tbuckley/cabot-search huggingface dataset:
Abstract 528: Identify and prioritize candidate neoantigens from cancer exome sequencing with unmatched accuracy
Authors: James White, Sam Angiuoli, Mark Sausen, Sian Jones, Lisa Kann, Manish Shukla, Maria Sevdali, Victor Velculescu, Luis Diaz, Theresa Zhang
Journal: Cancer Research (2016)

Abstract Somatic, nonsynonymous genetic alterations present in cancer can lead to the formation of novel protein sequences and thus production of immunogenic “non-self” neoantigens. Some of those neoantigens will be processed, presented on MHC molecules, and induce tumor-specific T cell responses. Because neoantigens play central roles in the cancer-immunity cycle, it is critical to identify the most potent immunogenic neoantigens effectively and accurately. Combining PGDx's highly accurate cancer exome analyses (CancerXome™) with in silico neoantigen prediction, we have launched ImmunoSelect-R™ that identifies and prioritizes the most relevant mutation-derived neoantigens. To ensure detection of true somatic mutations and prevent false positive mutations from confounding neoantigen identification, ImmunoSelect utilizes CancerXome that delivers unparalleled cancer whole exome sequencing accuracy, achieving 95% sensitivity and 97% positive predictive value at 10% mutant allele frequency with 150x coverage. ImmunoSelect also provides accurate HLA typing from whole exome sequencing with &amp;gt;99.9% sensitivity and specificity. Once exome-based mutations and novel open-reading-frames are identified and HLA genotypes defined, ImmunoSelect utilizes state of art bioinformatics pipelines for prediction and prioritization of the most relevant neoantigens. When applied to a set of experimentally validated neoantigens, ImmunoSelect identified 18 out of 19 of them as being strong neoantigen candidates, suggesting a sensitivity of greater than 90%. Moreover, ImmunoSelect consistently ranked experimentally validated neoantigens within top 20% of all neoantigen candidates derived from whole exome sequencing. In summary, ImmunoSelect is able to identify and prioritize candidate neoantigens from cancer exome sequencing results effectively and accurately, enabling personalized cancer vaccine development, adoptive T-cell transfer, and prediction of response to checkpoint inhibitors Citation Format: James White, Sam Angiuoli, Mark Sausen, Sian Jones, Lisa Kann, Manish Shukla, Maria Sevdali, Victor Velculescu, Luis Diaz, Theresa Zhang. Identify and prioritize candidate neoantigens from cancer exome sequencing with unmatched accuracy. [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 528.
Abstract 1972: Changes in the architecture, interactions and chromatin remodeling of SWI/SNF due to loss of Snf5
Authors: Blaine Bartholomew, Jim Persinger, Payel Sen, Mekonnen Dechassa Lemma, Jie Luo, Jeff Ranish
Journal: Cancer Research (2016)

Abstract The mammalian SWI/SNF complex is a family of an estimated ∼100 complexes, each with different combinations of related subunits. Efforts in sequencing many cancer genomes has revealed that mammalian SWI/SNF complexes is one of the most frequently mutated epigenetic factors found in a broad range of cancers. In order to understand more about the subunit organization of SWI/SNF and because yeast and mammalian SWI/SNF complexes share many conserved subunits and domains; we have studied the role of the Snf5 subunit in the yeast SWI/SNF to better understand the role of the mammalian homolog SNF5 that is a known tumor suppressor gene. The basis for the loss of mammalian SNF5 being a driver mutation in pediatric rhabdoid tumors is currently not well understood or how the loss of SNF5 effects the composition, recruitment and nucleosome remodeling activity of the SWI/SNF complex. We have assessed the effects on deletion of Snf5 on the compositional integrity of SWI/SNF and have evidence for Snf5 forming a sub-complex with two other highly conserved subunits of SWI/SNF that are lost from the complex when Snf5 is deleted. In addition we have mapped the inter-subunit and intra-subunit interactions of the yeast SWI/SNF complex with lysine specific homo bi-functional crosslinkers and mass spectrometry. These data confirm the formation of a tri-subunit Snf5 sub-complex and show that this module uniquely interacts with the ATPase domain of the catalytic subunit of SWI/SNF (Snf2). These observations lead to a further investigation into the regulation of the remodeling activity of SWI/SNF by the Snf5 subunit. We have found that Snf5 is required for the ATPase domain to make stable interactions with nucleosomal DNA. And the loss of these interactions in turn also causes a reduction in the remodeling efficiency of the SWI/SNF complex. We have done additional mapping of the interactions of Snf5 as part of the SWI/SNF complex and find that the highly conserved region of yeast Snf5 corresponding to the human SNF5 protein associates with the surface of the nucleosome near the histone H2A-H2B dimer. We will discuss the relevance of these findings in highlighting how an aberrant form of SWI/SNF could be created by loss of Snf5 and provide an example of how it alters the normal function and structure of SWI/SNF. Citation Format: Blaine Bartholomew, Jim Persinger, Payel Sen, Mekonnen Dechassa Lemma, Jie Luo, Jeff Ranish. Changes in the architecture, interactions and chromatin remodeling of SWI/SNF due to loss of Snf5. [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 1972.
Most patients taking warfarin do not maintain stable INR values
Authors: Jacqui Wise
Journal: BMJ (2016)

