tbuckley/cabot-search huggingface dataset:
Abstract 1173: The identification of circulating tumor cells in the cerebrospinal fluid of gastric cancer patients with brain metastasis and the evaluation of intra-patient tumor heterogeneity
Authors: Jang Ho Cho, Sun Young Kim, Kyung Kim, Jusun Kim, Su Jin Lee, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Seungtae Kim
Journal: Cancer Research (2018)

Abstract PURPOSE : The purpose of this study was to identify circulating tumor cells (CTC) and evaluate tumor heterogeneity in cerebrospinal fluid (CSF) of advanced gastric cancer (GC) patients with leptomeningeal seeding. METHOD : We used the DEPArray system to identify and align single enabled CTCs in CSF based on multi-parallel fluorescence analysis. CSF were stained with an antibody cocktail recognizing cytokeratin, EpCAM, and HER2. CTC subpopulations of CSF were quantified as both absolute cell count and relative frequency. Based on the stained morphology of each single CSFTCs, five groups (Group A~E) were categorized. RESULTS : CSF samples were obtained from a HER2 positive GC patient with leptomeningeal seeding. Each single CTC was collected according to the characteristics of morphology and the difference of marker expression. Group A CTC revealed HER2 positive, CK positive and EpCAM positive cells. The ratio of group A cells to total cells was 56.7%. Although the tumor of patient was HER2 positive cancer, HER2 negative CTCs in CSF (Group D + E) accounted for 21.8% of the total cells. Among CTCs we detected in CSF, there was no CTC revealing HER2 positive, CK negative and EpCAM negative. CONCLUSIONS : DEPArray analysis might be a novel tool to capture CTC in CSF samples and evaluate the intra-patient's tumor heterogeneity. These findings suggested that DEPArray analysis could be used as a useful tool for the precision medicine. Characterization of HER2 + CSFTCs on gastric cancer patientHER2CytokeratinEpCamCell#%/total cellGroupPositivePositivePositive13556.7APositivePositiveNegative20.8BPositiveNegativePositive4920.6CPositiveNegativeNegative00.0NegativePositivePositive52.1DNegativePositiveNegative00.0NegativeNegativePositive4719.7E Citation Format: Jang Ho Cho, Sun Young Kim, Kyung Kim, Jusun Kim, Su Jin Lee, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Seungtae Kim. The identification of circulating tumor cells in the cerebrospinal fluid of gastric cancer patients with brain metastasis and the evaluation of intra-patient tumor heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1173.
Abstract 1207: A systematic literature review of the prevalence of PIK3CA mutations and mutation hotspots in HR+/HER2- metastatic breast cancer
Authors: Lea Mollon, Alejandra Aguilar, Elizabeth Anderson, Joni Dean, Lisa Davis, Terri Warholak, Ayal A. Aizer, Emma Platt, Aditya Bardiya, Derek Tang
Journal: Cancer Research (2018)

Abstract Introduction: Clinical research on the predictive value of PIK3CA mutations in hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2–) metastatic breast cancer (mBC) has advanced in recent years. However, knowledge of epidemiological prevalence has not been systematically evaluated. This study aimed to report prevalence of PIK3CA mutation using different biopsy techniques as well as specific hotspot mutations across the available literature. Methods: A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts was performed by two independent researchers that included, but was not limited to, keywords: “breast neoplasm”, “PIK3CA protein”, “hormone receptor positive”, and “metastases”. English-language studies in HR+, HER2– mBC detailing the prevalence of PIK3CA mutations and published between January 1993 through August 2017 were included. Content analysis was employed to quantify collected data elements. Results: Of 558 studies included for full-text review, 36 met inclusion criteria. Most included studies (n = 18) were observational in nature. A total of 4,247 samples were tested for genetic mutations. Most studies used tissue biopsy samples (n = 33; 89%). Tumor samples accounted for 84.6% of all samples (n = 3597). Liquid biopsies were performed in 4 studies (11%) and accounted for 15.3% of all samples (n = 650). One study reported both liquid and tumor biopsy data. Overall, reported prevalence of the PIK3CA mutation ranged from 13.3% to 61.5%. Median prevalence was 36.4% (25th percentile = 28.6%; 75th percentile = 48.4%). Among studies using tissue biopsies, the majority reported prevalence from 16.7% to 61.5%. Among studies using liquid biopsies, the majority (n = 3) reported prevalence from 43.3% to 46.8%; one other study reported 13.3%. The most commonly tested hotspot mutations were H1047R and E545K. Among studies reporting specific hotspot mutation prevalence (n = 9), the H1047R hotspot mutation prevalence in these studies ranged between 25% and 75% while the E545K prevalence ranged between 11.1% and 50%. Conclusions: Although discrepancies exist with respect to mutation prevalence estimated across various tissue vs. liquid biopsy techniques, PIK3CA mutations and mutation hotspots (specifically H1047R and E545K) frequently occur in HR+/HER2– mBC. Citation Format: Lea Mollon, Alejandra Aguilar, Elizabeth Anderson, Joni Dean, Lisa Davis, Terri Warholak, Ayal A. Aizer, Emma Platt, Aditya Bardiya, Derek Tang. A systematic literature review of the prevalence of PIK3CA mutations and mutation hotspots in HR+/HER2- metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1207.
B cell adaptor for PI3-kinase (BCAP) modulates CD8+ effector and memory T cell differentiation
Authors: Mark D. Singh, Minjian Ni, Jenna M. Sullivan, Jessica A. Hamerman, Daniel J. Campbell
Journal: The Journal of Experimental Medicine (2018)

