tbuckley/cabot-search huggingface dataset:
Abstract 51: Role of hematopoietic cell kinase (HCK) in breast cancer dormancy
Authors: Sachin Khiste, Elliot Eton, Kevin Hodgetts, Hrvoje Lusic, Kodaganur Gopinath, S Krishnamurthy, Shiladitya Sengupta, Aaron Goldman
Journal: Cancer Research (2018)

Abstract Background: Triple negative breast cancer (TNBC) is an aggressive basal-like malignancy, which recurs more frequently than any other subtype of breast cancer. We recently discovered that TNBC can overcome drug pressure by switching to a hybrid basal-like (CD44Hi) and epithelial-like (CD24Hi) cell state, which is accompanied by a transient period of quiescence, or dormancy. These dormant, ‘hybrid' cells highly express the phosphorylated SRC family kinase, hematopoietic cell kinase (HCK). Methods: Here, we used a panel of novel HCK inhibitors to study the effect of signaling-disruption in drug tolerance and tumor cell dormancy. Using flow cytometry and immunofluorescent microscopy we examined how HCK inhibition perturbs common features associated with dormancy such as proliferation and cell cycle status, intracellular levels of reactive oxygen species, and state of glucose metabolism. Finally, we validated the results using an ex-vivo human tumor model that predicts clinical response and recreates the native tumor microenvirnoment, CANscriptTM. Results: We determined that targeted inhibition of HCK down-regulates the features of tumor cell dormancy and drug tolerance, eliminating cells with a hybrid mesenchymal-epithelial phenotype, diminishing polyploidy and hyper-G2 endoreduplication, and suppressing features of a dysregulated glycolytic state. Conclusion: Expression of HCK drives cancer cells to a quiescent cancer cells subpopulation, resulting in tolerance to chemotherapy. Targeted disruption of HCK overcomes these features of dormancy. HCK inhibitors could emerge as a novel treatment for chemotherapy-induced breast cancer dormancy. Citation Format: Sachin Khiste, Elliot Eton, Kevin Hodgetts, Hrvoje Lusic, Kodaganur Gopinath, S Krishnamurthy, Shiladitya Sengupta, Aaron Goldman. Role of hematopoietic cell kinase (HCK) in breast cancer dormancy [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 51.
Age and Treatment of Nonmelanoma Skin Cancer
Authors: Erica H. Lee, Anthony M. Rossi, Kishwer S. Nehal
Journal: JAMA Surgery (2018)

To the Editor The research letter by Chauhan et al1 highlights an important dilemma in managing nonmelanoma skin cancer (NMSC) in the elderly population. This study looked at the Veterans Affairs population presenting with a facial NMSC treated with excision and the effect of age.
Coinheritance of biallelic <i>SLURP1</i> and <i>SLC39A4</i> mutations cause a severe genodermatosis with skin peeling and hair loss all over the body
Authors: F.L. Harms, S. Nampoothiri, F. Kortüm, J. Thomas, V.V. Panicker, M. Alawi, J. Altmüller, D. Yesodharan, K. Kutsche
Journal: British Journal of Dermatology (2018)
Abstract 3964: Mesothelin targeting immunotoxin LMB-100 alters the profile of tumor-secreted proteins
Authors: Salma El-Behaedi, Rebekah Landsman, Michael Rudloff, Emily Kolyvas, Rakan AlBalawy, Christine Alewine
Journal: Cancer Research (2018)

Abstract Recombinant immunotoxins are antibody-based therapies that carry a bacterial toxin payload. LMB-100 is a next generation immunotoxin currently being tested in clinical trial. It targets the human cell surface antigen mesothelin (MSLN). MSLN is made by many solid tumors but has no expression in the parenchyma of vital organs. LMB-100 carries a Pseudomonas exotoxin payload that works by irreversibly modifying elongation factor-2 (EF-2), inactivating it and halting protein synthesis. To determine whether non-lethal doses of LMB-100 might inhibit tumor cell secretion of cytokines and growth factors that maintain the pancreatic cancer microenvironment, human pancreatic cancer cells were treated with LMB-100 and conditioned medium was assayed for tumor-secreted factors by ELISA and Luminex assays. Decreased levels of multiple secreted factors were detected including VEGF, PDGF, MMP-1, SPARC, and