tbuckley/cabot-search huggingface dataset:
The incidence of alpha-1-antitrypsin (A1AT) deficiency alleles in patients with pulmonary Langerhans cell histiocytosis
Authors: Elzbieta Radzikowska, Radoslaw Skoronski, Joanna Chorostowska-Wynimko, Elzbieta Wiatr, Beata Poplawska, Kazimierz Roszkowski-Sliz, Agnieszka Jarzemska
Journal: European Respiratory Journal (2013)

Introduction: Inherited alpha-1 antitrypsin deficiency (A1ATD) is one of the three most common genetic disorders in Caucasians. It considerably increases the risk of progressive obstructive lung diseases, mostly chronic obstructive pulmonary disease. There is no data regarding A1ATD prevalence in patients with pulmonary Langrhans cell histiocytosis (PLCH). PLCH is strongly connected with cigarette smoking and the polycystic lung lesions are observed in the course of the disease.

Material and methods: 34 blood samples were collected from adult patients (14 women and 20 men) with histologically confirmed PLCH. AAT serum concentration was measured by nephelometry and PI-phenotype identified by isoelectrofocusing. The PI*S and PI*Z alleles were confirmed by real-time PCR.

Results: Deficiency alleles PI*Z and PI*S were present in 3 patients (one woman and 2 men), respectively in 5,88% and 2,94%. Estimated incidence of deficiency alleles was 29,4/1000 (95% CI;10-69,5) for PI*Z and 14,7/1000(95%CI ;13,9-43,3) for PI*S. Our previous screening data in newborn shown the incidence of deficiency alleles was 13,7/1000 (95% CI 5,8-21,5) for PI*Z and 7,6/1000 (95% CI 1,7-13,5) for PI*S.

Conclusions: Incidence of alpha 1 AT deficiency alleles in patients with PLCH was two times higher than in unselected population of newborns.
Abstract 41: Dnajb6b Is A Novel Genetic Modifier For Cardiomyopathy That Regulates ER Stress Response
Authors: Yonghe Ding, Weibin Liu, Beninio Gore, Stephen C Ekker, Xiaolei Xu
Journal: Circulation Research (2014)

Background: Cardiomyopathy and heart failure affect millions of people worldwide. Because genetic modifiers contribute in large part to the highly variable phenotypic expression of cardiomyopathy in patients even with identical disease-causing mutations, the identification of modifier genes for this disease will greatly improve risk stratification, prognostic test development, and personalized therapy. However, only a rather limited number of modifier genes for cardiomyopathy have been identified sporadically. Objective: To identify genetic modifiers for cardiomyopathy using a novel insertional mutagenesis screening approach in adult zebrafish. Methods and Results: We screened 476 gene break-transposon (GBT) lines and isolated 44 zebrafish insertional cardiac (ZIC) mutants. Employing doxorubicin (DOX) stress to these ZIC mutants, we identified four candidate GBT lines that modified the progression of DOX-induced cardiomyopathy. Here, we report the detailed study of the GBT0411 mutant that exacerbated DOX-induced cardiomyopathy. GBT0411 mutant was tagged to the dnajb6b gene. Mutations in the short (sarcomeric) isoform of its human homologue gene DNAJB6 was recently reported to cause limb-girdle muscular dystrophy type 1D. Interestingly, our data showed that long (nuclei) isoform (dnajb6b[L]) was the major isoform expressed in the heart, and loss-of-function of which deteriorated the progression of DOX-induced cardiomyopathy. We further found that a cardiomyocyte-specific dnajb6b(L) transgene reverted the deleterious modifying effect of GBT0411 mutant, and exerted a cardioprotective function on chronic anemia induced cardiomyopathy. Mechanistically, Dnajb6b(L) could partially localize to endoplasmic reticulum (ER) upon ER stress, and function as an ER stress suppressor. Indeed, inhibition of ER stress by using a chemical chaperon mimics the cardioprotective effect of dnajb6b(L) transgene. Conclusions: By conducting an unbiased mutagenesis screening in adult zebrafish, we identified dnajb6b as a novel genetic modifier for cardiomyopathy. A cardioprotective function was identified by overexpressing its long isoform in cardiomyocytes, which might be conveyed by inhibition of ER stress response.
Response to Letter Regarding Article, “Circulating MicroRNA-30d Is Associated With Response to Cardiac Resynchronization Therapy in Heart Failure and Regulates Cardiomyocyte Apoptosis: A Translational Pilot Study”
Authors: Yonathan F. Melman, Ravi Shah, Kirsty Danielson, Junjie Xiao, Bridget Simonson, Andreas Barth, Khalid Chakir, Gregory D. Lewis, Zachary Lavender, Quynh A. Truong, Andre Kleber, Ranendra Das, Anthony Rosenzweig, Yaoyu Wang, David A. Kass, Jagmeet P. Singh, Saumya Das
Journal: Circulation (2016)
Patient preference as a determinant of breast cancer adjuvant chemotherapy use in older women: CALGB #369901
Authors: J. Mandelblatt, V. Sheppard, A. Hurria, G. Kimmick, C. Isaacs, K. Taylor, G. Luta, A. Noone, A. Kornblith, W. Barry
Journal: Journal of Clinical Oncology (2009)

