tbuckley/cabot-search huggingface dataset:
Effect of secure clinical messaging on chemotherapy adherence.
Authors: Sarah McLarty, Kayla E Friend, Neha Chadha, Santosh K Verma, Christine Sawicki, Kjel Andrew Johnson
Journal: Journal of Clinical Oncology (2019)

e18542 Background: Oncologists offer essential clinical information to patients face-to-face or by phone. Today, patients commonly prefer digital communication. To test the effectiveness of this in patients, we deployed proprietary secure messaging (SM) to communicate clinical messages to patients regarding prescribed oral chemotherapy in an effort to improve adherence. Methods: Chronic myelogenous leukemia (CML) patients receiving a tyrosine kinase inhibitor (TKI) were evaluated as two groups: a test group of patients starting therapy between Jan - Jun 2018 who received SM within 45 days therapy start who received SM refill reminders, adherence, condition management, laboratory testing reminders every 30 days, and information regarding side effects, versus a control group that included propensity matched patients initiating therapy between Jan - June 2017 and who received only non-clinical text message refill reminders within 45 days of therapy start. Adherence was compared 6 months after the initial prescription. Primary outcomes were medication possession ratio (MPR) (total day supply/ [(last fill date+last fill day supply)-first fill date]), number of prescriptions filled, % of patients optimally adherent (MPR ≥ 85%), and rate of discontinuation after first fill. The secondary outcome was days of therapy. A t-test evaluated MPR and length of therapy; logistic regression compared discontinuation after first fill and % optimally adherent. Results: 478 CML patients opted into SM and 478 where in the control group. MPR improved 1.6% absolute points (93.20 control v 94.80 test, p = 0.04); no change was seen in number of prescriptions filled (5.04 control v 5.17 test, p = 0.19). More patients receiving SM were optimally adherent (83.05 control v 88.31 test, p = 0.03); discontinuation after first fill was unchanged (6.90 control v 6.49 test, p = 0.79), as were days of therapy (156.51 control v 159.22 test), p = 0.35). Conclusions: Patients initiated on TKI therapy with receiving clinical SM had significantly higher adherence than the control group and were more likely to be optimally adherent, despite the high adherence rates of CML patients at baseline. Further analysis is needed to understand the durability of this adherence improvement.
Memo1-Mediated Tiling of Radial Glial Cells Facilitates Cerebral Cortical Development
Authors: Naoki Nakagawa, Charlotte Plestant, Keiko Yabuno-Nakagawa, Jingjun Li, Janice Lee, Chu-Wei Huang, Amelia Lee, Oleh Krupa, Aditi Adhikari, Suriya Thompson, Tamille Rhynes, Victoria Arevalo, Jason L. Stein, Zoltán Molnár, Ali Badache, E.S. Anton
Journal: Neuron (2019)
Abstract 4195: Clinical, endoscopic and histological aspects of colorectal cancer at the CHU de Cocody
Authors: Serge Franck Roland Fonkoua Fohom
Journal: Cancer Research (2019)