OPN. Conversely, levels of MIF, a stored cytokine released under stress conditions, increased dramatically upon LMB-100 treatment. To determine whether this also occurs in vivo, tumor-bearing athymic nude mice were treated with LMB-100 and levels of tumor-secreted factors in intratumoral fluid were measured. A statistically significant decrease in the same factors was found in treated mice compared to control mice. To determine whether these decreases in tumor-secreted factors could change the tumor microenvironment and alter the immune milieu, a mouse syngeneic model of pancreas cancer sensitive to LMB-100 was developed. LMB-100 treatment of this mouse cell model caused a statistically significant decrease in the angiogenesis factors VEGF and Angiopoietin-2 in conditioned medium. To determine if this also occurs in vivo, immune-competent mice bearing intraperitoneal or orthotopic tumors were treated with immunotoxin or vehicle then intratumoral fluid was assayed for secreted proteins contributed by both tumor and stromal cells. No detectable change in intratumoral fluid concentration was seen for VEGF, Antiopoietin-2 or a panel of 11 other secreted factors. In conclusion, LMB-100 does inhibit tumor cell production of secreted proteins, but this change is insufficient to alter the total concentration of secreted factors in the tumor microenvironment. Citation Format: Salma El-Behaedi, Rebekah Landsman, Michael Rudloff, Emily Kolyvas, Rakan AlBalawy, Christine Alewine. Mesothelin targeting immunotoxin LMB-100 alters the profile of tumor-secreted proteins [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 3964.
Synaptic N6-methyladenosine (m6A) epitranscriptome reveals functional partitioning of localized transcripts
Authors: Daria Merkurjev, Wan-Ting Hong, Kei Iida, Ikumi Oomoto, Belinda J. Goldie, Hitoshi Yamaguti, Takayuki Ohara, Shin-ya Kawaguchi, Tomoo Hirano, Kelsey C. Martin, Matteo Pellegrini, Dan Ohtan Wang
Journal: Nature Neuroscience (2018)
Abstract 12095: Altered Brain Functional Connectivity During Valsalva Maneuver in Heart Failure
Authors: Mary A Woo, Bumhee Park, Gregg C Fonarow, Rajesh Kumar
Journal: Circulation (2015)

Introduction: Heart failure (HF) patients have abnormal autonomic (ANS) activity, which is linked to damage in specific gray matter brain regions (such as the insulae). Abnormal ANS activity in HF may be due to changes in both structural injury and functional connectivity (FC; temporal correlations between neural structures which indicate connection status and sequence of activation). While insular/brain structural injury has been reported in HF, FC has not been explored. Hypothesis: FC between brain regions during an autonomic challenge will be less in HF in comparison to controls. Methods: We collected functional MRI data with Valsalva maneuver block design task in 12 HF (age 55.6±8.1 years; Females 3; BMI 25.2±3.8 kg/m2; LVEF, 26.7±11.5%) and 33 controls (51.6±5.5 years; Females 13; BMI 25.7±3.2 kg/m2), using a 3.0 Tesla MRI scanner. Group independent component analysis was applied to identify individual task-related FC maps, which were compared between HF and controls (ANCOVA; covariates, age and gender; P&lt;0.005) Results: No significant differences in age, gender, or BMI emerged between the two groups (P&gt;0.05). Decreased FC in HF (Figure 1; p&lt;0.005) were found in the left supramarginal gyrus/inferior parietal lobule, left middle temporal gyrus, bilateral thalamus, left fusiform gyrus, left ligual gyrus, right precuneus, left hippocampus, and left insula. However, increased FC in HF compared to controls were found in the left inferior frontal gyrus, right superior temporal gyrus, left cerebellar cortex, and right insula (P&lt;0.005). Conclusions: These findings suggest that autonomic, cognitive, and affective deficits in HF may be related to altered FC. The outcomes likely result from the prominent structural changes in both axons and nuclear structures reported earlier in HF. Future interventions may need to address structural and functional deficits in both gray and white matter regions in HF.