Most patients taking warfarin who have stable international normalised ratio (INR) values do not maintain them over time, a study published in JAMA has found. The finding challenges the belief that patients with good outcomes from warfarin should keep taking it rather than switching to non-vitamin K oral anticoagulants.1

Warfarin substantially decreases stroke risk in patients with atrial fibrillation, but it has a narrow therapeutic window (INR …
Carfilzomib, lenalidomide, and dexamethasone (KRd) vs lenalidomide and dexamethasone (Rd) in patients with relapsed multiple myeloma (RMM) and early progression during prior therapy: Secondary analysis from the phase 3 study ASPIRE (NCT01080391).
Authors: Heinz Ludwig, Meletios A. Dimopoulos, Tamas Masszi, Ivan Spicka, Albert Oriol Rocafiguera, Roman Hajek, Laura Rosinol, David Samuel DiCapua Siegel, Georgi Mihaylov, Vesselina Goranova-Marinova, Peter Rajnics, Aleksandr Suvorov, Ruben Niesvizky, Andrzej J. Jakubowiak, Jesus San Miguel, Mihaela Obreja, Sanjay Aggarwal, Philippe Moreau, Antonio Palumbo
Journal: Journal of Clinical Oncology (2016)

8045 Background: The randomized phase 3 ASPIRE trial demonstrated an improvement in median progression-free survival (PFS) for KRd compared with Rd in patients with RMM (26.3 months vs 17.6 months, P = 0.0001) (Stewart AK et al. N Engl J Med. 2015;372:142–52). In this post hoc analysis of ASPIRE, we studied KRd vs Rd in patients with early disease progression in the first prior line. Methods: Patients were ≥ 18 years old, had RMM, and received 1–3 prior lines. Patients were randomized 1:1 to 28-day cycles of KRd or Rd. Carfilzomib was given on days 1, 2, 8, 9, 15, and 16 during cycles 1–12 and days 1, 2, 15, and 16 during cycles 13–18 (27 mg/m2 [20 mg/m2 on days 1, 2 of cycle 1]). Patients in both arms received lenalidomide 25 mg on days 1–21 and dexamethasone 40 mg on days 1, 8, 15, and 22. The following subgroups were analyzed: patients who relapsed ≤ 1 year from starting the first line of prior therapy (early relapsers) and patients who relapsed ≤ 1 year from the first prior transplant (post-transplant early relapsers). Results: Relapse ≤ 1 year from starting the first prior regimen occurred for 87/396 patients in the KRd arm and 72/396 patients in the Rd arm. Median PFS for early relapsers was 24.1 months for KRd vs 12.5 months for Rd (hazard ratio [HR]: 0.75; 95% confidence interval [CI]: 0.50–1.13), and overall response rate (ORR) was 79.3% for KRd vs 61.1% for Rd ( ≥ complete response[CR], 21.8% vs 4.2%). Relapse ≤ 1 year from first prior transplant occurred for 48 KRd and 49 Rd patients. Median PFS for post-transplant early relapsers was 17.3 months for KRd vs 11.1 months for Rd (HR: 0.87; 95% CI: 0.54–1.41), and ORR was 83.3% for KRd vs 61.2% for Rd ( ≥ CR, 12.5% vs 4.1%). Grade ≥ 3 adverse events that occurred ≥ 5% more frequently in KRd than Rd (in either subgroup) were hypokalemia, neutropenia, febrile neutropenia, hypophosphatemia, and respiratory tract infection. Conclusions: In this post hoc subgroup analysis, addition of K to Rd led to clinically meaningful improvements in PFS and ORR in RMM patients who had early progression following prior therapy (including transplant) and may have more aggressive disease. Clinical trial information: NCT01080391.
Abstract 4553: Identification of CD30/TNFRSF8 as a primary target of the Myc oncoprotein and potential biomarker of Myc-driven cancer
Authors: Victoria Gennaro, Xiao-yong Zhang, Lauren DeSalle, Duonan Yu, Andrei Thomas-Tikhonenko, Christopher Vakoc, Steven B. McMahon
Journal: Cancer Research (2016)

