alizadeh, B.Z., van Amelsvoort, T., Bartels-Velthuis, A.A., Bruggeman, R., van Beveren, N.J., Luykx, J.J., Cahn, W., Simons, C.J.P., Kahn, R.S., Schirmbeck, F., van Winkel, R., Calem, M., Tognin, S., Modinos, G., Pisani, S., Kraan, T.C., van Dam, D.S., Burger, N., Amminger, G.P., Politis, A., Goodall, J., Borgwardt, S., Studerus, E., Gadelha, A., Brietzke, E., Asevedo, G., Asevedo, E., Zugman, A., Domínguez-Martínez, T., Monsonet, M., Cristóbal-Narváez, P., Racioppi, A., Kwapil, T.R., Kazes, M., Daban, C., Bourgin, J., Gay, O., Mam-Lam-Fook, C., Nordholm, D., Rander, L., Krakauer, K., Glenthøj, L.B., Glenthøj, B., Gebhard, D., Arnhold, J., Klosterkötter, J., Lasser, I., Winklbaur, B., Reichenberg, A., EU-GEI High Risk Study

Survivors of intimate partner violence (IPV) experience a vast array of emotional and behavioral consequences, including difficulties in areas related to emotion regulation, and they often qualify for comorbid psychological diagnoses. Although a modified version of DBT has been examined as a treatment for survivors of IPV experiencing emotional dysregulation, there has been little mention of how to treat comorbid disorders among this population. Given that body focused repetitive behaviors (BFRB’s), such as trichotillomania, can be conceptualized as poor coping mechanisms to soothe dysregulated emotions, it seems beneficial to understand how to treat these diagnoses in the context of IPV sequelae. To date, there are limited examinations of DBT enhanced cognitive behavioral therapy for those suffering from IPV exposure and trichotillomania. The following case provides a successful example for how and why such therapy can be conducted for the treatment of comorbid diagnoses following IPV exposure.

Recovery is a multidimensional construct that can be defined either from a clinical perspective or from a consumer-focused one, as a self-broadening process aimed at living a meaningful life beyond mental illness. We aimed to longitudinally examine the overlap and mutual distinctions between clinical and personal recovery. Of 1239 people with schizophrenia consecutively recruited from the FondaMental Advanced Centers of Expertise for SZ network, the 507 present at one-year did not differ from those lost to follow-up. Clinical recovery was defined as the combination of clinical remission and functional remission. Personal recovery was defined as being in the rebuilding or in the growth stage of the Stages of Recovery Instrument (STORI). Full recovery was defined as the combination of clinical recovery and personal recovery. First, we examined the factors at baseline associated with each aspect of recovery. Then, we conducted multivariable models on the correlates of stable clinical recovery, stable personal recovery, and stable full recovery after one year. At baseline, clinical recovery and personal recovery were characterized by distinct patterns of outcome (i.e. better objective outcomes but no difference in subjective outcomes for clinical recovery, the opposite pattern for personal recovery, and better overall outcomes for full recovery). We found that clinical recovery and personal recovery predicted each other over time (baseline personal recovery for stable clinical recovery at one year; P = .026, OR = 4.94 [1.30–23.0]; baseline clinical recovery for stable personal recovery at one year; P = .016, OR = 3.64 [1.31–11.2]). In short, given the interaction but also the degree of difference between clinical recovery and personal recovery, psychosocial treatment should target, beyond clinical recovery, subjective aspects such as personal recovery and depression to reach full recovery.

Supplemental Digital Content is available in the text., OBJECTIVES: To compare the performance of Sequential Organ Failure Assessment, systemic inflammatory response syndrome, Red Flag Sepsis, and National Institute of Clinical Excellence sepsis risk stratification tools in the identification of patients at greatest risk of mortality from sepsis in nonintensive care environments. DESIGN: Secondary analysis of three annual 24-hour point-prevalence study periods. SETTING: The general wards and emergency departments of 14 acute hospitals across Wales. Studies were conducted on the third Wednesday of October in 2017, 2018, and 2019. PATIENTS: We screened all patients presenting to the emergency department and on the general wards. MEASUREMENTS AND MAIN RESULTS: We recruited 1,271 patients, of which 724 (56.9%) had systemic inflammatory response syndrome greater than or equal to 2, 679 (53.4%) had Sequential Organ Failure Assessment greater than or equal to 2, and 977 (76.9%) had Red Flag Sepsis. When stratified according to National Institute of Clinical Excellence guidelines, 450 patients (35.4%) were in the “High risk” category in comparison with 665 (52.3%) in “Moderate to High risk” and 156 (12.3%) in “Low risk” category. In a planned sensitivity analysis, we found that none of the tools accurately predicted mortality at 90 days, and Sequential Organ Failure Assessment and National Institute of Clinical Excellence tools showed only moderate discriminatory power for mortality at 7 and 14 days. Furthermore, we could not find any significant correlation with any of the tools at any of the mortality time points. CONCLUSIONS: Our data suggest that the sepsis risk stratification tools currently utilized in emergency departments and on the general wards do not predict mortality adequately. This is illustrated by the disparity in mortality risk of the populations captured by each instrument, as well as the weak concordance between them. We propose that future studies on the development of sepsis identification tools should focus on identifying predicator values of both the short- and long-term outcomes of sepsis.

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery., Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.