Abstract Introduction: The colorectal cancer (CRC) is the 4th cancer in Côte d’Ivoire (WHO 2014). Its overall prevalence appears to be advancing in sub-Saharan Africa over the years. The CRC frequently occurs at an early age and is very often discovered at an advanced or even late stage, with a bad prognosis. Aims: To assess the clinical, endoscopic and histological aspects of CRC. Patients and methods: An observational retrospective study was conducted from the reports of lower GI (LGI) endoscopies performed at the GI Endoscopy Unit between 2008 and 2018. The diagnosis of CRC was retained on the basis of the macroscopic and/or the histological aspect of the tumor. The following parameters were collected : number and indication of LGI endoscopies, age, gender, macroscopic appearance, location and histological type of the tumor. Results: Over the study period, 2118 LGI endoscopies were carried out. We found 145 CRCs, corresponding to an endoscopic prevalence of 7%. The annual prevalence was 18,13 cases. A CRC was diagnosed every 14,6 LGI endoscopies performed. The sex ratio was 1,42. Median age was 56 years, with extremes of 14 and 92 years. Patients younger than 40 years (with a median age of 32 years) accounted for 18% of cases. Rectorrhagia was the main cause of LGI endoscopies found in 48 patients (33,1%), followed by an imaging discovery (ultrasound and/or abdominal CT scan) of a colorectal tumor in 38 patients (27,2%), abdominal pain or constipation in 15,3% of cases (21 patients), weight loss in 13 patients (9,5%), abdominal or anorectal mass in 8% of cases (11 patients), chronic diarrhea in 8% of cases (11 patients), metastatic tumor liver in 9 patients (6,6%), melaena in 4,4% of cases (6 patients) and anemia in 3 patients (2,2%). Macroscopically, rectal localization was the most common with 42,36% of cases, followed by sigmoid (36,1%), cecum (16,7%), right colon (11,8%), colon transverse (7%) and left colonic angle (2,8%). The ulcerative-budding form was the most common (88,65%), with strictures in 57,5% of cases and necrotic-hemorrhagic in 48,23% of cases; followed by the polypoid form (4,25%). There were no ulcerative and infiltrative form. The histological type was found in 30 patients (4,83%). Adenocarcinoma was the most common (93,3%). Stromal tumor was found in 3,3% of the cases. Conclusion: This work confirms that the prevalence of CRC has increased in Côte d’Ivoire, that it occurs at an early age and that it is discovered at an advanced stage. This work highlights the importance of screening for CRC as early as possible in front of a Rectorrhagia, even in young patients. Citation Format: Serge Franck Roland Fonkoua Fohom. Clinical, endoscopic and histological aspects of colorectal cancer at the CHU de Cocody [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 4195.
Abstract 2753: The molecular basis of blocking the TIM-3 checkpoint with the LY3321367 mAb in cancer immunotherapy
Authors: Jaafar N. Haidar, Stephen Antonysamy, Sneha Mathew, Lan Wu, Yi Zhang, Margaret C. Kearins, Leyi Shen, J. Michael Sauder, David Schaer, Kyla E. Driscoll, Michael Kalos
Journal: Cancer Research (2019)

Abstract The anti-T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) antibody LY3321367 is a promising immune-checkpoint inhibitor that is being clinically tested for the treatment of multiple solid tumors (NCT03099109). LY3321367 was phenotypically selected from a large set of phage library Fabs that are TIM-3 binders. Tim3 has multiple protein and non-protein binding partners; hence, we attempt in this study to deconvolute the molecular mechanism of action of LY3321367. Surprisingly, LY3321367 in ELISA assays partially blocks the TIM-3/GAL-9 complex but does not block the TIM-3/CEACAM-1 complex. We also utilized X-ray crystallography to solve the structure the LY3321367-Fab complex with the IgV domain of TIM-3 at 2.0Å resolution. After solving the unbound structure of the LY3321367-Fab, we demonstrated that its CDRs do not undergo any conformational changes upon binding human TIM-3. The structural alignment of the human TIM-3/LY3321367-Fab complex with the available murine TIM-3 structure unexpectedly suggests that the 6.0Å epitope of LY3321367 overlaps the phosphatidylserine (PS) binding site on TIM-3. Consequently, we developed a cell-based assay to demonstrate that LY3321367 completely blocks the binding of soluble human TIM-3 to PS displayed on the surface of Campothecin-treated DO11.10 cells. Our structural results suggest an important role for PS in TIM-3 biology which is blocked by LY3321367. When combined with the partial blocking of GAL-9, the structural data of LY3321367 suggests that the binding sites of PS and GAL-9 may be proximal to each other on TIM-3. Citation Format: Jaafar N. Haidar, Stephen Antonysamy, Sneha Mathew, Lan Wu, Yi Zhang, Margaret C. Kearins, Leyi Shen, J. Michael Sauder, David Schaer, Kyla E. Driscoll, Michael Kalos. The molecular basis of blocking the TIM-3 checkpoint with the LY3321367 mAb in cancer 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 2753.
Abstract 2979: Boosting replication and penetration of telomerase-specific replicative virus by paclitaxel induces synthetic lethality in peritoneal metastasis of gastric cancer
Authors: Toshihiro Ogawa, Satoru Kikuchi, Wataru Ishikawa, Hiroshi Tazawa, Motoyasu Tabuchi, Shinji Kuroda, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara
Journal: Cancer Research (2019)