Abstract Pathological activation of the transcription factor Myc induces a multitude of human malignancies. In Myc-driven tumor progression, there is a robust dependence on Myc activity; however, strategies developed to explicitly modulate Myc function in cancer have yielded little clinical success. Patients harboring Myc-dependent tumors would benefit from a therapy that circumvents molecular targeting of Myc expression and instead directs against a distinct downstream effector. Our preliminary data from an unbiased expression-profiling screen identify CD30 as a primary target of the Myc oncoprotein. CD30 is a member of the tumor necrosis factor superfamily and resides on the extracellular membrane; it is highly expressed in several lymphomas while acutely restricted in normal cells. Within the last few decades, CD30 has emerged as a diagnostic marker and therapeutic target of many lymphoproliferative diseases. However, the underlying mechanisms that regulate CD30 expression remain unclear. We report that CD30 is regulated at the transcriptional level by Myc. Through a genetic and biochemical approach, we define CD30 induction in a MYC-dependent manner across a variety of human cell lines of both lymphomagenic and non-lymphomagenic origin. Furthermore, deliberate modulation of Myc-activity demonstrates a positive correlation with CD30 surface protein expression in multiple malignancy models. With CD30 induction as a potential mechanism by which to identify and target Myc-driven oncogenesis, we can reshape detection and treatment of Myc-regulated cancer. Citation Format: Victoria Gennaro, Xiao-yong Zhang, Lauren DeSalle, Duonan Yu, Andrei Thomas-Tikhonenko, Christopher Vakoc, Steven B. McMahon. Identification of CD30/TNFRSF8 as a primary target of the Myc oncoprotein and potential biomarker of Myc-driven cancer. [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 4553.
Abstract 2945: Cell stress during HIPEC causes heat shock protein induction and reduced chemosensitivity in human colon cancer
Authors: Tanja Grimmig, Kerstin Kloos, Rebecca Thumm, Romana Moench, Christoph T. Germer, Ana Maria Waaga-Gasser, Martin Gasser
Journal: Cancer Research (2016)

