tbuckley/cabot-search huggingface dataset:
Abstract 2164: In-licensing and knockout validation of monoclonal hybridomas to improve antibody reproducibility
Authors: Sam Heaton, Sofia Koch, Jiangyan Ge, Joshua Rizzo, Michael Prater, Hanna Dreja, Bruce Hamilton, Alejandra Solache
Journal: Cancer Research (2019)

Abstract Antibodies are the most common tools in basic science and clinical research. Over the past several years there has been an ongoing discussion around antibody validation in light of poor experimental reproducibility between laboratories. This is in part due to the cross-reactivity between antibodies and off-target proteins and the variability between different antibody batches. The resulting experimental irreproducibility leads to wasted resources and compromises the advancement of science. Abcam partners with various research institutes and biotech companies to in-license hybridoma cell lines producing monoclonal antibodies. Through this in-licensing program, Abcam has taken steps to help ensure target-specificity of valuable clones. Our in-licensing program utilizes our ISO9001-accredited production method to ensure each batch performs in-line with previous batches. Where possible, all in-licensed antibodies are also tested in knockout (KO) material to confirm the specificity of the in-licensed clone and subsequent batches. Through our partnership with Horizon Discovery to test antibodies with KO cells, target genes are mutated via CRISPR-Cas9 within a haploid cell line, which results in a frameshift and a complete loss of gene expression. KO cell lines provide a true negative control for antibody validation that allows us to confirm the specificity of clones we in-license and produce. Alongside KO, we are making use of our expertise in recombinant antibodies to explore the conversion of selected in-licensed hybridomas to recombinant antibodies. A key issue with monoclonals is degradation of the clone over time, leading to inconsistent batches and irreproducible results. By sequencing and cloning the antibody, we expect to guarantee continued specificity and reproducibility; therefore, ensuring our licensors see long term impact and value generation for their innovations. Here we present KO data for several in-licensed published clones, validated in both western blot and immunocytochemistry. The antibodies have been tested in KO and wild-type cells to confirm their specificity. By providing researchers with reliable and specific antibodies that work as intended, we hope to minimize wasted resources and improve reproducibility. In addition to our KO data, we present data from the recombinant conversion of clone NAT105 to PD1 and show comparable, if not superior, performance when compared with the hybridoma. Citation Format: Sam Heaton, Sofia Koch, Jiangyan Ge, Joshua Rizzo, Michael Prater, Hanna Dreja, Bruce Hamilton, Alejandra Solache. In-licensing and knockout validation of monoclonal hybridomas to improve antibody reproducibility [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 2164.
Abstract P082: Racial Disparities in Stroke Recovery: A Large Study Versus Meta-Analysis
Authors: Pratik Y Chhatbar, Hernan Bayona, Yujing Zhao, Bruce Ovbiagele, Wuwei Feng, Robert J Adams, Daniel T Lackland
Journal: Circulation (2017)