The mechanisms controlling membrane recognition by proteins with one hydrophobic stretch at their carboxyl terminus (tail anchor, TA) are poorly defined. The Escherichia coli TAs of ElaB and YqjD, which share sequential and structural similarity with the Saccharomyces cerevisiae TA of Fis1, were shown to localize to mitochondria. We show that YqjD and ElaB are directed by their TAs to bacterial cell poles. Fis1(TA) expressed in E. coli localizes like the endogenous TAs. The yeast and bacterial TAs are inserted in the E. coli inner membrane, and they all show affiliation to phosphatidic acid (PA), found in the membrane of the bacterial cell poles and of the yeast mitochondria. Our results suggest a mechanism for TA membrane recognition conserved from bacteria to mitochondria and raise the possibility that through their interaction with PA, and TAs play a role across prokaryotes and eukaryotes in controlling cell/organelle fate.

Language is an essential part of psychotherapy and experts in cultural competence encourage the consideration of language as an element in cultural adaptation to therapy. Providing clients with services in their native language is associated with lower dropout and better outcomes. Therapies such as prolonged exposure therapy (PET) for posttraumatic stress disorder (PTSD) require clients to recount trauma memories to activate and correct overreactive fear networks in the brain. Research shows that the most genuine and detailed recall of these autobiographical memories occurs when people recollect in the same language in which the memory was encoded. Clients are less likely to drop out, tend to see better outcomes, and most closely follow the treatment protocol for PET when speaking in their native language. In an increasingly bilingual world, therapists may share a common language with a client but may be unable to speak the client’s native language. A novel solution for PET involves starting therapy in the therapist/client dyad’s shared language and then eventually conducting imaginal exposures in the client’s native language. The following case provides a successful example for how and why such therapy can be conducted.

Objectives Pre-analytical plasma glucose (PG) sampling methodology may significantly affect gestational diabetes mellitus (GDM) incidence, but no studies directly examined the impact on perinatal outcomes. We compared the effect on oral glucose tolerance test (OGTT) results of using for blood sampling the traditional sodium fluoride (NaF) tubes, batched at controlled temperature, and the more effective citrate-buffered tubes, in terms of GDM diagnosis and related outcomes. Methods We evaluated 578 pregnant women performing OGTT between 24- and 28-weeks’ gestation. Paired NaF and citrate blood samples were drawn and analyzed for PG. GDM diagnosis was made by applying the ‘one-step’ American Diabetes Association strategy. Data on perinatal outcomes were collected in a subset of 330 women who delivered in our hospital network. Results Using the standard NaF approach, 69 (11.9%) GDM women were detected. Using citrate PG values, 90 women were additionally identified as GDM, increasing the GDM prevalence to 27.5%. Perinatal outcomes were analyzed according to the different diagnostic allocation (NaF-diagnosed GDM, additional citrate-diagnosed GDM, and no GDM). NaF-diagnosed GDM showed a higher incidence of large for gestational age (LGA) (p=0.034), and of cesarean and preterm delivery (p Conclusions If a health care system plans to use citrate tubes for GDM diagnosis, considerations about clinical implications are mandatory by balancing higher sensitivity in detecting a poor glycemic control with effects on outcomes to avoid “overdiagnosis”.

Mobile phones have been used to monitor mobility changes during the COVID-19 pandemic but surprisingly few studies addressed in detail the implementation of practical applications involving whole populations. We report a method of generating a “mobility-index” and a “stay-at-home/resting-index” based on aggregated anonymous Call Detail Records of almost all subscribers in Hungary, which tracks all phones, examining their strengths and weaknesses, comparing it with Community Mobility Reports from Google, limited to smartphone data. The impact of policy changes, such as school closures, could be identified with sufficient granularity to capture a rush to shops prior to imposition of restrictions. Anecdotal reports of large scale movement of Hungarians to holiday homes were confirmed. At the national level, our results correlated well with Google mobility data, but there were some differences at weekends and national holidays, which can be explained by methodological differences. Mobile phones offer a means to analyse population movement but there are several technical and privacy issues. Overcoming these, our method is a practical and inexpensive way forward, achieving high levels of accuracy and resolution, especially where uptake of smartphones is modest, although it is not an alternative to smartphone-based solutions used for contact tracing and quarantine monitoring.

O-GlcNAcylation is an essential post-translational modification that has been implicated in neurodevelopmental and neurodegenerative disorders. O-GlcNAcase (OGA), the sole enzyme catalyzing the removal of O-GlcNAc from proteins, has emerged as a potential drug target. OGA consists of an N-terminal OGA catalytic domain and a C-terminal pseudo histone acetyltransferase (HAT) domain with unknown function. To investigate phenotypes specific to loss of OGA catalytic activity and dissect the role of the HAT domain, we generated a constitutive knock-in mouse line, carrying a mutation of a catalytic aspartic acid to alanine. These mice showed perinatal lethality and abnormal embryonic growth with skewed Mendelian ratios after day E18.5. We observed tissue-specific changes in O-GlcNAc homeostasis regulation to compensate for loss of OGA activity. Using X-ray microcomputed tomography on late gestation embryos, we identified defects in the kidney, brain, liver, and stomach. Taken together, our data suggest that developmental defects during gestation may arise upon prolonged OGA inhibition specifically because of loss of OGA catalytic activity and independent of the function of the HAT domain.

