tbuckley/cabot-search huggingface dataset:
Influenza Vaccine in Heart Failure
Authors: Daniel Modin, Mads Emil Jørgensen, Gunnar Gislason, Jan Skov Jensen, Lars Køber, Brian Claggett, Sheila M. Hegde, Scott D. Solomon, Christian Torp-Pedersen, Tor Biering-Sørensen
Journal: Circulation (2019)

Background: Influenza infection is a serious event for patients with heart failure (HF). Little knowledge exists about the association between influenza vaccination and outcome in patients with HF. This study sought to determine whether influenza vaccination is associated with improved long-term survival in patients with newly diagnosed HF. Methods: We performed a nationwide cohort study including all patients who were &gt;18 years of age and diagnosed with HF in Denmark in the period of January 1, 2003, to June 1, 2015 (n=134 048). We collected linked data using nationwide registries. Vaccination status, number, and frequency during follow-up were treated as time-varying covariates in time-dependent Cox regression. Results: Follow-up was 99.8% with a median follow-up time of 3.7 years (interquartile range, 1.7–6.8 years). The vaccination coverage of the study cohort ranged from 16% to 54% during the study period. In unadjusted analysis, receiving ≥1 vaccinations during follow-up was associated with a higher risk of death. After adjustment for inclusion date, comorbidities, medications, household income, and education level, receiving ≥1 vaccinations was associated with an 18% reduced risk of death (all-cause: hazard ratio, 0.82; 95% CI, 0.81–0.84; P &lt;0.001; cardiovascular causes: hazard ratio, 0.82; 95% CI, 0.81–0.84; P &lt;0.001). Annual vaccination, vaccination early in the year (September to October), and greater cumulative number of vaccinations were associated with larger reductions in the risk of death compared with intermittent vaccination. Conclusions: In patients with HF, influenza vaccination was associated with a reduced risk of both all-cause and cardiovascular death after extensive adjustment for confounders. Frequent vaccination and vaccination earlier in the year were associated with larger reductions in the risk of death compared with intermittent and late vaccination.
Sensitivity and Resistance of MET Exon 14 Mutations in Lung Cancer to Eight MET Tyrosine Kinase Inhibitors In Vitro
Authors: Toshio Fujino, Yoshihisa Kobayashi, Kenichi Suda, Takamasa Koga, Masaya Nishino, Shuta Ohara, Masato Chiba, Masaki Shimoji, Kenji Tomizawa, Toshiki Takemoto, Tetsuya Mitsudomi
Journal: Journal of Thoracic Oncology (2019)
Subcutaneous delivery of daratumumab in relapsed or refractory multiple myeloma
Authors: Saad Z. Usmani, Hareth Nahi, Maria-Victoria Mateos, Niels W. C. J. van de Donk, Ajai Chari, Jonathan L. Kaufman, Philippe Moreau, Albert Oriol, Torben Plesner, Lotfi Benboubker, Peter Hellemans, Tara Masterson, Pamela L. Clemens, Man Luo, Kevin Liu, Jesus San-Miguel
Journal: Blood (2019)
Becoming a preregistration house officer
Authors: Manoj Ramachandran
Journal: BMJ (2002)

Manoj Ramachandran takes an in-depth look at the difficult transition period from medical student to starting professional life as a preregistration house officer

Your final year as a medical student can be a very stressful time. Wearing a white coat, weighed down by the almost osmotic presence of the two Oxford handbooks in your pockets, you hunt in packs around the hospital wards, undeterred by the constant protests of patients prodded to the point of painful exhaustion. It doesn't really matter if they don't want to see you as you can always come back tomorrow.

You rapidly absorb information but still disbelieve your tutors when they repeatedly inform you that you currently have the greatest breadth (and sometimes depth) of knowledge that you will ever have in your career. Much of the information in your head is above and beyond what is required to pass finals comfortably. The fact that each consultant believes that in-depth knowledge of his or her own (sub) specialty is vital for finals doesn't help. You relieve the boredom of studying at weekends by joining the rest of your year at intensive revision courses, where you find yourself incessantly asking questions such as, “What have I been doing for the past five/six years?” and, “Why didn't they teach us this stuff at medical school?”

Finally, you find out that you've passed.

