tbuckley/cabot-search huggingface dataset:
CD25-Dependent Feedback Control of the B-Cell Receptor and Its Oncogenic Mimics in B-Cell Malignancies
Authors: Jae-Woong Lee, Kohei Kume, Zhengshan Chen, Gang Xiao, Kadriye Nehir Cosgun, Lai N Chan, Chun-Wei Chen, Raju Pillai, Wing C Chan, Stephen J Forman, Larry W Kwak, Francesca Zammarchi, Patrick Van Berkel, David M Weinstock, Ari M Melnick, Vu N Ngo, Huimin Geng, Selina Luger, Mark R. Litzow, Alexandre Belot, Gulbu Uzel, Michael T McManus, Elisabeth M. Paietta, Eric Meffre, Markus Muschen
Journal: Blood (2018)
Abstract 17227: Atrial Fibrillation in the Presence of Post-ST Segment Elevation Myocardial Infarction Left Ventricular Thrombus is Associated With Worse Outcomes
Authors: Aloysius Shen-Ting Leow, Ching-Hui Sia, Leonard Leong-Litt Yeo, Benjamin Yong-Qiang Tan, Rajinderdeep Kaur, Hui-Wen Sim, Tiong-Cheng Yeo, Mark Yan-Yee Chan, Edgar Lik-Wui Tay, Joshua Ping-Yun Loh
Journal: Circulation (2018)

Introduction: Left ventricular (LV) thrombus is a complication of ST-segment elevation myocardial infarction (STEMI) that leads to a higher risk of stroke. Atrial fibrillation (AF) is another independent risk factor for stroke, however there is a dearth of studies examining the outcomes of patients with concomitant AF and LV thrombus. Hypothesis: This study aims to investigate the impact of the presence of concomitant AF in post-STEMI patients with an LV thrombus on stroke and mortality outcomes. Methods: We screened 6007 transthoracic echocardiogram reports containing the “thrombus” keyword from July 2006 to September 2017. Relevant clinical data was collected from 196 post-STEMI patients positive for an LV thrombus, stratified into non-AF and AF groups. Results: AF patients (69.6 ± 11.8 years) were significantly older (p &lt; 0.01) than non-AF patients (55.5 ± 12.2 years) and more were found to have chronic kidney disease (p = 0.02), hypertension (p = 0.04) and dyslipidaemia (p = 0.03), with significantly higher baseline HAS-BLED score (p &lt; 0.01) and CHA2DS2-VASc score (p &lt; 0.01). Fewer AF patients were treated with triple therapy (p = 0.04). Despite this, there was no difference observed in resolution of the LV thrombus on repeat imaging (p = 0.30). However, Kaplan-Meier analysis showed a higher incidence of stroke (p = 0.02) and all-cause mortality (p &lt; 0.01) in AF patients. Conclusion: Post-STEMI patients with LV thrombus formation and AF have significant differences from non-AF patients and are associated with poorer outcomes. These findings should be validated in larger cohorts.
Abstract 1073: Role of CD44 in the transition of ductal carcinoma <i>in situ</i> to invasive breast carcinoma
Authors: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh
Journal: Cancer Research (2019)

Abstract Ductal carcinoma in situ (DCIS) transition to invasive tumor is an important issue for breast cancer. The human MCF10DCIS.com cell line (abbreviated as MCF10DCIS) is derived from the human MCF10A breast epithelial cell line. The MCF10DCIS xenografts are similar to human high grade comedo DCIS. In the xenograft assay, MCF10DCIS cells form DCIS-like lesion, remain as DCIS-like lesion in the first few weeks, and then progress into invasive carcinoma. Thus, it is an excellent model to study human breast cancer transition from DCIS to invasive carcinoma. To the best of our knowledge, it is also the only cell model for DCIS transition to invasive carcinoma. We investigated the role of CD44 in breast cancer transition from DCIS to invasive carcinoma by knockdown the expression of CD44 in the MCF10DCIS xenograft model. Our results show that knockdown of CD44 expression in the MCF10DCIS cells enhances DCIS transition to invasive carcinoma. Accordingly, a previous study has shown that CD44 expression is lower in invasive human breast tumors compared with DCIS, especially in luminal A subtype. We have also observed that CD44 expression is lower in the invasive carcinomas compared with DCIS. Furthermore, we provide evidence that CD44 plays a role in maintaining the integrity of the myoepithelial layer. Our study uncovered an unexpected role of CD44 in the prevention of DCIS transition to invasive carcinoma. Our findings have important implications for breast cancer. Note: This abstract was not presented at the meeting. Citation Format: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh. Role of CD44 in the transition of ductal carcinoma in situ to invasive breast 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 1073.
Prospective clinical study phase IIa open-label and not randomized of efficacy and toxicity of weekly paclitaxel chemotherapy in patients with advanced esophagogastric adenocarcinoma
Authors: C. Diaz, G. Calderillo-Ruiz, M. Herrera, M. Ramos-Ramirez, E. Ruiz-Garcia, A. Takahashi, V. Calderillo, L. Horacio
Journal: Annals of Oncology (2019)
Abstract 4436: Ubiquitin-specific peptidase 24 decreases c-Myc expression to inhibit lung cancer formation
Authors: Jan-Jong Hung, Wen-Chang Chang
Journal: Cancer Research (2019)