Scientific data analyses often combine several computational tools in automated pipelines, or workflows. Thousands of such workflows have been used in the life sciences, though their composition has remained a cumbersome manual process due to a lack of standards for annotation, assembly, and implementation. Recent technological advances have returned the long-standing vision of automated workflow composition into focus. This article summarizes a recent Lorentz Center workshop dedicated to automated composition of workflows in the life sciences. We survey previous initiatives to automate the composition process, and discuss the current state of the art and future perspectives. We start by drawing the “big picture” of the scientific workflow development life cycle, before surveying and discussing current methods, technologies and practices for semantic domain modelling, automation in workflow development, and workflow assessment. Finally, we derive a roadmap of individual and community-based actions to work toward the vision of automated workflow development in the forthcoming years. A central outcome of the workshop is a general description of the workflow life cycle in six stages: 1) scientific question or hypothesis, 2) conceptual workflow, 3) abstract workflow, 4) concrete workflow, 5) production workflow, and 6) scientific results. The transitions between stages are facilitated by diverse tools and methods, usually incorporating domain knowledge in some form. Formal semantic domain modelling is hard and often a bottleneck for the application of semantic technologies. However, life science communities have made considerable progress here in recent years and are continuously improving, renewing interest in the application of semantic technologies for workflow exploration, composition and instantiation. Combined with systematic benchmarking with reference data and large-scale deployment of production-stage workflows, such technologies enable a more systematic process of workflow development than we know today. We believe that this can lead to more robust, reusable, and sustainable workflows in the future. publishedVersion

The poles of Escherichia coli cells are emerging as hubs for major sensory systems, but the polar determinants that allocate their components to the pole are largely unknown. Here, we describe the discovery of a previously unannotated protein, TmaR, which localizes to the E. coli cell pole when phosphorylated on a tyrosine residue. TmaR is shown here to control the subcellular localization and activity of the general PTS protein Enzyme I (EI) by binding and polar sequestration of EI, thus regulating sugar uptake and metabolism. Depletion or overexpression of TmaR results in EI release from the pole or enhanced recruitment to the pole, which leads to increasing or decreasing the rate of sugar consumption, respectively. Notably, phosphorylation of TmaR is required to release EI and enable its activity. Like TmaR, the ability of EI to be recruited to the pole depends on phosphorylation of one of its tyrosines. In addition to hyperactivity in sugar consumption, the absence of TmaR also leads to detrimental effects on the ability of cells to survive in mild acidic conditions. Our results suggest that this survival defect, which is sugar- and EI-dependent, reflects the difficulty of cells lacking TmaR to enter stationary phase. Our study identifies TmaR as the first, to our knowledge, E. coli protein reported to localize in a tyrosine-dependent manner and to control the activity of other proteins by their polar sequestration and release.

Background: The additional benefits of certain frequently used chronic drugs such as statins or aspirin are investigated for their possible effect of influencing various types of cancer, including gastric cancer. The possible role of statins in the occurrence of pre-neoplastic gastric lesions has not been investigated. Aim: The study aims to determine the influence of chronic statin therapy on premalignant gastric lesions (glandular atrophy, intestinal metaplasia and dysplasia), adjusted with the most important aggressive environmental factors of the gastric mucosa (Helicobacter pylori [H. pylori] infection, low-dose aspirin [acetylsalicylic acid, ASA], biliary reflux, smoking, alcohol consumption). Method: The study included 566 patients with cardiovascular diseases who underwent an upper endoscopy: 222 patients with chronic statin therapy (atorvastatin 20–80 mg/day or rosuvastatin 5–20 mg/day for at least 6 months) and 344 patients without statin intake. A complete set of biopsies from the gastric antrum and corpus were routinely processed and examined, and demographical, clinical, and pathological variables were recorded. Results: Active H. pylori infection in gastric biopsies (p = 0.45), biliary reflux (p = 0.74), alcohol consumption (p = 0.43), or prior ulcer disease (p = 0.07; OR: 0.59; 95% CI: 0.33–1.04) were not associated with an increased risk for premalignant lesions, neither in the statin, nor the no-statin group. Smoking was associated with premalignant lesions in both groups (p = 0.01; OR: 2.24; 95% CI: 1.12–4.47; and p = 0.04; OR: 1.72; 95% CI: 1.01–2.94, respectively), while chronic use of ASA had no influence (p = 0.24, respective p = 0.35). In multivariate regression models, chronic treatment with statins had a protective effect (p = 0.006; OR: 0.59; 95% CI: 0.4–0.8), while smoking (p = 0.01; OR: 1.99; 95% CI: 1.17–3.39) and age >50 years (p H. pylori infection, gender, alcohol consumption, biliary reflux, or prior ulcer disease were not associated with premalignant lesions (p >0.05). Conclusions: In the studied population, chronic statin treatment seems to be associated with a decreased risk for premalignant gastric lesions, while age over 50 years and smoking, regardless of gender or ASA consumption, remain the most important risk factors for premalignant gastric lesions.

Objective: Report RESONATE-2 phase 3 study extended long-term follow-up of first-line ibrutinib vs chlorambucil in older patients with CLL/SLL. Methods: Patients (≥65 years [y]) with previously untreated CLL/SLL (without del[17p]) were randomly assigned 1:1 to once-daily ibrutinib 420 mg, until disease progression (PD) or unacceptable toxicity (n=136); or chlorambucil 0.5–0.8 mg/kg, up to 12 cycles (n=133). Outcomes included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety. Long-term responses were investigator-assessed per 2008 iwCLL criteria. Results: With up to 7y of follow-up (median, 74.9 months; range, 0.1–86.8), significant PFS benefit was sustained for patients treated with ibrutinib vs chlorambucil (HR 0.160 [95% CI: 0.111–0.230]). At 6.5y, PFS was 61% vs 9% for ibrutinib vs chlorambucil. PFS benefit was observed consistently, including ibrutinib-treated patients with high-risk genomic features of unmutated IGHV (HR 0.109 [95% CI: 0.063–0.189]) or del(11q) (HR 0.033 [95% CI: 0.010–0.107]). With ibrutinib, 6.5y OS was 78%; ORR was 92%, and complete response (CR/CRi) rate increased to 34%. Ongoing rates of grade ≥3 AEs of interest remained low for hypertension (5–6y interval: 5%, n=4; 6–7y: 4%, n=3) and atrial fibrillation (5–6y: 1%, n=1; 6–7y: 1%, n=1); no grade ≥3 major hemorrhage in 5–7y. One patient (1%) had dose reduction due to grade ≥3 AEs during years 5–6/6–7. Of 31 patients with dose reductions due to any-grade AEs over full follow-up, 22 (71%) had AE resolution/improvement. Primary reason for discontinuation was PD (5–6y: 5%, n=4; 6–7y: 6%, n=4). Any-grade AEs leading to discontinuations were 3% (n=2) in 5–6y and none in 6–7y. With up to 7y of follow-up, 47% of patients remain on single-agent ibrutinib. Conclusions: Long-term RESONATE-2 data demonstrate sustained PFS and OS benefit with first-line ibrutinib treatment for CLL, including for patients with high-risk genomic features. Responses continued to deepen over time. Rates of grade ≥3 AEs of interest continued to be low with rare further discontinuations and dose reductions due to AEs; most AEs leading to dose reduction resolved/improved. Ibrutinib remains well tolerated with no new safety signals. Funding: Pharmacyclics LLC, an AbbVie Company.