And slowly, the dread creeps in. Are you ready for that next step? You're going to start working (and getting paid) for the first time in your life. This, you realise, will be your first challenge. You wish that five or six years of medical school had prepared you more adequately for this leap. You will have to deal with clinical emergencies in real life, display your skills at practical procedures, and communicate effectively with …
Blocking CD70/CD27 Signaling in Combination with Hypomethylating Agents Eradicates Human CD34+ AML Stem and Progenitor Cells in Vitro and In Vivo
Authors: Magdalena Hinterbrandner, Nils Maria Kallen, Ursina Lüthi, Thomas Pabst, Luc Van Rompaey, Nicolas Leupin, Hans De Haard, Adrian F Ochsenbein, Carsten Riether
Journal: Blood (2017)
Abstract 15527: Mesenchymal Stem Cell-Derived Exosomes Protects Cardiomyocytes From Doxorubicin-Induced Cardiomyopathy by Upregulation of Survivin Expression via mir199a/424/21-5p-Akt Signaling Pathway
Authors: Ji Yoon Lee, Jihwa Chung, Kyounghwa Kim, Sunghyun Ahn, Kihwan Kwon
Journal: Circulation (2018)

Background: Cardiotoxicity is associated with long term clinical application of doxorubicin (DOX) in cancer patients. Mesenchymal stem cell (MSC)-derived exosomes have been suggested for treatment ...
Abstract 2137: Aberrant nuclear-expressed SLC29A2 as a therapeutic target in hepatocellular carcinoma
Authors: Roger Shen, Yuh-Shan Jou
Journal: Cancer Research (2019)

Abstract Hepatocellular carcinoma (HCC) is the second most prevalent causes of death in cancer worldwide, and there is lack of promising therapeutic target for patients. Here, we demonstrate that SLC29A2 (Solute Ligand Carrier Family 29 Member 2), an equilibrative nucleoside transporter, is commonly amplified and upregulated in varieties of cancers including hepatocellular carcinoma (HCC). SLC29A2 expression is increased and accumulated in nucleus during HCC progression, accompanied by interacting with phospho-STAT3, and further regulated STAT3-downstream genes to promote tumorigenic and metastatic features in HCC cell lines and preclinical orthotopic mouse model. Oncogenic properties of nuclear SLC29A2 could be suppressed by disrupting the nuclear translocation with nuclear importing mutant RanQ69L, SLC29A2 membrane anchoring mutant, and treating the inhibitor of SLC29A2. Treating inhibitor reduces nuclear SLC29A2-driven oncogenic features by reducing STAT3 phosphorylation, interrupting SLC29A2/STAT3 interaction, and nuclear translocation of SLC29A2 while SLC29A2 is amplified or upregulated in HCC cells. Combined treatment of FDA-approved late stage HCC medicine sorafenib with SLC29A2 inhibitor further suppresses tumor progression and metastasis to prolong mice survival in preclinical orthotopic model. Together, our results suggest that SLC29A2 is a theranostic target, and provide molecular insights for targeting nuclear SLC29A2. Citation Format: Roger Shen, Yuh-Shan Jou. Aberrant nuclear-expressed SLC29A2 as a therapeutic target in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2137.
Phase 2 study of zanubrutinib (BGB-3111) in patients with relapsed/refractory marginal zone lymphoma (R/R MZL).
Authors: Stephen Opat, Robert Marcus, Craig Anthony Portell, William Reed, Melannie Co, Jane Huang, Judith Trotman
Journal: Journal of Clinical Oncology (2019)