CD8+ T cells respond to signals via the T cell receptor (TCR), costimulatory molecules, and immunoregulatory cytokines by developing into diverse populations of effector and memory cells. The relative strength of phosphoinositide 3-kinase (PI3K) signaling early in the T cell response can dramatically influence downstream effector and memory T cell differentiation. We show that initial PI3K signaling during T cell activation results in up-regulation of the signaling scaffold B cell adaptor for PI3K (BCAP), which further potentiates PI3K signaling and promotes the accumulation of CD8+ T cells with a terminally differentiated effector phenotype. Accordingly, BCAP-deficient CD8+ T cells have attenuated clonal expansion and altered effector and memory T cell development following infection with Listeria monocytogenes. Thus, induction of BCAP serves as a positive feedback circuit to enhance PI3K signaling in activated CD8+ T cells, thereby acting as a molecular checkpoint regulating effector and memory T cell development.
Electrophysiological Mechanisms and Determinants of Vagal Maneuvers for Termination of Paroxysmal Supraventricular Tachycardia
Authors: Zu-ChiWen, Shih-AnnChen, Ching-TaiTai, Chern-EnChiang, Chuen-WangChiou, Mau-SongChang
Journal: Circulation (1998)

Background—The vagal maneuvers used for termination of paroxysmal supraventricular reentrant tachycardia (PSVT) appear to involve more complex mechanisms than we have known, and further study should be done to explore the possible mechanisms. Methods and Results—In this study, 133 patients with PSVT and 30 age- and sex-matched control subjects were included. We assessed the effects of different vagal maneuvers on termination of PSVT and compared baroreflex sensitivity and β-adrenergic sensitivity between the patients with PSVT and control subjects. Out of 85 patients with atrioventricular reciprocating tachycardia (AVRT), vagal maneuvers terminated in 45 (53%). Of these, 28 (33%) terminated in the antegrade limb and 17 (20%) terminated in the retrograde limb. Out of 48 patients with atrioventricular nodal reentrant tachycardia (AVNRT), vagal maneuvers terminated the tachycardia in the antegrade slow pathway (14%) or in the retrograde fast pathway (19%). Baroreflex sensitivity was poorer but isoproterenol ...
Abstract B20: The molecular function of ASPSCR1-TFE3 in alveolar soft part sarcoma
Authors: Miwa Tanaka, Takuro Nakamura
Journal: Clinical Cancer Research (2018)

