tbuckley/cabot-search huggingface dataset:
Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk‐stratification and management
Authors: Ayalew Tefferi, Tiziano Barbui
Journal: American Journal of Hematology (2015)

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms, respectively characterized by erythrocytosis and thrombocytosis. Other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation.PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. Differential diagnosis in ET includes reactive thrombocytosis, chronic myeloid leukemia, and prefibrotic myelofibrosis. Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) mutations occur in approximately 55%, 25%, and 3% of ET patients, respectively. The same molecular markers are also present in prefibrotic myelofibrosis, which needs to be morphologically distinguished from ET. Survival and leukemic/fibrotic transformation: Median survivals are ∼14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Life-expectancy in ET is inferior to the control population. JAK2/CALR mutational status does not affect survival in ET. Risk factors for survival in ET and PV include advanced age, leukocytosis, and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Thrombosis risk stratification: Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis: high-risk is defined by the presence of age >60 years or presence of thrombosis history; low-risk is defined by the absence of both of these two risk factors. Recent data consider JAK2V617F and cardiovascular risk factors as additional risk factors. Presence of extreme thrombocytosis might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding.The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. In low risk patients, this is accomplished by the use of low-dose aspirin and phlebotomy (hematocrit target <45%) in PV. In high risk (for thrombosis) patients, treatment with hydroxyurea is additionally recommended. Treatment with busulfan or interferon-α is usually effective in hydroxyurea failures and the additional value of JAK inhibitor therapy in such cases is limited. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis.
Miliary tuberculosis in immunocompetent and BCG vaccinated patients
Authors: Nawel Ben Salem, Nawel Chaouch, Manel Loukil, Mourad Zarrouk, Sana Cheikh Rouhou, Hajer Racil, Abdellatif Chabbou
Journal: European Respiratory Journal (2011)

Miliary (M) tuberculosis (TB) is a rare form of TB is in BCG vaccinated patients and occurs more frequently in immunocompromised patients. To evaluate frequency and clinical features of MTB in immunecompetent patients, we analyzed all cases of MTB diagnosed in a pulmonary department between 2000 and 2010, in patients with negative HIV test. We study 5 cases of 35 mean aged patients leading to an incidence of 2.6% among all TB patients seen in the same period. All were male, smokers and BCG vaccinated. One patient had diabetes and one had had viral C hepatitis. All had fever and poor general condition. One patient presented with acute respiratory failure. Chest x ray revealed bilateral interstitial micronodules in all cases. Tuberculin skin reaction was positive in 3 cases. Three cases were smeare positive. Medullary biopsy confirmed TB in 1 case. One case was retrospectively confirmed by good response to treatment. Extrapulmonary localization was: hepatic in 5 cases, splenic in 2 cases, lymph nodal in 1 case, cerebromeningeal, medullary,osteoarticular and renal in 1 case each. Treatment administered urgently was based on antituberculous drugs (HRZE) associated in 3 cases to corticosteroids. Outcome was favorable in all cases. One patient died 5 months after but due to another disease.  In conclusion, MTB in immunocompetent and vaccinated patients seems to be more easily confirmed with a better outcome compared to immunocompromised patients as reported in the literature, when anti TB treatment is established very early. Really, in patients with radiological M and fever TB should always evoked and treated urgently as such.
Clinical trials
Authors: D. Barer, J. A. Sacristan, I. Galende
Journal: BMJ (1999)

Editor—No one should argue with Peto and Baigent about the dangers of basing clinical practice on flawed “outcomes research” or isolated, undersized, randomised trials,1 but the simple megatrial may not be the ideal model for the next 50 years. Although such trials have taught us not to expect a predictable physiological response from our treatments but merely an improvement in the odds of successful outcome, the homogenising effect of large numbers may still disguise important variations in response. Attempts to explore these variations through subgroup analysis are widely condemned because of the perceived association with retrospective data dredging, so that the theoretical knowledge of clinicians and the individuality of patients are seen as increasingly less relevant to decisions about treatment.