Impact of DAAs on liver transplantation: Major effects on the evolution of indications and results. An ELITA study based on the ELTR registry
Authors: Luca Saverio Belli, Giovanni Perricone, Rene Adam, Paolo A. Cortesi, Mario Strazzabosco, Rita Facchetti, Vincent Karam, Mauro Salizzoni, Rafael Lopez Andujar, Costantino Fondevila, Paolo De Simone, Cristina Morelli, Joan Fabregat-Prous, Didier Samuel, Kosh Agarwaal, Enrique Moreno Gonzales, Ramon Charco, Krzysztof Zieniewicz, Luciano De Carlis, Christophe Duvoux
Journal: Journal of Hepatology (2018)
Abstract CT159: Olaparib combinations (OLAPCO)for homology-directed DNA repairdefects (HDR)
Authors: Joseph P. Eder, Geoffrey I. Shapiro, James M. Cleary, Vickie L. Keedy, Vickie L. Keedy, Ranjit Bindra, Brian Shuch, Jeffrey Sklar, Khanh Do, Juliane Juergensmeier
Journal: Cancer Research (2018)

Abstract INTRODUCTION: Genetic profiling of tumors used to identify treatment choices for cancer patients focus on kinase mutations and well-defined translocations; multiple clinical trials have been initiated for specific kinase-targeted agents. About 15-20% of patients have actionable mutations. HDR have been found in ~ 20 % of patient tumors molecularly profiled at the Yale Cancer Center. Mutations in HDR related genes often occur in addition to other mutations in signaling pathways. Specific targeted treatment options for these patients are limited, as breast and ovarian cancer mutations are the only indication for the HDR pathway targeted PARP inhibitors. Additional drugs are in development, but few clinical studies based on HDR other than BRCA1/2 mutations are open. METHODS: The OLAPCO study targets HDR in patients irrespective of tumor origin. The protocol includes four arms to which patients can be enrolled based on tumor profiling results: olaparib monotherapy (PARP inhibitor) for HDR; olaparib &amp; AZD5363 ( AKT inhibitor) for PIK3CA/AKT/PTEN pathway dysregulation and ARID1A mutations; olaparib &amp; AZD1775 ( wee1 inhibitor) for TP53 mutations and olaparib &amp; AZD6738 (ATR inhibitor) for HDR and olaparib pre-treated patients. The clinical endpoints are to determine tumor overall response rate (ORR) and clinical benefit rate (CBR) by RECIST after 16 weeks of treatment. RESULTS: Arms a and b are open to patient accrual. Together, 34 pts have been treated, 12 remain on treatment, with no new or &amp;gt; Gr 2 (CTCAE4) treatment-related toxicities. TABLE 1Olaparib total = 23; median # cycles= 2, range 1-10+ ; 7 ongoingMutationATMBRCA1IDH1/2FHPALB2CHK2BAP1ARID 1A#52821212ORR1 PRCBR10201000TABLE 2Olaparib &amp; AZD 5363 total = 12; median # cycles = 2, range 1-8+; 5 ongoingMutationAKT1AKT3AKT2 &amp; PALB2ARID 1AARID 1A &amp; PIK3CAPTEN#321411ORR1CBR10101 DISCUSSION: HDR defects are actionable mutations, increasing the number of patients for whom tumor profiling can identify a therapeutic option. This exploratory trial is expanding the therapeutic spectrum of olaparib alone and in combination, to include heretofore non-canonical alterations in HDR, beyond BRCA1/2. This trial design allows additional molecular targets, agents &amp; combinations to be rapidly evaluated. AstraZeneca support is gratefully acknowledged. Citation Format: Joseph P. Eder, Geoffrey I. Shapiro, James M. Cleary, Vickie L. Keedy, Vickie L. Keedy, Ranjit Bindra, Brian Shuch, Jeffrey Sklar, Khanh Do, Juliane Juergensmeier. Olaparib combinations (OLAPCO)for homology-directed DNA repairdefects (HDR) [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 CT159.
