tbuckley/cabot-search huggingface dataset:
JAK2 p.G571S in B-cell precursor acute lymphoblastic leukemia: a synergizing germline susceptibility
Authors: Minhui Lin, Karin Nebral, Christoph G. W. Gertzen, Ithamar Ganmore, Oskar A. Haas, Sanil Bhatia, Ute Fischer, Michaela Kuhlen, Holger Gohlke, Shai Izraeli, Jan Trka, Jianda Hu, Arndt Borkhardt, Julia Hauer, Franziska Auer
Journal: Leukemia (2019)

Germline predispositions are involved in the development of 5% of childhood leukemias [1], although their contribution is believed to be higher.However, to reveal the full spectrum of pathogenic germline variants, individualized genomic patient analyses, in the context of the respective familial background (trio-calling), are needed.Here, we present the finding of a germline predisposition to B-cell precursor acute lymphoblastic leukemia (BCP-ALL) that is exerted through two synergizing, separately transmitted germline variants (JAK2 p.G571S and STAT3 p.K370R).We demonstrate a modest proliferation potential of JAK2 p. G571S, which is additionally increased by STAT3 p.K370R through rewiring of intracellular signaling pathways and show that JAK2 G571S can rescue a STAT3 p.K370R-induced cell cycle arrest.Protein modeling of both variants structurally underlines the observed phenotypes.Furthermore, JAK2 p. G571S could be identified in a second patient with Down syndrome ALL, emphasizing its significance as a recurrent synergizing germline susceptibility variant.Taken together, we describe JAK2 p.G571S as a novel germline predisposition in BCP-ALL.Moreover, our data emphasize the synergistic interplay between separately
SAT-026-Mid-arm circumference and triceps skinfold thickness independently predicts mortality in hospitalized patients with decompensated cirrhosis
Authors: Camila Saueressig, Pâmela Kremer Ferreira, Joana Hoch Glasenapp, Thais Ortiz Hammes, Vivian Cristine Luft, Valesca Dall’alba
Journal: Journal of Hepatology (2019)
Failure with acquired resistance of an optimised bedaquiline-based treatment regimen for pulmonary <i>Mycobacterium avium</i> complex disease
Authors: Sanne M.H. Zweijpfenning, Jodie A. Schildkraut, Jordy P.M. Coolen, Carolien Ruesen, Ellen Koenraad, Anne Janssen, Mike M. Ruth, Arjan S. de Jong, Saskia Kuipers, Rob E. Aarnoutse, Cecile Magis-Escurra, Wouter Hoefsloot, Jakko van Ingen
Journal: European Respiratory Journal (2019)

<b>In its current dose, bedaquiline is probably not a viable treatment option for treatment-refractory MAC-PD; even with adequate exposure, treatment fails due to acquired resistance documented by increasing MICs and whole-genome sequencing</b>http://bit.ly/2YvaTMM
A genome-wide approach to link genotype to clinical outcome by simultaneously utilizing next generation sequencing and gene chip data of 6,697 breast cancer patients.
Authors: Balazs Gyorffy, Mate Kormos, Lorinc Pongor
Journal: Journal of Clinical Oncology (2015)