The trials that Peto and Baigent advocate focus on hard end points, such as deaths, which may be rare in some patient groups and of limited relevance in others. The ageing of the world’s population may be the greatest global challenge to be faced in the next 50 years, and we will become less concerned with the length of survival in old age than with its quality. Many treatments will be evaluated in terms of their effects on “healthy active life expectancy” or on the duration and severity of “terminal dependency” rather than on mere survival. Comparatively simple measures of dependency are available for this purpose, but trial follow up will mean more than just a body count.

Older people are physiologically diverse, and we will need to look for qualitative as well as quantitative differences in treatment response in different subgroups. Trials will need to estimate not just the average effect of treatments but the benefits and risks in all important subgroups, so, despite high event rates, even large trials will be unlikely to answer all the relevant questions about a particular treatment.

Over the next 50 years the monolithic megatrial should therefore be replaced by planned collaborations between smaller studies, addressing different aspects of the same broad research question and using an agreed system for classifying patient subgroups, interventions and outcomes.2,3 This would overcome the limitations of retrospective meta-analysis, and clinicians would participate to a greater extent in defining the research questions and agreeing on classifications. The risks and benefits of treatment would become clear, and the focus of uncertainty would gradually change. Clinicians could then use their clinical skills, as well as the latest accumulated research evidence, to select the best treatment for individual patients.
Abstract 3728: A discovery platform for allosteric modulators of c-Abl kinase function
Authors: Prerna Grover, Thomas E. Smithgall
Journal: Cancer Research (2014)

Abstract The c-Abl protein-tyrosine kinase regulates intracellular signaling pathways controlling cell growth, adhesion, and responses to genotoxic stress. The kinase activity of c-Abl is repressed by intramolecular interactions involving its non-catalytic SH3 and SH2 domains. The SH3 domain interacts with a polyproline type II helix formed by the SH2-kinase linker, while the SH2 domain interacts with the C-lobe of kinase domain away from the active site. In addition, the myristoylated N-terminal cap region (Ncap) binds a hydrophobic pocket in the C-lobe of the kinase domain, clamping the SH3 and SH2 domains against the back of the kinase domain. Small molecules that allosterically regulate c-Abl kinase activity through its non-catalytic domains may represent selective probes of c-Abl function in diverse tumor types. In this study, we developed a chemical library screening assay designed to identify chemical modulators of c-Abl kinase activity that either disrupt or stabilize the regulatory interaction of the SH3 domain with the SH2-kinase linker. This fluorescence polarization (FP) assay is based on a recombinant purified protein consisting of the c-Abl Ncap, SH3 and SH2 domains plus the linker (N32L protein) and a short fluorescein-labeled probe peptide that binds to the SH3 domain. In assay development experiments, we found that the probe peptide binds to the recombinant c-Abl N32L protein in vitro, producing a robust FP signal that can be competed with an excess of unlabeled peptide. The FP signal is not observed with control N32L proteins bearing either an inactivating mutation in the SH3 domain or enhanced SH3:linker interaction. The assay was optimized with respect to probe peptide sequence, probe and N32L protein concentrations, DMSO tolerance, and FP signal stability over time. Pilot library screens were then performed with the NCI Diversity Set III and an FDA-approved drug library (2800 compounds total). Seven compounds were identified that specifically reduced the FP signal by at least three standard deviations from the untreated controls. Secondary assays showed that one of these hit compounds enhances c-Abl kinase activity in vitro, suggesting that it disrupts regulation of kinase activity through the non-catalytic region. These results show that screening assays based on the non-catalytic domains of c-Abl can identify small molecule regulators of kinase function. Citation Format: Prerna Grover, Thomas E. Smithgall. A discovery platform for allosteric modulators of c-Abl kinase function. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3728. doi:10.1158/1538-7445.AM2014-3728
Inversion of chromosome 16 and uncommon rearrangements of the CBFB and MYH11 genes in therapy-related acute myeloid leukemia: rare events related to DNA-topoisomerase II inhibitors?
Authors: M Dissing, M M Le Beau, J Pedersen-Bjergaard
Journal: Journal of Clinical Oncology (1998)

