tbuckley/cabot-search huggingface dataset:
A new design for phase II single-arm clinical trials: Bayesian predictive sample size selection design.
Authors: Satoshi Teramukai, Takashi Daimon, Sarah Zohar
Journal: Journal of Clinical Oncology (2013)

6576 Background: The aim of phase II trials is to determine if a new treatment is promising for further testing in confirmatory clinical trials. Most phase II clinical trials are designed as single-arm trials using a binary outcome with or without interim monitoring for early stopping. In this context, we propose a Bayesian adaptive design denoted as PSSD, predictive sample size selection design (Statistics in Medicine 2012;31:4243-4254). Methods: The design allows for sample size selection followed by any planned interim analyses for early stopping of a trial, together with sample size determination before starting the trial. In the PSSD, we determined the sample size using the predictive probability criterion with two kinds of prior distributions, that is, an ‘analysis prior’ used to compute posterior probabilities and a ‘design prior’ used to obtain prior predictive distributions. In the sample size determination, we provide two sample sizes, that is, N and N max , using two types of design priors. At each interim analysis, we calculate the predictive probability of achieving a successful result at the end of the trial using analysis prior in order to stop the trial in case of low or high efficacy, and we select an optimal sample size, that is, either N or N max as needed, on the basis of the predictive probabilities. Results: We investigated the operating characteristics through simulation studies, and the PSSD retrospectively applies to a lung cancer clinical trial. As the number of interim looks increases, the probability of type I errors slightly decreases, and that of type II errors increases. The type I error probabilities of the probabilities of the proposed PSSD are almost similar to those of the non-adaptive design. The type II error probabilities in the PSSD are between those of the two fixed sample size (N or N max ) designs. Conclusions: From a practical standpoint, the proposed design could be useful in phase II single-arm clinical trials with a binary endpoint. In the near future, this approach will be implemented in actual clinical trials to assess its usefulness and to extend it to more complicated clinical trials.
Withdrawal notice for: “Circulating RNA differences between patients with stable and progressive lung function in IPF.” Britt Clynick, Helen E. Jo, Tamera J. Corte, Ian N. Glaspole, Christopher Grainge, Peter M.A. Hopkins, Paul N. Reynolds, Sally Chapman, E. Haydn Walters, Christopher Zappala, Gregory J. Keir, Wendy A. Cooper, Annabelle M. Mahar, Samantha Ellis, Nicole Goh, Svetlana Baltic, Marissa Ryan, Dino Tan and Yuben Moodley. Eur Respir J 2019; in press.
Journal: European Respiratory Journal (2019)

to inform them that they had identified an error in group allocation which then inevitably affected their between-group statistical calculations.This had a potential impact on the results reported in their manuscript.At that point, the extent of the error and the nature of the potential impact
ChiCMaxima: a robust and simple pipeline for detection and visualization of chromatin looping in Capture Hi-C
Authors: Yousra Ben Zouari, Anne M. Molitor, Natalia Sikorska, Vera Pancaldi, Tom Sexton
Journal: Genome biology (2019)

Capture Hi-C (CHi-C) is a new technique for assessing genome organization based on chromosome conformation capture coupled to oligonucleotide capture of regions of interest, such as gene promoters. Chromatin loop detection is challenging because existing Hi-C/4C-like tools, which make different assumptions about the technical biases presented, are often unsuitable. We describe a new approach, ChiCMaxima, which uses local maxima combined with limited filtering to detect DNA looping interactions, integrating information from biological replicates. ChiCMaxima shows more stringency and robustness compared to previously developed tools. The tool includes a GUI browser for flexible visualization of CHi-C profiles alongside epigenomic tracks.
RANKL Signaling Sustains Primary Tumor Growth in Genetically Engineered Mouse Models of Lung Adenocarcinoma
Authors: Julien Robert Rémi Faget, Caroline Anne-Lyse Contat, Nadine Zangger, Solange Peters, Etienne Meylan
Journal: Journal of Thoracic Oncology (2017)