9544 Background: Decisions about use of breast cancer chemotherapy in women 65 and older (“older”) can be complex due to comorbidity, uncertain efficacy and limited data on patient preference. Methods: Older women diagnosed with invasive, non-metastatic breast cancer between 2004 and 2008 were recruited from 53 CALGB sites for an observational study of preferences and chemotherapy use. Data on preferences and other factors were collected from patient interviews and clinical data were abstracted from charts. Generalized estimating equation regression was used to assess associations between chart-reported chemotherapy and independent variables; associations were also evaluated in 2 subgroups: “chemotherapy indicated” (estrogen receptor [ER] negative and/or node positive) and “consider chemotherapy” (ER positive and node negative). Results: Among 935 eligible women registered, 815 (87.2%) completed interviews. The mean age of the cohort was 73 years (range 65–100); 38% were node positive, 82% were ER positive and all had tumors ≥ 1 cm (44% were AJCC stage 1, 44% stage 2 and 12% stage 3). Based on ER and nodal status, chemotherapy was “indicated” for 47% and could be “considered” for 53%. Crude chemotherapy rates were 70% in the “indicated” group and 17% in the “considered” group, for an overall rate of 42%. Women who would choose chemotherapy for an increase in survival of ≤12 months were 4.1 times (95% CI 2.5–6.7, p&lt;.0001) more likely to receive chemotherapy than women who would only choose chemotherapy if it added more than 12 months, controlling for age, tumor factors, comorbidity and other covariates. Stronger preferences were seen among women with “indications” for chemotherapy (OR 7.9, 95% CI 3.7–17.0, p&lt;.001) than in those where treatment might be “considered” (OR 1.8, 95% CI 0.9–3.4, p=.08). Higher patient rating of communication with providers was independently related to a decision to use chemotherapy among women where chemotherapy could be “considered” but not among those where chemotherapy was “indicated”. Conclusions: Beyond clinical indications, older women's preferences and communication with providers are important correlates of chemotherapy use. [Table: see text]
Predictive utility of progesterone receptor (PR) and multigene expression in identifying benefit from adjuvant doxorubicin plus cyclophosphamide (AC) or docetaxel (AT) in intergroup trial E2197
Authors: L. J. Goldstein, R. J. Gray, R. Bugarini, S. Shak, S. S. Badve, F. L. Baehner, N. E. Davidson, G. W. Sledge, J. A. Sparano
Journal: Journal of Clinical Oncology (2008)