Abstract Lung cancer is a malignant lung tumor characterized by high incidence and motility. c-Myc is a transcription factor that plays an important role in oncogenic activation to influence cellular metabolism and proliferation. Ubiquitin-specific peptidase 24 (USP24) is one of the members of USPs family to regulate protein ubiquitination. However, it is lack of evidence to uncover the role of USP24 in cancer formation. In this study, we found that cell proliferation was significantly increased by USP24 knockdown in A549 cells as accompanied by the increase of c-Myc protein. In particular, the RNA level and protein stability of c-Myc were not affected by USP24 knockdown, suggesting that USP24 affects c-Myc through regulating the translational pathway. Furthermore, c-Myc participated in USP24-knocked down-induced proliferation, not migration. To further clarify the mechanism underlying the regulation of c-Myc by USP24, we investigated whether mTOR pathway is involved in c-Myc upregulation by USP24 knockdown. Herein rapamycin, the mTOR inhibitor, prevented c-Myc upregulation caused by USP24 knockdown, suggesting that USP24 affect the protein level of c-Myc by regulating mTOR-mediated translation. We found that the downstream signaling of mTOR is activated by USP24 knockdown, including S6K and RPS6 phosphorylation. In addition, USP24 knockdown induced the binding of activated PRS6 to 5′-UTR of c-Myc, indicating that USP24 regulates c-Myc through mTOR-mediated translation. However, USP24 did not affect the phosphorylation of mTOR at Ser-2448, implying that other phosphorylation residue(s) within mTOR might be regulated by USP24. Since mTOR pathway is critical for many cancers formation, understanding the role of USP24 in regulating mTOR pathway will contribute to develop strategies to fight lung cancer. Citation Format: Jan-Jong Hung, Wen-Chang Chang. Ubiquitin-specific peptidase 24 decreases c-Myc expression to inhibit lung cancer formation [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 4436.
Abstract 3771: Oncogenes and tumour-suppressors drive differential retinoblastoma evolution
Authors: Adriana Salcedo, John D. Watson, Hilary Racher, Diane Rushlow, Shadrielle Melijah G. Espiritu, Doroto H. Sendorek, Stephenie D. Prokopec, Donco Matveski, Fouad Yousif, Julie Livingstone, Brenda L. Gallie, Paul C. Boutros
Journal: Cancer Research (2019)

Abstract Unlike any other tumour type, retinoblastomas can be driven by only two tumour-initiating events: bi-allelic loss of the tumour suppressor RB1 or amplification of the MYCN oncogene. These mutations drive morphologically indistinguishable tumours that arise at different ages, providing a unique model system to evaluate the influence of initiating mutation on tumour evolution. We performed high-resolution copy number analysis of 101 retinoblastoma and whole genome sequencing of 23. These data reveal that different initiating mutations cause probabilistic changes in somatic point and copy number mutations, but large changes in genomic rearrangements and mitochondrial number. Independent of the initiating mutation, retinoblastomas harbour multiple subclonal populations that preferentially accrue point mutations after subclonal diversification. These subclonal structures suggest caution when choosing chemotherapeutic strategies for primary treatment. Overall, initiating mutations influence evolutionary trajectory more than specific driver mutations: RB1- and MYCN-driven tumours harbour distinct mutational processes, sequences of mutation acquisition and patterns of subclonal diversification. These data show how tumour-initiating mutations drive clinical behaviour by subtly biasing multiple evolutionary processes. Validation in other tumour types is underway. Citation Format: Adriana Salcedo, John D. Watson, Hilary Racher, Diane Rushlow, Shadrielle Melijah G. Espiritu, Doroto H. Sendorek, Stephenie D. Prokopec, Donco Matveski, Fouad Yousif, Julie Livingstone, Brenda L. Gallie, Paul C. Boutros. Oncogenes and tumour-suppressors drive differential retinoblastoma evolution [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 3771.
Abstract 13569: Neurologically Intact Survival and Time Interval From Collapse to Return of Spontaneous Circulation for Patients With Out-of-Hospital Cardiac Arrest; A Comparison of Shockable Cardiac Arrest and Non-Shockable Cardiac Arrest
Authors: Ken Nagao, Eizo Tachibana, Naohiro Yonemoto, Morimasa Takayama, Singo Furuya, Hiroshi Nonogi, Shinichi Shirai, Takeshi Kimura
Journal: Circulation (2013)

