tbuckley/cabot-search huggingface dataset:
Abstract 4798: Efficacy and safety of highly selective novel IRAK4 inhibitors for treatment of ABC-DLBCL
Authors: Wesley Roy Balasubramanian, Venkateshwar Rao Gummadi, Kavitha Nellore, Subhendu Mukherjee, Sivapriya Marappan, Aravind Basavaraju, Bharathi Raja Ainan, Girish Daginakatte, Sreevalsam Gopinath, Sanjeev Giri, Thomas Antony, Shekar Chelur, Susanta Samajdar, Chetan Pandit, Murali Ramachandra
Journal: Cancer Research (2016)

Abstract Interleukin-1 receptor associated kinases (IRAKs) are serine/threonine protein kinases belonging to the tyrosine-like kinase (TLK) family. IRAKs function as mediators of Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and play an important role in innate immune signaling. TLR/IL-1R stimulation leads to recruitment of MYD88, an adaptor molecule, to the activated receptor complex, which then complexes with IRAK4 and activates IRAK1. TRAF6 is then activated by IRAK1 leading to NFkB activation. Recent studies have reported the occurrence of gain of function oncogenic mutation (L265P) in MYD88 in ∼30% of activated B cell diffuse large B-cell lymphoma(ABC DLBCL) and ∼90% of Waldenstrom's macroglobulinemia (WM) leading to constitutive activation of IRAK4 and NFkB pathway. Among the DLBCL subtypes (GCB, ABC DLBCL and PMBL), ABC DLBCL is the most refractory. Inhibition of constitutive IRAK4 signalling can be used as a therapeutic strategy to treat ABC DLBCL Small molecule inhibitors of IRAK4 were synthesized based on hits originating from Aurigene's compound library. Structure guided drug design approach was used to further improve the potency. Lead compounds demonstrated moderate to very high selectivity towardsIRAK4 (S35 score of 0.03) when screened against a large panel of 329 kinases. Aurigene's lead compounds have excellent PK profile and good oral bioavailability in mice, leading to good in-vivo activity in TLR4 induced cytokine release model. Selected lead compounds were tested in a OCI-Ly3 xenograft model, which has a MYD88(L265P) mutation leading to constitutive activation of IRAK4 signaling. An advanced lead compound has demonstrated excellent efficacy in OCI-Ly3 model, with tumor stasis at low doses and tumor regression at higher doses. The compound is well tolerated and has a good therapeutic window as determined in a 14 day rodent toxicity study. In summary, a selective IRAK4 inhibitor has been identified with excellent efficacy and good safety profile. Citation Format: Wesley Roy Balasubramanian, Venkateshwar Rao Gummadi, Kavitha Nellore, Subhendu Mukherjee, Sivapriya Marappan, Aravind Basavaraju, Bharathi Raja Ainan, Girish Daginakatte, Sreevalsam Gopinath, Sanjeev Giri, Thomas Antony, Shekar Chelur, Susanta Samajdar, Chetan Pandit, Murali Ramachandra. Efficacy and safety of highly selective novel IRAK4 inhibitors for treatment of ABC-DLBCL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4798.
Abstract 4196: Real-time single-walled nanotube (SWNT)-based imaging system improves tumor detection and survival in ovarian cancer animal model
Authors: Lorenzo Ceppi, YoungJeong Na, Neelkanth M. Bardhan, Andrew Siegel, Nandini Rajan, Angela M. Belcher, Michael J. Birrer
Journal: Cancer Research (2016)

