tbuckley/cabot-search huggingface dataset:
Effect of inhibition of ErbB2-tyrosine kinase domain with lapatinib on cardiac dysfunction compared to the antibody trastuzumab in mice.
Authors: Carlo G. Tocchetti, Carmela Coppola, Domenica Rea, Noemi Castaldo, Lorena Guarino, Antonio Barbieri, Giuseppe Palma, Marianna Gala, Antonio Luciano, Aldo Giudice, Giovanna Piscopo, Immacolata Capasso, Stefania Scala, Maria Gaia Monti, Antonio Cittadini, Rosario Vincenz Iaffaioli, Claudia De Lorenzo, Claudio Arra, Nicola Maurea
Journal: Journal of Clinical Oncology (2012)

e11052 Background: Lapatinib (L) inhibits ErbB2-tyrosine kinase domain and has been reported (in the few existing trials) to be associated with a low risk of cardiac dysfunction (2%), while the prototypical Trastuzumab (T) increases the frequency of asymptomatic ejection fraction decrease by 3-18%, and the risk of heart failure by 2-4%. Here, we characterize our L murine cardiotoxicity model. Methods: Cardiac function was measured with fractional shortening (FS) by M-mode echocardiography, and with radial myocardial strain (%) with speckle tracking (ST) in sedated C57BL6 mice (2-4 mo. old) at day 0, and after 2 and 7 days of daily administration of L (100mg/kg/day orally), and in control mice. For comparison we used our well-established models with T (2.25 mg/kg/day, ip), and Doxorubicin (D, 2.17 mg/kg/day ip) as positive control. On excised hearts, we evaluated TNFα and CD68 by immunohistochemistry. Results: FS was reduced with D at 2 days: 52±0.2%, p&lt;.001 vs 60±0.4% (sham), while L and T decreased FS only at 7 days (56±2 and 49±1.5%, respectively, both p&lt;.05 vs 60±0.5% for sham). Interestingly, FS reduction with L was milder (p=.01) than with T. By immunohistochemistry, all treatments increased cardiac inflammation significantly vs controls. In particular, with T more myocytes were positive for TNFα (6±1%), and there were more CD68 cells/mm 2 (72±6) compared to L (2±.2% and 27±4, respectively, both p&lt;.02 vs T). D-treated hearts exhibited the highest values. Importantly, from a diagnostic point of view, with ST-echocardiogaphy, myocardial strain was reduced early at 2 days with L and T, predicting cardiotoxicity: 34±7% for L, 44±7% for T (p=NS), both p&lt;.05 vs sham (66±.6%). Conclusions: Specifically targeting the tyrosine kinase domain of ErbB2 with L is less cardiotoxic than T. Nevertheless, both dysfunctions occur later than D. Myocardial strain identifies systolic dysfunction earlier than conventional echo and can be useful to predict cardiotoxicity in these settings. From a clinical point of view, we plan to evaluate the impact of ST echocardiography in early prediction of anti-ErbB2 toxicity in patients, while dissecting myocardial toxicity mechanisms in our animal models.
Response to targeted therapy or chemotherapy following immunotherapy in patients with gastrointestinal cancers - a case series
Authors: Rayan Alsuwaigh, Joycelyn Lee, Gloria Chan, Cheng Ean Chee, Su Pin Choo
Journal: Journal for ImmunoTherapy of Cancer (2019)

The authors have retracted this article because of confidentiality obligations. The article content has been removed for legal reasons. All authors agree to this retraction. Response to targeted therapy or chemotherapy following immunotherapy in patients with gastrointestinal cancers - a case
Abstract 1922: MYB mimic peptides targeting human and murine MYB-NFIB positive tumor cells
Authors: Yue Jiang, Lauren Forbes, Jianping Li, Shelby Freeberg, Chunxia Cao, Maria Zajac-Kaye, Jonathan Licht, Alex Kentsis, Frederic Kaye
Journal: Cancer Research (2019)