557 Background: Although E2197 showed no difference in recurrence or overall survival, an exploratory analysis suggested differential benefit for AC in PR-pos disease and AT in PR-neg disease (Proc ASCO 2005, abstr 512) when PR was determined in local labs. We evaluated the predictive utility of PR protein expression by IHC in a central lab and quantitative RNA expression by RT-PCR for 371 genes (including the 21-gene recurrence score [RS]) in a representative sample of 734 patients who received at least 3–4 treatment cycles. Methods: Individual gene by treatment interactions were tested in Cox models for relapse-free interval (RFI). Permutation methods were used to control the false discovery proportion at <10%. Supervised principal components (SPC) was used to combine genes into an interaction predictor, which was evaluated via cross-validation (CV). Results: PR Analysis. There was a weak benefit for AT in PR-neg (AT vs AC hazard ratio [RR]=0.75; p=0.06) and AC in PR-pos disease (RR=1.37; p=0.05) by central IHC (Allred score > 2 positive) but not when genomic PR was evaluated by RT-PCR (> 5.5 units positive). RS and New Genes. There was little evidence that gene expression identified AT vs. AC benefit in the hormone receptor (HR)-neg, or HR-pos, RS < 18 subsets. In contrast, there were many genes that strongly predicted differential AT vs AC benefit in the HR-pos, RS > 18 subset; SPC analyses of a multigene model suggest a significant effect (CV continuous interaction permutation p=0.03), with the AT vs. AC RR in the highest and lowest third of the SPC values estimated in CV to be 0.23 and 2.48. Oncotype DX RS did not predict differential AC vs AT benefit in HR-pos disease. Conclusions: PR protein expression may identify a potentially clinically relevant association for differential taxane benefit, but requires validation in other datasets. A genomic classifier predicting differential benefit was identified in HR-pos tumors with a RS > 18, and if externally validated, might be useful in defining differential benefit in patients with HR-pos disease. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genomic Health, sanofi-aventis Genomic Health Institute, GlaxoSmithKline, sanofi-aventis Genomic Health Genomic Health Institute, GlaxoSmithKline, sanofi-aventis sanofi-aventis
Gene Transfer into Marrow Repopulating Cells: Comparison Between Amphotropic and Gibbon Ape Leukemia Virus Pseudotyped Retroviral Vectors in a Competitive Repopulation Assay in Baboons
Authors: Hans-Peter Kiem, Scott Heyward, Aaron Winkler, Jennifer Potter, James M. Allen, A. Dusty Miller, Robert G. Andrews
Journal: Blood (1997)
DNA-PKcs and PARP1 Bind to Unresected Stalled DNA Replication Forks Where They Recruit XRCC1 to Mediate Repair
Authors: Songmin Ying, Zhihui Chen, Annette L. Medhurst, Jessica A. Neal, Zhengqiang Bao, Oliver Mortusewicz, Joanna McGouran, Xinming Song, Huahao Shen, Freddie C. Hamdy, Benedikt M. Kessler, Katheryn Meek, Thomas Helleday
Journal: Cancer Research (2015)

Abstract A series of critical pathways are responsible for the detection, signaling, and restart of replication forks that encounter blocks during S-phase progression. Small base lesions may obstruct replication fork progression and processing, but the link between repair of small lesions and replication forks is unclear. In this study, we investigated a hypothesized role for DNA-PK, an important enzyme in DNA repair, in cellular responses to DNA replication stress. The enzyme catalytic subunit DNA-PKcs was phosphorylated on S2056 at sites of stalled replication forks in response to short hydroxyurea treatment. Using DNA fiber experiments, we found that catalytically active DNA-PK was required for efficient replication restart of stalled forks. Furthermore, enzymatically active DNA-PK was also required for PARP-dependent recruitment of XRCC1 to stalled replication forks. This activity was enhanced by preventing Mre11-dependent DNA end resection, suggesting that XRCC1 must be recruited early to an unresected stalled fork. We also found that XRCC1 was required for effective restart of a subset of stalled replication forks. Overall, our work suggested that DNA-PK and PARP-dependent recruitment of XRCC1 is necessary to effectively protect, repair, and restart stalled replication forks, providing new insight into how genomic stability is preserved. Cancer Res; 76(5); 1078–88. ©2015 AACR.
Toxic Substance Exposure and Multiple Myeloma: A Case-Control Study&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: P D Morris, T D Koepsell, J R Daling, J W Taylor, J L Lyon, G M Swanson, M Child, N S Weiss
Journal: JNCI Journal of the National Cancer Institute (1986)

By means of a population-based, multicenter case-control investigation, certain toxic substances were evaluated as risk factors for multiple myeloma. Interviews were completed on 698 subjects with newly diagnosed multiple myeloma, and 1,683 controls were selected from the same geographic areas as those of the cases. Respondents were asked if they had ever been "highly" exposed" to one or more of a list of toxic substances or to other substances not on the list. With the aid of a toxicologist, responses were then categorized into 20 exposure groups. Those who reported past exposure to pesticides had an estimated relative risk of 2.6 for multiple myeloma [95% confidence interval (CI) = 1.5-4.6]. Subjects exposed to a variety of compounds commonly used by painters had an estimated relative risk of 1.6 (95% CI = 1.1-2.4). An increased risk also was found for those who were exposed to sources of carbon monoxide (relative risk = 1.8, 95% CI = 1.0-3.2). Associations of borderline statistical significance were found for metals and organically high polymers (plastics and elastomers). No statistically significant associations were seen for exposure to fertilizers; dyes and inks; alkalies; acids; other caustic substances; chemical asphyxiants; aliphatic, chlorinated, or aromatic hydrocarbons; aldehydes and ketones; ethers; esters; oils; dusts; or asbestos.
Neoadjuvant radiotherapy ± tegafur-uracil plus leucovorin in rectal adenocarcinoma: Final results of a French multicenter phase III study
Authors: E. Gamelin, L. Mineur, C. Chevelle, P. Cailleux, L. Martin, L. Bastit, B. Roullet, A. Hasbini, J. Savary, P. Cellier
Journal: Journal of Clinical Oncology (2009)