Abstract Residual tumor detection in advanced stage ovarian cancer (OC) represents a critical challenge in the treatment of this disease. Optimal abdominal cytoreduction to reduce tumor to no evidence of macroscopic disease is the main endpoint of tumor debulking surgery, with demonstrated survival advantages, but the current clinically available imaging modalities have shown low tumor detection sensitivity of tumors smaller than 10 mm diameter. Instead, targeted molecule-based imaging systems offer higher detection rate and are likely to extend the aim of complete resection to the microscopic scale. We applied a custom designed imaging system to a preclinical ovarian cancer tumor model and observed higher microscopic tumor detection accuracy and survival advantage compared to non-image guided debulking surgery. A two component imaging system was developed. The contrast agent is an intra-peritoneal injectable nanomolecular probe, composed of a single walled carbon nanotube (SWNT) coupled with an engineered M13-bacteriophage carrying a modified peptide targeting secreted protein, acidic and rich in cysteine (SPARC), extracellular protein overexpressed in OC. The imaging device system is capable of detecting SWNT inherent fluorescence in near-infrared second window (NIR2) and of displaying real-time images to guide the intraoperative tumor debulking. In an orthotopic ovarian cancer animal model, the imaging system detected microscopic tumors in the millimeter and sub-millimeter scale resolution with a mean tumor diameter of 2.1 vs 3.6 mm (p&amp;lt; 0.01) compared to eye detected tumors. The imaging system demonstrated sensitivity of 97.2% and specificity of 69.7%, and a Receiver Operator Area under the Curve of 0.85 + 0.05. In a survival surgery animal model, the imaging guided resection surgery compared to non guided surgery showed a survival advantage for the experimental arm, with median survival time of 41.0 days vs 28.5 days, respectively (HR 0.22, 95% CI of ratio 0.04 to 1.08 Log Rank test: p: 0.063). The accuracy of the imaging system and its survival advantage are promising. The survival outcome improvement in this preclinical model supports the translation to first-in-human investigation. Moreover, the imaging system accuracy suggests further exploitation in targeted delivery therapies. Citation Format: Lorenzo Ceppi, YoungJeong Na, Neelkanth M. Bardhan, Andrew Siegel, Nandini Rajan, Angela M. Belcher, Michael J. Birrer. Real-time single-walled nanotube (SWNT)-based imaging system improves tumor detection and survival in ovarian cancer animal model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4196.
How Many Have You Done?
Authors: Anna Reisman
Journal: JAMA (2016)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Transcranial Color Doppler Sonography and Magnetic Resonance Imaging In Adult Patients With Sickle Cell Disease
Authors: Giovanna Graziadei, Francesca Marta Casoni, Pietro Ridolfi, Antonella Costa, Alessia Marcon, Stella Forti, Ilaria Gandolfi, Maria Domenica Cappellini, Federico Annoni
Journal: Blood (2013)
Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy
Authors: Andrea Farini, Clementina Sitzia, Barbara Cassani, Letizia Cassinelli, Rosita Rigoni, Federica Colleoni, Nicola Fusco, Stefano Gatti, Pamela Bella, Chiara Villa, Filomena Napolitano, Rita Maiavacca, Silvano Bosari, Anna Villa, Yvan Torrente
Journal: Molecular Therapy (2016)

Duchenne muscular dystrophy is an inherited fatal genetic disease characterized by mutations in dystrophin gene, causing membrane fragility leading to myofiber necrosis and inflammatory cell recruitment in dystrophic muscles. The resulting environment enriched in proinflammatory cytokines, like IFN-γ and TNF-α, determines the transformation of myofiber constitutive proteasome into the immunoproteasome, a multisubunit complex involved in the activation of cell-mediate immunity. This event has a fundamental role in producing peptides for antigen presentation by MHC class I, for the immune response and also for cytokine production and T-cell differentiation. Here, we characterized for the first time the presence of T-lymphocytes activated against revertant dystrophin epitopes, in the animal model of Duchenne muscular dystrophy, the mdx mice. Moreover, we specifically blocked i-proteasome subunit LMP7, which was up-regulated in dystrophic skeletal muscles, and we demonstrated the rescue of the dystrophin expression and the amelioration of the dystrophic phenotype. The i-proteasome blocking lowered myofiber MHC class I expression and self-antigen presentation to T cells, thus reducing the specific antidystrophin T cell response, the muscular cell infiltrate, and proinflammatory cytokine production, together with muscle force recovery. We suggest that i-proteasome inhibition should be considered as new promising therapeutic approach for Duchenne muscular dystrophy pathology.
Dual inhibition of IGFR and mTOR pathways.
Authors: A. Naing, P. LoRusso, S. Gupta, R. S. Benjamin, E. Rohren, H. X. Chen, L. Doyle, D. A. Berry, H. M. Amin, R. Kurzrock
Journal: Journal of Clinical Oncology (2010)