Abstract 5922: "Gammora": Selective killing of cancer cells bearing CD24 by viral integrase
Authors: Shiran Shapira, Eynat Finkelshtein, Abraham Loyter, Nadir Arber
Journal: Cancer Research (2018)

Abstract The HIV integrase is important in the integration of viral DNA to the host genome resulting in double-stranded breaks (DSB). Only 1-2 copies are integrated, due to inhibition of HIV-1 Rev protein, making the cells invisible to the immune system. CD24 is mostly expressed on cancer and not normal cells. We hypothesize that specific targeting of the viral particles using mAb to CD24 together with stimulating the enzyme activity and increasing the frequency of integration events, would increase the occurrence of DSB, that will lead to genomic instability, and ultimately to apoptosis of the target cells. Aim To develop a therapeutic platform, for selective eradication of cancer cells, which consists of targeted lentivirus particles and IN-derived peptides. Methods Integrase derived peptides (designated as INR2 and INS) were synthesized. Humanized anti-CD24 antibody (scFv) was engineered and fused to the lentivirus envelope. Stability, solubility and toxicity of the peptides were analyzed by HPLC-MS and MTD, respectively, as well as their activity and permeability into cells. Cell death was measured qualitatively by fluorescent microscopy and quantified by the enzymatic MTT assay. Colorectal, pancreatic and lung cancer cells were used for testing the potency of the lentiviral-based system. The efficacy of the suggested system was assessed in vivo, in nude mice bearing xenografts of lung cancer. The mice were treated systemically twice weekly. Results INS and INR2 stimulate viral integrase in vitro. A single IV administration of INR2 and INS was well tolerated without adverse effects. These lentivirus particles contain nonfunctional DNA with flanked LTRs allowing their integration into the target cells DNA and formation of DSB due to the action of the integrase whose activity was stimulated by the IN-derived peptides. Massive cell death (40-70%) in a dose- dependent manner was achieved. Raltegravir, an antiretroviral FDA-approved drug, was able to inhibit cell death (2-3 times). In vivo, the INR2 and INS combination led to a significant reduction (50%) in tumor volume. Live imaging (IVIS device) of the tumors and selected organs confirmed that the viruses indeed reach the tumor after systemic injection and that the anti-CD24 enhanced the selectivity of infection. Conclusions The use of IN-derived peptides together with the CD24-targeted lenti-therapy approach suggests a novel strategy that specifically promotes killing and removal of a wide range of cancer cells. Citation Format: Shiran Shapira, Eynat Finkelshtein, Abraham Loyter, Nadir Arber. "Gammora": Selective killing of cancer cells bearing CD24 by viral integrase [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 5922.