TPS7568 Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, mediating B-cell proliferation, migration, adhesion and survival. BTK inhibition has emerged as a strategy for targeting B-cell malignancies, including MZL. In preclinical studies, zanubrutinib was shown to be a potent, irreversible, highly specific BTK inhibitor with excellent oral bio-availability and favorable pharmacokinetic/pharmacodynamic properties. Clinical data to date have shown that complete and sustained 24-hour BTK occupancy is associated with durable responses and suggested that zanubrutinib is generally well tolerated with low rates of serious adverse events. Preliminary results from the MZL cohort enrolled in the open-label, multicenter, phase 1 study demonstrated responses in 7 of 9 patients for an overall response rate (ORR) of 78%. Cumulative safety data also showed that zanubrutinib monotherapy was associated with infrequent incidence of atrial fibrillation and major hemorrhage and infrequent drug discontinuation due to treatment-related adverse events. This study is designed to evaluate the safety and efficacy of zanubrutinib in patients with R/R MZL. Methods: This ongoing global phase 2, single-arm, open-label study is examining zanubrutinib monotherapy in patients with R/R MZL who have received one or more prior lines of systemic therapy. Patients are treated with oral zanubrutinib at 160 mg twice-daily until progressive disease, unacceptable toxicity, or withdrawal of consent. Eligible patients must have histologically confirmed MZL, have received prior anti-CD20 antibody therapy, and have measurable disease. Disease response is assessed per the 2014 Lugano Classification for non-Hodgkin lymphoma. The primary endpoint is ORR determined by independent review committee (IRC). Key secondary endpoints include ORR by investigator assessment, time to and duration of response, time to treatment discontinuation, progression-free survival (all determined by IRC and investigator assessments), and overall survival and safety. Recruitment is ongoing.
Abstract MP04: Individual Material and Social Deprivation is Associated with Poor Cardiovascular Health. The Paris Prospective Study III
Authors: Jean-philippe Empana, Bamba Gaye, Marie-Cecile Perier, Catherine Guibout, Frederique Thomas, Bruno Pannier, Pierre Boutouyrie, Xavier Jouven
Journal: Circulation (2016)

Purpose: Primordial prevention has been recognized as a public health priority, by the American Heart Association and more recently by the United Nations and World Health Organization. Reduction in social inequalities in health is a major challenge. We hypothesized that subjects in a socio-economical precarious position would be characterized by a poor cardiovascular health (CVH). Methods: We included 8748 men and women aged 50-75 years who enrolled the Paris Prospective Study III from June 2008 to May 2012 (Paris, France). The CVH status was defined as poor (0 or 1 ideal health metric), intermediate (2, 3 or 4 ideal health metrics) and ideal (5, 6 or 7 ideal health metrics). A validated multidimensional index (ranging from 0 to 100) of material and social deprivation including 11 questions derived from a principal component analysis (based on 42 questions) and covering employment, income, education, socio professional categories, accommodation, family composition, social networking, financial difficulties, life events and perceived health was used. The association of individual deprivation index (in quartiles) with poor and intermediate CVH as compared to ideal CVH was estimated by multivariable polytomic logistic regression analysis. Results: Mean age was 59.5 (standard deviation: 6.2), 61.5% were men and 40% had more than 12 years of school education. One-fourth of the study cohort was precarious (score of material deprivation&gt;30), slightly more women than men. The prevalence of poor and ideal CVH was respectively 43.3% and 8.6% in precarious subjects compared to 39.4% and 10.7% in the non precarious (p&lt;0.001). After adjusting for age, sex, depressive symptoms, migrant status and ethnicity, the odds of poor CVH was 1.38 (95%: 1.12-1.70), 1.55 (1.25-1.91) and 1.86 (1.48-2.32) for the second, third and fourth quartile of the individual deprivation index compared to the first quartile (p for trend&lt;0.001). This reflected an association with the behavioural but not the biological component of CVH. In sex stratified analyses, associations were stronger in magnitude and were significant for each upper quartile of the deprivation index whereas in men only the last quartile was significant (p for interaction=0.04). Furthermore and contrary to the main analysis, a significant association between individual deprivation and the biological component of CVH was noted in women but not in men (p for interaction=0.002). Conclusion: Subjects from the community in precarious situation are more frequently in poor cardiovascular health and should be targeted in priority for primordial prevention. The reasons behind the gender difference deserve additional investigations.
Abstract 17290: The Effect of Atrial Fibrillation at the Time of Imaging on Measurement of Myocardial T1 Time
Authors: Jay A Montgomery, Wissam Abdallah, Zachary T Yoneda, Moore B Shoemaker, Dawood Darbar, Mark Lawson
Journal: Circulation (2014)

INTRODUCTION: Atrial fibrillation (AF) is a common disease and is associated with cardiac fibrosis. Cardiac fibrosis can now be measured non-invasively using T1-mapping with cardiac magnetic resona...
Abstract 997: Three-dimensional high-throughput drug screening for bladder cancer
Authors: Sang-Cheol Lee, Young Saing Kim, In Gyu Hwang, Su Jin Lee, Se Hoon Park
Journal: Cancer Research (2019)