NSCLC is the leading cause of cancer mortality. Recent retrospective clinical analyses suggest that blocking the receptor activator of NF-κB (RANK) signaling pathway inhibits the growth of NSCLC and might represent a new treatment strategy.Receptor activator of NF-κB gene (RANK) and receptor activator of NF-κB ligand gene (RANKL) expression in human lung adenocarcinoma was interrogated from publicly available gene expression data sets. Several genetically engineered mouse models were used to evaluate treatment efficacy of RANK-Fc to block RANKL, with primary tumor growth measured longitudinally using microcomputed tomography. A combination of RANKL blockade with cisplatin was tested to mirror an ongoing clinical trial.In human lung adenocarcinoma data sets, RANKL expression was associated with decreased survival and KRAS mutation, with the highest levels in tumors with co-occurring KRAS and liver kinase B1 gene (LKB1) mutations. In KrasLSL-G12D/WT, KrasLSL-G12D/WT; Lkb1Flox/Flox and KrasLSL-G12D/WT; p53Flox/Flox mouse models of lung adenocarcinoma, we monitored an impaired progression of tumors upon RANKL blockade. Despite elevated expression of RANKL and RANK in immune cells, treatment response was not associated with major changes in the tumor immune microenvironment. Combined RANK-Fc with cisplatin revealed increased efficacy compared with that of single agents in p53- but not in Lkb1-deficient tumors.RANKL blocking agents impair the growth of primary lung tumors in several mouse models of lung adenocarcinoma and suggest that patients with KRAS-mutant lung tumors will benefit from such treatments.
PB1753 CHIDAMIDE MAY BE EFFECTIVE FOR RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA, ESPECIALLY FOR AML/ETO POSITIVE PATIENTS
Authors: W. Yao, J. Tong, H. Liu, Z. Sun
Journal: HemaSphere (2019)

Background: Epigenetic changes are encountered in acute myeloid leukemia (AML) and are thought to contribute to leukemogenesis. Decreased histone acetylation was frequently found in AML, especially in high‐risk cytogenetics, higher age, secondary or relapsed/refractory AML. HDAC inhibitors have been found to be effective in AML. But the data was limited in China. Aims: This retrospective study evaluated the clinical outcomes of chidamide combined with FLAG regimen for relapsed/refractory AML in our single center. Methods: From May 2018 to December 2018, 12 patients with relapsed/refractory AML including 6 AML/ETO positive received induction chemotherapy of “chidamide +FLAG” regimen (chidamide 30 mg/d twice a week for two weeks, fludarabine 30 mg/m 2 / d for 5 days, Ara‐C 2 g/m 2 /d for 5 days, G‐CSF 5‐10ug/kg/d continuedly until neutrophil recoverd). Results: A total of 7 patients achieved a complete remission (CR) after induction chemotherapy (CR rate 58.3%). In 6 AML/ETO positive patients, 5 patients achieved molecular remission (CR rate 83.3%). At the end of the follow‐up period, 8 patients underwent hematopoietic stem cell transplantation and 7 patients survived in CR. Summary/Conclusion: Chidamide might be suitable drugs in relapsed/refractory AML therapy, especially in AML/ETO positive patients.
KrakenUniq: confident and fast metagenomics classification using unique k-mer counts
Authors: F. P. Breitwieser, D. N. Baker, S. L. Salzberg
Journal: Genome biology (2018)

False-positive identifications are a significant problem in metagenomics classification. We present KrakenUniq, a novel metagenomics classifier that combines the fast k-mer-based classification of Kraken with an efficient algorithm for assessing the coverage of unique k-mers found in each species in a dataset. On various test datasets, KrakenUniq gives better recall and precision than other methods and effectively classifies and distinguishes pathogens with low abundance from false positives in infectious disease samples. By using the probabilistic cardinality estimator HyperLogLog, KrakenUniq runs as fast as Kraken and requires little additional memory. KrakenUniq is freely available at https://github.com/fbreitwieser/krakenuniq .
Abstract 3817: Audibility of the Fourth Heart Sound Correlates with the Level of Left Ventricular Diastolic Function
Authors: Ina T Porter, Kirstie A Schneider, Aziz R Maksoud, Renjith D Joseph, Peter A Lebourveau, David G Meyers
Journal: Circulation (2006)

Background: The correlation of the fourth heart sound (S4) with abnormal left ventricular (LV) compliance is based on studies using age > 65 years and clinical evidence of heart disease as indicato...
PB2442 BRONCHOSCOPIC TREATMENT WITH FRESH FROZEN PLASMA AND TISSUE PLASMINOGEN ACTIVATOR FOR A CHILD WITH TYPE 1 PLASMINOGEN DEFICIENCY
Authors: M. Hangul, A. B. Tuzuner, I. Somekh, C. Klein, T. Patıroglu, E. Unal, M. Kose
Journal: HemaSphere (2019)