Abstract Adenoid Cystic Cancer (ACC) is the most aggressive salivary gland tumor with no effective systemic therapy. MYB/MYBL1 fusion event underlies the etiology of ACC with few recurrent variants focused on NOTCH and chromatin remodeling pathways and low overall mutational tumor burden. No chemotherapy or targeted drugs have been approved for ACC. Therefore, there is an urgent need to develop novel therapeutic strategies. To study MYB biology and test new therapeutic agents we have developed and characterized the phenotype of a new murine conditional MYB-NFIB transgene model and have also generated a mammary tumor cell line expressing the human MYB fusion transgene with ACC-like features. We have also generated new human MYB-NFIB positive ACC tumor cell lines and xenografts from patient samples and have tested these tumor cells with newly developed MYB mimic peptides. We analyzed the phenotype of mice carrying conditional MMTV-CRE MYB-NFIB transgene alone or after crossing to heterozygosity with p16/ARF null alleles. We observed shortened survival in two different mouse transgene strains due to development of B-cell leukemia manifested by elevated WBC, low platelets, and marked splenomegaly. We also noted sporadic solid tumors including the development of a murine mammary tumor which generated a MYB-NFIB positive tumor cell line for testing new therapies. In addition, we have generated patient derived xenografts (PDX) and the successful generation of a human ACC tumor cell line from fresh ACC patient biopsies. Using shRNA reagents we observed reduced tumor cell growth and viability assayed by MTS assay following Notch1 and MYB knockdown. We also tested four candidate MYB inhibitors, celastrol, all-trans retinoic acid, and the peptidomimetic inhibitors, MYBMIM and CRYBMIM, against murine and human ACC tumor samples with immortalized normal cells as controls and will discuss these results. Citation Format: Yue Jiang, Lauren Forbes, Jianping Li, Shelby Freeberg, Chunxia Cao, Maria Zajac-Kaye, Jonathan Licht, Alex Kentsis, Frederic Kaye. MYB mimic peptides targeting human and murine MYB-NFIB positive tumor 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 1922.
Nom-invasive positive pressure ventilation can prevent reintubation after acute respiratory failure: results of a prospective and randomized study
Authors: S. R. P. O. Rosinha, S. M. A. Lobo, H. S. Sanches, M. Deraldini, A. M. A. Vidal, L. T. Tofoli, G. P. P. Shettino, Marcelo Britto Passos Amato, Carlos Roberto Ribeiro de Carvalho, C. S. V. Barbas
Journal: American Journal of Respiratory and Critical Care Medicine (2000)
Abstract 1218: EMP2 serves as a novel target for immunotoxin mediated ovarian cancer therapy
Authors: Khalid Mohamedali, Su-Yin Kok, Lawrence H. Cheung, Michael G. Rosenblum, Madhuri Wadehra
Journal: Cancer Research (2019)