Background: It is well known that Blacks have a higher stroke-related mortality compared to their White counterparts, but evidence on the influence of Black race on recovery after a stroke is not apparent. Objective: To verify our understanding on post-stroke rehabilitation trends between Blacks and Whites with the use of systematic review and meta-analysis. Methods: We performed literature search for cohort studies that investigated racial variation issues in stroke motor recovery between January 1970 and March 2016, in which outcome was measured by Functional Independence Measures (FIM) scale. We compared change scores (the difference score between discharge and admission) or endpoint scores (at the time of admission and discharge) as well as length of stay in days between Whites and Blacks by calculating standardized mean differences (Hedge’s g ) to derive a summary effect size. Random Effects model was used to account for data heterogeneity. Results: We identified 7 studies with a total 152,421 subjects, of which one influential study (Ottenbacher et al, 2008) offered a significant weight with 148,871 subjects. So, we performed meta-analysis on the remaining 6 studies (black diamond on the Figure ) and compared the results with this influential study (maroon square on the Figure ). We found that Blacks have higher FIM scores at admission and discharge, but poor change FIM scores, despite their shorter stay (about ¾ day) in rehab facility when compared to Whites. Our results contrasted findings of Ottenbacher et al. , which did not report change scores, that Whites have higher FIM scores at admission and discharge in spite of their comparable rehab facility stay. Conclusions: This meta-analysis identifies a significant evidence gap for current understanding of racial disparities in stroke recovery. At AHA SFRN WISSDOM (Wide spectrum Investigation of Stroke Outcome Disparities on Multiple Levels) center, we aim to address this gap by first-hand analyses of multiple datasets in the near future.
Severe Lipodystrophy Following Prolonged Subcutaneous Administration of Antisense Oligonucleotides
Authors: Anh Ly Nguyen, Marie-Anne Morren, Remco van Doorn
Journal: JAMA Dermatology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Abstract 950: In vivo efficacy and pharmacodynamic modulation of JNJ-64619178, a selective PRMT5 inhibitor, in human lung and hematologic preclinical models
Authors: Hillary J. Millar, Dirk Brehmer, Tinne Verhulst, Nahor Haddish-Berhane, Tony Greway, Dana Gaffney, An Boeckx, Erika Van Heerde, Thomas Nys, Joseph Portale, Ulrike Philippar, Tongfei Wu, Sylvie Laquerre, Kathryn Packman
Journal: Cancer Research (2019)

Abstract Protein arginine methyltransferase 5 (PRMT5), a type II methyltransferase, is responsible for symmetric arginine di-methylation of multiple cellular proteins involved in the regulation of cellular transcription. PRMT5 is involved in cellular processes such as survival, proliferation, and apoptosis, and an elevated tumor PRMT5 protein level has recently been correlated with poor survival of cancer patients. JNJ-64619178, a selective PRMT5 inhibitor, showed inhibition of cellular growth in several cell lines representing multiple cancer histologies in vitro. From this, a broad selection of xenograft models was chosen to demonstrate potent anti-tumor efficacy. Xenograft models representing small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML), and non-Hodgkin lymphoma were chosen to demonstrate anti-tumor efficacy. Biologically significant tumor growth inhibition up to 99% was observed in both solid and hematological xenograft models, including an aggressive disseminated model of AML, with oral doses of 1 to 10 mg/kg, once daily. Importantly, continued inhibition of tumor growth was observed for several weeks following dosing cessation. Dosing of JNJ-64619178 results in inhibition of Sym-Arg di-methylation of SMD1/3 proteins, core components of the spliceosome in the tumor, and general Sym-Arg di-methylation of serum proteins. These serve as pharmacodynamic markers of PRMT5 inhibition in xenograft models. Potent and prolonged inhibition of SMD1/3 di-methylation was observed in the SCLC model, during and after the dosing period. This has led to the exploration of alternative dosing regimens preclinically. PRMT5 inhibitor JNJ-64619178 is currently being investigated in a Phase I clinical trial, based on its high selectivity and potency, favorable pharmacokinetics and safety properties, and strong preclinical efficacy and pharmacodynamic data. Citation Format: Hillary J. Millar, Dirk Brehmer, Tinne Verhulst, Nahor Haddish-Berhane, Tony Greway, Dana Gaffney, An Boeckx, Erika Van Heerde, Thomas Nys, Joseph Portale, Ulrike Philippar, Tongfei Wu, Sylvie Laquerre, Kathryn Packman. In vivo efficacy and pharmacodynamic modulation of JNJ-64619178, a selective PRMT5 inhibitor, in human lung and hematologic preclinical models [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 950.
First clinical (phase 1b/2a) study of iberdomide (CC-220; IBER), a CELMoD, in combination with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).
Authors: Sagar Lonial, Niels W.C.J. van de Donk, Rakesh Popat, Jeffrey A. Zonder, Monique C. Minnema, Jeremy Larsen, Tuong Vi Nguyen, Min S. Chen, Amine Bensmaine, Mariana Cota, Pieter Sonneveld
Journal: Journal of Clinical Oncology (2019)