Background: Congenital plasminogen deficiency is a genetic disease with autosomal recessive inheritance pattern. Fibrous plaques that accumulate in the mucosal surfaces of oral cavity, eye and respiratory tract. Aims: We aimed to report the first bronchoscopic usage of fresh frozen plasma (FFP) and tissue plasminogen activator (t‐PA) for respiratory complications of a child with plasminogen deficiency. Methods: A child with plasminogen deficiency treated with FFP, t‐PA is reported. Results: A one‐year‐old male patient was admitted to the hospital for 1 week with cough and increased respiratory distress. Antibiotic therapy was started for bronchopneumonia. From his medical history it was learned that he had lingous conjunctivitis, in addition a ventriculo‐peritoneal shunt was inserted due to hydrocephalus in the antenatal period. His parents were cousins. The patient had significant paracardiac infiltrations, linear infiltrations in the parenchyma of the chest x ray. The patient was thought to have plasminogen deficiency by clinical findings and his plasminogen level was found to be 14% (N: 70‐130%). Type 1 plasminogen deficiency and related pulmonary involvement were considered. Bronchoscopy was performed. There were fibrin deposits in the trachea and bronchi. Recurrent pulmonary lavage was performed with FFP and t‐PA. Fibrin plugs occluding the bronchial cuffs were decreased and some of them disappeared. The patient recovered from respiratory distress that required high flow oxygen therapy, and discharged. Homozygous frameshift mutation in the PLG gene was detected. Summary/Conclusion: In this case, it has been firstly reported that total pulmonary lavage treatment with FFP and t‐PA can be a useful treatment method for paitents with plasminogen deficiency in the English literature.
THU0228 EXPRESSION OF APOBEC FAMILY MEMBERS AS REGULATORS OF ENDOGENOUS RETROELEMENTS AND MALIGNANCY IN SYSTEMIC LUPUS ERYTHEMATOSUS AND SJÖGREN’S SYNDROME
Authors: Clio Mavragani, Kyriakos Kirou, Adrianos Nezos, Surya V. Seshan, Teresa Wild, Sharon M. Wahl, Haralampos M. Moutsopoulos, Mary K. Crow
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Activation of type I and II interferon (IFN) pathways contributes to the pathogenesis of systemic autoimmune diseases. We have previously shown increased expression of the LINE-1 (L1) endogenous retrotransposon in systemic lupus erythematosus (SLE) kidneys and in minor salivary glands (MSG) from primary Sjögren's syndrome patients (SS) that strongly correlates with IFNα expression in the same tissues. Moreover, an imbalance between type I and II IFNs in SS salivary gland tissues has been related to non-Hodgkin's lymphoma (NHL) development. Members of a family of retroviral resistance factors (APOBECs) have been implicated in L1 control and are regulated by both type I and II IFNs. <h3>Objectives:</h3> We investigated whether these mechanisms are involved in the response to inappropriate expression of L1 retroelements in primary SS and SLE, as well as in SS related lymphomagenesis. <h3>Methods:</h3> MSG and kidney biopsy specimens were obtained from 41 patients with primary SS and 23 patients with SLE, respectively. Peripheral blood mononuclear cells (PBMC) and sera were also collected from 73 SLE patients. Relative mRNA expression was quantified by real-time polymerase chain reaction for full-length L1 transcripts, along with members of the APOBEC family [APOBEC3A, APOBEC3B, APOBEC3G, AID (activation-induced cytidine deaminase)] and IFNα and γ transcripts. Type I IFN activity was assessed in lupus plasma by a reporter cell assay. The induction of APOBEC3A and B by IFNα in healthy control PBMCs was also assessed. <h3>Results:</h3> APOBEC3A, previously implicated in control of endogenous retroelements, was increased in SS MSG and lupus nephritis kidney tissues and in SLE PBMC and strongly correlated with L1 retroelement expression in both SS and SLE tissues. APOBEC3A was also associated with IFNα mRNA expression in SS MSG tissues and lupus kidneys and with type I IFN activity in lupus plasma. While APOBEC3A expression was induced by IFNα, such a relationship was not observed with APOBEC3B. Moreover, a strong correlation was detected between AID and APOBEC3G with IFNγ expression in SS MSG tissue, a relationship particularly relevant to development of NHL. <h3>Conclusion:</h3> Increased expression of APOBEC3A reflects a host-intrinsic and IFNα-dependent mechanism regulating potentially harmful L1 retroelements in patients with SS and SLE. Moreover, IFNγ-related induction of APOBEC3G, together with AID, might contribute to SS-related lymphomagenesis by increasing mutational load or epigenetic alterations. These data reveal a previously unappreciated role of APOBEC family proteins in the pathogenesis of autoimmune disorders. <h3>Disclosure of Interests:</h3> None declared
PS941 ANTI‐CD19 CAR‐T THERAPY BRIDGING TO ALLO‐HSCT IMPROVES LONG‐TERM OUTCOME OF B‐ALL PATIENTS WITH HIGH LEUKEMIA BURDEN OR POOR PROGNOSTIC MARKERS
Authors: H. Mei, Y. Hu, H. Jiang, F. Zhou, T. Guo, Y. Wu, L. Liu, L. Ai, W. Shi, C. Li, L. Tang, W. Xiong, L. Xia, R. Jin
Journal: HemaSphere (2019)