3007 Background: Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type I insulin-like growth factor receptor (IGF-1R)-dependent mechanism. Combining the mTOR inhibitor temsirolimus with cixutumumab, a fully humanized IgG1 monoclonal antibody directed at the IGF-IR, was expected to enhance mTOR-targeted anticancer activity by modulating resistance to mTOR inhibition. Objectives of this NCI-CTEP-sponsored R21-funded multicenter clinical trial were to define MTD, biologic effects, antitumor activity and metabolic activity of temsirolimus and cixutumumab, individually and combined. Methods: A “3+3” design used a fixed dose of 25 mg IV weekly of temsirolimus with an escalating weekly dose of IV cixutumumab at 3, 4, and 6 mg/kg with no intrapatient dose escalation. 36 pts with advanced cancer (14 M/ 22 F, median age=54, median # of prior therapies=5) were enrolled across 3 dose cohorts. In cohort 3 (recommended phase II dose of cixutumumab 6 mg/kg IV weekly with FDA-approved dose of temsirolimus 25 mg IV weekly), 21 additional pts were enrolled in three separate groups for serial biopsies and PET scans as part of PD analysis. Results: Most frequent toxicities were hypercholesterolemia, hypertriglyceridemia, hyperglycemia, and mucositis. Two of three pts with Ewing's sarcoma (EWS) had tumor reduction >20%. Antitumor activity (≥ SD) was also noted in adrenalcortical carcinoma, prostate, and breast cancers. Preliminary correlative data suggest that cixutumumab alone or combined with temsirolimus increased plasma IGF-1 and IGF-BP 3. Changes in pAKT and pS6K were observed in tumor biopsy tissue by immunohistochemistry. PET analysis showed one unit increase in absolute value of SUV from baseline to day 11 may decrease the probability of achieving stable disease by 50%. Conclusions: Temsirolimus 25 mg IV weekly combined with cixutumumab 6 mg/kg IV weekly was well tolerated, demonstrating antitumor activity in several tumor types. An increase in SUV of PET at day 11 may predict negative clinical benefit. An expanded cohort of EWS pts will be treated at the FDA-approved dose of temsirolimus at 25 mg IV weekly with the recommended phase II dose of cixutumumab at 6 mg/kg IV weekly. Supported by 5UO1CA062461-14(RK), 5UO1CA062487-17(PL), and 1R21CA13763301A1(AN). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ImClone Systems
Abstract 731: Transcriptional control of inflammatory signaling in the megakaryocyte and erythroid lineages: implications for the tumor microenvironment
Authors: Bon Q. Trinh, Nicolas Barengo, Sang Bae Kim, Ju-Seog Lee, Patrick A. Zweidler-McKay, Honami Naora
Journal: Cancer Research (2016)