Abstract Recent progress in understanding the molecular mechanisms that underlie bladder cancer carcinogenesis offers the prospect of specifically targeting signaling pathways to achieve more effective and rational treatment. In a novel, 3-dimensional high-throughput drug screening (3D HTS) platform to identify novel agents affecting bladder cancer cells, 24 molecularly-targeted agents were screened in seven human bladder cancer cell lines (UCUM3, T24, SW780, RT4, J82, 5637 and 253J-BV). The efficacy of 24 targeted agents on the bladder cell lines varied dramatically on their genomic alterations. BEZ235 (mTOR and PI3K inhibitor) showed antitumor effect in most of cell lines except UMUC3. Another mTOR inhibitor, AZD2014 (inhibitors of mTORC1 and mTORC2) also had IC50 &amp;lt;2 μM in 3 cell lines (5637, J82 and RT4). However, FGFR targeted agents (AZD4547 and BGJ398) did not show the efficacy in cell lines with FGFR3 alterations (J82, SW780 and RT4). In HER2 mutated/amplified cell line (5637), dacomitinib, lapatinib and neratinib showed anti-tumor effect. Immunoblot assay showed that lapatinib and neratinib suppressed phosphorylated HER2 and downstream molecules such as p-AKT or p-ERK. In conclusion, 3D HTS drug screening platform could be a useful preclinical tool to evaluate various kinds of drugs rapidly, and eventually provide a valuable insight into precision medicine along with comprehensive genomic analysis. Note: This abstract was not presented at the meeting. Citation Format: Sang-Cheol Lee, Young Saing Kim, In Gyu Hwang, Su Jin Lee, Se Hoon Park. Three-dimensional high-throughput drug screening for bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 997.
Abstract 16610: Waitlist Characteristics and Outcomes Following the 2016 Revision of US Pediatric Heart Allocation Policy
Authors: Defne A Magnetta, Justin Godown, Shawn West, Matthew Zinn, Susan Miller, Brian Feingold
Journal: Circulation (2018)

Background: US pediatric heart allocation was revised in March 2016 to more appropriately categorize candidates with the most urgent need for heart transplantation (HT), including children with congenital heart disease (CHD) listed status 1A on inotropic support. We sought to assess the impact of these revisions on waitlist (WL) characteristics and mortality. Methods: Children (&lt;18 yo) listed for heart transplantation (HT) in the UNOS database between 12/16/11 and 11/7/17 were stratified based on whether they were listed before (PRE) or after (POST) criteria revision. Comparisons were made using Chi-Square or Wilcoxon rank sum tests and WL mortality was compared by competing outcomes analyses. Results: After criteria revision: 1) the proportions of status 1A candidates decreased at listing (69 vs. 53%, p&lt;0.001) and HT (89 vs. 82%, p&lt;0.001); 2) patients with CHD comprised a greater proportion of 1A candidates at listing (47 vs. 64%, p&lt;0.001) and at HT (42 vs. 51%; p&lt;0.008); 3) the use of status 1A exceptions among CM patients increased (5 vs. 24%, p&lt;0.001); and overall WL mortality and WL mortality for those listed status 1A were unchanged (fig 1a-b). When stratified by diagnosis, overall CHD WL mortality improved with no difference in CM WL mortality following criteria revision, and CHD WL mortality remains nearly twice that of CM candidates (fig 1c-d). However, when comparing CHD and CM candidates listed 1A without exception, CHD WL mortality was unchanged while CM WL mortality increased (fig 1e-f). Conclusions: As intended, there are fewer status 1A listings and enrichment of CHD patients in the status 1A group following criteria revision. Though overall WL mortality for CHD candidates improved, it remains nearly twice that of CM. Also, the lack of improvement in WL mortality for status 1A CHD candidates may be due to the marked increase in status 1A exemptions for CM candidates. Additional policy changes may further narrow the disparity in WL survival between CHD and CM.
Ivosidenib (IVO; AG-120) in IDH1-mutant newly-diagnosed acute myeloid leukemia (ND AML): Updated results from a phase 1 study.
Authors: Gail J. Roboz, Courtney Denton Dinardo, Eytan M. Stein, Stéphane de Botton, Alice S. Mims, Gabrielle T. Prince, Jessica K. Altman, Martha Lucia Arellano, Harry Paul Erba, Daniel Aaron Pollyea, Anthony Selwyn Stein, Justin M. Watts, Amir Tahmasb Fathi, Hagop M. Kantarjian, Martin S. Tallman, Bin Fan, Hua Liu, Bin Wu, Eyal C. Attar, Richard M. Stone
Journal: Journal of Clinical Oncology (2019)

