tbuckley/cabot-search huggingface dataset:
Abstract 5005: Aging promotes changes to peritoneal and omental collagen structure that contribute to increased ovarian cancer metastatic success
Authors: Elizabeth Harper, Elizabeth Loughran, Annemarie Leonard, Tyvette Hilliard, Marwa Asem, Yueying Liu, Jing Yang, Yuliya Klymenko, Jeff Johnson, Emma Sheedy, Zonggao Shi, Matthew Leevy, Matthew Ravosa, M. Sharon Stack
Journal: Cancer Research (2018)

Abstract Ovarian cancer (OvCa) is the deadliest cancer of the female reproductive system, ranking fifth in overall cancer deaths among women. Unlike the majority of cancers, OvCa metastasizes via diffusion through the peritoneal cavity, resulting in multiple metastatic sites, including the omentum and peritoneum. These metastasizing OvCa cells induce rapid mesothelial cell retraction and readily adhere to the sub-mesothelial collagen of the extracellular matrix. Epidemiologic data identifies age as a significant risk factor in OvCa, as about half of diagnoses are in women over the age of 63. Despite this, age is understudied in the OvCa field. Using a C57Bl/6 mouse model of aging, young (Y) mice ranging from 3-6 months of age, and aged (A) mice ranging from 20-23 months of age, corresponding to women aged 20-30 years (Y) and 60-67 years (A) were used to study the role aging has on metastasis. Fluorescently tagged C57Bl/6 syngeneic ID8 p53-/- mouse OvCa surface epithelial cells were injected intraperitoneally in young and aged mice and disease progression was evaluated for 5.5 weeks. Organ-specific tumor burden was quantified with ImageJ, revealing increased tumor burden in aged mice compared to their young counterparts. These results were reproduced in the FVB mouse model using syngeneic PTENshRNA/KRASG12V modified FVB OvCa oviductal epithelial cells. Second Harmonic Generation Microscopy (SHG) was used to visualize collagen of the peritoneal and omental tissues from young and aged C57Bl/6 mice. Distinct structural differences were shown in omental collagen in the Y vs A cohorts and validated with Scanning Electron Microscopy (SEM). Additionally, Nanoindentation illustrated mechanical differences between young and aged peritoneal samples. In conclusion, aging induces changes in the structure and mechanical strength of peritoneal and omental collagen, which contribute to OvCa metastasis. Citation Format: Elizabeth Harper, Elizabeth Loughran, Annemarie Leonard, Tyvette Hilliard, Marwa Asem, Yueying Liu, Jing Yang, Yuliya Klymenko, Jeff Johnson, Emma Sheedy, Zonggao Shi, Matthew Leevy, Matthew Ravosa, M. Sharon Stack. Aging promotes changes to peritoneal and omental collagen structure that contribute to increased ovarian cancer metastatic success [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 5005.
Abstract 4538: LiquidGxTMqPCR, an extremely sensitive qPCR-based liquid biopsy platform
Authors: Yang Song, Danielle Quintanilha, Si Chen, Jun Huang
Journal: Cancer Research (2018)