Abstract Alveolar soft part sarcoma (ASPS) is a soft-tissue sarcoma that affects predominantly adolescents and young adults with lower legs and buttocks as frequent primary sites. ASPS is characterized by alveolar structure of tumor cells, abundant vascularization, and high frequency of hematogenous metastasis. As for gene abnormality, ASPSCR1-TFE3 fusion gene is observed in all ASPS cases. To understand the exact mechanisms of ASPSCR1-TFE3 and tumorigenesis of ASPS, we have developed an ex vivo mouse model for human ASPS (Tanaka et al., Cancer Res 2017;77(4). In mouse ASPS, the tumor cells frequently showed tumor intravasation, with the intravascular tumor cells presenting as organoid structures covered with hemangiopericytes, which is also observed in human ASPS. Moreover, culture supernatant of mouse ASPS cells strongly induced hemangiopericyte migration in vitro. The search for hemangiopericyte-inducing factors which are released from ASPS cells is in progress. We identified Gpnmb that plays an important role in intravasation of ASPS tumor cells as a direct target of the ASPSCR1-TFE3 fusion transcription factor. The ChIP-seq analysis detected an ASPSCR1-TFE3 binding peak at the Gpnmb promoter, and Gpnmb expression was significantly upregulated in ASPS tumors. Enhanced localization of GPNMB at the front of tumor invasion and intravasation in both mouse and human ASPS. Knockdown of Gpnmb suppressed transendothelial migration of ASPS tumor cells, indicating that Gpnmb is required for intravasation. TFE3 is a member of the TFE/MITF family, which has been found involved in human cancer such as renal cell carcinoma and malignant melanoma. The present model enabled us to evaluate tumorigenic activity of TFE/MITF family proteins. To examine the oncogenic activity of ASPSCR1 fusion genes, artificial chimeric genes were generated consisting of the 5 ASPSCR1 and 3 TFE/MITF sequences. The ASPSCR1-TFE3 and ASPSCR1-TFEB but not ASPSCR1-TFEC and ASPSCR1-MITF induced sarcoma. The results suggest the presence of TFE3/TFEB-specific cofactors and mechanisms for tumorigenesis. In order to identify such novel cofactors and functional motifs, human ASPS cell-nuclear extract was incubated with TFE3 or MITF proteins and TFE3- or MITF-bound fractions were analyzed by mass spectrometry. The TFE3-specific interaction partners were identified and their roles in tumorigenesis, angiogenesis, and/or metastasis are subjected to the subsequent analysis. These studies will provide valuable information for our understanding of the biology of ASPS and functions of TFE/MITF family transcription factors. Citation Format: Miwa Tanaka, Takuro Nakamura. The molecular function of ASPSCR1-TFE3 in alveolar soft part sarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B20.
Anticholinergic Effects of Class III Antiarrhythmic Drugs in Guinea Pig Atrial Cells
Authors: KatsumiMori, YukioHara, ToshihiroSaito, YoshiakiMasuda, HaruakiNakaya
Journal: Circulation (1995)

Background It is well known that vagal stimulation increases the vulnerability to atrial fibrillation via muscarinic receptor–mediated shortening of refractory period. Recently it has been reported that some class III antiarrhythmic drugs effectively terminate or prevent atrial flutter and fibrillation by prolonging atrial effective refractory period. However, effects of class III antiarrhythmic drugs on the muscarinic acetylcholine receptor–operated K+ current (IK.ACh), which is important for the repolarization phase of the action potential in atrial cells, have not been thoroughly examined. Methods and Results Effects of three class III antiarrhythmic drugs, d,l-sotalol, E-4031, and MS-551, on the carbachol (1 μmol/L)–induced action potential shortening and outward K+ current were examined in guinea pig atrial cells by conventional microelectrode and patch clamp techniques. In isolated left atria, d,l-sotalol (100 μmol/L), E-4031 (3 μmol/L), and MS-551 (30 μmol/L) partially reversed the carbachol-induce...
Abstract 2931: MTX-211, a dual and selective inhibitor of EGFR and PI3 kinase, shows promising activity in combination with MEK inhibition in preclinical models of pancreatic cancer
Authors: Christy Frankowski-McGregor, Joel Maust, Elizabeth Ziemke, Rachel Mumby, Amy Delaney, Alnawaz Rehemtulla, Christopher Whitehead, Judith S. Sebolt-Leopold
Journal: Cancer Research (2018)