8006 Background: IBER is a novel cereblon E3 ligase modulator (CELMoD) with enhanced tumoricidal and immunostimulatory activities. Preclinically, IBER overcomes immunomodulatory drug (IMiD) resistance and has synergy with daratumumab (DARA), bortezomib (BORT), and DEX. Methods: A phase 1b/2a multicenter, open-label, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and preliminary efficacy of IBER. Eligible pts had RRMM and must have received ≥ 2 prior regimens including lenalidomide (LEN) and/or pomalidomide (POM), and a proteasome inhibitor (PI). All pts had progressed on or within 60 days of last MM therapy. Escalating doses of IBER were given on days 1–21, in combination with DEX 40 mg (20 mg in pts age &gt; 75 years) on days 1, 8, 15, and 22, of each 28-day cycle. Dose escalation was reviewed by a dose escalation committee. Results: As of Jan 2019,58 pts received IBER + DEX. Median age was 64.5 years (range 33–79), and median number of prior regimens was 5 (2–12). Prior therapies included autologous stem cell transplant (79%), LEN (100%), POM (69%), PIs (100%), and DARA (66%). IBER dose ranged from 0.3 to 1.2 mg; MTD/RP2D was not reached. Median duration of therapy was 12+ weeks (range 4–109). Grade 3–4 adverse events (AEs) were reported in 41 (72%) pts and were not related to dose. Grade 3–4 neutropenia, thrombocytopenia, neuropathy, and fatigue occurred in 26%, 11%, 2%, and 0% pts, respectively. Three pts discontinued treatment due to AEs. Clinical activity occurred early and was observed across all dose levels (Table); 20 of 51 pts remain on treatment (2–27+ cycles). Conclusions: IBER + DEX showed favorable efficacy and safety in heavily pretreated pts with RRMM who failed multiple prior therapies. This study is ongoing, including combinations of IBER with DARA or BORT. Clinical trial information: NCT02773030. [Table: see text]
Abstract 1582: Catechol-O-methyltransferase (COMT) genotypes modify the effects of beta-carotene supplementation on cancer incidence in a controlled trial: findings from the ATBC Study
Authors: Stephanie J. Weinstein, Jiaqi Huang, Kathryn Tayo Hall, Howard D. Sesso, Demetrius Albanes
Journal: Cancer Research (2019)

Abstract Large cancer prevention trials of vitamin supplementation have yielded mixed results over the past three decades. Whether and how genetic variation that influences oxidative stress or vitamin absorption, transport, and metabolism can modify responses to supplementation remains to be elucidated. Catechol-O-methyltransferase (COMT) genotypes have been shown to impact the effects of vitamin E (i.e., alpha-tocopherol) supplementation on cancer, and the present pharmacogenetic analysis examines interactions among COMT, beta-carotene supplements, and risk of cancer. In a case-control study nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of 29,133 Finnish men, we examined overall cancer risk based on the randomized assignment to beta-carotene supplementation (BC; 20 mg daily for 5-8 years) and two common genetic variants in COMT, rs4680 and rs4818 (genotyped by Illumina scans). Based on 2396 cases and 2235 non-cases, Cox proportional hazards models that adjusted for age, smoking intensity and duration, and randomized assignment to the trial vitamin E supplement were conducted to estimate overall cancer risk for the trial and 10-year post-trial periods combined. For rs4680, BC supplementation (versus no BC) was associated with higher cancer risk only in men with the AA (met/met) genotype (HR 1.29, 95% CI 1.08-1.53, P=0.004) as compared with the AG (met/val) and GG (val/val) genotypes (respectively, HR 1.04, 95% CI 0.93-1.16, P=0.52; and, HR 0.99, 95% CI 0.86-1.15, P=0.94). We observed a somewhat similar pattern for rs4818, with the BC supplement being associated with higher cancer risk in men with the GG and GC genotypes (respectively, HR 1.21, 95% CI 0.94-1.55, P=0.14; and, HR 1.15, 95% CI 1.01-1.30, P=0.03), but not the CC genotype (HR 0.99, 95% CI 0.88-1.11, P=0.80). Our findings indicate that the AA (met/met) genotype of COMT rs4680 and the G allele of rs4818 potentiate the increased cancer risk resulting from BC supplementation. Citation Format: Stephanie J. Weinstein, Jiaqi Huang, Kathryn Tayo Hall, Howard D. Sesso, Demetrius Albanes. Catechol-O-methyltransferase (COMT) genotypes modify the effects of beta-carotene supplementation on cancer incidence in a controlled trial: findings from the ATBC Study [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 1582.
Abstract 3876: Thymoquinone induces the expression of clock genes in breast cancer cells
Authors: Aliaa A. Alamoudi, Hanan A. Bashmail, Ghada M. Ajabnoor, Hani Choudhry, Mohammed A. Hassan, Alia M. Aldahlawi, Ahmed A. Al-abd
Journal: Cancer Research (2019)