Summary Background Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. Methods This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187. Findings Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8–28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8–6·7). The most common grade 3–4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study. Interpretation Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited. Funding CTI BioPharma Corp.

Altres ajuts: The authors thank the patients who participated in this study and their supportive families, as well as the investigators, subinvestigators, and coordinators at each of the study sites. The authors thank Jerry Ping of Pharmacyclics LLC, an AbbVie Company, for his contributions to the statistical analyses and Joris Diels of Janssen and Suzy Van Sanden of Janssen-Cilag Ltd for their contributions to the crossover-adjusted overall survival analysis using the rank-preserving structural failure time method. John C. Byrd is supported by the Four Winds Foundation, D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, Sullivan CLL Research Foundation, and R35 CA197734. Editorial support was provided by Melanie Sweetlove, MSc, and was funded by Pharmacyclics LLC, an AbbVie Company. T.M. has received honoraria from Janssen, AbbVie, Gilead, Alexion, Novartis, and Roche; and has been in a consulting role for MorphoSys and Sunesis. J.R.B. has received honoraria from Janssen and Teva; has been in a consulting role for AbbVie, Acerta, Astellas, BeiGene, Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, Novartis, Pfizer, Pharmacyclics LLC, an AbbVie Company, Redx, Sun, Sunesis, TG Therapeutics, and Verastem; has received research funding from Gilead, Loxo, Sun, and Verastem; and has served on data safety monitoring committees for MorphoSys and Invectys. S.O. has been in a consulting role for Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences, Vaniam Group, AbbVie, Alexion, Verastem, and Eisai; has received research funding from Kite, Regeneron, and Acerta; and has been in a consulting role and received research funding from Gilead, Pharmacyclics LLC, an AbbVie Company, TG Therapeutics, Pfizer, and Sunesis. J.C.Ba. has received honoraria from Janssen; has been in a consulting role for Genentech, Gilead, Bayer, Pharmacyclics LLC, an AbbVie Company, AbbVie, AstraZeneca, and Sandoz; and has received research funding from Pharmacyclics LLC, an AbbVie Company, Oncternal Therapeutics, and AbbVie. P.M.B. has been in a consulting role for Pharmacyclics LLC, an AbbVie Company, and AbbVie, and has received research funding from Pharmacyclics LLC, an AbbVie Company. N.M.R. has received honoraria from and has been in a consulting role for Bristol-Myers Squibb (BMS), Genentech, AbbVie, Gilead, AstraZeneca, and Celgene; has received research funding from BMS and Merck; and has been a paid speaker for Gilead and Celgene. S.C. has received honoraria from Pharmacyclics LLC, an AbbVie Company, and Janssen; has been in a consulting role for AbbVie, Celgene, Genentech, Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Astellas, and AstraZeneca; has received research funding from AbbVie, Acerta, Celgene, Gilead, Janssen, Pharmacyclics LLC, an AbbVie Company, and Takeda; has provided expert testimony for Genentech; has received travel, accommodations and other expenses from AbbVie, BeiGene, Celgene, Genentech, Janssen, and Pharmacyclics LLC, an AbbVie Company; and has other relationships with BeiGene. C.S.T. has received honoraria from Janssen and Pharmacyclics LLC, an AbbVie Company, and research funding from Janssen. S.P.M. has received honoraria from and has been in a consulting role for Roche, AbbVie, Janssen, Gilead, and GlaxoSmithKline; has received research funding from Roche, AbbVie, and Janssen; and has been a paid speaker for Roche, AbbVie, Janssen, and Gilead. U.J. has received honoraria and research funding from Janssen, and has been in a consulting role for Janssen. T.J.K. has been in a consulting role for AbbVie, Genentech-Roche, Gilead, Pharmacyclics LLC, an AbbVie Company, and Celgene and has received research funding from AbbVie, Genentech-Roche, Pharmacyclics LLC, an AbbVie Company, and Oncternal. C.M. has been in a consulting role for Pharmacyclics LLC, an AbbVie Company, Janssen, and AbbVie. M.M. has received honoraria from and has been in a consulting role for AbbVie, Janssen, Gilead, Roche, and AstraZeneca; has been a paid speaker for AbbVie, Janssen, and Gilead; has received research funding from Roche; and has received travel, accommodations, and expenses reimbursement from AbbVie, Janssen, and AstraZeneca. J.A.B. has received honoraria from Janssen; has been in a consulting role for Janssen; has received research funding from Gilead, TG Therapeutics, Pharmacyclics LLC, an AbbVie Company, and BeiGene; has been a paid speaker for Gilead, TG Therapeutics, Pharmacyclics LLC, an AbbVie Company, Novartis, and Janssen; and has received travel, accommodations, and expenses reimbursement from Gilead, TG Therapeutics, Pharmacyclics LLC, an AbbVie Company, Novartis, and Janssen. J.C.By. has been in consulting role for Janssen; has reported research funding from Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, and BeiGene; and has been a paid speaker for Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, and Janssen; and received travel, accommodations, and expenses reimbursement from Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, and TG Therapeutics. P.H. has received honoraria from, has been in a consulting role for and has received research funding from Janssen, Pharmacyclics LLC, an AbbVie Company, and AbbVie; and has received travel, accommodations, and expenses reimbursement from Janssen and AbbVie. S.D. is an employee of Pharmacyclics LLC, an AbbVie Company, and owns stock in AbbVie, Celgene, Gilead, GlaxoSmithKline, and Exelixis. A.S. is an employee of Pharmacyclics LLC, an AbbVie Company, and owns stock in AbbVie. J.P.D. is an employee of Pharmacyclics LLC, an AbbVie Company, and owns stock in AbbVie and was formerly employed by and owned stock in CTI BioPharma. J.W. has been in a consulting role for Pharmacyclics LLC, an AbbVie Company, and Janssen; and has received research funding from Pharmacyclics LLC, an AbbVie Company, Janssen, AbbVie, Morphosys, Karyopharm, and Loxo. Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).