4104 Background: Neoadjuvant chemoradiotherapy (CRT) with tegafur-uracil (UFT) plus leucovorin (LV) has shown promising results in patients with rectal adenocarcinoma (RAC). We therefore conducted a phase III trial to compare neoadjuvant CRT with UFT/LV versus radiotherapy (RT) alone. Methods: One hundred seventy seven pts with RAC stage T3 (T4 if anal extension) N&lt;2, M0 were randomized to either RT alone (RT) (1.8 Gy/d, 45 G total) 5 days/w for 5 weeks or combined to CT (CRT) with daily UFT 300 mg/m 2 plus leucovorin 75 mg for 5 weeks. TME surgery was performed 6–8 weeks after treatment. Adjuvant CT permitted at investigator discretion. Primary endpoint was pathological complete response rate (pCR), secondary endpoints included downstaging, QOL, sphincter preservation, recurrence rates, disease-free and overall survival. Results: Of 177 pts, 87 pts were allocated to RT and 90 to CRT. Compliance: RT dose intensity 98.8 % (n=86) in RT arm vs 95.6 % (n=86) in CRT arm with UFT mean dose 295.7 ± 19.8 mg/m 2 . 172 pts underwent surgery (97.2%), 5 pts were not resected (4 liver and 1 lung metastases plus 1 CVA). Both RT and CRT were well tolerated. No neutropenia and only 1 grade IV diarrhea in the CRT arm were observed. Treatment related death occurred in 4 patients, 3 in the RT arm and 1 in the CRT arm respectively. With a median follow-up at 22.3 mo, median OS is not yet reached. Conclusions: Neoadjuvant radiotherapy combined with UFT increases significantly the pCR rate with an acceptable toxicity. Further survival data will be presented. This is the first randomized study of neoadjuvant CRT highlighting the improvement of the pCR rate with UFT. [Table: see text] [Table: see text]
Inhibition of Pim1 kinase, new therapeutic approach in virus-induced asthma exacerbations
Authors: Maaike de Vries, Nicole Bedke, Natalie P. Smithers, Matthew Loxham, Peter H. Howarth, Martijn C. Nawijn, Donna E. Davies
Journal: European Respiratory Journal (2016)

Therapeutic options to treat virus-induced asthma exacerbations are limited and urgently needed. Therefore, we tested Pim1 kinase as potential therapeutic target in human rhinovirus (HRV) infections. We hypothesised that inhibition of Pim1 kinase reduces HRV replication by augmenting the interferon-induced anti-viral response due to increased activity of the janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway. Air–liquid interface (ALI) cultures of primary bronchial epithelial cells (PBECs) from healthy individuals and moderate-to-severe asthmatic volunteers were infected with HRV-16 with or without a specific Pim1 inhibitor; viral replication and induction of anti-viral responses were measured using RT-qPCR. Viral titres were measured by 50% tissue culture infective dose and release of interferon-γ-induced protein 10 (IP-10) and RANTES protein assessed by ELISA. Phosphorylation of STAT-1 was determined using western blotting. Viral replication was reduced in ALI cultures of healthy and asthmatic PBECs treated with the Pim1 inhibitor. Using cultures from healthy donors, enhanced STAT-1 phosphorylation upon inhibition of Pim1 kinase activity resulted in increased mRNA expression of interferon-β, interleukin-29, IP-10 and RANTES 12 h after infection and increased protein levels of IP-10 and RANTES 24 h after infection. We have identified Pim1 kinase as novel target to reduce viral replication in ALI cultures of PBECs. This may open new avenues for therapeutic interventions in virus-induced asthma exacerbations.
Higher Mycophenolic Acid (MPA) Trough Levels Result In Lower Day 100 Severe Acute GVHD Without Increased Toxicity In Double-Unit Cord Blood Transplantation (CBT) Recipients
Authors: Stephen J. Harnicar, Doris M Ponce, David Gregornik, Sherry Mathew, Katherine L Evans, Junting Zheng, Sean Devlin, Melissa Pozotrigo, Andromachi Scaradavou, Nancy A. Kernan, Nelly G. Adel, Juliet N Barker
Journal: Blood (2013)
Asthma phenotypes in childhood: conceptual thoughts on stability and transition
Authors: Ben Daniel Spycher, Claudia Elisabeth Kuehni
Journal: European Respiratory Journal (2016)