Abstract In recent years, circulating cell-free tumor DNA has emerged as an excellent source of biomarkers for cancer detection, diagnosis and monitoring. One great challenge of detecting cell-free tumor DNA molecules is that they are usually found in a large background of wild-type DNA; therefore, assays with high sensitivity and low limit of detection are required. We have developed an extremely sensitive qPCR-based liquid biopsy platform, LiquidGxTM qPCR, to detect and track key driver mutations from patient blood. The platform takes advantage of our patent-pending technology BESTTM (Blocker-based Enrichment System of Tumor DNA) to specifically enrich mutant alleles from as low as 0.01% to more than 90%. With this platform, we currently have developed a CLIA-approved non-small cell lung cancer panel (EGFR T790M/L858R/C797S/Exon19Del, KRAS G12X/G13CD, BRAF V600E, ALK-EML4 fusion), and a colorectal cancer recurrence monitoring panel (KRAS G12X/G13CD, NRAS G12DV/Q61KR, PIK3CA E542K/E545K/H1047R, BRAF V600E). Our validation data show that the NSCLC panel has superior performance, with a LOD as low as 0.005%, analytical sensitivity more than 95% and analytical specificity of 100%. We have used this panel to test samples from nearly 200 NSCLC patients, and the results are highly concordant with those obtained by error-reducing NGS-based tests, despite some samples only detected via LiquidGxTM qPCR due to superior LOD. Other features of LiquidGxTM qPCR include (1) simultaneous enrichment of multiple mutants in the same reaction; (2) cost-effective and no special equipment required; and (3) fast turnaround time that takes as little as 0.5 days to get the results. In summary, we have developed a potent liquid biopsy platform for highly sensitive genomic biomarker test. With the technology, we have developed two cancer panels and this platform is also available as an assay development service. Citation Format: Yang Song, Danielle Quintanilha, Si Chen, Jun Huang. LiquidGxTMqPCR, an extremely sensitive qPCR-based liquid biopsy platform [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 4538.
Metronomic cyclophosphamide and capecitabine combined with lapatinib in heavily pretreated metastatic breast cancer (MBC) HER2-positive patients: 2-year update.
Authors: Katia Cagossi, Giorgia Razzini, Alessia Ferrari, Maria Grazia Lazzaretti, Meri Leporati, Rosangela Silvestri, Manlio Iadanza, Fabrizio Artioli
Journal: Journal of Clinical Oncology (2013)

e11515 Background: Current therapeutic goals for MBC, as an incurable disease, are symptoms and prolonged disease control together with good quality of life. Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. We evaluated the efficacy and tolerability of the combination of anti-angiogenetic activity of metronomic chemotherapy with a tyrosine kinase inhibitor such as lapatinib in heavily pre-treated MBC HER-2 positive patients. Methods: Metastatic breast cancer patients HER-2 positive with CEA or Ca15.3 elevated, prior systemic therapy for advanced disease, ECOG performance status &lt; 1 and life expectancy longer than 3 months. MBC patients were treated with metronomic oral capecitabine (1500 mg daily) and cyclophosphamide (50 mg daily) plus lapatinib (1250 mg daily). The treatment was given until disease progression. Primary objective was time to progression (TTP) and safety. Results: Fifteenpatients were included. Median age was 52 years old (range 42-77). Median number of previous chemotherapy lines was 5 (range 2-10). Median time to tumor progression was 6 months (2-14). No complete response was observed. Eight out of fiftten patients (60%) with pre-existing only bone metastases achieved a stable disease and/or partial response and were still on treatment after 6 month of therapy. At the same time 100% of these patients exhibited significant reduction of serum marker concentrations. No grade 3-4 skin toxicity was reported. Hematological and gastro-intestinal toxicity was well tolerated (G1-2). No reduction of dose was needed. Conclusions: The combination of lapatinib with metronomic chemotherapy may lead to effective palliation despite extensive pretreatment at least in bone metastatic patients. The treatment appears to be less toxic than lapatinib and capecitabine at full dosage, especially in heavily pretreated MBC patients. The preliminary results suggest the need of a clinical trial to confirm a role of this combination to delay lapatinib resistance.
Abstract 381: Uptake of biguanides in mitochondria appears to be related to increased glucose uptake and medium acidification but not necessarily related to inhibition of growth of bladder and colon cancer cells
Authors: Michael A. Lea, Haneulsol Kim, Charles desBordes
Journal: Cancer Research (2018)