7523 Background: Ibrutinib, a once-daily Bruton’s tyrosine kinase inhibitor, is the only targeted therapy with significant progression-free survival (PFS) and overall survival (OS) benefit in multiple randomized phase 3 studies versus established therapies in patients (pts) with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Extended long-term follow-up data for the RESONATE-2 study of first-line ibrutinib vs chlorambucil in older pts with CLL/SLL are reported. Methods: In the phase 3 RESONATE-2 study, older pts (≥65 years [y]) with previously untreated CLL/SLL and without del(17p) (N=269) were randomly assigned 1:1 to once-daily single-agent ibrutinib 420 mg until disease progression (PD) or unacceptable toxicity (n=136) or chlorambucil 0.5–0.8 mg/kg up to 12 cycles (n=133). Outcomes included PFS, OS, overall response rate (ORR), and safety. Long-term responses were investigator-assessed per 2008 iwCLL criteria. Results: With up to 7y of follow-up (median, 74.9 months; range, 0.1–86.8), significant PFS benefit was sustained for pts treated with ibrutinib vs chlorambucil (hazard ratio [HR] 0.160 [95% confidence interval (CI): 0.111–0.230]). At 6.5y, PFS was 61% in pts treated with ibrutinib vs 9% in pts treated with chlorambucil. This PFS benefit was observed across all subgroups, including in ibrutinib-treated pts with high-risk genomic features of unmutated IGHV (HR 0.109 [95% CI: 0.063–0.189]) or del(11q) (HR 0.033 [95% CI: 0.010–0.107]). OS at 6.5y was 78% with ibrutinib treatment. ORR was 92% for ibrutinib-treated pts with complete response (CR/CRi) rate increasing to 34% with this follow-up. Ongoing rates of grade ≥3 adverse events (AEs) of interest remained low for hypertension (5–6y interval: 5%, n=4; 6–7y: 4%, n=3) and atrial fibrillation (5–6y: 1%, n=1; 6–7y: 1%, n=1); no grade ≥3 major hemorrhage occurred in 5–7y. Dose reductions due to grade ≥3 AEs occurred in 1% (n=1) of pts during the 5–6y and 6–7y intervals. Across full follow-up, 31 pts had dose reductions due to any-grade AEs of whom 22/31 (71%) had resolution or improvement the AE. Primary reason for discontinuations in 5–7y was PD (5–6y: 5%, n=4; 6–7y: 6%, n=4). Any-grade AEs leading to discontinuations were seen in 3% (n=2) of pts from 5–6y and none in 6–7y. With over 7y of follow-up, 47% of pts remain on single-agent ibrutinib. Conclusions: Extended long-term data from RESONATE-2 demonstrate the sustained PFS and OS benefit of first-line ibrutinib treatment for pts with CLL, including for pts with high-risk genomic features. Responses continue to deepen over time. Rates of grade ≥3 AEs of interest continued to be low at up to 7y follow-up and further discontinuations and dose reductions due to AEs were rare; most AEs leading to dose reduction resolved or improved. Ibrutinib remains well tolerated with no new safety signals observed. Clinical trial information: NCT01722487, NCT01724346.

Amyloid β 1-42 peptide (Aβ1-42) accumulates in Alzheimer's disease (AD) that is toxic to the basal forebrain cholinergic (BFC) neurons in substantia innominata-nucleus basalis magnocellularis complex (SI-NBM). Transient Receptor Potential Ankyrin1 (TRPA1) receptor is present in murine brain, however its role in neurotoxic processes is unclear. We investigated the Aβ1-42-induced neurotoxicity in TRPA1 wild-type (TRPA1+/+) and knockout (TRPA1-/-) mice. Expression and neuroanatomical localization of TRPA1 receptor were examined using RT qPCR. Cholinergic fibre loss was determined on acetylcholinesterase (AChE) stained brain slices, and choline acetyltransferase (ChAT) immunohistochemistry was used to assess the cholinergic cell loss. Novel object recognition (NOR), radial arm maze (RAM) and Y-maze tests were used to investigate memory loss. Aβ1-42-injected WT mice showed marked loss of cholinergic fibres and cell bodies, which was significantly attenuated in TRPA1-/- animals. According to the NOR and RAM tests, pronounced memory loss was detected in Aβ1-42-injected TRPA1+/+ mice, but not in TRPA1-/- group. Our findings demonstrate that TRPA1 KO animals show substantially reduced morphological damage and memory loss after Aβ1-42 injection in the SI-NBM. We conclude that TRPA1 receptors may play an important deteriorating role in the Aβ1-42-induced cholinergic neurotoxicity and the consequent memory loss in the murine brain.

