tbuckley/cabot-search huggingface dataset:
Abstract 4467: Survival of patients with microsatellite instable (MSI) metastatic colorectal cancer (mCRC) upon systemic non-immunotherapy
Authors: G. E. Wensink, M. A. Elferink, A. M. May, L. Mol, P. A. Hamers, C. J. Punt, G. R. Vink, J. M. Roodhart, M. Koopman
Journal: Cancer Research (2019)

Abstract Introduction: Data on survival of patients with MSI mCRC treated with systemic non-immunotherapy are scarce, which complicates the interpretation of recent immunotherapy trials. Our study examined survival in MSI mCRC patients in a retrospective observational cohort. Methods: We performed a study involving 186 mCRC MSI patients (n=54 from the phase 3 CAIRO, CAIRO2 and CAIRO3 trials and n=132 from The Netherlands Cancer Registry 2015 and 2016). Overall survival from diagnosis of mCRC (OS), from start of first-line (OS1) and second-line therapy (OS2) to death of any cause were examined. Progression-free survival from start of first line (PFS1) and second-line therapy (PFS2) to progression or death of any cause were examined. Results: Of the 186 patients, 57% were females, median age 67 years, 19% had liver-only metastasis, 31% peritoneal metastasis and 23% underwent metastasectomy. In 113 patients with known BRAF status, 51% had BRAF mutated tumors. The proportion of patients receiving first, second and third-line systemic treatment was 68%, 27% and 7%, respectively. For all patients, median OS was 13.8 months (95% confidence interval [C.I.] 11.8 - 16.3). In patients receiving at least one line of treatment median OS was 15.6 months (13.8 - 19.3), OS1 was 13.9 months (11.6-16.6) and PFS1 was 6.4 months (5.5 - 9.2). In the 48 patients receiving second-line therapy, median OS was 16.5 months (13.9 - 21.5), OS2 was 6.1 months (5.4 - 9.7) and PFS2 was 2.2 months (1.9 - 4.2). Patients starting second-line treatment with a performance score of 0-1, thus eligible for CHECKMATE-142, had an OS2 of 6.7 months (5.0 - 12.1). Discussion: A direct comparison between our cohort and the CHECKMATE-142 cohort is not possible due to key differences in the patient populations: CHECKMATE-142 patients often received more than one therapy line prior to inclusion and displayed fewer BRAF mutant tumors. However, the survival from start of second-line in our cohort of approximately 7 months is inferior to the published CHECKMATE-142 results, where median OS was not reached after a median follow-up of 1 year in the nivolumab and the nivolumab and ipilimumab cohorts. Conclusion: We present data on systemic non-immunotherapy in the largest cohort of trial and population-based mCRC MSI patients to date. Our results suggest that immunotherapy may offer a survival benefit for mCRC MSI patients. Citation Format: G. E. Wensink, M. A. Elferink, A. M. May, L. Mol, P. A. Hamers, C. J. Punt, G. R. Vink, J. M. Roodhart, M. Koopman. Survival of patients with microsatellite instable (MSI) metastatic colorectal cancer (mCRC) upon systemic non-immunotherapy [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 4467.
Abstract 4471: Commercial gene expression tests for prostate cancer prognosis provide paradoxical estimates of race-specific risk
Authors: Jordan H. Creed, Anders E. Berglund, Robert J. Rounbehler, Shivanshu Awasthi, John L. Cleveland, Jong Y. Park, Kosj Yamoah, Travis A. Gerke
Journal: Cancer Research (2019)