e12074 Background: Cancer somatic mutations may results in an altered protein product impinging on a set of additional genes capable to “leverage” the effects of the mutation. To evaluate this inception, one has to capture the signature of all genes displaying altered expression in relation to a given mutation and asses the prognostic potential for this multigene signature. We combined available genotype data generated by next generation sequencing (NGS) with microarray based gene expression data to establish a framework to assess this leveraged effect on clinical outcome. Methods: NGS data generated by the TCGA and gene chip data obtained from GEO were utilized. Transcriptomic fingerprint for mutation status is carried out by running ROC analysis on mutation and RNA-seq data. The average expression (gene chip data) of the significant genes is designated as a genotype‘s metagene. Correlation to survival is assessed by computing Cox regression for both up- and down-regulated signatures. An online interface enables running the analysis for any selected gene (http://www.g-2-o.com). Results: The database contains 763 NGS samples containing mutational status for 22,938 genes and RNA-seq data for 10,987 genes. The gene chip database contains 5,934 patients with 10,987 genes plus clinical characteristics. The system was validated to reassure correlation between RNA-seq and microarray data (r2= 0.73, p < 1E-16). A set of established genes known to influence survival were used as test set (TP53: p < 1E-16 and PIK3CA: p = 8.1E-07). Conclusions: By connecting genotype to gene expression signature and employing this signature for survival analysis we established a pipeline enabling the rapid functional validation of a discovered mutation for any gene in a large breast cancer cohort.
A Lack of Decline in Major Nontraumatic Amputations in Texas: Contemporary Trends, Risk Factor Associations, and Impact of Revascularization
Authors: Marlene Garcia, Brian Hernandez, Tyler G. Ellington, Anupama Kapadia, Joel Michalek, Susan Fisher-Hoch, Joseph B. McCormick, Anand Prasad
Journal: Diabetes Care (2019)

OBJECTIVE Nontraumatic major lower extremity amputations (LEAs) have been reported to be declining nationally; however, trends in Texas have been less well described. We evaluated demographic and clinical risk factors and revascularization associations for LEAs by using inpatient hospital discharge data in Texas from 2005 to 2014. RESEARCH DESIGN AND METHODS Inpatient hospital discharge data were obtained from the Texas Center for Health Statistics. Multivariate logistic regression analyses were performed to evaluate clinical, ethnic, and socioeconomic risk factors associated with LEA. The impact of revascularization (surgical and/or endovascular) on LEA was analyzed. RESULTS Between 2005 and 2014, of 19,939,716 admissions, 46,627 were for nontraumatic major LEAs. Over time, LEAs were constant, and revascularization rates during index admission declined. The majority of LEAs occurred in males and in individuals aged 60–79 years. Risk factors associated with LEA included diabetes, peripheral arterial disease, chronic kidney disease, and male sex (P &amp;lt; 0.001). Insurance status, hyperlipidemia, coronary artery disease, and stroke/transient ischemic attack were associated with lower odds of amputation (P &amp;lt; 0.001). Hispanic (odds ratio [OR] 1.51 [95% CI 1.48, 1.55], P &amp;lt; 0.001) and black (OR 1.97 [95% CI 1.92, 2.02], P &amp;lt; 0.001) ethnicities were associated with a higher risk for amputation when compared with non-Hispanic whites. Revascularization, either surgical or endovascular (OR 0.52 [95% CI 0.5, 0.54], P &amp;lt; 0.001), was also associated with lower odds for amputation. CONCLUSIONS Amputation rates in Texas have remained constant, whereas revascularization rates are declining. A higher risk for LEA was seen in minorities, including Hispanic ethnicity, which is the fastest growing demographic in Texas. Revascularization and having insurance were associated with lower odds for amputation.
Inhibition of Siglec-15 to prevent bone loss in the 5T2MM model of multiple myeloma.
Authors: Gilles Tremblay, Anna Moraitis, Karin Vanderkerken, Mario Filion
Journal: Journal of Clinical Oncology (2015)