Caudal block is commonly used to provide postoperative analgesia after pediatric surgery in the lower abdomen. Typically administered as a single-shot technique, 1 limitation of this block is the short duration of analgesia. To overcome this, dexamethasone has been used as an adjuvant to prolong block duration. However, there are concerns about steroid-related morbidity and the optimal route of dexamethasone administration (eg, caudal or intravenous) is unknown.We conducted a systematic review and random-effects meta-analysis of randomized controlled trials recruiting pediatric surgical patients receiving a caudal block for surgical anesthesia or postoperative analgesia. Included studies compared dexamethasone (caudal, intravenous, or both) to control. Duration of analgesia was the primary outcome. Database sources were Medline, Embase, the Cochrane Library, and Google Scholar searched up to August 18, 2017, without language restriction. Screening of studies, data extraction, and risk of bias assessment were performed independently and in duplicate by 2 authors. Risk of bias was assessed using Cochrane methodology and the strength of evidence was scored using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.The initial search retrieved 93 articles. Fourteen randomized controlled trials that comprised 1315 pediatric patients met the inclusion criteria. All but 1 study involved lower abdominal operations (orchidopexy, inguinal hernia repair, and hypospadias repair). The caudal and intravenous dose of dexamethasone ranged from 0.1 to 0.2 mg/kg and 0.5 to 1.5 mg/kg, respectively, and all studies were pooled in the main analysis. Dexamethasone prolonged the duration of analgesia by both the caudal route (5.43 hours, 95% confidence interval [CI], 3.52-7.35; P.001; I = 99.3%; N = 9; n = 620; GRADE quality = moderate) and intravenous route (5.51 hours; 95% CI, 3.56-7.46; P.001; I = 98.9%; N = 5; n = 364; GRADE quality = moderate) versus control. Secondary benefits of dexamethasone included reduced narcotic rescue analgesia requirement in the postanesthetic care unit (relative risk [RR], 0.30; 95% CI, 0.18-0.51; P.001; I = 0.0%; N = 5; number needed to treat for benefit [NNTB] = 5; 95% CI, 4-7), less subsequent postoperative rescue analgesia requirement (RR, 0.46; 95% CI, 0.23-0.92; P = .03; I = 96.0%; N = 9; n = 629; NNTB = 3; 95% CI, 2-20; n = 310), and lower rates of postoperative nausea and vomiting (RR, 0.47; 95% CI, 0.30-0.73; P = .001; I = 0.0%; NNTB = 11; 95% CI, 8-21; N = 9; n = 628). Adverse events linked to the dexamethasone were rare.Caudal and intravenous dexamethasone are similarly effective for prolonging the duration of analgesia from caudal blockade, resulting in a doubled to tripled duration. Given the off-label status of caudal dexamethasone, intravenous administration is recommended-although only high intravenous doses (0.5 mg/kg up to 10 mg) have been studied.

Although the list of proteins that localize to the bacterial cell poles is constantly growing, little is known about their temporal behavior. EI, a major protein of the phosphotransferase system (PTS) that regulates sugar uptake and metabolism in bacteria, was shown to form clusters at the Escherichia coli cell poles. We monitored the localization of EI clusters, as well as diffuse molecules, in space and time during the lifetime of E. coli cells. We show that EI distribution and cluster dynamics varies among cells in a population, and that the cluster speed inversely correlates with cluster size. In growing cells, EI is not assembled into clusters in almost 40% of the cells, and the clusters in most remaining cells dynamically relocate within the pole region or between the poles. In non-growing cells, the fraction of cells that contain EI clusters is significantly higher, and dispersal of these clusters is often observed shortly after exiting quiescence. Later, during growth, EI clusters stochastically re-form by assembly of pre-existing dispersed molecules at random time points. Using a fluorescent glucose analog, we found that EI function inversely correlates with clustering and with cluster size. Thus, activity is exerted by dispersed EI molecules, whereas the polar clusters serve as a reservoir of molecules ready to act when needed. Taken together our findings highlight the spatiotemporal distribution of EI as a novel layer of regulation that contributes to the population phenotypic heterogeneity with regard to sugar metabolism, seemingly conferring a survival benefit.

Objective: A rat model is here used to test a hypothesis that Momordica charantia (Bitter melon (BM)) extract favorably alters processes in cardiovascular tissue and is systemically relevant to the pathophysiology of type 2 diabetes (T2DM) and related cardiovascular disease. Methods: Male Lean and Zucker Obese (ZO) rats were gavage-treated for six weeks with 400 mg/kg body weight bitter melon (BM) extract suspended in mucin–water vehicle, or with vehicle (Control). Animals were segregated into four treatment groups, 10 animals in each group, according to strain (Lean or ZO) and treatment (Control or BM). Following six-week treatment periods, peripheral blood was collected from selected animals, followed by sacrifice, thoracotomy and mounting of isolated working heart setup. Results: Body mass of both Lean and ZO rats was unaffected by treatment, likewise, peripheral blood fasting glucose levels showed no significant treatment-related effects. However, some BM treatment-related improvement was noted in postischemic cardiac functions when Lean, BM-treated animals were compared to vehicle treated Lean control rats. Treatment of Lean, but not ZO, rats significantly reduced the magnitude of infarcted zone in isolated hearts subjected to 30 min of ischemia followed by 2 h of working mode reperfusion. Immunohistochemical demonstration of caspase-3 expression by isolated heart tissues subjected to 30 min of ischemia followed by 2 h of reperfusion, revealed significant correlation between BM treatment and reduced expression of this enzyme in hearts obtained from both Lean and ZO animals. The hierarchy and order of caspase-3 expression from highest to lowest was as follows: ZO rats receiving vehicle > ZO rats receiving BM extract > Lean rats treated receiving vehicle > Lean rats administered BM extract. Outcomes of analyses of peripheral blood content of cardiac-related analytics: with particular relevance to clinical application was a significant elevation in blood of ZO and ZO BM-treated, versus Lean rats of total cholesterol (high density lipoprotein HDL-c + low density lipoprotein LDL-c), with an inferred increase in HDL-c/LDL-c ratio—an outcome associated with decreased risk of atherosclerotic disease. Conclusions: BM extract failed to positively affect T2DM- and cardiovascular-related outcomes at a level suggesting use as a standalone treatment. Nevertheless, the encouraging effects of BM in enhancement of cardiac function, suppression of post-ischemic/reperfused infarct size extent and capacity to modulate serum cholesterol, will likely make it useful as an adjuvant therapy for the management of T2DM and related cardiovascular diseases.