Abstract Background: Current National Comprehensive Cancer Network (NCCN) guidelines recommend three gene expression-based tests for prostate cancer (PCa) prognosis in men with low or favorable intermediate risk disease: Decipher, Oncotype DX Prostate, and Prolaris. The three tests feature varying numbers of genes with minimal overlap. Importantly, development and validation efforts for all three panels were undertaken in predominantly European American men (EAM) cohorts, and limited research exists on the value of such signatures in African American men (AAM), who have poorer PCa outcomes. Here, we explored differences in gene expression between EAM and AAM for the three panels recommended by the NCCN for PCa prognosis. Methods: 232 EAM and 95 AAM patients provided radical prostatectomy specimens. Gene expression was quantified using Nanostring for 60 genes spanning the Oncotype DX Prostate, Prolaris, and Decipher panels. Differential expression and intrapanel co-expression by race were assessed using Mann-Whitney tests and Spearman’s correlations, respectively. A continuous expression-based risk score was approximated for each panel with higher scores indicating worse outcomes. Race-specific risks were compared using Mann-Whitney tests and Spearman’s correlations. Results: Clinical and pathologic features were similar between AAM and EAM. Differential expression by race was observed for 48% of genes measured, though the magnitudes of expression differences were small. Co-expression patterns were more strongly preserved by race group for Oncotype DX and Decipher versus Prolaris (integrative correlations of 0.87, 0.73, and 0.62, respectively). Paradoxically, poorer prognosis was estimated in EAM versus AAM for Prolaris and Oncotype DX (p = 0.01 for both), whereas worse prognosis was predicted for AAM versus EAM using Decipher (p &amp;lt; 0.001). Discussion: Due to observed racial differences across three commercial gene expression panels for PCa prognosis, caution is warranted when applying these panels in clinical decision-making in AAM. Replication of our findings directly on the commercial panels with long-term follow-up is warranted. Citation Format: Jordan H. Creed, Anders E. Berglund, Robert J. Rounbehler, Shivanshu Awasthi, John L. Cleveland, Jong Y. Park, Kosj Yamoah, Travis A. Gerke. Commercial gene expression tests for prostate cancer prognosis provide paradoxical estimates of race-specific risk [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 4471.
Outcomes After Inguinal Hernia Repair With Mesh Performed by Medical Doctors and Surgeons in Ghana
Authors: Jessica H. Beard, Michael Ohene-Yeboah, Stephen Tabiri, Joachim K. A. Amoako, Francis A. Abantanga, Carrie A. Sims, Pär Nordin, Andreas Wladis, Hobart W. Harris, Jenny Löfgren
Journal: JAMA Surgery (2019)

Inguinal hernia is the most common general surgical condition in the world. Although task sharing of surgical care with nonsurgeons represents one method to increase access to essential surgery, the safety and outcomes of this strategy are not well described for hernia repair.To compare outcomes after inguinal hernia repair with mesh performed by medical doctors and surgeons in Ghana.This prospective cohort study was conducted from February 15, 2017, to September 17, 2018, at the Volta Regional Hospital in Ho, Ghana. Following successful completion of a training course, 3 medical doctors and 2 surgeons performed inguinal hernia repair with mesh according to the Lichtenstein technique on 242 men with primary, reducible inguinal hernia.The primary end point was hernia recurrence at 1 year. The noninferiority limit was set at 5 percentage points. Secondary end points included postoperative complications at 2 weeks and patient satisfaction, pain, and self-assessed health status at 1 year.Two-hundred forty-two patients were included; 119 men underwent operations performed by medical doctors and 123 men underwent operations performed by surgeons. Preoperative patient characteristics were similar in both groups. Two-hundred thirty-seven patients (97.9%) were seen at follow-up at 2 weeks, and 223 patients (92.1%) were seen at follow-up at 1 year. The absolute difference in recurrence rate between the medical doctor group (1 [0.9%]) and the surgeon group (3 [2.8%]) was -1.9 (1-tailed 95% CI, -4.8; P < .001), demonstrating noninferiority of the medical doctors. There were no statistically significant differences in postoperative complications (34 [29.1%] vs 29 [24.2%]), patient satisfaction (112 [98.2%] vs 108 [99.1%]), severe chronic pain (1 [0.9%] vs 4 [3.7%]), or self-assessed health (85.9 vs 83.7 of 100) for medical doctors and surgeons.This study shows that medical doctors can be trained to perform elective inguinal hernia repair with mesh in men with good results and high patient satisfaction in a low-resource setting. This finding supports surgical task sharing to combat the global burden of hernia disease.
Evaluating patients' unmet needs in hidradenitis suppurativa: Results from the Global Survey Of Impact and Healthcare Needs (VOICE) Project
Authors: Amit Garg, Erica Neuren, Denny Cha, Joslyn S. Kirby, John R. Ingram, Gregor B.E. Jemec, Solveig Esmann, Linnea Thorlacius, Bente Villumsen, Véronique del Marmol, Aude Nassif, Maia Delage, Thrasyvoulos Tzellos, Dagfinn Moseng, Øystein Grimstad, Haley Naik, Robert Micheletti, Sandra Guilbault, Angie Parks Miller, Iltefat Hamzavi, Hessel van der Zee, Errol Prens, Naomi Kappe, Christine Ardon, Brian Kirby, Rosalind Hughes, Christos C. Zouboulis, Georgios Nikolakis, Falk G. Bechara, Lukasz Matusiak, Jacek Szepietowski, Amelia Glowaczewska, Saxon D. Smith, Noah Goldfarb, Steven Daveluy, Christina Avgoustou, Evangelos Giamarellos-Bourboulis, Steven Cohen, Yssra Soliman, Elena Gonzalez Brant, Oleg Akilov, Christopher Sayed, Jerry Tan, Afsaneh Alavi, Michelle A. Lowes, José Carlos Pascual, Hassan Riad, Shani Fisher, Arnon Cohen, So Yeon Paek, Barry Resnik, Qiang Ju, Lanqi Wang, Andrew Strunk
Journal: Journal of the American Academy of Dermatology (2019)
Chronic Comorbidity Among Patients With Cancer
Authors: Lisa S. Rotenstein, Yichen Zhang, Joseph O. Jacobson
Journal: JAMA Oncology (2019)