Abstract Biguanides including metformin have been used in the treatment of Type 2 diabetes and they are under investigation as anti-cancer agents. Investigation on the mechanism of action of biguanides has largely focused on inhibition of complex 1 in the mitochondrial electron transport chain with subsequent activation of AMP-dependent protein kinase. Studies by Bridges et al. (BMC Biology 14:65, 2016) indicate that inhibitory effects on complex 1 in cells require uptake of biguanides into the mitochondria. In the present work the action of two biguanides that enter the mitochondria (buformin and phenformin) were compared with the action of two biguanides with poor uptake (phenyl biguanide and proguanil). Effects on growth, glucose uptake and medium acidification were studied with two human colon cancer cells (Caco-2 and HT29) and seven bladder cancer cell lines (5637, HT1197, HT1376, RT4, T24, TCCSUP and UM-UC-3). After incubation for 72 hours with 25 µM and 50 µM concentrations of the biguanides, growth inhibition was greatest with proguanil followed by phenformin and with little or no growth inhibition at these concentrations with buformin and phenylbiguanide. In contrast, increased glucose uptake and acidification of the medium was observed with buformin and phenformin with no change or decreased medium acidification with phenyl biguanide and proguanil. Studies with buformin over a concentration range from 10 µM to 500 µM indicated that there was generally growth inhibition at concentrations greater than 50 µM. Studies on medium acidification and glucose uptake revealed biphasic responses with increases at lower concentrations that were reversed at higher concentrations of buformin where growth inhibition was observed. The data suggested that the effect of biguanides on glucose metabolism requires mitochondrial uptake while the mechanism for growth inhibition by biguanides remains to be established. Citation Format: Michael A. Lea, Haneulsol Kim, Charles desBordes. Uptake of biguanides in mitochondria appears to be related to increased glucose uptake and medium acidification but not necessarily related to inhibition of growth of bladder and colon cancer cells [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 381.
Efficacy and safety of inotuzumab ozogamicin (InO) in older patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) enrolled in the phase 3 INO-VATE trial.
Authors: Elias Jabbour, Anjali S. Advani, Matthias Stelljes, Wendy Stock, Michaela Liedtke, Nicola Gökbuget, Giovanni Martinelli, Susan Mary O'Brien, Kongming Wang, Tao Wang, M. Luisa Paccagnella, Barbara Sleight, Erik Vandendries, Daniel J. DeAngelo, Hagop M Kantarjian
Journal: Journal of Clinical Oncology (2016)

7029 Background: InO, an anti-CD22 antibody-calicheamicin conjugate, has demonstrated superior response vs standard care for R/R ALL in the phase 3 INO-VATE trial (complete remission [CR]/CR with incomplete hematologic recovery [CRi], 81% [95% CI; 72–88]; minimal residual disease [MRD] negativity in responders, 78% [68–87]; median remission duration [DoR], 4.6 [3.9–5.4] mo). Herein, the efficacy and safety of InO in patients (pts) aged ≥55 vs <55 y are assessed. Methods: Per protocol, the intent-to-treat analyses of CR/CRi included the first 218 of 326 pts randomized (ITT218). The safety population included 139 pts who received ≥1 InO dose (max 1.8 mg/m2/cycle [0.8 mg/m2 on d1; 0.5 mg/m2on d8 and 15 of a 21–28 d cycle for ≤6 cycles]). MRD negativity was assessed by central flow cytometry (<0.01%). Data as of October 2, 2014 are presented (trial ongoing). Results: 109 pts in the ITT218 received InO (median age, 47 [range, 18–78] y; pts ≥55 y, 43 [39%]). Remission rates and DoR were similar whereas MRD-negativity rates in responders were numerically higher in older pts (Table). In the safety population, grade (Gr) ≥3 adverse events (AEs) were most frequently cytopenias (neutropenia, 46%; thrombocytopenia, 37%; febrile neutropenia, 24%); these Gr ≥3 AEs were more common in pts ≥55 (n=53) vs <55 y (n=86): thrombocytopenia (49% vs 29%), neutropenia (53% vs 42%), febrile neutropenia (28% vs 21%). Pts ≥55 vs <55 y had similar discontinuation rates due to AEs (both 17%). For pts ≥55 vs <55 y, any grade hepatobiliary AE rates were similar (both 26%): hyperbilirubinemia (both 15%), and veno-occlusive liver disease (VOD) including post-SCT VOD (both 11%; 2 fatal in pts <55 y [1 after second SCT]). Conclusions: InO was highly effective in older pts with R/R ALL for whom treatment options are currently limited; responses and safety profiles were generally similar to younger pts and the overall study population. Clinical trial information: NCT01564784.% (95% CI)a <55 y (n=66) ≥55 y (n=43) CR/CRib 80 (69–89) 81 (67–92) CR 35 (24–48) 37 (23–53) CRi 45 (33–58) 44 (29–60) MRD-negativity in responders 74 (60–85) 86 (70–95) Median DoR, mo 4.6 (2.8–5.4)c 4.4 (3.6–5.9)d aITT218; bBest response in 1–6 cycles; cn=51; dn=34
Abstract 1670: Discovery of novel water-soluble derivatives of mebendazole as selective CLK1/4 kinase inhibitors and their anticancer cancer activity
Authors: Lijun Sun, Jae Eun Cheong, Michela Zaffagni, Kun Zhou, Bruce Zetter
Journal: Cancer Research (2018)

