tbuckley/cabot-search huggingface dataset:
Abstract 2419: Predicting clinical response based on ex vivo drug response in renal cell carcinoma using kinase activity profiling
Authors: Rob Ruijtenbeek, Liesbeth Houkes-van Kerkhoff, Maria Hilhorst, Peter Mulders, Jeannette Oosterwijk-Wakka, Lambertus Kiemeney, Egbert Oosterwijk
Journal: Cancer Research (2015)

Abstract Introduction: Sunitinib, a potent multitargeted receptor tyrosine kinase inhibitor, is the first line treatment for metastatic renal cell carcinoma (mRCC). Because sunitinib responses and toxicity are highly variable, there is a need for biomarkers predicting sunitinib response or predicting the optimal sequence preference when using alternative tyrosine kinase inhibitors. The aim of this study was to investigate the correlation between ex vivo drug response and clinical response in renal cell carcinoma (RCC) and to explore alternative treatment options. This study has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 259939. Methods: Protein tyrosine kinase activity profiles were generated on PamChip® peptide microarrays of lysed tumor resection tissues (1-5mm3) from 22 mRCC patients. The ex vivo effect of kinase inhibitors (sunitinib, axitinib, sorafenib, pazopanib, erlotinib and crenolanib) was determined and analyzed with Bionavigator software. A two-group (sunitinib responders versus non-responders) comparison applied on the inhibition ratios identified the significantly different peptide phosphorylations. Peptides were clustered according to their correlation with clinical response. Results: As little as 5 μg protein input (0.05 mm3 tissue) was used per kinase activity profile. The ex vivo sunitinib effect positively correlated with clinical responses especially in the subgroup which received sunitinib as 1st line treatment (4 responders vs. 4 non-responders). 18 of the 105 peptides were significantly (p&amp;lt;0.05) less phosphorylated upon ex vivo sunitinib treatment in 4 responders compared to 4 non-responders. Pathway analysis of the peptide phosphorylation patterns revealed sunitinib target involvement. Ex vivo erlotinib, axitinib or crenolanib showed reversed inhibition patterns i.e. more inhibition in the non-responder than in the responder group. In summary, we have shown that predicting clinical response to sunitinib based on the ex vivo response to sunitinib is feasible. This requires further investigation with a larger sample set. Furthermore, the ex vivo response to a drug panel suggests that identification of novel treatment options for non-responders might be feasible. Citation Format: Rob Ruijtenbeek, Liesbeth Houkes-van Kerkhoff, Maria Hilhorst, Peter Mulders, Jeannette Oosterwijk-Wakka, Lambertus Kiemeney, Egbert Oosterwijk. Predicting clinical response based on ex vivo drug response in renal cell carcinoma using kinase activity profiling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2419. doi:10.1158/1538-7445.AM2015-2419
Pharmacokinetic analysis of irinotecan administered in FOLFIRI regimen in combination with bevacizumab from patients enrolled in a genotype-driven phase I study
Authors: B. Posocco, A. Buonadonna, E. Marangon, L. Giodini, S. Scalone, M.R. Sharma, F. Innocenti, G. Toffoli
Journal: Annals of Oncology (2015)
200. Generation of CAR-T Cells Lacking T Cell Receptor and Human Leukocyte Antigen Using Engineered Meganucleases
Authors: Christina Pham, Aaron Martin, Jeyaraj Antony, Daniel MacLeod, Audrey Brown, Michael Nicholson, Jo Ann Hux, Caitlin Turner, Wendy Sharer, Bruce McCreedy, Victor Bartsevich, Ginger Tomberlin, Janel Lape, Jeff Smith, Derek Jantz
Journal: Molecular Therapy (2016)