e19534 Background: Multiple myeloma (MM) is a B-cell malignancy associated with infiltration and growth of plasma cells in the bone marrow resulting in end-organ damage including devastating osteolytic bone disease. We examined the ability of 25B2, an antibody targeting Siglec-15, to prevent bone loss in the 5T2MM syngeneic model of MM. Methods: C57BlKaLwRij male mice (n = 10/group) were injected with 5T2MM cells and 24h later treated for 12 weeks with the PBS, 25B2 (10 mg/kg, q3d), bortezomib (BTD, 0.7 mg/kg, q3d) or a combination of 25B2 and BTD. Results: 25B2 treatment caused a 3.7-, 5.4- and 1.2-fold increase in bone volume (%BV/TV) compared to PBS-treated mice in the tibia, femur and lumbar vertebra (LV), respectively. Increases in bone volume were also seen with BTD with 3.1-, 4.1- and 1.4-fold increases in the tibia, femur and LV, respectively. Combination of the two agents further increased %BV/TV by 6.9-, 10.5- and 1.5-fold in the tibia, femur and LV, respectively, when compared to the PBS treated mice. All of the changes were statistically significant with the exception of those in the LV. Unlike BTD treatment, which inhibits the growth of 5T2MM cells in this model, there was no direct effect of 25B2 on tumor burden in 5T2MM mice when the % plasmacytosis and the serum paraprotein levels were measured. However, 25B2 caused a significant decrease in the number of bone lesions by 49.5%. The number of lesions in the BTD group decreased by 71.7%, but there was no significant difference between the 25B2 and BTD groups. The number of lesions decreased by 89.4% in the combination group. Conclusions: Consistent with the mechanism of action of Siglec-15 antibodies, osteoclasts were rendered inactive, however cross-talk with bone-forming osteoblasts was likely maintained. This unique mechanism of action would be particularly appropriate for MM, where osteolytic disease is not only the result of increased osteoclast activity but also decreased osteoblast-mediated bone formation. The 5T2MM model is one of the most representative of the human pathology and therefore, the effect observed in response to the Siglec-15 antibody holds the promise that such a treatment in MM patients could provide benefit and further delay skeletal related events.
SAT-288-Liver stiffness measurement predicts long-term survival and complications in non-alcoholic fatty liver disease
Authors: Sarah Shili, Grace Lai-Hung Wong, Hiriart Jean-Baptiste, ken liu, Faiza Chermak, Sally Shu, Juliette Foucher, Yee-Kit Tse, Pierre-Henri Bernard, Terry CF Yip, Merrouche Wassil, Henry Chan, Vincent Wai-Sun Wong, Victor De Ledinghen
Journal: Journal of Hepatology (2019)
Do responses in PET/CT correlate with pathological complete response after neoadjuvant chemotherapy in locally advanced breast cancer?
Authors: Serap Kaya, Eda tanrikulu Simsek, Umit Ugurlu, Zerrin Ozgen, Suleyman Halil, Mehmet Besiroglu, Sinan Koca, Nalan Babacan, Faysal Dane, Handan Kaya, Serdar Turhal, Fulden Yumuk
Journal: Journal of Clinical Oncology (2015)

e12038 Background: Neoadjuvant chemotherapy (NACT) is recommended in locally advanced breast cancer (LABC) recently. Overall survival is increased in patients who have pathological complete response (pCR). We investigated if the differences in SUV levels on PET/CT correlates with pCR after NACT. Methods: Dataof 43 patients treated with NACT and were evaluated by PET/CT before and after NACT were analysed,retrospectively. Demographic features, tumor characteristics and changes of SUV levels on PET/CT before and after NACT for both primary tumor and axilla were evaluated. The decrease in SUV levels over 50% for both breast and axilla was accepted as
APC mutations in myeloid malignancies: Incidence and impact on leukemogenesis.
Authors: Aziz Nazha, Bartlomiej Przychodzen, Hideki Makishima, Mayur Narkhede, Matt E. Kalaycio, David James Seastone, Hetty Carraway, Aaron Thomas Gerds, Sudipto Mukherjee, Anjali S. Advani, Jennifer Carew, Mikkael A. Sekeres, Jaroslaw P. Maciejewski
Journal: Journal of Clinical Oncology (2015)