Background: Early achievement of return of spontaneous circulation (ROSC) after cardiac arrest is critical to neurologically intact survival, but few data are available concerning this interval com...
A phase I/II study of blinatumomab in combination with pembrolizumab for adults with relapsed refractory B-lineage acute lymphoblastic leukemia: University of California Hematologic Malignancies Consortium Study 1504.
Authors: Marc Saul Schwartz, Deepa Jeyakumar, Lloyd Earl Damon, Gary J. Schiller, Matthew Joseph Wieduwilt
Journal: Journal of Clinical Oncology (2019)

TPS7064 Background: Outcomes for adults with relapsed/refractory B-cell ALL (R/R B-ALL) remain poor despite new targeted therapies. Blinatumomab is an anti-CD19/CD3 bifunctional T-cell engaging antibody that was superior to conventional salvage therapy for remission and overall survival in a Phase III study of patients with R/R B-ALL. The CR/CRh rate for blinatumomab was 65.5% with &lt; 50% marrow lymphoblasts but dropped to 34.4% with ≥ 50% marrow lymphoblasts. Clinical and pre-clinical findings suggest that PD-L1 overexpression on lymphoblasts and in the bone marrow may mediate resistance to blinatumomab by inhibiting T-cell activation. We hypothesize that addition of pembrolizumab will improve CR/CRh rates to blinatumomab in R/R B-cell ALL. Methods: We are conducting a phase I/II multicenter trial to evaluate the safety and efficacy of blinatumomab with pembrolizumab in adults with R/R B-ALL and a high bone marrow lymphoblast percentage (NCT 03160079). The primary endpoint is ORR (CR+CRh) after 1-2 cycles with secondary endpoints of AEs, MRD-negative CR/CRh rate, 2-year DFS, 2-year OS, and allogeneic HCT rate. Exploratory studies are evaluating cytokine expression, PD-1 expression on T-cells, PD-L1 and PD-L2 protein expression on lymphoblasts, and T-cell populations at diagnosis and in response to therapy. Eligibility includes: adults with R/R CD19+ B-ALL after ≥ 1 prior line of therapy, R/R Ph+ B-ALL must fail a 2 nd - or 3 rd -generation TKI or be TKI intolerant, &gt; 50% lymphoblasts on screening bone marrow sample. Blinatumomab is given by continuous IV at 9 mcg/day days 1-7 of cycle 1, 28 mcg/day days 8-28 of cycle 1, then at 28 mcg/day days 1-28 in subsequent cycles. Pembrolizumab 200 mg IV is given on days 15 and 36 of each 42-day cycle. Patients in CR/CRh after 1-2 cycles will complete 5 cycles. Patients not in CR/CRh after 2 cycles of therapy or progressing after Day 15 of cycle 1 go off study. CNS prophylaxis with IT methotrexate is given at screening and once per cycle. A phase I run-in of 3-6 patients precedes accrual of 18-21 patients for a target of 24. The study opened in July 2017 and 4 patients have been treated. No DLTs have occurred to date. Clinical trial information: NCT03160079.
Abstract 1212: Anti-SIRPα antibodies as a potential weapon for cancer immunotherapy via accelerated screening in humanized mouse models
Authors: James Jin, Benny(Yi) Yang, Chaoshe Guo, Yuelei Shen, Jian Ni
Journal: Cancer Research (2019)