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Abstract 3226: The IRF8-osteopontin-CD44 axis functions as an immune checkpoint to control CD8+ T cell activation and tumor immune evasion
Authors: John D. Klement, Amy V. Paschall, Priscilla S. Redd, Mohammed L. Ibrahim, Chunwan Lu, Dafeng Yang, Esteban Celis, Scott I. Abrams, Keiko Ozato, Kebin Liu
Journal: Cancer Research (2019)

Abstract Despite breakthroughs in immune checkpoint inhibitor (ICI) immunotherapy, not all human cancers respond to ICI immunotherapy and only fraction of patients with responsive tumors have a durable response to current ICI immunotherapy. This clinical conundrum suggests that additional immune checkpoints may exist, particularly in cancers resistant to current ICI immunotherapy, such as colorectal cancer. We report here that interferon regulatory factor 8 (IRF8) deficiency led to impairment of cytotoxic T lymphocyte (CTL) activation in a peptide vaccine model and allowed allograft transplant tumor tolerance. These effects were associated with upregulation of the CTL surface marker CD44. However, analysis of chimeric mice with competitive reconstitution of wild type and IRF8 KO bone marrow cells as well as mice with IRF8 deficiency only in T cells indicated that IRF8 plays no intrinsic role in CTL activation. Instead, IRF8 functioned as a repressor of osteopontin (OPN), the physiological ligand for CD44 on T cells, in CD11b+Ly6CloLy6G+ myeloid cells and OPN acted as a potent T cell suppressor. In vitro stimulation of CTLs in the presence of OPN resulted in decreased expression of activation markers CD69 and CD25 and inhibited proliferation and interferon gamma (IFNg) secretion. Expression of OPN was found to be upregulated in both myeloid cells and colon epithelial cells following silencing of IRF8 expression. IRF8 bound to the Spp1 promoter, which encodes OPN, to repress OPN expression in colon epithelial cells. Correspondingly, human colon carcinoma cells exhibited decreased IRF8 and increased OPN expression. These increased OPN levels inhibited human PBMC proliferation and IFNg secretion. The elevated expression of OPN in human colon carcinoma was correlated with decreased patient survival. Our data indicates that myeloid and tumor cell-expressed OPN acts as a novel immune checkpoint to suppress T cell activation and confer host tumor immune tolerance. Blockade of this checkpoint may expand the pool of patients who may benefit from ICI immunotherapy. Citation Format: John D. Klement, Amy V. Paschall, Priscilla S. Redd, Mohammed L. Ibrahim, Chunwan Lu, Dafeng Yang, Esteban Celis, Scott I. Abrams, Keiko Ozato, Kebin Liu. The IRF8-osteopontin-CD44 axis functions as an immune checkpoint to control CD8+ T cell activation and tumor immune evasion [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 3226.
Use of a Mouse Model and Human Umbilical Vein Endothelial Cells to Investigate the Effect of Arsenic Exposure on Vascular Endothelial Function and the Associated Role of Calpains
Authors: Zhihui Cai, Yanqing Zhang, Yutian Zhang, Xiaofeng Miao, Shu Li, Hui Yang, Qinjie Ling, Peter R. Hoffmann, Zhi Huang
Journal: Environmental Health Perspectives (2019)