Abstract Ovarian cancer (OC) currently accounts for only ~2% of all new cancer cases per year, but once diagnosed, patients only show a 5 year survival of 30%. Subdivided into four subtypes: serous, endometrioid, clear cell, and mucinous carcinoma, high-grade serous ovarian cancer (HGSOC) accounts for 70-80% of the ovarian cancer deaths. Immunoconjugates represent an innovative therapeutic approach to deliver a deadly payload to a tumor cell with more specificity and potentially less avenues for resistance than either can exert individually. However, it has been a challenge to find candidates as well as implement conjugation strategies to achieve these goals for a number of cancers. Epithelial membrane protein-2 (EMP2) is over-expressed in a number of cancers in women including 70% of ovarian tumors, with up to 88% of advanced serous carcinomas showing high expression of the antigen. With an eye towards therapy, we have recently developed an IgG1 targeting the extracellular domain of EMP2 with single digit nM affinity. As the antibody-antigen complex rapidly internalizes, we sought to improve on the efficacy of the naked antibody. Granzyme B (GrB) is a serine protease that plays a critical role in the body’s defense against viral infection and tumor development by initiating the apoptotic cascade via both caspase-dependent and -independent mechanisms. Accordingly, we developed novel fusion proteins composed of the anti-EMP2 backbone as the targeting moiety and granzyme B as the cytotoxic payload. The designs comprised (a) the anti-EMP2 IgG1 with GrB fused to the Fc domain through a cleavable linker, and (b) active GrB fused to the IgG heavy chain (Fc) domain containing 2 single-chain antibodies against EMP2, a format that results in a longer plasma retention time. The constructs were expressed by transient transfection in HEK293E cells and purified to homogeneity. Flow cytometry and ELISA demonstrated binding properties of the fusion protein with high specificity and sensitivity to EMP2 expression. The enzymatic activity of the fusion construct was similar to commercially-available GrB. Internalization of the immunotoxins was confirmed, and they showed high cytotoxicity to EMP2-positive cells compared to EMP2-negative cells. We predict that these designs may improve therapeutic outcomes for EMP2+ tumors. Citation Format: Khalid Mohamedali, Su-Yin Kok, Lawrence H. Cheung, Michael G. Rosenblum, Madhuri Wadehra. EMP2 serves as a novel target for immunotoxin mediated ovarian cancer therapy [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 1218.
Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35
Authors: Yuzo Koda, Nobuhiro Nakamoto, Po-Sung Chu, Aya Ugamura, Yohei Mikami, Toshiaki Teratani, Hanako Tsujikawa, Shunsuke Shiba, Nobuhito Taniki, Tomohisa Sujino, Kentaro Miyamoto, Takahiro Suzuki, Akihiro Yamaguchi, Rei Morikawa, Katsuaki Sato, Michiie Sakamoto, Takayuki Yoshimoto, Takanori Kanai
Journal: Journal of Clinical Investigation (2019)

Acute liver failure (ALF) is a life-threatening condition, and liver transplantation is the only therapeutic option. Although immune dysregulation is central to its pathogenesis, the precise mechanism remains unclear. Here, we show that the number of peripheral and hepatic plasmacytoid DCs (pDCs) decrease during acute liver injury in both humans and mice. Selective depletion of pDCs in Siglechdtr/+ mice exacerbated concanavalin A-induced acute liver injury. In contrast, adoptively transferred BM-derived pDCs preferentially accumulated in the inflamed liver and protected against liver injury. This protective effect was independent of TLR7 and TLR9 signaling, since a similar effect occurred following transfer of MyD88-deficient pDCs. Alternatively, we found an unexpected immunosuppressive role of pDCs in an IL-35-dependent manner. Both Il12a and Ebi3, heterodimeric components of IL-35, were highly expressed in transferred pDCs and CD4+CD25+ Tregs. However, the protective effect of pDC transfer was completely lost in mice depleted of Tregs by anti-CD25 antibody. Moreover, pDCs derived from IL-35-deficient mice had less of a protective effect both in vivo and in vitro even in the presence of Tregs. These results highlight a unique aspect of pDCs in association with Tregs, serving as a guide for immunotherapeutic options in ALF.
Physical confinement induces malignant transformation in mammary epithelial cells
Authors: Yen-Chun Lu, Tinyi Chu, Matthew S. Hall, Dah-Jiun Fu, Quanming Shi, Alan Chiu, Duo An, Long-Hai Wang, Yehudah Pardo, Teresa Southard, Charles G. Danko, Jan Liphardt, Alexander Yu Nikitin, Mingming Wu, Claudia Fischbach, Scott Coonrod, Minglin Ma
Journal: Biomaterials (2019)
Abstract 4518: IL-4/IL-13 stimulated tumor-associated macrophages enhance breast cancer cell invasion through Rho-GTPase signaling
Authors: Andrew C. Little, Pragathi Pathanjeli, Zhifen Wu, Liwei Bao, Laura Goo, Joel A. Yates, Sofia D. Merajver
Journal: Cancer Research (2019)