We have known for a long time that asthma-like symptoms in the first years of life predict later asthma poorly. Many preschool wheezers become asymptomatic by school age. A few will develop classic atopic asthma, which is likely to persist into later childhood and even adulthood, but the large majority of preschool children with asthma-like symptoms are difficult place into clear-cut categories. The clinical picture varies from child to child, and remissions and relapses are common. During past decades, many attempts have been made to define asthma phenotypes. Initial attempts were simple and based on a combination of expert opinion and observations made in early cohort studies [1]. More recently, researchers have used statistical clustering techniques, which should provide a more objective classification because they obtain phenotypes from observed data according to a predefined method. Most of us would agree that letting the data speak is a good idea. We want a classification that reflects true patterns of disease as they occur in the population. However, in spite of their promises, these methods are not entirely objective. They require investigators to make certain choices such as which variables to include or which age intervals to consider, and these choices matter. The potential of latent transition analysis of asthma phenotypes will be seen larger cohort studies <http://ow.ly/VUzAH>
Histology and Cytochemistry of Human Skin. XIII. The Blood Supply of the Hair Follicle2
Authors: William Montagna, Richard A. Ellis
Journal: JNCI Journal of the National Cancer Institute (1957)

Journal Article Histology and Cytochemistry of Human Skin. XIII. The Blood Supply of the Hair Follicle Get access William Montagna, William Montagna Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard A. Ellis Richard A. Ellis Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 19, Issue 3, September 1957, Pages 451–463, https://doi.org/10.1093/jnci/19.3.451 Published: 01 September 1957 Article history Received: 27 May 1957 Published: 01 September 1957
Attenuation of Marek's Disease Virus and Study of Its Properties in Two Different Cell Cultures
Authors: K. Nazerian
Journal: JNCI Journal of the National Cancer Institute (1970)

Cytopathology of Marek's disease virus (MDV) was changed in duck embryo fibroblast (DEF) culture, and pathogenicity of the virus was lost as a result of long cell-culture passage. The virus was propagated in chicken embryo fibroblast (CEF) cultures by cocultivation with MDV-infected DEF, and some differences were observed between properties of the virus in these two cultures. Cell-free virus was recovered in growth medium of infected CEF, and MDV microplaques in this culture consisted of round cells. No cell-free virus was recovered in growth medium of infected DEF, and the microplaque consisted of syncytial cells. Behavior of MDV in these two cultures is discussed.
Outcomes of COPD exacerbations - a report from the ERS COPD audit in Austria
Authors: Robab Breyer-Kohansal, Marie-Kathrin Breyer, Otto Burghuber, Sylvia Hartl
Journal: European Respiratory Journal (2013)

Introduction  COPD is currently the fourth leading cause of death worldwide. Exacerbations are known to negatively impact patients’ prognosis and mortality. However, no studies are available investigating mortality of patients hospitalised due to acute COPD exacerbations (AECOPD) in Austria.  Objectives  Therefore, the aim of our study was to analyze, besides patients length of hospital stay and 90 days readmission rate, patients hospital mortality rate after admission for AECOPD throughout Austria compared to European peers.  Methods  16.018 European (432 hospitals, 13 European countries) and 823 Austrian patients (26 hospitals) with AECOPD were included in the ERS COPD Audit, a prospective observational study. Length of stay, 90 days readmission rate, and hospital mortality rate were recorded.  Results  Patients’ characteristics with respect to lung function and GOLD stage were comparable between Austrian and European peers. Median length of stay was higher in Austria compared to Europe (11.2 ±9 days vs. 9.4±9 days; p  Conclusions  In Austrian COPD exacerbations, length of stay and 90 days hospital re-admission rate was higher compared to European peers. Furthermore, mortality rate is high and gender related differences in mortality rate were observed in both, female Austrian and European patients.
Response To Azacitidine Is Independent Of TP53 Mutations In Higher-Risk Myelodysplastic Syndromes (MDS) and Secondary Acute Myeloid Leukemia (sAML)
Authors: Catharina Müller-Thomas, Martina Rudelius, Ina Rondak, Torsten Haferlach, Julie Schanz, Burkhard Schmidt, Markus Kremer, Ulrich Germing, Uwe Platzbecker, Christian Peschel, Katharina Götze
Journal: Blood (2013)