Abstract Pancreatic cancer is one of the deadliest forms of cancer, with median 5-year survival rates less than 10%. This disease is recalcitrant to chemotherapeutic approaches and recently approved therapies afford only modest improvements in survival. KRAS is the most commonly mutated gene in pancreatic tumors with an incidence rate exceeding 90%. Despite intensive efforts, KRAS has remained undruggable. Kinases acting both upstream and downstream of RAS continue to be exploited for the development of novel agents to attenuate signaling through this critical oncogene. While EGFR and MEK inhibitor monotherapies have been evaluated in the clinic for the treatment of pancreatic cancer, efficacy has been modest despite their relevance to MAP kinase (MAPK) pathway-altered tumors. Novel therapies are urgently needed to address adaptive signaling mechanisms that diminish the effectiveness of kinase-targeted approaches. MTX-211 is a first-in-class dual inhibitor of PI3K and EGFR kinase with a promising pharmaceutical profile and proven ability to potentiate the effectiveness of MEK inhibitor therapy in KRAS mutant colorectal tumors. The present study was undertaken to extend our evaluation of MTX-211 to include pancreatic cancer model systems. We have found that MTX-211 exhibits low micromolar potency against an extensive panel of primary models of pancreatic cancer and is highly synergistic with the MEK inhibitor trametinib. Preliminary data suggest that this synergy is driven by the ability of MTX-211 to target compensatory transcriptional activation of HER3 that occurs in response to MEK inhibition. A genetically engineered KRAS and p53 mutant (KPC) mouse model was transduced with a lentiviral construct encoding a caspase reporter, which was used to show that the combination of MTX-211 and trametinib elicited a significant increase in apoptosis over single agent controls. Results from an animal study conducted with the KPC model further showed that the combination of MTX-211 and trametinib significantly slowed growth of these aggressive tumors. Employing both KPC and patient-derived xenograft models of pancreatic cancer, efforts are underway to optimize therapeutic outcome in response to MTX-211-based combination treatment regimens. Citation Format: Christy Frankowski-McGregor, Joel Maust, Elizabeth Ziemke, Rachel Mumby, Amy Delaney, Alnawaz Rehemtulla, Christopher Whitehead, Judith S. Sebolt-Leopold. MTX-211, a dual and selective inhibitor of EGFR and PI3 kinase, shows promising activity in combination with MEK inhibition in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2931.
Abstract CT085: Randomized phase II trial of hydroxychloroquine in combination with gemcitabine/nab-paclitaxel to inhibit autophagy in pancreatic cancer: A SU2C-funded trial
Authors: Thomas B. Karasic, Mark H. O'Hara, Arturo Loaiza-Bonilla, Kim A. Reiss-Binder, Ursina R. Teitelbaum, Erkut Borazanci, Ana M. De Jesus-Acosta, Colleen Redlinger, Jessica A. Burrell, Daniel D. Von Hoff, Daniel A. Laheru, Ravi K. Amaravadi, Jeffrey A. Drebin, Peter J. O'Dwyer
Journal: Cancer Research (2018)

Abstract Autophagy, a regulated metabolic process that enables energy conservation in adverse environmental circumstances, has been shown in animal models to confer resistance to chemotherapy, which can be reversed by hydroxychloroquine (HCQ). After establishing safety in a Phase I run-in, 112 patients were randomized to receive standard gemcitabine (1000mg/m2) and nab-paclitaxel (125 mg/m2) weekly x 3 every 4 weeks, with (n=55 evaluable) or without (n=55 evaluable) HCQ 600mg bid. Median age was 65 (range 43-86) of whom 47% were aged &amp;gt; 65, 40% were female, 93% Caucasian, ECOG PS 0/1 51%/49%, and did not differ between the arms. Treatment-related side-effects were consistent with prior studies, and were balanced by arm, except for Grade 3/4 neutropenia (42 vs 23%), nausea (9 vs 0%), and fatigue (7 vs 0%), all higher with HCQ. Partial responses were observed in 21/46 (46%) with HCQ, and 8/48 (17%) without HCQ. The primary endpoint, overall survival at 12 months, was 41% (95% CI 27-53%) in the HCQ arm and 51% (95% CI 36-63%) in the non-HCQ arm. Median progression-free survival was 5.7 months (95% CI 4.0-9.3) in the HCQ arm and 6.4 months in the non-HCQ arm (95% CI 4.5-7.6). Median overall survival was 11.1 months (95% CI 9.0-14.2) in the HCQ arm and 14.4 months (95% CI 9.5-15.6) in the non-HCQ arm. Genomic testing was performed on a subset of the patients (41%), in whom outcomes did not differ by p53 mutational status. We conclude that based on the primary endpoint, the addition of the autophagy reversal agent HCQ did not improve the survival of patients with metastatic pancreatic cancer. Response rates in patients who received HCQ were higher, and toxicity was tolerable. Autophagy reversal might be explored in the management of locally-advanced disease. Citation Format: Thomas B. Karasic, Mark H. O'Hara, Arturo Loaiza-Bonilla, Kim A. Reiss-Binder, Ursina R. Teitelbaum, Erkut Borazanci, Ana M. De Jesus-Acosta, Colleen Redlinger, Jessica A. Burrell, Daniel D. Von Hoff, Daniel A. Laheru, Ravi K. Amaravadi, Jeffrey A. Drebin, Peter J. O'Dwyer. Randomized phase II trial of hydroxychloroquine in combination with gemcitabine/nab-paclitaxel to inhibit autophagy in pancreatic cancer: A SU2C-funded trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT085.
Abstract 5343: Mutational signatures in EGFR sensitizing mutation positive lung adenocarcinoma
Authors: Eun Young Kim, Arum Kim, Yoon Soo Chang
Journal: Cancer Research (2018)