Background: Arsenic (As) is a well-known environmental contaminant. Chronic exposure to As is known to increase the risk of cardiovascular diseases, including atherosclerosis, hypertension, diabetes, and stroke. However, the detailed mechanisms by which As causes vascular dysfunction involving endothelial integrity and permeability is unclear. Objectives: Our goal was to investigate how exposure to As leads to endothelial dysfunction. Methods: Arsenic trioxide (ATO) was used to investigate the effects and mechanisms by which exposure to As leads to endothelial dysfunction using a mouse model and cultured endothelial cell monolayers. Results: Compared with the controls, mice exposed chronically to As (10 ppb in drinking water supplied by ATO) exhibited greater vascular permeability to Evans blue dye and fluorescein isothiocyanate–labeled bovine serum albumin (FITC-BSA). In addition, endothelial monolayers treated with ATO (0.13μM As) exhibited greater intracellular gaps and permeability to low-density lipoprotein or transmigrating THP-1 cells. Furthermore, activity and protein levels of calpain-1 (CAPN-1) were significantly higher in aortas and human umbilical vein endothelial cells (HUVECs) treated with ATO. These results were consistent with effects of ATO treatment and included a rapid increase of intracellular calcium ([Ca2+]i) and higher levels of CAPN-1 in the plasma membrane. Endothelial cell dysfunction and the proteolytic disorganization of vascular endothelial cadherin (VE-cadherin) in HUVECs in response to ATO were partially mitigated by treatment with a CAPN-1 inhibitor (ALLM) but not a CAPN-2 inhibitor (Z-LLY-FMK). Conclusions: This study found that in mice and HUVEC models, exposure to ATO led to CAPN-1 activation by increasing [Ca2+]i and CAPN-1 translocation to the plasma membrane. The study also suggested that inhibitor treatment may have a role in preventing the vascular endothelial dysfunction associated with As exposure. The findings presented herein suggest that As-induced endothelial dysfunction involves the hyperactivation of the CAPN proteolytic system. https://doi.org/10.1289/EHP4538
A new method for diagnosis of anterior cruciate ligament tear: MRI with maximum flexion of knee in the prone position: A case control study
Authors: Burak Gunaydin, Gulcan Gucer Sahin, Abdulkadir Sari, Adnan Kara, Yasar Mahsut Dincel, Mehmet Umit Cetin, Cagatay Tekin, Yavuz Selim Kabukcuoglu
Journal: International Journal of Surgery (2019)
Abstract 14188: Bicuspid Aortic Valve Disease Relatives Show No Evidence of an Inherited Aortopathy
Authors: Malenka M Bissell, Luca Biasiolli, Abhishek Oswal, Hugh C Watkins, Stefan Neubauer, Saul Myerson
Journal: Circulation (2015)

Introduction: Bicuspid aortic valve (BAV) disease is known to be heritable and often shows a concomitant aortopathy. Whether this aortopathy is more prevalent in BAV family members (irrespective of inheritance of the BAV) is unclear, and little is known about aortic function. Hypothesis: Bicuspid aortic valve disease relatives show signs of inherited aortopathy despite having a tricuspid aortic valve. Methods: We prospectively enrolled 118 family members with a normal functioning tricuspid aortic valve and 55 age and sex-matched healthy volunteers. The average age was 38.7 years (range 6-90) with a mean pulse pressure 57±1.14 mmHg. Advanced aortic assessment included aortic diameters, pulse wave velocity, arterial stiffness, maximum rate of systolic dysfunction (MRSD) and distensibility by CMR, total peripheral resistance by Vicorder © as well as circulating matrix metalloproteinases (MMP) 2 and 9 from a peripheral blood sample. A subset of 10 family members also underwent comprehensive 4D flow CMR assessment. Results: Compared to sex, age and blood-pressure matched healthy volunteers all family members had normal aortic diameters at the sinuses, ascending and descending aorta. There were no differences between family members and healthy volunteers in any of the aortic function measures: pulse wave velocity (arch 5.9±0.79 vs 5.0±0.36 m/s; p=0.31), aortic strain (ascending aorta 0.16±0.03 vs 0.19±0.03; p=0.41), maximum rate of systolic dysfunction (ascending aorta 0.23 vs 0.22%/ms; p=0.61),distensibility (ascending aorta 4.0±0.65 vs 4.4±0.62 1/mmHg; p=0.65), total peripheral resistance (1.03±0.05 vs 1.06±0.04 pru; p=0.56), MMP2 and MMP9. In the subset of family members undergoing advanced 4D flow CMR assessment, there was no difference in flow angle (8.75±1.33 vs 7.75±0.78°; p=0.53), flow displacement (2.73±0.61 vs 2.44±0.24 mm; p= 0.67) and wall shear stress compared to healthy volunteers (0.69±0.07 vs 0.59±0.02 N/m 2 ; p=0.22). Conclusion: Family members with (normal) trileaflet aortic valves of patients with a bicuspid aortic valve have normal aortic size and function. This is a further indicator that in haemodynamic factors may be a larger contributor to the aortopathy in BAV disease than underlying genetic factors.
Abstract 4657: MB21D2 amplification and recurrent mutation exhibit oncogenic activity through centrosome and cilia alteration
Authors: Daniel Esguerra Gracilla, Praveen Kumar Korla, Louis Lai, Jim Jinn-Chyuan Sheu
Journal: Cancer Research (2019)