Abstract Background: Peritoneal metastasis is the most frequent form of distant metastasis and recurrence in gastric cancer and its prognosis is extremely poor. A promising result in phase III trial using intraperitoneal (i.p.) paclitaxel (PTX) for the peritoneal metastasis of gastric cancer has been reported in recent year; however, it is not sufficiently effective to eradicate disseminated gastric cancer. In this study, we investigated whether novel i.p. oncolytic virotherapy could be synthetically lethal with PTX for the peritoneal metastasis of gastric cancer. Methods: OBP-401 (TelomeScan) is a green fluorescence protein (GFP)-expressing attenuated adenovirus with oncolytic potency that is driven by telomerase promoter. We assessed its synergistic effect with PTX using human gastric cancer cell lines (GCIY and KATO III) and xenograft peritoneal metastasis model. The mechanism underlying the synergistic antitumor effect was evaluated by in vitro viral replication, induction of mitotic catastrophe, and in vivo viral penetration into disseminated nodules. Results: OBP-401 synergistically suppressed the viability of human gastric cancer cells in combination with PTX. PTX was synthetically lethal with OBP-401 by enhancing viral replication ability in cancer cells and the combination therapy increased mitotic catastrophe induction, resulted in accelerating autophagy and apoptosis. Peritoneally disseminated nodules were selectively visualized as GFP-positive spots by the i.p. administration of OBP-401 in the orthotopic human gastric cancer peritoneal dissemination model. And, PTX enhanced the penetration of OBP-401 deeply into the disseminated nodules. Moreover, non-invasive in vivo imaging system (IVIS) demonstrated that the combination therapy of i.p. OBP-401 administration with PTX significantly inhibited tumor growth of peritoneal metastasis and the amount of malignant ascites. Conclusions: Intraperitoneal virotherapy with PTX may be a promising treatment strategy for the peritoneal metastasis of gastric cancer. Clinical trials to obtain the proof of concept are warranted in peritoneally disseminated gastric cancer patients. Citation Format: Toshihiro Ogawa, Satoru Kikuchi, Wataru Ishikawa, Hiroshi Tazawa, Motoyasu Tabuchi, Shinji Kuroda, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara. Boosting replication and penetration of telomerase-specific replicative virus by paclitaxel induces synthetic lethality in peritoneal metastasis of gastric 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 2979.
Abstract 270: Temozolomide resistant MGMT negative/MMR proficient cancer cells rely on ATR signaling and homologous recombination for DNA repair and survival
Authors: Lara El Touny, Erik Harris, Curtis Hose, John Connelly, Diana Vengsarkar, Anne Monks, Ralph E. Parchment, James H. Doroshow, Beverly A. Teicher, Annamaria Rapisarda
Journal: Cancer Research (2019)

Abstract MGMT loss is used to predict response to temozolomide (TMZ), however, some patients do not benefit, suggesting that additional criteria for selection remain to be identified. Using patient derived and well-established cancer lines cancer lines we observed a 100% association between mismatched repair (MMR) defects and TMZ resistance; however, only 16% of MGMT-/MMR+ lines were sensitive to TMZ at clinically relevant concentrations. Activation of DNA damage and repair signaling was noted in both sensitive and resistant bladder cancer cell lines in response to TMZ but protracted DNA damage, accompanied by persistent G2/M arrest, was observed only in the sensitive models. ATR inhibition sensitized MGMT-/MMR proficient resistant models to TMZ resulting in measurable DNA damage, prolonged G2/M arrest and persistent growth inhibition: an effect that was mediated by Chk1. Homologous recombination and repair has been shown to play an important role in repairing TMZ-induced DNA damage. We demonstrate that ATR inhibition abrogated homologous recombination (HR) activity in a MGMT-/MMR proficient TMZ resistant bladder model and that a TMZ sensitive bladder model had minimal HR (assessed by pDR-GFP/SceI assay). Moreover, HR -deficiency (mediated by BRCA1 defects or RAD51 inhibition) conferred sensitivity to TMZ in combination with an ATR inhibitor. Our in vitro data suggest that a MGMT-/MMR+/HR-Deficiency profile identifies models that respond to TMZ/ATR inhibitor combination. Indeed, one Patient-derived Xenograft (PDX) model (available in the Patient Derived Models Repository), selected by this criterion (MGMT-/MMR+ and LOH&amp;gt;40%) showed delayed tumor growth and increased survival in the TMZ-VX970 combination arm, compared to single agents. Overall, our data suggest that MGMT-/MMR+ cells rely on ATR-dependent signaling for repair of TMZ-induced DSBs and that HR defects should be evaluated as criteria for selecting patients that will benefit from an ATR inhibitor/TMZ combination regimen. Funded by NCI Contract No. HHSN261200800001E. This research was supported, in part, by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. Citation Format: Lara El Touny, Erik Harris, Curtis Hose, John Connelly, Diana Vengsarkar, Anne Monks, Ralph E. Parchment, James H. Doroshow, Beverly A. Teicher, Annamaria Rapisarda. Temozolomide resistant MGMT negative/MMR proficient cancer cells rely on ATR signaling and homologous recombination for DNA repair and survival [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 270.
Targeted next generation sequencing of sarcomas for identification of therapeutic targets.
Authors: Vinod Ravi, Siraj M. Ali, Naveen Ramesh, Funda Meric-Bernstam, Gary A. Palmer, Patrick Hwu, Shreyaskumar Patel, Andrew Futreal
Journal: Journal of Clinical Oncology (2013)