Abstract The high metastatic potential of inflammatory and other aggressive breast cancer is the major determinant of mortality. Recently, it has become clear that signals from the tumor microenvironment (TME) harbor the capacity to enhance cancer cell dissemination. Of the various cells that comprise the TME, macrophages are the most abundant in solid tumors. Therefore, we aimed to better understand the relationship between macrophage-breast cancer cell crosstalk. Intriguingly, in our previous work we showed that inflammatory breast cancer (IBC) cells are hyper-migratory in response to macrophage conditioned media. Additionally, we found this process is regulated by the Rho-GTPase, RhoC. Recent advances in tumor associated macrophage (TAM) biology have led to the understanding that TAM populations in the TME are diverse, primarily due to directional differentiation promoted by unique secreted components from the various cells in the TME. Therefore, this study aimed to understand which subpopulation of M2-like TAMs had the greatest impact on breast cancer cell aggressiveness. Our data show that stimulation of the triple negative breast cancer (TNBC) cell model, MDA-MB-231, and the IBC TNBC cell line, SUM-149, with media extracts from IL-4/IL-13 stimulated M2 macrophages (M2a) elicit the strongest migratory and invasive responses. Subsequently, we stimulated RhoA or RhoC knockout (CRISPR) MDA-231 and SUM-149 cells with M2a conditioned media to address their role in regulating migratory/invasive responses. In brief, we find that RhoA and RhoC, in part, regulate M2a-TAM induced responses. Secretome analysis of M2a-TAM conditioned media reveals high levels of vascular endothelial growth factor (VEGF) and chemokine (C-C motif) ligand 18 (CCL-18). Functional studies suggest that VEGF and CCL-18 synergistically enhance cellular invasiveness. Moreover, pretreatment with the ROCK inhibitor Y-27632 or GSK429286A drastically inhibited VEGF, CCL-18, or M2a induced migratory responses. These data suggest that the Rho-GTPases regulate M2a-mediated breast cancer cell invasion and potentially offer a novel approach for the treatment of metastatic breast cancer through potential prevention of progression. Citation Format: Andrew C. Little, Pragathi Pathanjeli, Zhifen Wu, Liwei Bao, Laura Goo, Joel A. Yates, Sofia D. Merajver. IL-4/IL-13 stimulated tumor-associated macrophages enhance breast cancer cell invasion through Rho-GTPase signaling [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 4518.
Loop Ileostomy vs Total Abdominal Colectomy—A Valid Alternative?
Authors: Marja A. Boermeester
Journal: JAMA Surgery (2019)

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Abstract 14499: Beneficial Cardiac Effects of Endothelin Converting Enzyme Inhibition in Experimental Heart Failure
Authors: Nassiba Merabet, Anna-Lena Hassouna, Lionel Nicol, Jean-Paul Henry, Francoise Lallemand, Christian Thuillez, Paul Mulder
Journal: Circulation (2012)

Introduction. Endothelin (ET) plasma concentrations are of predictive value in terms of clinical outcome and survival in heart failure (HF), and remain increased in humans with HF receiving optimal...
Abstract DDT01-02: Discovery and first structural disclosure of AZD7648: A potent and selective DNA-PK inhibitor
Authors: Frederick W. Goldberg, Elaine Cadogan, Raymond Finlay, Antonio Ramos Montoya, David Beattie, Gillian Lamont, Charlene Fallan, Jacqueline Fok, Mercedes Vazquez-Chantada, Derek Barratt, Emma Dean, Jane Norris, Andrew Campbell, Anna Cronin, Joanna Harding, Attilla Ting, Simon Hollingsworth, Barry Davies
Journal: Cancer Research (2019)