Abstract Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising procedure for the treatment of peritoneal carcinomatosis (PC). Heat shock proteins (HSPs) and other proteins involved in cellular repair mechanisms seem to induce cytoprotective processes during HIPEC therapy. Therefore, the aim of this study was to analyze the effects of HIPEC-related conditions on tumor cell proliferation and the expression of HSPs in human colon cancer. Methods: Human colon cancer cell lines HT29, SW480 and SW620 were exposed to different temperatures (37°C, 41°C, and 43°C) as well as defined cytostatic agents (Oxaliplatin, Mitomycin C, and 5-Fluorouracil). After cellular regeneration (30 min, 24 h, 48 h and 72 h) RNA isolation and whole cell extraction was performed. Gene and protein expression analysis of HSP27, 70, 72 and 90 as well as PCNA, Ki-67, BCl-2 and BCl-Xl were carried out using RT-qPCR and Western blot. Additionally, MTS cell proliferation assays were performed 24 h, 48 h, 72 h and 96 h post treatment. Moreover, AnnexinV apoptosis assays were conducted. Results: All colon cancer cells exposed to hyperthermic conditions showed initially up-regulated HSP gene expression. Highest expression was found after exposure to 43°C. Combined cytostatic and hyperthermic treatment demonstrated additional increase in HSP27 expression and in other HSPs to a lesser degree. Tumor cells exposed to cytostatic agents showed overall higher HSP gene expression compared to cells without chemotoxic treatment. Similar effects were detected for the expression of the proliferation marker PCNA and anti-apoptotic protein BCl-Xl. Apoptosis assay demonstrated decreased numbers of apoptotic cells at 43°C compared to normothermia. Additionally, proliferation assays revealed reduced chemosensitivity in cells treated with hyperthermia. Conclusion: Desired effects of hyperthermia used in HIPEC therapy to achieve anti-proliferative and apoptosis inducing effects seem to be negatively influenced by cell stress mediated repair mechanisms in colon cancer. Our in vitro findings suggest analyzed HSPs to be significantly involved in this hyperthermia and chemotoxicity mediated cellular repair mechanisms. While initial increase in HSP expression can counteract cytotoxic effects during HIPEC therapy their prolonged expression may promote lasting resistance to cellular stress. Citation Format: Tanja Grimmig, Kerstin Kloos, Rebecca Thumm, Romana Moench, Christoph T. Germer, Ana Maria Waaga-Gasser, Martin Gasser. Cell stress during HIPEC causes heat shock protein induction and reduced chemosensitivity in human colon cancer. [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 2945.
Abstract 1714: The role of Hedgehog signaling in the regulation of human colon cancer stem cells
Authors: Joseph L. Regan, Stephanie Staudte, Dirk Schumacher, Ulrich Keilholz, Johannes Haybaeck, Hans Lehrach, Marie-Laure Yaspo, David Henderson, Andreas Steffen, Joern Toedling, Ralf Lesche, Reinhold Schaefer, Christian R. Regenbrecht, Dominik Mumberg, Martin Lange
Journal: Cancer Research (2016)

Abstract Recent data support a hierarchical model of colon cancer in which tumor growth is driven by a subpopulation of cancer stem cells (CSCs) that may also be the source of relapse following treatment. Elucidation of the cellular heterogeneity within a tumor would therefore facilitate better characterization of patient subtypes and lead to more personalized and effective treatments. Here, as part of the OncoTrack* consortium, we report the use of Matrigel-based 3D in vitro models of patient-derived colon cancer for the characterization of molecular pathways important in the regulation of CSC self-renewal and survival. Cellular subpopulations were isolated from patient-derived 3D-culture models based on expression of the CSC marker aldehyde dehydrogenase (ALDH) and then functionally tested for tumor initiation and self-renewal capacity by limiting dilution serial xenotransplantation. These studies demonstrate CSCs to be ALDH+. ALDH+ and ALDH- cells from 3D-culture and xenograft models were then subjected to RNA sequencing for whole transcriptome analysis. These analyses demonstrated ALDH+ CSCs cells to be enriched for stem cell associated genes (ALDH1A1, LGR5, BMI1, CD44, CD166), developmental processes (embryonic, tissue development, EMT) and signaling pathways (Wnt signaling). In particular, the Hedgehog signaling pathway was found to be enriched in both 3D in vitro and xenograft models. The role of Hedgehog signaling in colon cancer remains controversial. It has been reported as a negative regulator of Wnt signaling and to be inactive in colon cancer cells lines. Here, using small molecule inhibitors and lentivirus mediated gene knockdown, we report on the role of Hedgehog signaling in the regulation of colon CSC self-renewal and identify non-canonical Hedgehog signaling as a positive regulator of Wnt signaling. *The research leading to these results has received funding from the European Union's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under grant agreement n°115234. Citation Format: Joseph L. Regan, Stephanie Staudte, Dirk Schumacher, Ulrich Keilholz, Johannes Haybaeck, Hans Lehrach, Marie-Laure Yaspo, David Henderson, Andreas Steffen, Joern Toedling, Ralf Lesche, Reinhold Schaefer, Christian R. Regenbrecht, Dominik Mumberg, Martin Lange. The role of Hedgehog signaling in the regulation of human colon cancer stem cells. [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 1714.
Use of Opioid Agonist Therapy for Medicare Patients in 2013
Authors: Anna Lembke, Jonathan H. Chen
Journal: JAMA Psychiatry (2016)