PURPOSE To evaluate the frequency of inversion of chromosome 16 (inv[16]) and the type of rearrangement of the CBFB and MYH11 genes in therapy-related acute myeloid leukemia (t-AML) and to evaluate a possible relationship to specific types of previous chemotherapy. PATIENTS AND METHODS Cytogenetic studies were performed in 180 consecutive patients with therapy-related myelodysplasia (t-MDS) or t-AML in Copenhagen and in 270 consecutive patients in Chicago. Leukemic cells were available for studies of the molecular biology in 72 patients, including four with inv(16). RESULTS An inv(16)(p13q22) was observed in only two of 180 cases of t-MDS and t-AML in Copenhagen and in only four of 270 cases of t-MDS and t-AML in Chicago. Four patients with t-AML and inv(16) previously had received combination chemotherapy, which included an alkylating agent, and in two a DNA topoisomerase II inhibitor was included (mitoxantrone and etoposide). One patient had received paclitaxel followed by etoposide and one patient had received radiotherapy only. One patient, previously treated with mitoxantrone and cyclophosphamide for breast cancer, presented a new and, to our knowledge not previously reported, type of fusion transcript, with breakpoint at nt 399 of the CBFB gene and at nt 2134 of the MYH11 gene. Two patients previously treated with alkylating agents both presented the less common type D transcript, whereas the most common A transcript, observed in 80% of acute myeloid leukemia (AML) de novo with inv(16), only was observed in the patient treated with paclitaxel and etoposide for leiomyosarcoma. Bone marrow or blood cells from 68 patients with t-MDS and t-AML without an inv(16) all were found to be negative for chimeric rearrangement between the CBFB gene and the MYH11 gene. CONCLUSION The present study and a review of the literature shows that inv(16) is an uncommon aberration in t-AML and, like balanced translocations to chromosome bands 11q23 and 21q22 and the t(15;17), often is associated with prior chemotherapy with DNA topoisomerase II inhibitors. Breakpoints within the MYH11 gene may vary between t-AML and AML de novo.
Genetic susceptibility to periodontitis
Authors: Marja L. Laine, Wim Crielaard, Bruno G. Loos
Journal: Periodontology 2000 (2011)

Abstract In this systematic review, we explore and summarize the peer‐reviewed literature on putative genetic risk factors for susceptibility to aggressive and chronic periodontitis. A comprehensive literature search on the PubMed database was performed using the keywords ‘periodontitis’ or ‘periodontal disease’ in combination with the words ‘genes’, ‘mutation’, ‘SNP’ or ‘polymorphism’. The studies selected were written in English, had a case–control design, and reported genotype distribution. Only studies with at least 100 individuals in either the case or control group were included. Research on genetic polymorphisms has only had limited success in identifying significant and reproducible genetic factors for susceptibility to aggressive periodontitis and chronic periodontitis. Taking together the data published on gene polymorphisms in aggressive and chronic periodontitis, we conclude that there are differences among the various studies for the rare allele carriage rates. Nevertheless, there is some evidence that polymorphisms in the IL1B , IL1RN , FcγRIIIb , VDR and TLR4 genes may be associated with aggressive periodontitis susceptibility, and polymorphisms in the IL1B , IL1RN , IL6 , IL10 , VDR , CD14 , TLR4 and MMP1 genes may be associated with chronic periodontitis susceptibility as a single genetic factor in certain populations. Future studies should apply stricter disease classifications, use larger study cohorts, adjust for relevant risk factors in aggressive and chronic periodontiti,s and include analysis of multiple genes and polymorphisms. Establishing consortia and performing collaborative studies may help to conquer the limitations of small sample size and limited statistical power.
Impact of climate change on COPD in Berlin-Brandenburg – Developing a telemonitoring based approach for early intervention*
Authors: Nora Döhnert, Marcel Haug, Uta Liebers, Friedrich Köhler, Reinhold Kreutz, Gilbert Schönfelder, Marcel Langner, Wilfried Endlicher, Christian Witt
Journal: European Respiratory Journal (2011)