Sex differences exist in chronic pain pathologies, and gonadal estradiol (E2) alters the pain sensation. The nocisensor transient receptor potential vanilloid 1 (TRPV1) receptor plays a critical role in triggering pain. Here we examined the impact of E2 on the function of TRPV1 receptor in mice sensory neurons in vitro and in vivo. Both mechano- and thermonociceptive thresholds of the plantar surface of the paw of female mice were significantly lower in proestrus compared with the estrus phase. These thresholds were higher in ovariectomized (OVX) mice and significantly lower in sham-operated mice in proestrus compared with the sham-operated mice in estrus phase. This difference was absent in TRPV1 receptor-deficient mice. Furthermore, E2 potentiated the TRPV1 receptor activation-induced mechanical hyperalgesia in OVX mice. Long pretreatment (14 hours) with E2 induced a significant increase in TRPV1 receptor messenger RNA expression and abolished the capsaicin-induced TRPV1 receptor desensitization in primary sensory neurons. The short E2 incubation (10 minutes) also prevented the desensitization, which reverted after coadministration of E2 and the tropomyosin-related kinase A (TrkA) receptor inhibitor. Our study provides in vivo and in vitro evidence for E2-induced TRPV1 receptor upregulation and sensitization mediated by TrkAR via E2-induced genomic and nongenomic mechanisms. The sensitization and upregulation of TRPV1 receptor by E2 in sensory neurons may explain the greater pain sensitivity in female mice.

7510 Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton’s tyrosine kinase inhibitor, has redefined treatment paradigms for CLL/SLL. We report final analysis with up to 6 years of follow-up on ibr from the phase 3 RESONATE study of single-agent ibr vs ofatumumab (ofa) in pts with relapsed/refractory (R/R) CLL/SLL. Methods: Pts were randomized to receive oral ibr 420 mg daily until PD or intravenous ofa for up to 24 weeks. Long-term efficacy endpoints were investigator-assessed. Results: Among 391 pts randomized to receive ibr (n=195) or ofa (n=196), 86% and 79%, respectively, were in the genomic high-risk population (del(17p), del(11q), TP53 mutation, and/or unmutated IGHV). At final analysis, median follow-up was 64 mo (range, 0.3-72) on ibr. Of pts randomized to ofa, 68% crossed over to receive ibr. Significant sustained PFS benefit was observed with ibr vs ofa, with median PFS 44.1 vs 8.1 mo (HR 0.15; 95% CI 0.11-0.20; P˂0.0001) and was consistent across baseline subgroups. Median PFS in genomic high-risk population was 44.1 vs 8.0 mo on ibr vs ofa (HR 0.11; 95% CI 0.08-0.15). ORR with ibr was 88% (CR/CRi in 11%). Initial ibr treatment conferred better OS than ofa when censored for crossover (HR 0.64; 95% CI 0.42-0.98). Median duration of ibr was 41 mo (range 0.2-71); 41% of pts received ibr >4 yrs. AE profile with ibr remained consistent with prior reports. Cumulatively during long-term ibr therapy, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of pts, respectively; major hemorrhage occurred in 10%. Most common reasons for ibr discontinuation (DC) prior to study closure were PD (37%) and AEs (16%); DC due to AEs occurred in 6%, 3%, 4%, 4%, 6% and 4% of pts during yrs 0-1, 1-2, 2-3, 3-4, 4-5 and 5-6, respectively. Conclusions: With up to 6 years of follow-up, extended ibr treatment showed sustained efficacy in pts with R/R CLL, including in pts with high-risk genomic features. Safety remained acceptable with low rates of DC due to AEs, and with no new safety signals over long-term therapy. These results establish long-term benefit and tolerability for continuous ibr treatment in pts with R/R CLL. Clinical trial information: NCT01578707.

We showed that somatostatin (SST) exerts anti-inflammatory and anti-nociceptive effects through somatostatin receptor subtypes 4 and 1 (sst(4)/sst(1)). Since cortistatin (CST) is a structurally similar peptide, we aimed at comparing the sst(1)- and sst(4)-binding and activating abilities, as well as the effects of SST-14 and CST-14 on inflammatory and nociceptive processes. CST-14 concentration-dependently displaced radiolabeled SST-14 binding, induced similar sst(1) and sst(4)-activation with a less potency, and exerted significantly greater inhibitory effect on endotoxin-stimulated interleukin (IL)-1β production of murine peritoneal macrophages. Capsaicin-induced calcitonin gene-related peptide release from peripheral sensory nerve terminals of isolated rat tracheae was significantly decreased by 2 μM CST and 100 nM SST, but concentration-response correlation was not found. Mustard oil-evoked acute neurogenic plasma protein extravasation in the rat hindpaw skin, carrageenan-induced mouse paw edema, mechanical hyperalgesia, and IL-1β, tumor necrosis factor-α production, as well as mild heat injury-evoked thermal hyperalgesia were similarly attenuated by both peptides. In the latter case, i.pl. and i.p. injections exerted equal inhibitory actions. CST-14 and SST-14 similarly diminish both acute neurogenic and cellular inflammatory processes, as well as mechanical and heat hyperalgesia, in which their inhibitory effect on sensory nerve endings is likely to be involved. However, CST-14 exerts remarkably greater inhibition on cytokine production.