Abstract Signal regulatory protein α (SIRPα) is a transmembrane protein with an extracellular region comprising three Ig-like domains and a cytoplasmic region containing immunoreceptor tyrosine-based inhibition motifs which mediate binding of the protein tyrosine phosphatases SHP1 and SHP2. SIRPα is especially abundant in myeloid cells such as macrophages and DCs, whereas it is expressed at very low levels in T, B, NK, and NK T cells. SIRPα inhibits phagocytosis in macrophages upon interacting with its ligand CD47, which is commonly upregulated on the surface of malignant cells. Thus, antibodies that block the CD47-SIRPα interaction should enhance macrophage phagocytosis in the tumor microenvironment and inhibit tumor growth, making anti-SIRPα antibodies promising as potential new tools for cancer immunotherapy. We are interested in subverting the negative feedback of the CD47-SIRPa axis, in order to treat cancer patients. Using Biocytogen’s antibody research platform, we obtained several high-affinity anti-human SIRPα mAb by high-throughput flow cytometry screening. Next, these murine antibodies were screened directly in single or double humanized mice models (B-hSIRPα or B-hSIRPα/hCD47) bearing a syngeneic humanized cancer cell line (MC38-hCD47), where we discovered candidates that have potent anti-tumor activity in vivo. Chimeric antibodies and humanized antibodies based on these candidates were generated and further examined in vivo. In addition, we uncovered synergistic anti-tumor activity of anti-human SIRPα mAbs in combination with anti-mouse PD-1 mAb in B-hSIRPα/hCD47 mice. In brief, our existing studies demonstrate that SIRPα is an ideal target for preclinical cancer models. Clinical evaluation of the translational merits for these novel anti-SIRPα antibodies is pending. Citation Format: James Jin, Benny(Yi) Yang, Chaoshe Guo, Yuelei Shen, Jian Ni. Anti-SIRPα antibodies as a potential weapon for cancer immunotherapy via accelerated screening in humanized mouse models [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 1212.
Abstract 3064: Epigenetic manipulation can sensitize AML cells to differentiate with ATRA
Authors: Kalsi Heimdal, Bikalpa Ghimire, Edjay Ralph Hernandez, Heidi J. Gill Super
Journal: Cancer Research (2019)

Abstract Human acute myeloid leukemia (AML), the most common type of acute leukemia, has approximately eight subtypes, many of which have poor prognosis. Most of these subtypes are associated with specific, recurrent chromosome translocations. These translocations result in fusion genes, which encode oncoproteins that block differentiation and promote proliferation of immature cells. The Myeloid Lymphoid Leukemia gene (MLL) is frequently involved in these translocations, and is considered a driver of the AML. Differentiation promoting drugs, such as all-trans-retinoic acid (ATRA) are an attractive alternative to cytotoxic chemotherapy, but few types of AML, other than acute promyelocytic leukemia (APL), respond to ATRA. We hypothesize that specific genes must be activated or inhibited in AML for drugs like ATRA to induce differentiation, and that gene activation or inhibition may be the result of specific epigenetic modification. We also hypothesize that AML with different genetic alterations may respond differently to specific epigenetic inhibitors. Our initial studies have focused on two MLL-driven AML cell lines, MV4;11 and THP-1, showing translocations t(4;11) and t(9;11), respectively, and one non-MLL related AML cell line, U937. MV4;11, THP-1, and U937 were treated with specific epigenetic modifiers, including tranylcypromine (TCP), an inhibitor of histone demethylase KMD1A/LSD1, N-acetyl-dinaline (CI-994), a general histone deacetylase inhibitor, and 3-deazaneplanocin A (DZNep), a S-adenosylhomocystein hydrolase inhibitor that depletes EZH2 and thus its associated H3K27me3 activity. Evidence for differentiation was noted in a variety of assays, including reduced cell proliferation as measured directly and by MTT assay, upregulation of myeloid-specific cell surface markers such as CD11b as measured by fluorescence-activated cell sorting (FACS), myeloid-related nuclear morphological changes noted with cytospin analysis of cells, and decreased AML-associated gene expression with qPCR. All three drugs seemed to sensitize U937 and THP-1 cells to differentiate when treated with ATRA. MV4;11 cells were sensitized to differentiate by CI-994 and DZNep with or without ATRA, although there was no indication of CD11b upregulation. However, MV4;11 was not sensitized by TCP to differentiate with or without ATRA. These experiments suggest epigenetic inhibitors may increase sensitivity to ATRA differentiation therapy, but since the two MLL cell lines responded differently the response may still be dependent on the specific MLL partner gene driving the AML. Citation Format: Kalsi Heimdal, Bikalpa Ghimire, Edjay Ralph Hernandez, Heidi J. Gill Super. Epigenetic manipulation can sensitize AML cells to differentiate with ATRA [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 3064.
Pectus excavatum is associated with sleep-related breathing disorders in children
Authors: Hiroo Wada, Manami Kimura, Ryutaro Shirahama, Ai Ikeda, David Gozal, Takeshi Tanigawa
Journal: European Respiratory Journal (2019)