Abstract Thymoquinone is naturally occurring bioactive compound which showed cumulative preclinical evidence of anticancer effects. However, its exact anti-cancer activity remains to be elusive and is currently being studied. In this study, we assessed the role of thymoquinone as a potential therapy in human breast cancer cell lines in addition to its role in altering molecular clock genes expression, which in turn has been associated with tumorgenesis. Sulfa-Rhodamine-B assay (SRB) assay was used to evaluate the cytotoxic effect of thymoquinone in breast cancer cell lines (MCF-7 and T47D). Following 72 h of exposure, thymoquinone showed cytotoxic effects against MCF-7 and T47D with IC50’s of 44.4±3 µM and 152±11 µM respectively. Further investigation showed that thymoquinone showed some affect on the cell cycle distribution in both cell lines. It significantly increased the cell population in S-phase in MCF-7cells (P&amp;lt;0.05), while causing a significant G1 phase arrest in T47D cells (p&amp;lt;0.01). Interestingly, treatment of both cell lines with non-cytotoxic concentrations of thymoquinone resulted in a significant increased expression of clock genes, measured by reverse transcription–quantitative PCR (RT-qPCR). Thymoquinone appeared to increase the expression of BMAL-1 (1.4±0.1 fold), CLOCK (3.4±0.9 fold), PER-1(5.6±0.5 fold), CRY-1 (4.4±0.4 fold), CRY-2(2.2±0.6 fold) in MCF-7 cells. Similarly, thymoquinone increased the expression of BMAL-1 (1.4±0.3 fold), CLOCK (1.4±0.3 fold), PER-1(1.4±0.3 fold), CRY-1 (1.5±0.4 fold), and CRY-2 (1.8±0.1 fold) in T47D cells . In conclusion, thymoquinone possesses a potential in combating breast cancer alone. Despite the promising anti-proliferative activity of thymoquinone against breast cancer cells, the better understanding of these effects is needed to provide a novel approach for the treatment of breast cancer as a disease. Here, we postulate that the drug could be modulating clock genes expression, which ultimately can affect key molecules in cell cycle and cell proliferation. Further studies are needed to confirm this and to elucidate the exact underlying mechanism. Citation Format: Aliaa A. Alamoudi, Hanan A. Bashmail, Ghada M. Ajabnoor, Hani Choudhry, Mohammed A. Hassan, Alia M. Aldahlawi, Ahmed A. Al-abd. Thymoquinone induces the expression of clock genes in breast cancer cells [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 3876.
Abstract 17061: Primary Pci Strategy for Non-st Elevation Acute Coronary Syndrome in Elderly Patients (>75y/o): An Analysis of the Aboard Study
Authors: Johanne Silvain, Guillaume Cayla, Olivier Barthelemy, Anne Bellemain-Appaix, Farzin Beygui, Simon Elhadad, Hervé Le Breton, Eric Vicaut, Jean-Philippe Collet, Gilles Montalescot
Journal: Circulation (2010)

Aim: The multicenter randomized ABOARD Study demonstrated that in Non ST-Elevation Acute Coronary Syndrome (NSTEACS) patients, a primary PCI strategy is feasible and associated with a shorter hospi...
Abstract LB-201: BIL06v immunizations generate antibodies specific for non-functional P2X7 (nfP2X7) that target solid tumors <i>in vivo</i>
Authors: Chris J. Oliphant, Elle Freeman, Simon Gilbert, Romain Lara, Edwin Huang, Julian Barden, Shaun McNulty
Journal: Cancer Research (2019)