Abstract Lung cancer has high mutational burden, which is featured by smoking signature. However, lung cancer with EGFR mutations is common in nonsmokers and women, which suggests that mutational stresses other than smoking are involved. We analyzed repeated deep sequencing data of EGFR sensitizing mutation positive lung adenocarcinoma tissue to identify characteristic mutational signatures, proposed by Alexandrov et al. Targeted next-generation sequencing was performed using Ion AmpliSeq Custom Panel of 0.6 Mb size containing 70 major genes including EGFR in 69 cases harboring sensitizing EGFR mutation. Publicly available data from EGFR sensitizing mutation were extracted from GDC data portal. Mutational signature was analyzed using maftools package. EGFR-TKI domain analysis revealed 53 mutations. C&amp;gt; T mutation was found in 26.4%, but C&amp;gt; T transition at CpG site that suggests aging effect was found in 2%, and C&amp;gt; T or C&amp;gt; G mutation in TCW motif reflecting APOBEC activity were found in 1.4%. C&amp;gt; A transversion corresponding to Signature 4 was also found in only one case, suggesting that the possibility of EGFR mutation by smoking effect is very low. The T&amp;gt; C substitution in ApT, indicating signature 5, was detected in 4%. The EGFR-TKI sensitizing mutation (E19del, L858R) has lower frequency of co-mutation while other EGFR-TKI domain mutations were frequently associated with multiple co-mutations. T&amp;gt;G substitution, indicating signature 28 and commonly found in Korean gastric cancer, was found in 39.1%. When the mutational signatures of a total 70 genes were analyzed, the C&amp;gt; T mutation was the most commonly detected (73.1%) and similarity with signature 5 was highest. These findings suggest that the mutational signature of EGFR sensitizing mutant lung cancer, which is frequent in Far East Asia, may be different from that of Western data. Additional data and analysis will be updated until the annual meeting. Citation Format: Eun Young Kim, Arum Kim, Yoon Soo Chang. Mutational signatures in EGFR sensitizing mutation positive lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5343.
N-Methyl-1-Deoxynojirimycin (MOR-14), an α-Glucosidase Inhibitor, Markedly Reduced Infarct Size in Rabbit Hearts
Authors: MasazumiArai, ShinyaMinatoguchi, GenzouTakemura, YoshihiroUno, TatsuyaKariya, HisatoTakatsu, TakakoFujiwara, MasayaHigashioka, YoshiakiYoshikuni, HisayoshiFujiwara
Journal: Circulation (1998)

Background—N-methyl-1-deoxynojirimycin (MOR-14), an α-glucosidase inhibitor, reduces the glycogenolytic rate by inhibiting the α-1,6-glucosidase of glycogen-debranching enzyme in the liver, in addition to possessing an antihyperglycemic action by blocking α-1,4-glucosidase in the intestine. Because the reduction of the glycogenolytic rate may be one of the mechanisms of myocardial protection in ischemic preconditioning, the compounds inhibiting myocardial α-1,6-glucosidase may be protective against ischemic damage. Thus, we investigated whether MOR-14 could inhibit α-1,6-glucosidase and reduce the infarct size in rabbit hearts without collateral circulation. Methods and Results—MOR-14 dose-dependently decreased the α-1,6-glucosidase activity in rabbit heart extract. A tracer study demonstrated the myocardial uptake of a considerable amount of MOR-14 sufficient to fully inhibit α-1,6-glucosidase. To assess the infarct size–reducing effect of MOR-14, 54 rabbits were subjected to 30-minute coronary occlusion...