Abstract DNA-dependent kinase (DNA-PK) plays an important role in the cellular response to DNA damage through the detection and repair of double strand breaks, and is a critical component of the DNA damage response (DDR). Double strand breaks can be induced by a range of agents, including chemotherapy, radiation or PARP inhibitors such as olaparib (Lynparza), and thus a DNA-PK inhibitor is likely to sensitise to these agents. DNA-PK inhibitors may also be effective as monotherapy in tumours with high endogenous levels of DNA damage resulting from defects in other DNA repair pathways. Our screening strategy focussed on identifying hits with good selectivity versus structurally related kinases. Significant improvements were made to permeability, metabolic stability and PK properties, whilst improving potency and selectivity with a structure-guided approach. This optimisation resulted in AZD7648, which is a potent inhibitor of DNA-PK (0.6 nM in biochemical assay, 89 nM in A549 cells) and &amp;gt;100x selective against 396 other kinases in a Thermofisher selectivity panel. In addition, AZD7648 has good crystalline solubility, metabolic stability and predictable pharmacokinetics in preclinical species. In murine xenograft models, PD was assessed using pRPA (S4/8) and was potently inhibited (in vivo IC50 = 52 nM). Tumour growth inhibition was observed with AZD7648 as monotherapy, and regressions were observed in combination with either olaparib or radiation. The efficacy observed when combining AZD7648 with olaparib was correlated to free cover over the in vivo IC90. AZD7648 is a potent and highly selective DNA-PK inhibitor, with good crystalline solubility, permeability and metabolic stability, good bioavailability and predictable pharmacokinetics in preclinical species, and potent knockdown of pRPA and regressions in murine xenograft models when combining with olaparib or radiation. These features make AZD7648 a suitable clinical candidate, and clinical studies evaluating AZD7648 as a potential cancer treatment are planned in 2019. Citation Format: Frederick W. Goldberg, Elaine Cadogan, Raymond Finlay, Antonio Ramos Montoya, David Beattie, Gillian Lamont, Charlene Fallan, Jacqueline Fok, Mercedes Vazquez-Chantada, Derek Barratt, Emma Dean, Jane Norris, Andrew Campbell, Anna Cronin, Joanna Harding, Attilla Ting, Simon Hollingsworth, Barry Davies. Discovery and first structural disclosure of AZD7648: A potent and selective DNA-PK inhibitor [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 DDT01-02.
The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor?
Authors: A. Elkrief, L. Derosa, G. Kroemer, L. Zitvogel, B. Routy
Journal: Annals of Oncology (2019)

Immune-checkpoint inhibitors (ICI) now represent the standard of care for several cancer types. In pre-clinical models, absence of an intact gut microbiome negatively impacted ICI efficacy and these findings permitted to unravel the importance of the commensal microbiota in immuno-oncology. Recently, multiple clinical studies including more than 1800 patients in aggregate demonstrated the negative predictive impact of treatments with broad-spectrum antibiotics (ATB) on cancer patients receiving ICI. Altogether, these results have led to the hypothesis that ATB-induced dysbiosis might influence the clinical response through the modulation of the gut microbiome. Controversy still remains, as ATB treatment might simply constitute a surrogate marker of unfit or immunodeficient patients. In this review, we summarize recent publications addressing the impact of the gut microbiome on ICI efficacy, discuss currently available data on the effect of ATB administered in different time-frames respect to ICI initiation, and finally, evoke the therapeutic implications of these findings.
Abstract 3397: The mechanism of PI3K activation at the atomic level
Authors: Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov
Journal: Cancer Research (2019)

Abstract PI3Ks are a family of lipid kinases in the PI3K/Akt/mTOR pathway that regulates cellular processes. PI3Kα harbors the frequent somatic oncogenic driver mutations conferring gain of function. It is an obligate heterodimer with the regulatory p85α subunit and catalytic p110α subunit. Here, we determine the PI3Kα activation mechanism by nSH2 release at the atomic resolution. The PIP2 substrate binding site is far from ATP and the membrane binding surface is buried in the inactive PI3Kα, raising the question of how catalysis is executed. Our results show that release of nSH2 domain from PI3Kα triggers significant conformational change in p110α, exposing kinase domain for membrane interaction. The C-lobe of kinase domain shows the structural rearrangement to reduce the distance between the ATP and the substrate binding site, offering an explanation to how phosphoryl transfer is executed. This explains how oncogenic mutations promote PI3Kα activation by facilitating nSH2 release and offers an innovative, PI3K isoform-specific drug discovery principle that prevents substrate phosphorylation by targeting isoform-specific residues in the substrate binding site. Citation Format: Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov. The mechanism of PI3K activation at the atomic level [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 3397.
The Dilemma of Diagnosing Idiopathic Intracranial Hypertension Without Papilledema in Patients With Chronic Migraine
Authors: Sweta Sengupta, Christopher Eckstein, Timothy Collins
Journal: JAMA Neurology (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 Neurology 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 Neurology journal