10577 Background: Sarcomas are a diverse group of mesenchymal tumors with significant heterogeneity. Evolving personalized cancer care strategies require identification of recurrent genomic alterations that can be targeted therapeutically. Due to the rarity of these tumors and lack of fresh or frozen tissue in routine clinical practice, DNA sequencing has been a challenge. Objective: To demonstrate the feasibility of a next-generation sequencing (NGS) platform that utilizes archival formalin-fixed paraffin-embedded (FFPE) tissue to evaluate the spectrum of DNA alterations seen in sarcomas. Methods: Study population included 35 consecutive patients with advanced sarcoma presenting to the sarcoma center at MD Anderson Cancer Center beginning August 2012 with archival FFPE tissue available for NGS. DNA was extracted from FFPE samples and used for hybridization capture and NGS on the Illumina HiSeq 2000 platform. A total of 182 cancer-associated genes and 37 introns of 14 commonly rearranged genes were evaluated for genomic alterations. In the absence of an individual–matched normal control, germline variations were removed using dbSNP and the remaining variants were classified on the basis of current knowledge of specific variants from cancer databases such as COSMIC. Results: 35 patients (10 Angiosarcomas, 9 Leiomyosarcomas, 3 synovial sarcomas, 13 other subtypes) underwent DNA extraction with a median yield of 3376 ng tumor DNA. The average sequencing depth was &gt;900X. 43% of patients had point mutations/indels previously described in COSMIC and/or in known mutation hotspots. 54% of patients showed structural variants such as amplifications, deletions or rearrangements. 68% of genomic alterations are in genes that are actionable. We identified an apparently novel variant in KDR T771R in 2/10 patients with angiosarcoma. KDR amplifications were identified in 20% of patients with angiosarcoma. Outcomes of matched targeted therapy of patients with actionable targets will be presented with more mature follow-up. Conclusions: Targeted NGS of DNA from archival FFPE tissue is feasible with the potential for identifying actionable targets and discovery of novel mutations.
Abstract 3972: Investigation of tumor intrinsic PD1/PD-L1 in canine urothelial carcinomas as a spontaneous translational model for human invasive bladder cancer
Authors: Yu Jia Wang, Katarzyna Pietrzak, Mikolaj Kocikowski, David Argyle, Ted Hupp, Maciej Parys
Journal: Cancer Research (2019)