Abstract Metastatic cancers remain clinically challenging and account for more than 90% of all cancer deaths. Drugs used to treat advanced metastatic cancers often generate drug resistance and relapse. Therefore, there is a critical need for novel therapeutic approaches for patients with advanced stage cancers that do not respond to any currently available anticancer therapies. Mebendazole and structurally related benzimidazole analogues, which are FDA approved compounds used to treat helminthic infections in the gastrointestinal track, are effective in inhibiting in vitro cancer cell proliferation. Unfortunately, their therapeutic applications in metastatic cancer are limited by their extremely low solubility and poor bioavailability. Further, the mechanism of the anticancer activities of this class of compounds is poorly defined. Here, we report the design and synthesis of water-soluble benzimidazoles as novel anticancer agents. Among them, the novel oxetanyl substituted compound, OBD9 (Methyl (5-(4-(methyl(oxetan-3-yl)amino)benzoyl)-1H-benzo[d]imidazol-2-yl)carbamate), demonstrated potent cytotoxicity towards a variety of highly aggressive cancer lines including prostate, lung, and ovarian cancers (IC50: 0.9-3.8 μM). In the NCI60 cancer cell panel screen, OBD9 broadly inhibited the proliferation of leukemia, melanoma, and breast and colon cancers. The aqueous solubility of OBD9 achieved 361 μM vs &amp;lt;1μM for mebendazole. In a mouse xenograft model of the highly metastatic human prostate cancer PC3MLN4, OBD9 (30 mg/kg/day, three times/week for two weeks) significantly inhibited the growth of established tumors (treatment-to-control ratio: 0.36) without noticeable toxicity. We performed broad kinase screening (KINOMEscan, DiscoverX) to explore the mechanism of action and discovered OBD9 as a potent and highly selective inhibitor of Cdc-like kinase 1 and 4 (CLK1 and 4). The Selectivity Score of OBD9 at 10 μM concentration in the 403 non-mutant kinases is 0.002; and its IC50 is 1.5 and 1.2 μM for CLK1 and CLK4, respectively. CLKs are nuclear serine/threonine (S/T) kinases that regulate gene splicing and are frequently over activated in cancers. Our results suggest that OBD9 impedes cancer growth at least in part by inhibiting CLK1/4. Citation Format: Lijun Sun, Jae Eun Cheong, Michela Zaffagni, Kun Zhou, Bruce Zetter. Discovery of novel water-soluble derivatives of mebendazole as selective CLK1/4 kinase inhibitors and their anticancer cancer activity [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 1670.
Abstract 198: MUC13 promotes pancreatic tumor-stromal interactions by influencing tumor microenvironment
Authors: Sheema S. Khan, Kyle Doxtater, Sonam Kumari, Saini Setua, Mohammed Sikander, Shabnam Malik, Murali Yallapu, Stephen Behrman, Subhash Chauhan, Meena Jaggi
Journal: Cancer Research (2018)