The manufacture of CAR-T cells depends on peripheral blood donations that contain T cells of sufficient quality and quantity. Currently, many CAR-T programs rely on autologous T cells, but several technical and commercial challenges hinder development. The majority of CAR-T trials have enrolled leukemia or lymphoma patients, many of which are unsuitable donors for CAR-T production due to their disease state or to previous treatments with lymphodepleting agents. In addition, a custom CAR-T production run for each patient is time consuming, lacks standardization and may present regulatory challenges. An alternative strategy is to source T cells from healthy donors and produce large batches of allogeneic CAR-T cells. Allogeneic T cells, however, will display mismatched human leukocyte antigens (HLA) that will be recognized by the recipients' immune systems, contributing to immune rejection of engrafted CAR-T cells. Additionally, donor T cells will recognize the mismatched HLAs present in the recipient, contributing to graft-versus-host immune pathology. Both undesired immune responses are predicated on interactions between HLA and T cell receptors (TCR), and while the therapeutic effectiveness of CAR-T cells with targeted deletions in TCR genes has been reported by several groups, studies featuring both TCR and HLA deletion are limited. Here, we describe the use of meganucleases engineered to target regions of the TCR α chain constant region and β-2 microglobulin genes to generate TCR and HLA class I knockout primary human T cells. Both nucleases generate knockouts with approximately 75% efficiency and are well-tolerated by primary T cells from at least four separate donors. Purified double knockout cells do not demonstrate functional disadvantages in terms of proliferation or cytokine production, but do exhibit reduced allostimulatory potential toward HLA-mismatched T cells. Together, these findings demonstrate the feasibility of generating therapeutic quantities of CAR-T cells with reduced allo-reactive potential and collateral toxicity to normal tissues in recipients.
On Giving
Authors: Emma Goldsmith Rooney
Journal: Annals of Internal Medicine (2016)

On Being a Doctor15 November 2016On GivingEmma Goldsmith Rooney, BSEmma Goldsmith Rooney, BSFrom Emory University School of Medicine, Atlanta, Georgia.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M16-0227 Audio Reading - “On Giving” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "On Giving," by E.G. Rooney. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail I stare at you as they wheel you down the hallway toward our operating room. You are a little twisted in the bed, and, as you get closer, I see that you're all lanky limbs and stubble and messy brown hair. My heart sinks because I know by looking at you that you're close to my brother's age, and you look like him, too. I have so many questions. Did your family just say goodbye? Are your parents upstairs crying? Are there brothers and sisters and friends and cousins? Did your room have flowers in it? Or did it all ... Author, Article, and Disclosure InformationAffiliations: From Emory University School of Medicine, Atlanta, Georgia.Corresponding Author: Emma Goldsmith Rooney, BS, 100 Woodruff Circle, Atlanta, GA 30322. PreviousarticleNextarticle Advertisement Audio Reading - “On Giving” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "On Giving," by E.G. Rooney. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 15 November 2016Volume 165, Issue 10Page: 740KeywordsBreathingHeartLungsNursesRespirationScarsSurgeonsSurgeryThoraxVentilators ePublished: 15 November 2016 Issue Published: 15 November 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract B20: The necrosome promotes pancreatic Oncogenesis via CXCL1 and mincle-induced immune Suppression
Authors: Lena Seifert, Gregor Werba, Shaun Tiwari, Ly Nancy Ngoc Giao, Dalia Alqunaibit, Sara Alothman, Donnele Daley, Mautin Hundeyin, Vishnu R. Mani, Rocky Barilla, George Miller
Journal: Cancer Research (2016)

Abstract Neoplastic pancreatic epithelial cells are widely believed to die via Caspase 8-dependantapoptotic cell death and chemotherapy is thought to further promote tumor apoptosis. Conversely, disruption of apoptosis is a basic modality cancer cells exploit for survival. However, the role of necroptosis, or programmed necrosis, in pancreatic ductal adenocarcinoma (PDA) is uncertain. There are a multitude of potential inducers of necroptosis in PDA including ligation of TNFR1, CD95, TRAIL receptors, Toll-like receptors, ROS, and Chemotherapeutics. We doscovered that the principal components of the necrosome, RIP1 and RIP3, are highly expressed in PDA and are further upregulated by chemotherapy. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. However, belying these findings, in vivo RIP3 deletion or RIP1 inhibition was protective against oncogenic progression and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumor microenvironment (TME) associated with intact RIP1/RIP3 signaling was in-part contingent on necroptosis-induced CXCL1 expression whereas CXCL1 blockade was protective against PDA. Moreover, we found that cytoplasmic SAP130 was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle – its cognate receptor – was upregulated in tumor-infiltrating myeloid cells. Mincle ligation by SAP130 promoted oncogenesis whereas Mincle deletion was protective and phenocopied the immunogenic reprogramming of the TME characteristic of RIP3 deletion. Cellular depletion experiments suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects in the context of RIP3 or Mincle deletion. As such, T cells which are dispensable to PDA progression in hosts with intact RIP3 or Mincle signaling become reprogrammed into indispensable mediators of anti-tumor immunity in absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signaling which critically promote macrophage-induced adaptive immune suppression enabling PDA progression. Citation Format: Lena Seifert, Gregor Werba, Shaun Tiwari, Ly Nancy Ngoc Giao, Dalia Alqunaibit, Sara Alothman, Donnele Daley, Mautin Hundeyin, Vishnu R. Mani, Rocky Barilla, George Miller.{Authors}. The necrosome promotes pancreatic Oncogenesis via CXCL1 and mincle-induced immune Suppression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B20.
Patterns of response to anti-PD1 treatment: Comparison of three radiological response criteria and effect on overall survival (OS) in metastatic melanoma patients (MM).
Authors: Minnie Kibiro, Leila Khoja, David Hogg, Marcus O. Butler, Ur Metser, Eshetu G. Atenafu, Anthony M. Joshua
Journal: Journal of Clinical Oncology (2015)