Abstract Urothelial carcinoma (UC) is the fourth most common malignancy in human and the most common form of urinary bladder cancer in dogs. This neoplasia tends to be invasive at advanced stages hence novel therapeutic approaches are urgently needed. As urothelial carcinomas share many similarities between the dog and human in the immunological responses, dogs are a perfect model for studying immunotherapeutic approaches. Recently immuno-checkpoint blockade using anti-PD1/PD-L1 antibodies have shown a promising effect and durable responses in the treatment of UC. Although until recently the PD1/PD-L1 axis was considered to be mostly affecting immune cells, recent reports identified, that PD-1/PD-L1 interaction is also capable of pro-tumorigenic signaling in melanoma and other cancers. Yet, little is known regarding this phenomenon in UC. In our study, we aim at identification of the expression level of PD-1 in canine UC and subsequently characterize the effect of overexpression and CRISPR-based knock-out of PD-1 and PD-L1. Using flow cytometry and immunocytochemistry, we identified that PD-1 is expressed on the surface of canine UC cell line. Interestingly, incubation with high concentration of PD-1 antibody decreased the proliferation rate of the tumor. After transfection with a PD-1 overexpression vector, we notice a significant morphological change and decrease in proliferation and colony formation. Our result provides the first report on PD-1 intrinsic signaling play as an important role in tumor growth of canine UC and thus may also be responsive to immune checkpoint blockade. The effect identified further strengthens the dog as a potential translational model for UC immunotherapy. Citation Format: Yu Jia Wang, Katarzyna Pietrzak, Mikolaj Kocikowski, David Argyle, Ted Hupp, Maciej Parys. Investigation of tumor intrinsic PD1/PD-L1 in canine urothelial carcinomas as a spontaneous translational model for human invasive 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 3972.
Abstract 17491: Long-term Mortality of Patients With Single-Chamber versus Dual-Chamber Implantable Cardioverter-Defibrillators
Authors: Antonio L Perez, Steven A Lubitz, Mary L Guy, Jeremy N Ruskin, Jonathan J Passeri, Patrick T Ellinor
Journal: Circulation (2013)

Nationwide, dual-chamber ICDs comprise the majority of defibrillator implantations. Although dual-chamber ICDs are associated with increased periprocedural complications including death, the relati...
Abstract 3061: Role of ID4 (inhibitor of DNA binding protein 4) in FKBP52-AR pathway
Authors: Shravan Kumar Komaragiri
Journal: Cancer Research (2019)

Abstract Introduction: Inhibitor of DNA binding/differentiation protein 4 (ID4), acts as a dominant negative regulator of basic helix loop helix (bHLH) family of transcription factors. In normal prostate epithelial cells, ID4 collaborates with androgen receptor (AR) and p53 to exert its tumor suppressor activity. Previous studies have shown that ID4 promotes tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR through selective interaction with FKBP52. Pharmacological inhibition of FKBP52, by MJC13, attenuated the tumor growth, weight, and volume of LNCaP cells lacking ID4(L(-)ID4) xenografts. The L(-)ID4 cells also gains CRPC phenotype through FKBP52-mediated AR signaling. In this study we investigated the role of ID4 in pharmacological inhibition of FKBP52 with GMC1 (Initial hit molecule by in-silico screening with the most potent inhibition of FKBP52) in regulating the AR pathway. Experimental procedures: GMC1 drug treatments in LNCaP(-)ID4 and CW22RV1 generated xenograft tumors were further analyzed for tumor volume and tumor weight. We also performed immunohistochemistry on GMC1 treated xenografts to determine AR, PSA, FKBP51 and FKBP52 protein expression. Our in vivo studies with GMC1 drug treatments in castrated male SCID mice injected with LNCaP-ID4 and CW22RV1 cells showed decreased tumor size and volume when compared to untreated mice tumors. Results: IHC results on GMC1 treated LNCaP(-)ID4 and CW22RV1 generated xenograft tumors showed no change in ID4 expression with decrease expression of AR, PSA, FKBP51, FKBP52 and KI67 when compared to untreated xenograft tumors. These results suggest that inhibition of FKBP52-regulated AR activity (via GMC1) demonstrated a significant reduction in the tumor volume of subcutaneous xenografts in vivo. Overall, ID4 appears as a potential tumor suppressor gene that selectively regulates AR activity through direct interaction with FKBP52, and its loss, promotes CRPC through FKBP52-mediated AR signaling. Conclusions: In conclusion, we demonstrate that loss of ID4 in LNCaP cells elevates FKBP52 levels, transcriptionally potentiates AR activity which in turn then leads to progression of androgen-independent prostate cancer. GMC1 is a novel inhibitor that inhibits the binding of FKBP52 to AR thereby prevents the AR transcriptional hyperactivity in PCa Acknowledgement: These studies were supported by DOD, Grant # W81XWH-17-1-0437 Citation Format: Shravan Kumar Komaragiri. Role of ID4 (inhibitor of DNA binding protein 4) in FKBP52-AR pathway [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 3061.