Abstract MB21D2 (Mab-21 containing domain 2), a member of the Mab family, is predicted to form protein complexes with different partners, thus performs diverse functions in cells. In silico analyses using TCGA data revealed MB21D2 amplification/overexpression in various types of human cancer and correlated with poor survivals in patients with head and neck and endometrial cancer. More interestingly, a recurrent Q311E mutation was found in the Mab-21 domain critical for protein-protein interactions and downstream signaling. When expressed in oral cancer TW206 and CAL27 cells (low endogenous MB21D2), wild-type MB21D2 moderately increased cell proliferation, migration, and invasion as compared to the vector control. Significantly, the mutant variant (Q311E) showed stronger oncogenic effects on those processes and formed bigger spheres in a 3-D culture condition. Data mining, functional network predictions, and Western blotting confirmed the involvement of MB21D2 in centrosome-associated ciliogenesis via a crosstalk between PIK3CA and PKA (GSK and CREB) signaling pathways. Blockage of such interactome by specific inhibitors against PIK3CA or PKA reduced oncogenic activities mediated by MB21D2. Our data therefore suggest MB21D2 amplification/overexpression or the Q311E mutation as cancer drivers promoting cancer development through alteration of centrosome and primary cilia activity. Citation Format: Daniel Esguerra Gracilla, Praveen Kumar Korla, Louis Lai, Jim Jinn-Chyuan Sheu. MB21D2 amplification and recurrent mutation exhibit oncogenic activity through centrosome and cilia alteration [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 4657.
Abstract 15792: Chronic Cardiac Ischemia in the Background of Hyperglycemia Specifically Activates Histones and Transcription Factor-IIb Acetylation
Authors: Patrice Bilesimo, Vahid Agbortoko, Vasile I Pavlov, Laura A Scrimgeour, Frank W Sellke, Usheva Anny
Journal: Circulation (2017)

Introduction: There is a significant increase in the prevalence of metabolic syndrome (MetS) in the U.S. The mechanisms that underlie the inflammatory shift during cardiac ischemia in patients with...
Abstract 223: Antibody intracellular activated drug conjugate (AiADC) as novel ADC technology
Authors: Atsushi Suwa, Kazuo Komiya, Kenta Kadotsuji, Shoko Ochiai, Yosuke Takanashi, Eiji Sugaru, Hitoshi Ban
Journal: Cancer Research (2019)

Abstract Antibody drug conjugate (ADC) consisting of antibody and modifier (potent cytotoxic drug with chemical linker) is expected to selectively eliminate cancer cells expressing corresponding cell-surface antigen. More than 60 ADCs are in clinical trials and about 75 percent of its modifiers are based on three series (auristatin, maytansine, and pyrrolobenzodiazepine). Whereas some ADCs show promising clinical benefits, several ADCs may not have shown maximum value of ADC due to their narrow therapeutic windows. The function of modifiers impacts on total characteristics of ADC such as the efficacy, tolerability, and pharmacokinetics (PK). Therefore, further exploration of new types of modifier for ADC technology platform is needed. We designed hydrophilic modifiers which can be activated only inside of target cells. The ADC consisting of certain IgG1 monoclonal antibodies and this modifier (DSP-ADC) showed selective and potent cytotoxicity to target cells with IC50s at picomolar range. The DSP-ADC with the average drug-to-antibody ratio (DAR) of 7-8 was stable in blood circulation and showed favorable PK profiles in mice. Additionally, administration of the DSP-ADC led to dose-dependent suppression of cancer cell proliferation in mice xenograft models and achieved complete remissions at 3 mg/kg without body weight reduction. The toxicity studies of DSP-ADC in rats showed no effect on hematologic parameters up to 100 mg/kg. These modifiers are applicable to various monoclonal antibodies. Taken together, our modifiers can be fundamental component for ADC technology. We present here the novel ADC technology named as antibody intracellular activated drug conjugate (AiADC). Citation Format: Atsushi Suwa, Kazuo Komiya, Kenta Kadotsuji, Shoko Ochiai, Yosuke Takanashi, Eiji Sugaru, Hitoshi Ban. Antibody intracellular activated drug conjugate (AiADC) as novel ADC technology [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 223.