Abstract Objective: Pancreatic cancer (PanCa) is the third leading cause of cancer-related deaths in the U.S. MUC13, mucin, is aberrantly expressed in PanCa and its overexpression leads to tumorigenic and metastatic behavior of cancer cells. Herein, we investigate the role of MUC13 in tumor microenvironment (TME) that favors PanCa progression/metastasis and drug resistance. Methods: MUC13 expressing (Panc-1) and knockdown PanCa cells (HPAF-II) and pancreatic stromal cells (PSCs), derived from freshly collected human pancreatic tissues, were utilized for the study. Using immunoblotting, ELISA, qPCR and RT-PCR techniques, we assessed the MUC13-induced alterations in the expression of important molecules that are involved in promotion of pancreatic tumor stromal interactions and drug resistance. Cytation 3 live cell imaging was performed for 3D tumor-stromal cell co-culture and invasion assays. Xenograft mice tumor tissues generated using ectopically expressing MUC13 and null cells were used for the study. Results: Our results demonstrate that MUC13 activates SHH signaling pathway in PanCa cells via upregulation of SHH and its related important downstream targets such as CXCR-4, Gli-1, SMO, PTCH1/2, NFκB and p-AKT in PanCa cells using immunoblotting and PCR. We also observed increased expression of SHH, Gli-1, CXCR-4 and α-SMA in MUC13-expressing xenograft tumors using Immunohistochemistry. Ectopic MUC13-expressing PanCa cells grown in co-culture with PSCs showed enhanced secretion of IL-6 and CXCL-12 (ELISA), increase in invasion (Matrigel invasion assay) and migratory (Boyden chamber assay) potential of both the cultured PanCa as well as stromal cells. Additionally, ectopically MUC13-expressing cells were resistant to treatment with gemcitabine as depicted by proliferation assay and qPCR results showed enhanced expression of ribonucleoside-diphosphate reductase (RRM1/2) and miR-21, which are known to be involved in gemcitabine resistance. Overall, our results suggest that MUC13 modulates tumor-stromal crosstalk, promoting tumor growth, invasion and drug resistance in TME. Conclusion: Our results suggest that MUC13 expression might influence signaling supportive of interactive TME, leading to increased tumor growth and drug resistance. These findings illustrate mechanisms by which MUC13 promotes tumorigenic TME and contributes to PanCa cell survival, metastasis and drug resistance. Citation Format: Sheema S. Khan, Kyle Doxtater, Sonam Kumari, Saini Setua, Mohammed Sikander, Shabnam Malik, Murali Yallapu, Stephen Behrman, Subhash Chauhan, Meena Jaggi. MUC13 promotes pancreatic tumor-stromal interactions by influencing tumor microenvironment [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 198.
Angiotensin Skin Tests
Authors: Benjaminjablons
Journal: Circulation (1962)

The studies reported above indicate that the angiotensin skin test (A.S.T.) is a simple practical measure which has proved of value in differentiating between normotensive and hypertensive individuals. The duration of the blanching of skin by the test differs significantly in normotensives as compared with hypertensives. The test has served as an index [see figure in the PDF file] of differentiation between an emotionally induced elevation of blood pressure and one which may go on to an established hypertensive state. The A.S.T. is a more reliable test in the diagnosis of the latent, labile, or prehypertensive state than is the cold pressor test. Angiotensin-induced hypertension induces a prolongation of the A.S.T. as compared with control periods.
Abstract 459: Therapy-induced senescence is reversible in vitro and in vivo
Authors: Tareq Saleh, Moureq R. Alotaibi, Sarah L. Kyte, Emmanuel K. Cudjoe, Ajinkya Kawale, Jingwen Xu, Zeinab Elsayed, Joseph W. Landry, Scott C. Henderson, Vasily Yakovlev, Lynne W. Elmore, David A. Gewirtz
Journal: Cancer Research (2018)