11047 Background: Adenomatous polyposis coli (APC) gene is a tumor suppressor gene that plays an integral role in the WNT-signaling pathway. Germline mutations in APC are responsible for the autosomal dominant familial adenomatous polyposis, while somatic mutations are are linked to the initiation and progression of colorectal cancer (CRC). Haploinsufficiency of APC impairs hematopoiesis in animal models suggesting that loss of APC function contributes to the development of myelodysplasia (Wang J,et al. Blood 2010); however, patients (Pts) with germline APC mutations are not predisposed to develop myeloid malignancies. It is not known whether somatic mutations in APC gene can drive leukemogenesis. Methods: We screened our genomic database for the presence of somatic mutations in APC genes in pts with myeloid malignancies. A panel of 62 gene mutations obtained by NG targeted deep sequencing was included. Variant allele frequencies adjusted by zygosity were used to define clonal architecture. Results: Among 886 pts with myeloid malignancies, 15 (2%) had somatic mutations in APC. Of these, 8 had MDS, 4 AML, and 3 MDS/MPN; with median age of 69 years (range 39-84); none had a documented family history or personal history of CRC. In metaphase cytogenetic (MC) analyses, 11 pts had normal karyotype, 2 del(7q), 1 (-7), 1 inv(1q), and none had chr 5 abnormalities by either MC or SNP. Mutations in APC included: 8 missense, 3 nonesense, and 4 non-frameshift in/dels. Majority of APC mutations showed heterozygous configuration, resulting in the same consequences with hemizygous deletion of the locus. We then compared these mutations to germline variants recorded in the GEO database. No variants matched our data. Clonal architecture analysis showed that APC mutations can be either founder or subclonal. In founder cases, APC mutations were always accompanied by subclonal mutations described in myeloid malignancies e.g. SF3B1, TET2, DNMT3A, and RUNX1, etc. suggesting that APC alone is not sufficient to drive leukemogenesis. Conclusions: Somatic mutations in APC gene are rare in myeloid malignancies. They can be either founder or subclonal. In founder cases, a second hit with recurrent myeloid mutations is required to drive leukemogenesis.
SAT-304-The association between visceral fat and evolution of patients with non-alcoholic fatty liver disease
Authors: Marta Hernández Conde, Elba Llop, Beatriz Tormo, Javier Abad Guerra, Christie Perello, Marta López-Gómez, Luis Rodríguez, José Luis Martínez Porras, Natalia Fernández Puga, Carlos Ferre, José Luis Calleja Panero
Journal: Journal of Hepatology (2019)
Re: Sebastian Berg, Alexander P. Cole, Marieke J. Krimphove, et al. Comparative Effectiveness of Radical Prostatectomy Versus External Beam Radiation Therapy Plus Brachytherapy in Patients with High-risk Localized Prostate Cancer. Eur Urol 2019;75:552–5
Authors: Amar U. Kishan, William A. Hall, Daniel E. Spratt
Journal: European Urology (2019)
FRI-125-The phase angle determined by bioelectrical impedance is a predictive factor of hospitalization, falls and mortality in patients with cirrhosis
Authors: Eva Roman, Maria Poca, Gerard Amorós, Javier Rosell, Cristina Gely, Berta Cuyas, Silvia Vidal, Eulalia Urgell, Elvira Hernández, Rosalia Santesmases, Candido Juárez, Carlos Guarner, German Soriano
Journal: Journal of Hepatology (2019)
Practice pattern treating older women with early stage breast cancer at Johns Hopkins.
Authors: YaoYao Guan Pollock, Amanda Blackford, Stacie Jeter, Ashley Cimino-Mathews, Melissa Camp, Susan Harvey, Fariba Asrari, Jean Wright, Vered Stearns
Journal: Journal of Clinical Oncology (2015)