9073 Background: Radiological assessment of patterns of response (R) to checkpoint inhibitors remain imperfect. irRC accounts for pseudoprogression but does not evaluate change in density. We aimed to evaluate individual lesion and inter patient R by RECIST 1.1, irRC, CHOI and modified CHOI (mCHOI) and correlate R with OS. Methods: 37 patients (pts) with 567 measurable lesions treated with pembrolizumab in a phase 1 trial were studied. Bidimensional tumor diameter and density measurements were obtained at baseline and serial assessment CT scans. Overall R was assigned as per final CT scan assessment. Association of each criterion with OS was determined. Results: R varied according to site of metastases; lung lesions had the highest rate of complete response (CR) compared to other sites (69/163 (42%) lesions vs 71/404 (18%) p < .0001) and R varied at first assessment by RECIST compared to irRC (table). Delayed R post first scan were seen in 2/37 (5%) deemed PD by RECIST and 2/14 (14%) pts deemed PD by irRC at 1st assessment. 1/6 pts deemed to have PD by irRC at second assessment also had delayed R. 24 (65%) pts met CHOI density and size criteria for R at first follow-up. mCHOI criteria (> 15% density decrease and decrease in tumor size > 10%) showed R of 38% (14/37). Change in tumor size and density on 1st follow-up assessment was associated with OS with each 1000 mm2 increase in tumor size from baseline increasing the hazard of dying by 25.9% (HR = 1.259, [95% CI = 1.116-1.420], p = 0.0002). Similarly each 100HU increase in density increased the HR by 99% (HR = 1.99, [95% CI 1.246-3.176], p = 0.0039). R defined by any criteria had superior OS (CHOI, p = 0.0084; mCHOI, p = 0.0183; irRC, p < 0.0001 and RECIST, p = 0.0003). Conclusions: R by any criteria was prognostic and pseudoprogression was seen. The novel patterns of R and changes on treatment in tumor density suggest complex anti-tumor R of immunotherapy and require further validation. CR (%) PR/SD/PD (%) Site of Metastases Lung 42 58 Liver 24 76 Other solid organ 22 78 Peritoneal 37 63 Node 7 93 Subcutaneous 21 79 Other 11 89 R at first assessment scan RECIST 1.1 9/12/16 (24/32/44) irRC 10/13/14 (27/35/38)
Consolidation therapy with yttrium-90-ibritumomab tiuxetan in follicular lymphoma following induction with modern chemoimmunotherapy regimens: A single-institution experience.
Authors: N. V. Koshy, B. S. Nair, J. Angelo, R. Shi, Z. Yang, G. M. Mills, F. Turturro
Journal: Journal of Clinical Oncology (2011)