Abstract While cellular senescence has long been recognized as an irreversible form of growth arrest, evidence in the literature has suggested that subpopulations of senescent tumor cells may retain proliferative capacity. To directly address this question, H460 non-small cell lung cancer cells induced into senescence by exposure to etoposide, and enriched based on β-galactosidase staining and size, were shown to recover reproductive capacity, which was accompanied by resolution of the DNA-damage-response (downregulation of p53 and p21Waf1/Cip1 induction), attenuation of the senescence-associated secretory phenotype (SASP) as well as downregulation of miRNA34 expression and an increase in c-myc. The senescence-enriched lung cancer cells were also capable of tumor growth upon transplantation into immunodeficient mice. Re-emergence from etoposide-induced senescence was also observed using HCT116 colon cancer cells, as evidenced by concomitant downregulation of a senescence-associated reporter (BTG1-RFP). Collectively, these findings indicate that therapy-induced senescence (TIS) may ultimately be a transient process in that at least a subpopulation of tumor cells can resume proliferation. We propose that some forms of tumor dormancy that lead to disease recurrence may reflect cells that enter into and ultimately escape from senescence. Citation Format: Tareq Saleh, Moureq R. Alotaibi, Sarah L. Kyte, Emmanuel K. Cudjoe, Ajinkya Kawale, Jingwen Xu, Zeinab Elsayed, Joseph W. Landry, Scott C. Henderson, Vasily Yakovlev, Lynne W. Elmore, David A. Gewirtz. Therapy-induced senescence is reversible in vitro and in vivo [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 459.
Endothelin-1 Inhibits the Slow Component of Cardiac Delayed Rectifier K+ Currents via a Pertussis Toxin–Sensitive Mechanism
Authors: TakashiWashizuka, MinoruHorie, MasatoWatanuki, ShigetakeSasayama
Journal: Circulation Research (1997)

Abstract Endothelin-1 (ET-1) is a 21–amino acid peptide hormone released from myocardial and endothelial cells, whose receptors (both ETA and ETB) are expressed in the myocardium. We report here that ET-1 inhibits the cardiac delayed rectifier K+ current (IK) via a pertussis toxin (PTX)–sensitive mechanism. Ventricular myocytes enzymatically isolated from guinea pig hearts were voltage-clamped by the conventional whole-cell and nystatin–perforated patch technique (intrapipette and extrapipette K+ concentrations, 150 and 5.4 mmol/L, respectively) in the presence of nifedipine (2 μmol/L). Amplitudes of tail and steady state (2-second pulse) currents were measured as IK. ET-1 suppressed the basal IK by 20.9±2.3% in a concentration-dependent manner, with an IC50 of 1.1±0.3 nmol/L (n=19), although it did not suppress the basal IK using the nystatin method. E-4031 (5 μmol/L), a blocker of the rapid component of IK (IKr), did not prevent the inhibitory action of ET-1. ET-1 reduced by 63.4±6.5% the slow component...
Abstract 17602: Impaired Global Load-independent Left Ventricular Contractility Index Across Different Severity Of Aortic Stenosis With Preserved Left Ventricle Ejection Fraction
Authors: Hui W Sim, Elaine Z Boey, Benjamin Q Tan, Nicholas J Ngiam, Weiqin Lin, William K Kong, Liang Zhong, Ru S Tan, Kian K Poh
Journal: Circulation (2016)

Introduction: Management of aortic stenosis (AS) requires a comprehensive assessment of the intrinsic cardiac contractility. Measurement of left ventricle ejection fraction (LVEF) can be misleading...