Abstract Thrombocytosis, characterized by high platelet counts, and anemia, caused by low numbers of red blood cells, are associated with poor outcomes in various solid tumors and also occur in several myeloid disorders. The megakaryocyte and erythroid lineages give rise to platelets and red blood cells, respectively, but the mechanisms that cause increased megakaryopoiesis and concurrently decreased erythropoiesis in malignancies are poorly understood. We and others have previously identified that DLX4, a developmental transcription factor encoded by a homeobox gene, is aberrantly expressed in several types of solid tumors and myeloid malignancies but the mechanisms of DLX4 are poorly understood. In this study, we identified that DLX4 expression increases during megakaryopoiesis and decreases during erythropoiesis. Overexpression and knockdown experiments using normal CD34+ stem/progenitor cells and bipotent K562 cells demonstrated that DLX4 induces lineage markers and morphologic features of megakaryocytes, and concomitantly represses erythroid marker expression and hemoglobin levels. Gene Ontology and Gene Set Enrichment Analyses of genome-wide changes in gene expression induced by DLX4 showed that DLX4 induces a megakaryocytic transcriptional program and inhibits an erythroid transcriptional program. Bioinformatic analysis also revealed that DLX4 induces gene signatures that are associated with NF-kappaB signaling. The ability of DLX4 to promote megakaryocyte development and to inhibit erythroid differentiation was diminished by blocking NF-kappaB activity or by repressing IL1B, a transcriptional target of DLX4. These findings indicate that DLX4 promotes megakaryocyte development at the expense of erythroid generation in part by inducing inflammatory signaling. Studies are ongoing to investigate the transcriptional control by homeobox genes of inflammatory signaling in thrombocytosis and anemia that are associated with solid tumors and myeloid disorders. Citation Format: Bon Q. Trinh, Nicolas Barengo, Sang Bae Kim, Ju-Seog Lee, Patrick A. Zweidler-McKay, Honami Naora. Transcriptional control of inflammatory signaling in the megakaryocyte and erythroid lineages: implications for the tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 731.
The therapeutic potential of epigenetic manipulation during infectious diseases
Authors: Joby Cole, Paul Morris, Mark J. Dickman, David H. Dockrell
Journal: Pharmacology & Therapeutics (2016)

Epigenetic modifications are increasingly recognized as playing an important role in the pathogenesis of infectious diseases. They represent a critical mechanism regulating transcriptional profiles in the immune system that contributes to the cell-type and stimulus specificity of the transcriptional response. Recent data highlight how epigenetic changes impact macrophage functional responses and polarization, influencing the innate immune system through macrophage tolerance and training. In this review we will explore how post-translational modifications of histone tails influence immune function to specific infectious diseases. We will describe how these may influence outcome, highlighting examples derived from responses to acute bacterial pathogens, models of sepsis, maintenance of viral latency and HIV infection. We will discuss how emerging classes of pharmacological agents, developed for use in oncology and other settings, have been applied to models of infectious diseases and their potential to modulate key aspects of the immune response to bacterial infection and HIV therapy.
Structural Basis for Induction of Peripheral Neuropathy by Microtubule-Targeting Cancer Drugs
Authors: Jennifer A. Smith, Barbara S. Slusher, Krystyna M. Wozniak, Mohamed H. Farah, Gregoriy Smiyun, Leslie Wilson, Stuart Feinstein, Mary Ann Jordan
Journal: Cancer Research (2016)

Abstract Peripheral neuropathy is a serious, dose-limiting side effect of cancer treatment with microtubule-targeting drugs. Symptoms present in a “stocking-glove” distribution, with longest nerves affected most acutely, suggesting a length-dependent component to the toxicity. Axonal transport of ATP-producing mitochondria along neuronal microtubules from cell body to synapse is crucial to neuronal function. We compared the effects of the drugs paclitaxel and ixabepilone that bind along the lengths of microtubules and the drugs eribulin and vincristine that bind at microtubule ends, on mitochondrial trafficking in cultured human neuronal SK-N-SH cells and on axonal transport in mouse sciatic nerves. Antiproliferative concentrations of paclitaxel and ixabepilone significantly inhibited the anterograde transport velocity of mitochondria in neuronal cells, whereas eribulin and vincristine inhibited transport only at significantly higher concentrations. Confirming these observations, anterogradely transported amyloid precursor protein accumulated in ligated sciatic nerves of control and eribulin-treated mice, but not in paclitaxel-treated mice, indicating that paclitaxel inhibited anterograde axonal transport, whereas eribulin did not. Electron microscopy of sciatic nerves of paclitaxel-treated mice showed reduced organelle accumulation proximal to the ligation consistent with inhibition of anterograde (kinesin based) transport by paclitaxel. In contrast, none of the drugs significantly affected retrograde (dynein based) transport in neuronal cells or mouse nerves. Collectively, these results suggest that paclitaxel and ixabepilone, which bind along the lengths and stabilize microtubules, inhibit kinesin-based axonal transport, but not dynein-based transport, whereas the microtubule-destabilizing drugs, eribulin and vincristine, which bind preferentially to microtubule ends, have significantly less effect on all microtubule-based axonal transport. Cancer Res; 76(17); 5115–23. ©2016 AACR.
Expanding Therapy for Neuroendocrine Tumors
Authors: Alissa Poh
Journal: Cancer Discovery (2016)