e18553 Background: Radioimmunotherapy (RIT) remains underused in the U.S and other countries despite many studies documenting the important therapeutic role it can play in the management of many B- cell lymphomas. It is unclear whether benefits of consolidation RIT apply to patients treated with modern induction regimens which include rituximab. The objective of the study is to evaluate outcome with use of consolidation RIT following induction with modern chemoimmunotherapy regimens in follicular lymphoma. Methods: This is a retrospective study of patients with follicular lymphoma treated with consolidation yttrium-90-Ibritumomab Tiuxetan following induction with either rituximab cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) or rituximab,cyclophosphamide, vincristine, prednisone (R-CVP) based modern chemoimmunotherapy regimens. Results: Since 2006, 10 patients with follicular lymphoma (stage III/IV-90%) were treated with consolidation RIT following induction with either R-CHOP or R-CVP based regimens. One patient did not have any response to either induction or RIT. Nine patients achieved complete response (CR) after induction and following consolidation RIT, 6 were able to maintain CR until last follow up. Three patients relapsed later anywhere between 12 and 24 months following consolidation RIT. The estimated median progression free survival following RIT was 23 months and after the longest follow up of 42 months the median overall survival has not been reached yet. Seven patients were 65 years or older with median age being 64 (range 37-87). The main adverse event was grade 3/4 neutropenia and thrombocytopenia with complete hematologic recovery achieved latest by 3 months following completion of RIT treatment. Conclusions: Radioimmunotherapy is an effective way of consolidation following induction with modern rituximab based chemoimmunotherapy regimens in follicular lymphoma and could be considered as an alternative to maintenance rituximab. This approach is well tolerated even in elderly individuals with advanced disease and needs to be validated in prospective clinical trials.
Abstract 5035: Effect of FXR agonist on colitis and colorectal carcinogenesis in mice
Authors: Tsuneyuki Miyazaki, Takahiro Kochi, Hiroyasu Sakai, Yohei Shirakami, Masahito Shimizu, Takuji Tanaka, Hisataka Moriwaki
Journal: Cancer Research (2015)

Abstract Background &amp; Aims: Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and bile acids are endogenous ligand of FXR. FXR is highly expressed in the intestine and liver where FXR is essential for maintaining bile acid homeostasis. FXR activation has recently reported to inhibit intestinal inflammation and tumor development. The aim of this study was to investigate whether FXR agonist prevents colitis and colorectal carcinogenesis in mice. Methods: We achieved two experiments. One experiment (Ex.1) used mouse colitis model with short term administration of FXR agonist, Nelumal A, and the other (Ex.2) employed mouse carcinogenesis model with long term administration. In Ex.1, male 5 week old A/J mice received drinking water containing 1.5% DSS for one week and were fed diets containing 100 or 400 ppm Nelumal A for 4 weeks. In Ex.2, male 5 week old A/J mice were administered once intraperitoneal injec¬]]tions of AOM (20 mg/kg body weight) and after one week, mice received drinking water containing 1.5% DSS for one week and were fed diets containing 100 or 400 ppm Nelumal A for 15 weeks. Results: In Ex.1, DSS-treated mice all had colitis and multiple colonic mucosal ulcers. Both mucosal ulcer and inflammation grade in colon were significantly reduced in 400 ppm Nelumal A-treated mice, and also tended to be reduced in 100 ppm Nelumal A-treated mice. Body weight loss and colon length had no significant difference. The results of Ex.2 showed that the number of colonic mucosal ulcer, adenoma, and adenocarcinoma and total tumor number were decreased in 400 ppm Nelumal A-treated mice, but there was no statistically significant difference. The expression levels of FXR mRNA in colonic mucosa were increased by Nelumal A treatment. Moreover, administration of Nelumal A significantly decreased the expression levels of tumor necrosis factor α, monocyte chemoattractant protein 1, and proliferating cell nuclear antigen, and increased the level of Bax in colonic epithelium. Conclusion: FXR agonist prevents chemically induced intestinal inflammation and carcinogenesis by inhibition of proinflammatory cytokine production and cell proliferation and promotion of apotosis in colonic mucosa. Citation Format: Tsuneyuki Miyazaki, Takahiro Kochi, Hiroyasu Sakai, Yohei Shirakami, Masahito Shimizu, Takuji Tanaka, Hisataka Moriwaki. Effect of FXR agonist on colitis and colorectal carcinogenesis in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5035. doi:10.1158/1538-7445.AM2015-5035
386. Toxicology for DUX4-Targeted MicroRNAs
Authors: Lindsay M. Wallace, Jacqueline S. Domire, Danielle A. Griffin, Louise R. Rodino-Klapac, Scott Q. Harper
Journal: Molecular Therapy (2016)