Abstract P2X7 is an ATP-gated purinergic receptor characterized by a biphasic response. Short term exposure to high ATP concentrations triggers opening of a cation channel, whilst prolonged exposure triggers opening of a non-selective pore that disrupts intracellular homeostasis, leading to cell death. Increasing numbers of studies have described a role for P2X7 in malignant tumors, including breast, prostate, colorectal and lung, and P2X7 has been shown to play critical roles in mediating various cancer cellular responses, such as cell proliferation, migration, invasion, and survival. We have described a form of P2X7 that is highly expressed on several cancers, which we term non-functional P2X7 (nfP2X7) that is unable to open a non-selective pore. Non-functional-P2X7 can form when P2X7-expressing cells undergo prolonged exposure to high ATP concentrations found in the local tumor microenvironment. This conformational change results in the exposure of a unique epitope composed of amino acids 200-216, known as the E200 peptide epitope. The E200 peptide epitope has been shown to be a safe and selective target for antibodies against solid tumors. Using the E200 peptide epitope we have prepared a peptide vaccine adjuvanted by Alhydrogel 2%, which we have termed BIL06v, for the therapeutic treatment of solid tumors. A similar vaccination approach was used to generate antibodies for a topical therapeutic that was shown to be safe with indications of efficacy in a Phase 1 clinical trial to treat basal cell carcinoma. Using preclinical in vivo models, we have investigated the tractability of BIL06v as a therapeutic against tumors. In mice and human, BIL06v can break immune tolerance and drive the production of antibodies specific for nfP2X7. A formal toxicology study has demonstrated both immunogenicity and safety in rats following repeated treatment with BIL06v. Furthermore, BIL06v treatment has been shown to improve host outcomes in syngeneic mouse models of disease. Therefore, targeting nfP2X7 with a peptide conjugate vaccine, such as BIL06v, presents a novel and safe therapeutic approach for the treatment of multiple malignancies. Citation Format: Chris J. Oliphant, Elle Freeman, Simon Gilbert, Romain Lara, Edwin Huang, Julian Barden, Shaun McNulty. BIL06v immunizations generate antibodies specific for non-functional P2X7 (nfP2X7) that target solid tumors in vivo [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 LB-201.
Abstract 522: PI3K/Akt signaling in tumor cells promotes immune evasion by limiting infiltration, recognition and killing by T cells
Authors: Nithya Sivaram, Patrick McLaughlin, Ya-Ping Jiang, Lisa Ballou, Kien Pham, Chen Liu, Adrianus van der Velden, Richard Lin
Journal: Cancer Research (2019)

Abstract The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapy. In this study, a syngeneic orthotopic implantation model of pancreatic cancer was used to show that PI3K/Akt signaling in tumor cells down-regulate immunogenicity to evade T cell surveillance. Genetic silencing of PI3K catalytic isoform Pik3ca in KrasG12D/Trp53R172H-driven pancreatic tumors leads to infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast, Pik3ca-null tumors implanted in T cell-deficient mice progress and kill 100% of the animals. Adoptive transfer of tumor antigen-experienced T cells eliminates Pik3ca-null tumors in immunodeficient mice. Pik3ca silencing or inhibition of its effector, Akt, increases the expression of MHC Class I and CD80 on the surface of murine and human pancreatic cancer cells. Down-regulating MHC Class I and CD80 expression, or increasing Akt activity, in Pik3ca-null tumors increases their susceptibility to T cell-mediated regression in vivo. These results indicate that PI3K/Akt signaling in tumor cells limits T cell recognition and clearance of pancreatic cancer. Strategies that selectively target the PI3K/Akt signaling pathway in tumor cells may improve immunotherapy for pancreatic cancer. Citation Format: Nithya Sivaram, Patrick McLaughlin, Ya-Ping Jiang, Lisa Ballou, Kien Pham, Chen Liu, Adrianus van der Velden, Richard Lin. PI3K/Akt signaling in tumor cells promotes immune evasion by limiting infiltration, recognition and killing by T cells [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 522.