Cardiovascular Risk and Statin Eligibility of Young Adults After an MI
Authors: Avinainder Singh, Bradley L. Collins, Ankur Gupta, Amber Fatima, Arman Qamar, David Biery, Julio Baez, Mary Cawley, Josh Klein, Jon Hainer, Jorge Plutzky, Christopher P. Cannon, Khurram Nasir, Marcelo F. Di Carli, Deepak L. Bhatt, Ron Blankstein
Journal: Journal of the American College of Cardiology (2017)
LRPAP1 is a frequent proliferation-inducing antigen of BCRs of mantle cell lymphomas and can be used for specific therapeutic targeting
Authors: Lorenz Thurner, Sylvia Hartmann, Natalie Fadle, Maria Kemele, Theresa Bock, Moritz Bewarder, Evi Regitz, Frank Neumann, Anna Nimmesgern, Lutz von Müller, Christiane Pott, Yoo-Jin Kim, Rainer Maria Bohle, Mariusz Wasik, Stephen J. Schuster, Martin-Leo Hansmann, Klaus-Dieter Preuss, Michael Pfreundschuh
Journal: Leukemia (2018)
Systematic approach demonstrates enrichment of multiple interactions between non-<i>HLA</i> risk variants and <i>HLA-DRB1</i> risk alleles in rheumatoid arthritis
Authors: Lina-Marcela Diaz-Gallo, Daniel Ramsköld, Klementy Shchetynsky, Lasse Folkersen, Karine Chemin, Boel Brynedal, Steffen Uebe, Yukinori Okada, Lars Alfredsson, Lars Klareskog, Leonid Padyukov
Journal: Annals of the Rheumatic Diseases (2018)

Objective In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of HLA-DRB1 alleles, called shared epitope (SE) alleles, is a highly influential genetic risk factor. Here, we investigated whether non- HLA single nucleotide polymorphisms (SNP), conferring low disease risk on their own, interact with SE alleles more frequently than expected by chance and if such genetic interactions influence the HLA-DRB1 SE effect concerning risk to ACPA-positive RA. Methods We computed the attributable proportion (AP) due to additive interaction at genome-wide level for two independent ACPA-positive RA cohorts: the Swedish epidemiological investigation of rheumatoid arthritis (EIRA) and the North American rheumatoid arthritis consortium (NARAC). Then, we tested for differences in the AP p value distributions observed for two groups of SNPs, non-associated and associated with disease. We also evaluated whether the SNPs in interaction with HLA-DRB1 were cis-eQTLs in the SE alleles context in peripheral blood mononuclear cells from patients with ACPA-positive RA (SE-eQTLs). Results We found a strong enrichment of significant interactions (AP p&lt;0.05) between the HLA-DRB1 SE alleles and the group of SNPs associated with ACPA-positive RA in both cohorts (Kolmogorov-Smirnov test D=0.35 for EIRA and D=0.25 for NARAC, p&lt;2.2e-16 for both). Interestingly, 564 out of 1492 SNPs in consistent interaction for both cohorts were significant SE-eQTLs. Finally, we observed that the effect size of HLA-DRB1 SE alleles for disease decreases from 5.2 to 2.5 after removal of the risk alleles of the two top interacting SNPs (rs2476601 and rs10739581). Conclusion Our data demonstrate that there are massive genetic interactions between the HLA-DRB1 SE alleles and non- HLA genetic variants in ACPA-positive RA.
Efficacy of metformin in combination with immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) in metastatic malignant melanoma
Authors: Muhammad Zubair Afzal, Rima R. Mercado, Keisuke Shirai
Journal: Journal for ImmunoTherapy of Cancer (2018)

Metformin is one of the biguanides commonly used in patients with type II Diabetes Mellitus. Apart from its hypoglycemic properties, metformin also inhibits the cell cycle by restricting protein synthesis and cell proliferation via regulating the LKB1/AMPL pathway. Furthermore, it also enhances the PD-1 blockade through a reduction of tumor hypoxia. Metformin has shown a significant favorable impact on treatment-related outcomes in solid tumors, but these outcomes have not been replicated in the limited clinical studies done on malignant melanoma. Moreover, none of these studies have reported on the efficacy of the combined use of metformin and immune checkpoint inhibitors (ICIs).This is a retrospective cohort study that includes patients diagnosed with metastatic malignant melanoma and treated with ipilimumab, nivolumab, and/or pembrolizumab (Cohort A); or ipilimumab, nivolumab, and/or pembrolizumab plus metformin (Cohort B) between January 1st 2011 through December 15th 2017. In this study, patients are stratified based on anti-PD-1 only and anti-CTLA4/anti-PD-1 combination therapies in each cohort. Objective response rate (ORR) is the primary endpoint. Disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) are the secondary endpoints.Cohort A had 33 patients (60%), while cohort B had 22 (40%). Overall patient characteristics were similar between both cohorts. ORR was higher in cohort B (68.2% vs. 54.5%, P = 0.31). The DCR was higher in cohort B as well (77.3% vs. 60.6%, P = 0.19). Median OS (46.7 months vs. 28 months), and median PFS (19.8 months vs. 5 months) were longer in cohort B. However, on univariate and multivariate analyses, none of these differences were statistically significant. The mean number of new metastatic sites which appeared during therapy were significantly higher in cohort A (A:1.51 vs. B:0.59, P = 0.009).We have observed favorable treatment-related outcomes (ORR, DCR, median PFS and median OS) in patients who have received metformin in combination with ICIs without reaching significance, probably, due to small sample size. Hence, large prospective clinical trials are required to study the synergistic effect of metformin in combination with ICIs before it can be recommended as routine additive therapy.