Background: Anti‐CD19 chimeric antigen receptor T cell (CAR‐T) therapy was an effective treatment method for relapsed and/or refractory B‐cell acute lymphoblastic leukemia (r/r B‐ALL) patients, but its ability to maintain long‐term leukemia‐free survival was limited. New strategies that can help CAR‐T therapy achieve lasting effect are urgently warranted. Aims: Our study aimed to answer the question that whether subsequent allo‐HSCT could improve the long‐term prognosis of the minimal residual disease‐negative (MRD‐) CR patients after CAR‐T therapy. image Methods: In the first stage, patients received split doses of CAR‐T cells after lymphodepleting chemotherapy, consisting of fludarabine and cyclophosphamide. In the second stage, MRD‐ CR patients who had no history of allo‐HSCT and had no contraindications or other restrictions would, on their own accord, receive allo‐HSCT from 1 to 3 months after CAR‐T therapy. Results: 58 r/r B‐ALL patients were treated with anti‐CD19 CAR‐T cells, and 51 (87.9%) achieved complete remission (CR) (47 MRD‐ CR). The 6‐month and 12‐month overall survival (OS) rates were 68.9% and 61.1% respectively. During the follow‐up (median, 7.7 months), 21 of the 47 MRD‐ CR patients received consolidative allo‐HSCT and 17 remained leukemia‐free, while the other 26 patients received CAR‐T therapy alone and only 10 remained in CR. (Fig. 1A) There was no difference in OS between the MRD‐ CR patients who received allo‐HSCT and those who didn’t, but event‐free survival (EFS) and relapse‐free survival (RFS) were significantly prolonged by allo‐HSCT in the subgroups with either high pre‐infusion bone marrow MRD (≥ 5%) or poor prognostic markers ( P &lt; 0.05). (Fig.1B∼E) However, no difference was found in OS, EFS and RFS in subgroup with MRD &lt; 5% and without poor prognostic markers. Summary/Conclusion: These data demonstrate that CAR‐T therapy bridging to allo‐HSCT is a safe and effective therapeutic strategy for r/r B‐ALL patients, and can achieve better efficacy in terms of maintaining long‐term EFS and RFS. Patients with high pre‐infusion MRD or with poor prognostic markers can benefit from the early consolidative allo‐HSCT after CAR‐T therapy. Trials were registered at www.clinicaltrials.gov as # NCT02965092 and # NCT03366350.
Gene Regulatory Network Analysis Identifies Sex-Linked Differences in Colon Cancer Drug Metabolism
Authors: Camila M. Lopes-Ramos, Marieke L. Kuijjer, Shuji Ogino, Charles S. Fuchs, Dawn L. DeMeo, Kimberly Glass, John Quackenbush
Journal: Cancer Research (2018)