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder affecting 1 in 7500. Symptoms typically arise in young adulthood and most patients show clinical features before age 30. FSHD is characterized by progressive wasting and weakness of facial and shoulder-girdle muscles, though all skeletal muscle can be affected. Currently there is no treatment for FSHD. The pathogenic events leading to FSHD have only recently started coming into focus. Several studies now support an FSHD pathogenesis model involving aberrant expression of the DUX4 gene, which encodes a myotoxic transcription factor. The emergence of DUX4 enabled the development of FSHD therapies. Previously our lab demonstrated proof of principle for the use of a DUX4-targeted RNA interference (RNAi)-based gene therapy. We have pursued two engineered microRNAs that showed strong therapeutic efficacy determined by their ability to suppress pathogenic levels of DUX4, and prevent myopathy in mice. To continue down a translational path this study was designed to determine the safety of microRNA therapy to muscle (which has not been previously determined) by delivering high doses for preliminary non-GLP toxicity studies. Both local intramuscular injections and systemic isolated limb perfusions were performed to identify safe sequence and dosing parameters for lead DUX4-targeted microRNAs at acute (3 week) and long-term (5 month) timepoints. To further circumvent potential off-target organ toxicity we have optimized these vectors to restrict expression to skeletal muscle. The safety parameters along with the promoter optimization provide necessary data for translating an RNAi-based therapy for FSHD.
PTH-015 Specialist gastroenterology involvement in<i>Streptococcus bovis</i>positive cultures
Authors: A Sinha, W Gransden, N Cortes, S Weaver
Journal: Gut (2010)

<h3>Introduction</h3> There is well documented evidence linking <i>Streptococcus bovis</i> (<i>S bovis</i>) bacteraemia to colonic neoplasms and polyps. As patients with <i>S bovis</i> bacteraemia can be found across various specialities, our aim was to audit the consistency of appropriate specialist referral for assessment of colonic pathology. <h3>Methods</h3> All cases of <i>S bovis</i> bacteraemia occurring between October 2000 and June 2009 were identified using information provided by the department of microbiology. Medical records were reviewed for clinical details, evidence of features of endocarditis and referral to gastroenterologists. The standard of best practice was all cases should be referred for appropriate specialist review. <h3>Results</h3> There were 20 cases of <i>S bovis</i> bacteraemia from the total of 3454 positive cultures (0.6%). There were 11 male and 9 female and all were Caucasian with a mean age of 80.7 years. Four (20%) had endocarditis and four had abnormal liver enzymes. Seventeen patients had a microbiology report in the notes and 13 had Microbiologist advice to consider cardiac and/or colonic pathology. The gastroenterology team9s opinion was sought for 10 (50%) patients and 10 patients underwent one or more investigations including gastroscopy, colonoscopy, flexible sigmoidoscopy and CT of the abdomen. 60% of these investigations were performed on gastroenterology team9s advice and the rest were done on the admitting team9s initiative. In seven patients (35%) their prognosis at the time the bacteraemia was judged to be so poor as to preclude further investigation. Of the 10 patients who were investigated, six (60%) had positive findings. Two patients had colorectal adenocarcinoma (one rectum and one sigmoid); one had a stricture diagnosed on CT abdomen; and three had significant polyps (one or more tubulovillous adenomas with low grade dysplasia &gt;1 cm). 60% of the patients in the study (12) were already deceased at the time of the audit and one patient had had a repeat colonoscopy after 1 year and had further polyps removed. <h3>Conclusion</h3> A lack of uniformity was observed in proper referral for gastroenterologist assessment and investigation. The age and multiple comorbidities of these patients made further investigations clinically inappropriate in 35% in this study. In the absence of proper guidelines regarding investigation of patients with <i>S bovis</i> bacteraemia for bowel pathology, we recommend seeking formal gastroenterology advice in all such patients. At the Royal Bournemouth Hospital, the department of microbiology has decided to inform the gastroenterology team of all <i>S bovis</i> positive cultures. Following these measures, this audit will be repeated.
Sex and Race Differences in the Association Between Statin Use and the Incidence of Alzheimer Disease
Authors: Julie M. Zissimopoulos, Douglas Barthold, Roberta Diaz Brinton, Geoffrey Joyce
Journal: JAMA Neurology (2016)

To our knowledge, no effective treatments exist for Alzheimer disease, and new molecules are years away. However, several drugs prescribed for other conditions have been associated with reducing its risk.