7028 Background: IVO is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) approved for the treatment of adults with mIDH1 relapsed or refractory AML. We report the safety and efficacy of IVO in pts with ND AML not eligible for standard therapy enrolled in the first-in-human, phase 1, dose escalation and expansion study of pts with mIDH1 advanced hematologic malignancies (NCT02074839). Methods: Enrollment completed on 08May2017. Overall response rate (ORR) comprised complete remission (CR) + CR with incomplete hematologic or platelet recovery + partial response + morphologic leukemia-free state. CR with partial hematologic recovery (CRh) was CR except absolute neutrophil count &gt; 0.5 × 10 9 /L and platelet count &gt; 50 × 10 9 /L. Results: Baseline characteristics for 34 pts with ND AML who received IVO 500 mg once daily were: 19 men/15 women; median age 76.5 yrs (range 64-87); 56% ≥75 yrs of age; 76% had secondary AML and 53% prior MDS; 47% had ≥1 hypomethylating agent for an antecedent hematologic disorder. As of 02Nov2018, 7/34 (21%) pts remained on treatment; 3 (9%) had discontinued treatment for allogeneic stem cell transplant. Median duration of IVO exposure was 4.3 mo (range 0.3–40.9). Adverse events of any grade and causality in ≥25% of pts were diarrhea (53%), fatigue (47%), nausea (38%), decreased appetite (35%), leukocytosis, anemia, thrombocytopenia, peripheral edema (all 26%). Most were grade 1–2 and unrelated to treatment. IDH differentiation syndrome (DS) was seen in 6/34 (18%) pts, grade ≥3 in 3 (9%); IVO was held due to DS in 3 pts. QT prolongation was seen in 6 pts. In 33 pts confirmed mIDH1-positive by the companion diagnostic test, CR rate was 30% (95% CI 16%, 49%), CR+CRh 42% (95% CI 26%, 61%), and ORR 55% (95% CI 36%, 72%), with median durations not estimable (95% CI lower bound 4.2, 4.6, and 4.6 mo, respectively); 12-mo response durations were 78%, 62%, and 63%, respectively. Of 21 pts who were transfusion dependent at baseline, 43% became transfusion independent for ≥56 consecutive days on treatment. Updated co-occurring mutation and mutation clearance data will be reported. Conclusions: IVO was well tolerated and induced durable remissions in elderly pts with poor-prognosis mIDH1 ND AML. Clinical trial information: NCT02074839.
Abstract 4098: A heavy chain only antibody against CTLA4 with outstanding preclinical efficacy and safety profile
Authors: George Liu, Xin Gan, Yun He, Jiuqiao Zhao, Huayan Duan, Yiping Rong
Journal: Cancer Research (2019)

Abstract Anti-CTLA-4 antibodies are one of the only three types of immune checkpoint inhibitors (together with anti-PD-1 and anti-PD-L1 antibodies) with proven monotherapy value in cancer therapy. Despite demonstrated efficacy, their broad application in monotherapies and combinational therapies are hampered by the safety profiles. Evidence in animal models suggests that efficacy of anti-CTLA-4 antibodies is at least partially due to depletion of regulatory T cells (Treg) via ADCC function, whereas clinically adverse events are positively correlated with systemic exposure. Here we embarked to develop the next generation anti-CTLA-4 antibody with better efficacy and safety profile. Fully human Heavy Chain only antibody (HCAb) 4003-2 was generated using the Harbour HCAb transgenic mouse platform. 4003-2 specifically binds to CTLA-4 and blocks its binding to B7.1/B7.2. It was optimized to have enhanced ADCC function that affords superior ability to deplete Treg cells both in vitro and in vivo. 4003-2 showed in murine tumor models significantly more potent anti-tumor activity than other CTLA4 antibodies, at least partly driven by substantially enhanced depletion of intra-tumoral Treg cells. In addition, due to its shorter serum half-life, 4003-2 has less systemic drug exposure in vivo at efficacious doses, suggesting potentially improvement of safety profile in clinical applications. The augmented efficacy and safety profile of 4003-2 present it as an excellent candidate for the development of next generation anti-CTLA4 therapy. Citation Format: George Liu, Xin Gan, Yun He, Jiuqiao Zhao, Huayan Duan, Yiping Rong. A heavy chain only antibody against CTLA4 with outstanding preclinical efficacy and safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4098.