Understanding sex differences in colon cancer is essential to advance disease prevention, diagnosis, and treatment. Males have a higher risk of developing colon cancer and a lower survival rate than women. However, the molecular features that drive these sex differences are poorly understood. In this study, we use both transcript-based and gene regulatory network methods to analyze RNA-seq data from The Cancer Genome Atlas for 445 patients with colon cancer. We compared gene expression between tumors in men and women and observed significant sex differences in sex chromosome genes only. We then inferred patient-specific gene regulatory networks and found significant regulatory differences between males and females, with drug and xenobiotics metabolism via cytochrome P450 pathways more strongly targeted in females. This finding was validated in a dataset of 1,193 patients from five independent studies. While targeting, the drug metabolism pathway did not change overall survival for males treated with adjuvant chemotherapy, females with greater targeting showed an increase in 10-year overall survival probability, 89% [95% confidence interval (CI), 78-100] survival compared with 61% (95% CI, 45-82) for women with lower targeting, respectively (P = 0.034). Our network analysis uncovers patterns of transcriptional regulation that differentiate male and female colon cancer and identifies differences in regulatory processes involving the drug metabolism pathway associated with survival in women who receive adjuvant chemotherapy. This approach can be used to investigate the molecular features that drive sex differences in other cancers and complex diseases.Significance: A network-based approach reveals that sex-specific patterns of gene targeting by transcriptional regulators are associated with survival outcome in colon cancer. This approach can be used to understand how sex influences progression and response to therapies in other cancers. Cancer Res; 78(19); 5538-47. ©2018 AACR.
Immune Checkpoint (PD-1, PD-L1, PD-L2, and CTLA-4) Expression in Plasma Cell Myeloma
Authors: Min Young Lee, Chan-jeoung Park, Young-Uk Cho, Eunkyoung You, Seongsoo Jang, Jung-Hee Lee, Jung Yong Hong, Dok Hyun Yoon, Cheolwon Suh
Journal: Blood (2017)
Abstract 19107: Serum Myeloperoxidase/Paraoxonase 1 Ratio Is an Independent Predictor for Repeat Revascularization After Percutaneous Coronary Intervention
Authors: Yoko Haraguchi, Ryuji Toh, Minoru Hasokawa, Hideto Nakajima, Tomoyuki Honjo, Kazunori Otsui, Kunihiro Nishimura, Tatsuro Ishida, Ken-ichi Hirata
Journal: Circulation (2010)

There is growing recognition that not only the circulating quantity but the functional quality of high-density lipoprotein (HDL) is important for prevention of coronary artery disease (CAD). Howeve...
Proceedings of the British Thoracic Society
Authors: F Howell, R O'laoide, P Kelly, T Healy, L Clancy, A France, D Mcleod, M Calder, A Seaton, D Sykes, R Wilson, D Watson, G Taylor, J Macdermot, P Coles
Journal: Thorax (1986)

The Republic of Ireland has the highest incidence of and mortality from TB in these islands.In the study period, based on WHO methods for compiling mortality from TB, the figures were: nationally new cases of TB 12 063, deaths 1749 (15 %), Peamount new cases of TB 4089 (3201), deaths 225 (5.50o).As many have questioned the validity of the WHO methods our study evaluated all deaths for the period (1354), of which 336 were TB related.In 95 TB was a remote event, in 149 TB was active but not the primary cause of death and in 92 TB was the true cause of death.This is a true death rate of 2.2%, the lowest reported.Most of the 92 were elderly, male, poor and smokers.The significant predictive factors were (i) bilateral extensive cavitatory disease 7707o, (ii) patient referral delay mean 9.7 weeks, (iii) 1 referral delay mean 2.4 weeks, (iv) secondary referral delay mean 2.2 weeks, (v) the diagnosis was made in 91 cases prior to referral but only three had correct treatment at referral although 9107. of cases were referred from the hospital services, (vi) of those dying from TB 50%0 were dead by the end of week two.The conclusions are:1.This is the first study in these islands to look at the true mortality from TB and death certification simultaneously.2. Our study shows that the international method of compiling mortality data is misleading and needs urgent revision.3. Our study highlights the tragic consequences of an unacceptable delay in initiating correct treatment in extensive TB.
Alexithymia and the Split Brain
Authors: W.D. TenHouten, K.D. Hoppe, J.E. Bogen, D.O. Walter
Journal: Psychotherapy and Psychosomatics (1985)

The Hoppe-Bogen finding of alexithymia in 12 commissurotomy patients is examined, using 6 sentential-level items corresponding to 6 of the 8 key alexithymia items in the Beth Israel 'Psychosomatic Questionnaire'. 8 of the same commissurotomy patients and 8 precision-matched normal control subjects were shown a 3-min videotaped film about death. Content analyses of the subjects' spoken and written responses to this film were carried out, with directional support found for all items; however, only 2 of these differences in group means were statistically significant. The items were factor analyzed, and a 1-factor solution obtained. Factor score comparisons replicated the earlier study, as commissurotomy patients were found to be more alexithymic than normal controls.