Herein we describe the structure-activity relationship (SAR) of amino-caprolactam analogs derived from amino-caprolactam benzene sulfonamide 1, highlighting affects on the potency of γ-secretase inhibition, selectivity for the inhibition of APP versus Notch processing by γ-secretase and selected pharmakokinetic properties. Amino-caprolactams that are efficacious in reducing the cortical Aβ(x-40) levels in FVB mice via a single 100 mpk IP dose are highlighted.

Transgenic mice with a small hairpin RNA construct interfering with the expression of transient receptor potential vanilloid 1 (TRPV1) were created by lentiviral transgenesis. TRPV1 expression level in transgenic mice was reduced to 8% while the expression of ankyrin repeat domain 1 (TRPA1) was unchanged. Ear oedema induced by topical application of TRPV1 agonist capsaicin was completely absent in TRPV1 knockdown mice. Thermoregulatory behaviour in relation to environmental thermopreference (30 vs. 35°C) was slightly impaired in male knockdown mice, but the reduction of TRPV1 function was not associated with enhanced hyperthermia. TRPV1 agonist resiniferatoxin induced hypothermia and tail vasodilatation was markedly inhibited in knockdown mice. In conclusion, shRNA-mediated knock down of the TRPV1 receptor in mice induced robust inhibition of the responses to TRPV1 agonists without altering the expression, gating function or neurogenic oedema provoked by TRPA1 activation. Thermoregulatory behaviour in response to heat was inhibited, but enhanced hyperthermia was not observed.

The morphological features and distribution of cocaine- and amphetamine-regulated transcript peptide immunoreactivity (CART-IR) were studied in the lateral septum (LS) of male rats using light and electron microscopic immunocytochemistry and computer-aided densitometry. CART-IR was detected along the rostrocaudal axis of the LS in varicose axonal fibers only, although immunoreactive cell bodies and dendrites were not detected. Pericellular basket-like arrangements around immunonegative cell bodies were present. From among the targets of such pericellular baskets, glutamic acid decarboxylase (GAD)-immunopositive and NPY-immunoreactive somata were identified. Thin varicose axons were present in each section, whereas thick varicose axons were restricted to the sections of rostral position only. CART-IR was observed in varicose fibers forming a dense subependymal plexus, from which solitary varicose fibers entered the ependymal layer. The fine structure of varicosities was similar to that of other neuropeptide-containing fibers. Small varicosities established asymmetrical synaptic contacts mainly with dendrites and dendritic spines, and larger varicosities established symmetrical synapses with somata and dendritic shafts. CART-to-CART connections were not revealed. The density curve of the CART-IR along the rostrocaudal axis of LS was found to be paraboloid. CART is known as one of the most anorexigenic peptides. These results serve as basis for further physiological studies concerning the biological significance of lateral septal CART peptide in the regulation of food intake.

Absztrakt A microsatellita-instabilitas (MSI) hozzajarul a vastagbelrak kialakulasahoz, befolyasolja annak varhato korlefolyasat es a szemelyre szabott daganatellenes kezeles korulmenyeit. Az MSI a daganat morfologiai megjelenesenek megvaltozasaval is egyutt jar, ezert a rutin hematoxilin-eozin (H&E) alapu szovettani vizsgalat alkalmas lehet a microsatellita-status valoszinűsitesere. Munkank celja volt, hogy a rutin szovettani diagnosztikai gyakorlat szamara hasznalhato modon bemutassuk azokat a klinikopatologiai jellegzetessegeket, amelyek megkonnyitik a microsatellita-stabil es -instabil colorectalis carcinomak felismereset. Az Orszagos Onkologiai Intezet Sebeszi es Molekularis Daganatpatologiai Centrumaban vizsgalt vastagbelrak-esetek kozul 384 daganat lokalizaciojat, klinikai stadiumat, microsatellita-statusat, valamint a daganat felfedezesekor a betegek eletkorat figyelembe veve valasztottunk ki 26 herediter nem-polyposus colorectalis carcinomat (HNPCC), 22 sporadikus MSI-H (magasfoku microsatellita-...

Many signals reflecting energy balance and stress are integrated at the hypothalamic orexigenic NPY neurons. To determine transcriptional changes of the NPY gene in response to stress, we followed the time course and compared the expression of heteronuclear (hn)- and messenger (m)RNA levels by in situ hybridization histochemistry and by real time PCR in mice following insulin-induced hypoglycemia and restraint. Hypoglycemia in fasted mice resulted in a rapid increase of NPY hnRNA that peaked at 1 h, declined thereafter by 2–4 h after insulin injection and run parallel to that of NPY mRNA. Throughout the time course examined, NPY expressing cells in the medial basal hypothalamus remained overwhelmingly localized to the arcuate nucleus. Following restraint NPY mRNA slightly increased, however hnRNA levels decreased up to 2 h, suggesting increased stability of mature NPY mRNA. These results highlight rapid changes and differential regulation of NPY expression in response to metabolic and stress challenges.

7521Background: B2M is often elevated in pts with CLL and correlates with disease stage and burden. Normalization of B2M at 6 mo during ibr treatment was associated with improved progression-free s...