Lower DHEA-S levels predict disease and worse outcomes in post-menopausal women with idiopathic, connective tissue disease- and congenital heart disease-associated pulmonary arterial hypertension
Authors: Grayson L. Baird, Christine Archer-Chicko, R. Graham Barr, David A. Bluemke, Andrew E. Foderaro, Jason S. Fritz, Nicholas S. Hill, Steven M. Kawut, James R. Klinger, Joao A.C. Lima, Christopher J. Mullin, Pamela Ouyang, Harold I. Palevsky, Amy J. Palmisicano, Diane Pinder, Ioana R. Preston, Kari E. Roberts, K. Akaya Smith, Thomas Walsh, Mary Whittenhall, Corey E. Ventetuolo
Journal: European Respiratory Journal (2018)

High oestradiol (E2) and low dehydroepiandrosterone-sulfate (DHEA-S) levels are risk factors for pulmonary arterial hypertension (PAH) in men, but whether sex hormones are related to PAH in women is unknown. Post-menopausal women aged ≥55 years with PAH were matched by age and body mass index to women without cardiovascular disease. Plasma sex hormone levels were measured by immunoassay. Lower levels of DHEA-S (p&lt;0.001) and higher levels of E2 (p=0.02) were associated with PAH. In PAH cases (n=112), lower DHEA-S levels were associated with worse haemodynamics (all p&lt;0.01) and more right ventricular dilatation and dysfunction (both p=0.001). Lower DHEA-S levels were associated with shorter 6-min walking distance (6MWD) (p=0.01) and worse functional class (p=0.004). Each Ln(1 µg·dL −1 ) decrease in DHEA-S was associated with a doubling in the risk of death (hazard ratio 2.0, 95% CI 1.5–2.7; p&lt;0.001). Higher levels of E2 were associated with shorter 6MWD (p=0.03) and worse functional class (p=0.01). High E2 and low DHEA-S levels are associated with the risk and severity of PAH in post-menopausal women. Hormonal modulation should be studied as a treatment strategy in PAH.
Dnmt1 links BCR-ABLp210 to epigenetic tumor stem cell priming in myeloid leukemia
Authors: Carolina Vicente-Dueñas, Inés González-Herrero, Lalit Sehgal, Idoia García-Ramírez, Guillermo Rodríguez-Hernández, Belén Pintado, Oscar Blanco, Francisco Javier García Criado, María Begoña García Cenador, Michael R. Green, Isidro Sánchez-García
Journal: Leukemia (2018)

Research in CVD group is partially supported by FEDER, “Miguel Servet” Grant (CP14/00082 - AES 2013-2016) from the Instituto de Salud Carlos III (Ministerio de Economia y Competitividad), “Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III” (PI17/00167), and by the Lady Tata International Award for Research in Leukaemia 2016–2017. Research in ISG group is partially supported by FEDER and by MINECO (SAF2012-32810, SAF2015-64420-R and Red de Excelencia Consolider OncoBIO SAF2014-57791- REDC), Instituto de Salud Carlos III (PIE14/00066), ISCIII- Plan de Ayudas IBSAL 2015 Proyectos Integrados (IBY15/00003), by Junta de Castilla y Leon (BIO/SA51/15, CSI001U14, UIC-017, and CSI001U16), and by the German Carreras Foundation (DJCLS R13/26). ISG lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. IGR was supported by BES-Ministerio de Economia y Competitividad (BES2013-063789). GRH was supported by FSE-Conserjeria de Educacion de la Junta de Castilla y Leon (CSI001-15).