9529 Background: The National Comprehensive Cancer Network (NCCN) Guidelines incorporated omission of radiation therapy (RT) after breast-conservation surgery in woman age ≥ 70 years with stage I, estrogen receptor positive breast cancer who plan to receive endocrine therapy (ET). This guideline change was based on The Cancer and Leukemia Group B C9343 trial. A follow up study demonstrated that there is a wide variation in implementing this change across 13 different NCCN institutions. We evaluated the practice pattern at Johns Hopkins, and sought to construct an internal guideline. Methods: We identified women treated at our institution from 2009-2013 age ≥ 70 years at the time of diagnosis and met the C9343 inclusion criteria. RT omission rate was calculated for each year. We explored associations between RT omission and year, age, tumor size, race, nodal status and tumor type with t tests and Fisher’s exact tests. Results: A total of 544 women age ≥ 70 years sought treatment at our institution, and 98 (18%) were candidates for RT omission based on the NCCN guidelines. Mean age was 76.2 years (Range 70-95). Overall RT omission rate was 36/98 (37%), but varied greatly by year (Range 8-56%, p = 0.03). This variation in omission rate was still present after excluding women who did not tolerate ET (Range 9-67%, p = 0.02). Older age was associated with higher RT omission rate (mean age 78.7 vs. 74.8, p = 0.002). Women who did not undergo nodal evaluation had higher RT omission rate (68%) than women who had nodal evaluation (29%) even when the evaluated node(s) were negative (p = 0.003). The RT omission rate did not vary by race (Caucasians: 24/69, 35%; Non-Caucasians: 11/27, 40%; p = 0.64), tumor type (ductal: 27/72, 38%; non-ductal: 9/26, 35%; p > 0.99), or tumor size ( < 1cm: 17/37, 46%; 1-1.4cm: 10/34,29%; 1.5-2cm: 8/25, 32%; p = 0.35). Conclusions: The implementation of the NCCN guideline, which was based on category I evidence, is not consistent at our institution. Our results suggest that other tools should be used to apply the guidelines more consistently. To achieve this, we have developed a Quality Improvement Protocol that incorporates life expectancy estimate and a brief geriatric assessment to the treatment of all woman age ≥ 70 years at our breast centers.
ERCC1 in patients with Malignant Pleural Mesothelioma (MPM) treated by neoadjuvant chemotherapy followed by extrapleural pneumonectomy (EPP).
Authors: Seiji Matsumoto, Toru Nakamichi, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Nobuyuki Kondo, Tohru Tsujimura, Takashi Nakano, Seiki Hasegawa
Journal: Journal of Clinical Oncology (2015)

e18542 Background: Cisplatin plus pemtrexte is first line chemotherapy for Malignant Pleural Mesothelioma (MPM). In multimodality include extrapleural pneumonectomy (EPP), chemotherapy is essential. Excision repair cross-complementing group 1 gene (ERCC1) is important for platinum-induced DNA adduct repair. We evaluate the association of overall survival (OS) and the expression of TS, ERCC1 in MPM multimodality therapy. Methods: Forty six MPM patients underwent multimodality includes Extrapleural Pneumonectomy (EPP) at Hyogo College of Medical, Nishinomiya, Japan from April 2004 to October 2013. All patients received neoadujvant chemotherapy (Cisplatin/Pemetrexed) followed by EPP. Paraffin embedded surgical sample was used for immunohistochemistry to evaluate the expression of TS, ERCC1. Overall survival (OS) from the time of surgery was determined by Kaplan-Meier method and results compared by log-rank test. Results: The median OS of 46 MPM patients was 24.5 months (95% confidence interval [CI], 0.0082-47.2 months). The high ERCC1 expression related better survival than the low ERCC1 expression (43.6 vs.15.2 months, P=0.023). There was no correlation between TS expression and OS (39.2 vs. 22.0 months for low and high levels, respectively; P=0.80).Twenty six patients received postoperative hemithorax radiation. In subgroup analysis of patients who did not receive hemisothax radiation, ERCC1 positive was better than ERCC1 negative (15.4 months vs. 10.0 months, P=0.089). Conclusions: The high expression of ERCC1 was associated with prolonged survival in neoadujvant chemotherapy (Cisplatin/Pemetrexed) followed by EPP. It appears that the expression of ERCC1 had prognostic value.
Dermatological manifestations of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis ( <scp>POIKTMP</scp> ): a case series of 28 patients
Authors: E. Chasseuil, J.A. McGrath, A. Seo, X. Balguerie, N. Bodak, H. Chasseuil, M. Denis‐Musquer, A. Goldenberg, R. Goussot, A.D. Irvine, N.P. Khumalo, M.C. King, S. Küry, D. Lipsker, S. Mallet, B.M. Mayosi, A. Nanda, E. Puzenat, E. Salort‐Campana, R. Sidbury, A. Shimamura, S. Bézieau, S. Mercier, S. Barbarot
Journal: British Journal of Dermatology (2019)
4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue
Authors: Maria Grandoch, Ulrich Flögel, Sam Virtue, Julia K. Maier, Tomas Jelenik, Christina Kohlmorgen, Kathrin Feldmann, Yanina Ostendorf, Tamara R. Castañeda, Zhou Zhou, Yu Yamaguchi, Emmani B. M. Nascimento, Vivekananda G. Sunkari, Christine Goy, Martina Kinzig, Fritz Sörgel, Paul L. Bollyky, Patrick Schrauwen, Hadi Al-Hasani, Michael Roden, Susanne Keipert, Antonio Vidal-Puig, Martin Jastroch, Judith Haendeler, Jens W. Fischer
Journal: Nature Metabolism (2019)
Thromboembolic events in advanced non-small cell lung cancer
Authors: V.K. Srinivasalu, N. Subramaniam, S. Raghuram, S. Kolathu, B. Ponnada, A. Philip, W.M. Jose, K. Pavithran
Journal: Annals of Oncology (2019)