Abstract Results from two phase III studies suggest that everolimus, an mTOR inhibitor, and 177Lutetium-DOTATATE, a radiopharmaceutical, may be effective new options for patients with advanced neuroendocrine tumors of the gastrointestinal tract. Both therapies were well tolerated and significantly prolonged progression-free survival.
Abstract 413: Validation of an antibody independent tool for patient selection: RNA in situ hybridization detects Met expression levels predictive for response to Met inhibition by Bay 853474
Authors: Oliver von Ahsen, Thomas Krahn, Christoph Schatz
Journal: Cancer Research (2016)

Abstract This study was performed in order to validate RNA in situ hybridization (RNA ISH) as tool for patient selection. Met expression was analyzed in a matched sample set of FFPE versus fresh frozen tumor samples comprising 20 cases of gastric cancer. Classical immunohistochemistry using the antibody SP44 and RNA ISH (RNAscope by ACD) were used to detect c-met expression in FFPE material. The results were confirmed by sandwich-immunoassays on Met and its phosphorylation on tyrosine 1349 (MSD) as well as mass spectrometry. The level of functional relevance was determined by testing a set of cell lines comprising some with genomic amplification of the met gene as well as some non-amplified lines showing different expression levels. Among gastric cancer cell lines only those with met amplification respond to treatment with the small molecule Met inhibitor Bay 853474. The cell line result generates a responder hypothesis that can be used to define a cutoff for clinical samples. 2 of the 20 investigated clinical samples were shown to have high level Met expression by RNA ISH and IHC that could be confirmed by sandwich-immunoassays also showing high level of functional activity by phosphotyrosine 1349. Met expression in these cases was also confirmed by mass spectrometry. Expression levels and functional activity in these 2 cases were in the range that predicts response to treatment as established with gastric cancer cell lines. Determination of predictive biomarkers by immunohistochemistry can be limited due to lack of high quality antibodies of sufficient specificity. Due to its high specificity, RNA in situ hybridization is a technique that can be used to confirm the findings obtained by immunohistochemistry and may potentially even replace immunohistochemistry it if no suitable antibodies are available or not specific enough e.g. to discriminate between closely related protein isoforms. We show the biological relevance of RNA in situ hybridization on FFPE samples by correlation with immunohistochemistry, ELISA based approaches and mass spectrometry. RNA ISH is shown to be specific and sensitive enough to identify cases of functionally relevant MET overexpression levels in gastric cancers and can be used to select patients for treatment. Citation Format: Oliver von Ahsen, Thomas Krahn, Christoph Schatz. Validation of an antibody independent tool for patient selection: RNA in situ hybridization detects Met expression levels predictive for response to Met inhibition by Bay 853474. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 413.
Significance of Isolated Calf Vein Thrombosis—Further Evidence
Authors: Xuan-Binh D. Pham, Christian de Virgilio
Journal: JAMA Surgery (2016)

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 Surgery 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 Surgery journal