Despite public policy efforts to prevent opioid overdose and addiction, opioid overdose rates reached record high numbers in 2014. 1 The population that uses Medicare, the federal insurance program for Americans who have certain disabilities or are 65 years or older, has among the highest and most rapidly growing prevalence of opioid use disorder, with more than 6 of every 1000 patients (more than 300 000 of 55 million) diagnosed 2 and with hospitalizations increasing 10% per year. 3Data on patients with commercial insurance plans (the other likely source for national population data) show just more than 1 of every 1000 patients diagnosed. 2Prevention initiatives are essential for reducing the number of new patients with opioid use disorder, but treatment will be required for those already addicted to opioids.Opioid agonist therapy (OAT), including buprenorphine-naloxone (Suboxone) and methadone, is the most effective pharmacotherapy for opioid addiction. 4 An analysis of Medicare data on buprenorphine-naloxone prescribing allows us to make inferences on prescribers' use of this treatment.Medicare Part D (prescription drug coverage) does not pay for methadone maintenance treatment for opioid addiction.Hence, buprenorphine-naloxone (or buprenorphine alone, in the case of pregnancy) is the only covered OAT option for patients with opioid use disorder.We hypothesized that the rates of buprenorphine-naloxone prescribing would be below the projected need.
Abstract 1839: Analysis of cell cycle-related gene expressions in MDM2-transfected LNCaP-MST cells after inhibition of HSP90
Authors: Thiagarajan Venkatesan, Ali Alaseem, Khalid Alhazzani, Priya Dondapati, Saad Alobid, Appu Rathinavelu
Journal: Cancer Research (2016)

Abstract MDM2 gene is a cellular proto-oncogene amplified in 25-40% of all human cancers and regulates cell proliferation, senescence, and apoptosis through targeting p53. It is widely speculated that MDM2 protein is not only responsible for tumorigenesis via p53 inactivation, but also for increasing the metastatic ability of originally non-metastatic tumor cells. HSP90 is a molecular chaperone that regulates the maturation, activation and stability of critical signaling proteins that drive the development and progression of prostate cancer. 17-Allyamino-17-demethoxygeldanamycin (17-AAG) is an inhibitor of HSP90, which causes proteasomal degradation of client proteins such as AR, HER2, Akt etc., leading to cell cycle arrest and substantial growth inhibition. HSP90 is also believed to be involved in the stabilization of MDM2 and therefore, inhibition of HSP90 is expected to accelerate degradation of MDM2 and disrupt its function. Hence, our study was designed to determine the expression profile of the genes in the cell cycle pathway following treatment of MDM2 overexpressing LNCaP-MST prostate cancer cells with 17-AAG (10 μM at 24 hrs). In the present study, Human cell cycle PCR array was used to examine the alterations in gene expression pattern following exposure to the 17-AAG in MDM2 overexpressed prostate cancer cells. In our experiments we observed that the genes impacted by MDM2 overexpression were reversed by HSP90 inhibition. The expression of genes such as CDC25A, CDC25C, AURKB and Survivin levels were significantly down-regulated after 17-AAG treatment, while p21 and GADD45A were up-regulated compared to the control LNCaP-MST. A heat map and scatterplot analysis clearly confirmed the alterations in the expression levels of these genes following 17-AAG treatment. It is expected that more thorough understanding of the consequences of HSP90 blockade, particularly those that are independent of its role as a regulator of p53, will reveal its therapeutic significance. Our results offer convincing evidence to suggest that the inhibition of HSP90 can induce cell cycle arrest in LNCaP-MST cells. (The financial support from the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida is gratefully acknowledged). Citation Format: Thiagarajan Venkatesan, Ali Alaseem, Khalid Alhazzani, Priya Dondapati, Saad Alobid, Appu Rathinavelu. Analysis of cell cycle-related gene expressions in MDM2-transfected LNCaP-MST cells after inhibition of HSP90. [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 1839.
P1315 : Design of the INCA trial (impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver cirrhosis and ascites): prospective, double-blind, randomised clinical trial evaluating the impact of genotype-stratified care
Authors: M. Casper, M. Mengel, C. Fuhrmann, E. Herrmann, M. Reichert, B. Appenrodt, F. Grünhage, F. Lammert
Journal: Journal of Hepatology (2015)