<b>By demonstrating the association between sleep-related breathing disorders (SRBDs) and pectus excavatum (PE) in children, SRBDs were identified as a possible risk for developing PE. All clinicians who find PE in children should consider SRBD screening.</b>http://bit.ly/2LFS7yE
Seventy-five-year-old man with unexplained weight loss and alopecia
Authors: Elmer Hoekstra, Jaap van der Laan, Michael van der Voorn
Journal: Gut (2019)

A 75-year-old white carpenter presented with unexplained weight loss of 25 kg in the last 6 months. He lost his appetite, but denied any other gastrointestinal complaints and his stools were normal. Strikingly, he had lost his fingernails, had complaints of hair loss and had purple discolouration of his hand palms and soles of his feet. On physical examination, we saw a cachectic patient who had lost his fingernails (figure 1).



Figure 1 
Loss of fingernails.



Laboratory findings were unremarkable, with normal serum albumin and electrolytes, no anaemia and no vitamin deficiencies. Imaging using chest X-ray and abdominal ultrasound were normal. Oesophago-gastro-duodenoscopy showed hypertrophic (strawberry-like) pangastritis and enteritis (figure 2), while colonoscopy showed a highly …
Abstract 9728: The Timing of Valve Repair for Severe Degenerative Mitral Regurgitation and the Long-term Left Ventricular Function
Authors: Takeshi Kitai, Yukikatsu Okada, Tomoko Tani, Shuichiro Kaji, Atsushi Yamamuro, Natsuhiko Ehara, Kitae Kim, Makoto Kinoshita, Toru Kita, Yutaka Furukawa
Journal: Circulation (2012)

Background: The current ACC/AHA guideline recommends early mitral valve (MV) repair for asymptomatic severe mitral regurgitation (MR) in the absence of left ventricular (LV) dysfunction. However, the effects of early MV repair on the long-term LV function and the threshold of the preoperative parameters to maintain favorable long-term LV function have not been clarified. This study aimed to evaluate the incidence and predictors of postoperative LV dysfunction as well as the clinical outcomes. Methods: A total of 908 patients who underwent MV repair for severe degenerative MR in our institution between 1996 and 2010 were retrospectively reviewed. Among them, both preoperative and 3-year postoperative echocardiographic data were available in 437 patients. Pre- and postoperative echocardiographic data and clinical outcomes were evaluated. Results: Receiver-operating characteristics curve analysis identified preoperative LV ejection fraction (EF) &gt;65% (area under curve (AUC), 0.65; P&lt;0.001) and LV end-systolic dimension (ESD) &lt;38 mm (AUC, 0.68; P&lt;0.001) as cut off values for predicting LVEF ≥60% 3 years after surgery. Patients were divided into 2 groups according to the preoperative LV measures; group A (n=193), LVEF &gt;65% and LVESD &lt;38mm and group B (n=280), LVEF ≤65% and/or LVESD ≥38mm. There were significantly higher rates of postoperative LV dysfunction in group B (A vs B, 24% vs 49%, P&lt;0.001). Moreover, the 10-year event-free survival rate, defined as a composite of death, hospitalization because of heart failure, and recurrent MR was significantly lower in group B than those in group A (A vs B, 86% vs 70%, P=0.02). Among patients in group A, preoperative LVESD was the only independent predictor of postoperative LV dysfunction. Conclusion: Simple preoperative echocardiography measures allow the prediction of postoperative LV dysfunction. Patients with preoperative LVEF &gt;65% and LVESD &lt;38 mm may offer better long-term postoperative LV function.
Abstract 14517: Regional Reduction of Systolic Compacta Thickness Helps to Distinguish Isolated Left Ventricular Non-Compaction From Dilated Cardiomyopathy Using Cardiac Magnetic Resonance Imaging
Authors: Xiaoyin Bai, Wei Chen, Ligang Fang, Xue Lin, Peng Gao, Quan Fang
Journal: Circulation (2013)

Background: Marked trabeculation, chamber dilation and ventricular contractile impairment are presented in left ventricular non-compaction (LVNC) and dilated cardiomyopathy (DCM), which sometimes m...