Climate change affects human health. Especially patients with chronic lung diseases seem to be more influenced. Extreme weather, e.g. heat waves, leads to an increase of COPD exacerbations and hospital admissions. In this context a prospective investigation of risks due to climate change for moderate/severe COPD is required, which allow us to determine susceptible subgroups and the development of an early intervention system to prevent exacerbations.  Therefore we designed a combined clinical research module, based on telemonitoring of COPD patients and complex analyses of scaled regional atmospheric conditions (i.e. temperature, humidity, particulate matter) of the metropolitan area Berlin-Brandenburg. We implemented the validated BODE-Index into a telemonitoring system, including home spirometry, a Mobile Medical Assistant (MMA) for self-evaluation and a triaxial pedometer for the quantification of physical activity. This randomized clinical trail contains a cohort of 220 COPD patients, divided into a control group (visit every 3 month) and an intervention group (daily telemonitoring).  The implementation of the telemonitoring system for COPD has been started as proof of concept. Patient compliance is excellent and the system is well accepted.  Concluding our results, this new approach for measuring the impact of climate change could lead to new interventional strategies and improve prognosis and quality of life in COPD. Nevertheless, further clinical research concerning the impact of climate change is strongly needed to improve the adaptive response in vulnerable patients with COPD.  *The study is funded by the BMBF (Federal Ministry of Education and Research).
Blastogenic Transformation Assay for Detection of Immunologic Reactivity to Avian Oncornaviruses2
Authors: Diana M. Lopez, M. Michael Sigel, Paul Meyers
Journal: JNCI Journal of the National Cancer Institute (1973)

Journal Article Blastogenic Transformation Assay for Detection of Immunologic Reactivity to Avian Oncornaviruses Get access Diana M. Lopez, Diana M. Lopez Laboratory of Virology, Department of Microbiology, University of Miami School of Medicine, Miami, Florida 33155 Search for other works by this author on: Oxford Academic PubMed Google Scholar M. Michael Sigel, M. Michael Sigel Laboratory of Virology, Department of Microbiology, University of Miami School of Medicine, Miami, Florida 33155 Search for other works by this author on: Oxford Academic PubMed Google Scholar Paul Meyers Paul Meyers Laboratory of Virology, Department of Microbiology, University of Miami School of Medicine, Miami, Florida 33155 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 51, Issue 1, July 1973, Pages 303–305, https://doi.org/10.1093/jnci/51.1.303 Published: 01 July 1973 Article history Received: 02 April 1973 Accepted: 13 April 1973 Published: 01 July 1973
What are the risks?
Authors: P. Sedgwick, K. Joekes
Journal: BMJ (2015)

Researchers investigated the effectiveness of offering financial incentives in helping pregnant smokers to quit. A randomised controlled trial was performed. The intervention consisted of routine care plus incentives of up to £400 (€559; $600) for women who attended specialist pregnancy stop smoking services and were abstinent from smoking at 34-38 weeks’ gestation. The control group received routine care only, which included offers of face to face appointments to discuss smoking and cessation, free nicotine replacement therapy, and weekly support phone calls. The setting was a materially deprived inner city population in the west of Scotland. Participants were 612 self reported pregnant smokers aged at least 16 years who were less than 24 weeks pregnant. Women were randomised to the intervention (n=306) or control (n=306). Consent, including consent to use any data collected, was subsequently withdrawn by three women allocated to the control group, resulting in a sample size of 303 for analysis of the primary outcome.1

The primary outcome was abstinence from smoking at 34-38 weeks’ gestation. The percentage of smokers who were abstinent at 34-38 weeks’ gestation was significantly higher in the financial incentives group than in the control group (22.55% (n=69) v 8.58% (n=26), absolute risk difference 13.97%; relative risk 2.63, 95% confidence interval 1.73 to 4.01; P<0.001). The researchers concluded that financial incentives were effective in helping pregnant smokers quit.