Background: Cancer is a prothrombotic condition and its treatment is often complicated in the presence of thromboembolisms (TE) which adds to its morbidity and mortality. We aimed to assess the incidence of TE's in patients with NSCLC treated at our institute. Methods: A retrospective observational study of patients with NSCLC treated between January 2011 and December 2016 were included. Time of onset of TE's either at diagnosis or after the start of platinum-based chemotherapy was noted, Khorana score was calculated in all patients with TE's. A TE occurring between first dose of chemotherapy and 4 weeks after the last dose was considered to be chemotherapy associated. Results: On analysis of records from the EMR, we found a total of 1542 NSCLC patients who were treated at our institute, with a male to female ratio of 3.5 : 1. All patients with TE's had stage IV disease at the time of presentation. Fifty-nine (3.8%) patients out of 1542 developed TE's, 53 had venous TE and 6 had cerebral arterial infarction. Twenty-five (1.6%) had TE's at the time of diagnosis while 34 (2.9%) out of 1180 developed TE while on treatment with platinum based chemotherapy. The mean age was 60 years (Range:34-81 yrs) with a male predominance (59%). Majority of patients developed TE's within 100 days from the start of chemotherapy with a median time of 66 days. (Range:14-143 days) Intermediate and high risk groups on assessment of Khorana score was 61% and 39% respectively. The median overall survival for patients with TE was 129 days in comparison to 234 days for patients without thromboembolisms. Conclusions: Thromboembolism is associated with a poor prognosis in patients with advanced lung cancer. Patients receiving platinum-based chemotherapy are predisposed to higher incidences of thromboembolic events which raises a valid question of the need of thromboprophylaxis in a selected group of patients. Legal entity responsible for the study: Amrita Institute of Medical Science. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
TCTAP A-029 Impact of Neutrophil-to-lymphocyte Ratio on In-hospital Mechanical Complications in Patients with ST-segment Elevation Myocardial Infarction (STEMI) Undergoing Primary Percutaneous Coronary Intervention
Authors: Gwang-Seok Yoon, Seong-Huan Choi, Jin-Hee Park, Manjong Lee, Yong-Soo Baek, Sung Woo Kwon, Sang-Don Park, Seong-Ill Woo, Dae-Hyeok Kim, Jun Kwan
Journal: Journal of the American College of Cardiology (2019)
A novel endoloop pretest to treat severe gastroesophageal reflux disease symptoms before anti-reflux mucosectomy
Authors: Min Min, Yan Liu
Journal: Endoscopy (2019)

A 44-year-old man with a 6-year history of gastroesophageal reflux disease (GERD; score of 30 on GERD questionnaire) underwent an upper gastrointestinal (GI) endoscopy, which revealed esophagitis (Los Angeles grade A). After failure of maximal medical therapy for GERD, the patient underwent a new minimally invasive, reversible endoscopic treatment, with the aim of predicting whether his symptoms could be alleviated, in order to ultimately decide whether to undergo irreversible surgery or endoscopic treatment.