Which of …
Comparison of Preparative Regimens in Transplants for Children With Acute Lymphoblastic Leukemia
Authors: Stella M. Davies, Norma K. C. Ramsay, John P. Klein, Daniel J. Weisdorf, Brian Bolwell, Jean-Yves Cahn, Bruce M. Camitta, Robert Peter Gale, Sergio Giralt, Carsten Heilmann, P. Jean Henslee-Downey, Roger H. Herzig, Raymond Hutchinson, Armand Keating, Hillard M. Lazarus, Gustavo A. Milone, Steven Neudorf, Waleska S. Perez, Ray L. Powles, H. Grant Prentice, Gary Schiller, Gérard Socié, Marcus Vowels, Joseph Wiley, Andrew Yeager, Mary M. Horowitz
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Preparative regimens involving total-body irradiation (TBI) produce significant late toxicities in some children who receive bone marrow transplants, including impaired growth and intellectual development. Busulfan is often used as an alternative to TBI, but there are few data regarding its relative efficacy. PATIENTS AND METHODS: We compared outcomes of HLA-identical sibling transplants for acute lymphoblastic leukemia (ALL) in children (&lt; 20 years of age) who received cyclophosphamide plus TBI (CY/TBI) (n = 451) versus those who received busulfan plus cyclophosphamide (Bu/CY) (n = 176) for pretransplant conditioning. Patients received transplants between 1988 and 1995 and their results were reported to the International Bone Marrow Transplant Registry by 144 participating institutions. The CY/TBI and Bu/CY groups did not differ in gender, immune phenotype, leukocyte count at the time of diagnosis, chromosome abnormalities, remission status, or length of initial remission. T-cell depletion was used more frequently in the CY/TBI group; the Bu/CY group included a higher proportion of children who were less than 5 years of age. The median follow-up period was 37 months. RESULTS: The 3-year probabilities of survival were 55% (95% confidence interval [CI], 50% to 60%) with TBI/CY and 40% (95% CI, 32% to 48%) with Bu/CY (univariate P = .003). The 3-year probabilities of leukemia-free survival were 50% (95% CI, 45% to 55%) and 35% (95% CI, 28% to 43%), respectively (univariate P = .005). In a multivariate analysis, the risks of relapse were similar in the two groups (relative risk [RR], 1.30 for Bu/CY v CY/TBI; P = .1). Treatment-related mortality was higher in the Bu/CY group (RR, 1.68; P = .012). Death and treatment failure (relapse or death, inverse of leukemia-free survival) were more frequent in the Bu/CY group (RR, 1.39; P = .017 for death; RR, 1.42; P = .006 for treatment failure). CONCLUSION: These data indicate superior survival with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical sibling bone marrow transplants in children with ALL.
Feasibility study of FEC-chemotherapy with dose-intensive epirubicin as initial treatment in high-risk breast cancer
Authors: E. van der Wall, D.J. Richel, Y.H. Kusumanto, E.J.T. Rutgers, J.H. Schornagel, C.C.E. Schaake-Koning, J.L. Peterse, S. Rodenhuis
Journal: Annals of Oncology (1993)
Functional status in high and low risk patient with chronic obstructive pulmonary disease
Authors: Filiz Erdem, Deniz Inal-Ince, Ebru Calik, Naciye Vardar-Yagli, Melda Saglam, Sulenur Subasi, Hulya Arikan, Lutfi Coplu
Journal: European Respiratory Journal (2013)

Aim: Acute exacerbations have an important effect on functional status of patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to compare physical and functional capacity in high and low risk patients with COPD.

Methods: Forty-nine clinically stable patients with COPD (35 M, 14 F, age=60.6±11.1 years, FEV1=57.3±20.2%) participated in the study. Subjects’ demographic and physical characteristics were recorded. Patients were divided in to two groups according to acute exacerbation risk (number of exacerbations per year and GOLD stage). Pulmonary function testing and six-minute walk test (6MWT) were performed. Respiratory muscle strength (MIP and MEP) was measured. Perception of dyspnea using the modified Medical Research Council dyspnea scale and perception of fatigue using the Fatigue Severity Scale (FSS) were determined. Health status was evaluated using the Clinical COPD Questionnaire (CCQ). Level of activities of daily living was determined using London Chest Activities of Daily Living Scale (LCADL).

Results: Body weight, FEV1, FVC, PEF, FEF25-75%, MIP, and 6MWT distance of high risk patients were significantly lower but their CCQ score, FSS score, and LCADL-physical score were significantly higher than those of low risk patients (p<0.05).

Conclusion: The COPD patients with high risk for acute exacerbation have lower weight, impaired lung function, inspiratory muscle strength, functional exercise capacity, health status and activities of daily living, and experienced higher levels of fatigue. Pulmonary rehabilitation components which may be effective in high risk and low risk COPD phenotypes may be different.