tbuckley/cabot-search huggingface dataset:
Treatment of human immunodeficiency virus (HIV)–associated Burkitt lymphoma (BL) in the era of combined antiretroviral therapy (cART) and rituximab.
Authors: M. W. Evans, M. R. Baer, I. Gojo, A. Rapoport, A. S. Kimball, A. Zimrin
Journal: Journal of Clinical Oncology (2011)

e18521 Background: The best treatment for HIV-associated BL has not yet been defined. cART allows more aggressive treatment, including hyperCVAD. Recently, rituximab has improved outcomes in HIV patients when added to EPOCH. To our knowledge, this study constitutes the largest single institution experience treating HIV-associated BL in the cART and rituximab era. Methods: We identified 122 patients with HIV and non-Hodgkin’s Lymphoma (NHL) treated at our institution from 2000 to 2010. Review of these records yielded 23 patients with HIV-associated BL. Results: Of the 23 patients, 21 were treated with curative intent; 1 patient opted for hospice; 1 patient received single agent rituximab prior to rapid progression of disease. Of the patients treated with curative intent, 14 received R-EPOCH and 7 received R-hyperCVAD. Median CD4 cell count for R-EPOCH and R-hyperCVAD treated patients was 179 X 106 cells/L (17 to 525) and 300 X 106 cells/L (3 to 430), respectively. 7 (50%) R-EPOCH patients had CD4 cell count < 200 X 106 cells/L, versus 2 (29%) R-hyperCVAD patients. For the R-EPOCH patients, lymphoma stage was IV in 8, III in 5 patients and II in 1 patient. For the R-Hyper-CVAD patients, 6 had stage IV disease and 1 had stage IE disease. Complete response (CR) was achieved in 10 R-EPOCH patients (71%) and 3 R-HyperCVAD patients (43%). 4 (29%) patients treated with R-EPOCH and 3 (43%) treated with R-Hyper-CVAD had primary refractory disease. One R-EPOCH patient was lost to follow up and one R-hyperCVAD patient succumbed to an infectious cause of death prior to assessment of response. Significant complications included neutropenic fever in 6 (86%) versus 4 (29%) patients and tumor lysis in 3 (43%) versus 2 (14%) patients for R-hyperCVAD and R-EPOCH, respectively. Other infectious complications included disseminated histoplasmosis in one R-EPOCH patient, toxoplasmosis and fungemia in two separate R-hyperCVAD patients. Conclusions: Our findings suggest that treatment with R-EPOCH may result in a higher rate of CR and lower rate of infectious complications and tumor lysis than R-hyperCVAD for patients with HIV-associated BL.
Treatment of FLT3-ITD Positive AML Relapsing After Allogeneic Hematopoietic Stem Cell Transplant (HSCT) with Sorafenib.
Authors: Manish R Sharma, Farhad Ravandi, Alexandre Chiattone, Partow Kebriaei, Uday Popat, Sergio Giralt, Qaiser Bashir, Muzaffar H. Qazilbash, Yago Nieto, Carrie Hai-Lai Yuen, Simrit Parmar, Hagop M. Kantarjian, Jorge Cortes, Tapan Kadia, Gautam Borthakur, Richard E. Champlin, Marcos De Lima
Journal: Blood (2010)
Inherited CD70 deficiency in humans reveals a critical role for the CD70–CD27 pathway in immunity to Epstein-Barr virus infection
Authors: Kazushi Izawa, Emmanuel Martin, Claire Soudais, Julie Bruneau, David Boutboul, Rémy Rodriguez, Christelle Lenoir, Andrew D. Hislop, Caroline Besson, Fabien Touzot, Capucine Picard, Isabelle Callebaut, Jean-Pierre de Villartay, Despina Moshous, Alain Fischer, Sylvain Latour
Journal: The Journal of Experimental Medicine (2016)

Epstein-Barr virus (EBV) infection in humans is a major trigger of malignant and nonmalignant B cell proliferations. CD27 is a co-stimulatory molecule of T cells, and inherited CD27 deficiency is characterized by high susceptibility to EBV infection, though the underlying pathological mechanisms have not yet been identified. In this study, we report a patient suffering from recurrent EBV-induced B cell proliferations including Hodgkin’s lymphoma because of a deficiency in CD70, the ligand of CD27. We show that EBV-specific T lymphocytes did not expand properly when stimulated with CD70-deficient EBV-infected B cells, whereas expression of CD70 in B cells restored expansion, indicating that CD70 on B cells but not on T cells is required for efficient proliferation of T cells. CD70 was found to be up-regulated on B cells when activated and during EBV infection. The proliferation of T cells triggered by CD70-expressing B cells was dependent on CD27 and CD3 on T cells. Importantly, CD27-deficient T cells failed to proliferate when stimulated with CD70-expressing B cells. Thus, the CD70–CD27 pathway appears to be a crucial component of EBV-specific T cell immunity and more generally for the immune surveillance of B cells and may be a target for immunotherapy of B cell malignancies.
Abstract 1240: Boric acid inhibits cell proliferation through RB1 protein in head and neck cancer
Authors: Esra Gunduz, Omer Faruk Hatipoglu, Sadık Cigdem, Kubra Erdogan, Mustafa Semih Elitok, Reidar Grenman, Husamettin Erdamar, Mehmet Gunduz
Journal: Cancer Research (2015)

Abstract Boric acid is a very common chemical used in a wide variety of applications as well as in medicine. In this study, the usage of boric acid as a potential alternative cancer therapeutic was investigated by examining its effect in head and neck cancer cell line proliferation and tumor suppressor gene expression. Head and neck cancer cell lines UT-SCC 6A, 6B, 9A, 16A, 16B, 24A, 54C, 74A, and 74B were treated with varying doses of boric acid, ranging from 200 ug/mL to 1800 ug/mL and XTT assay was used to measure the dose response. Subsequently, RNA was isolated from treated cells and was converted to cDNA to evaluate the expression of P53, RB1, ING1 and ING3 via Real-time PCR. Also protein was isolated from the same cell lines for Western Blot analysis. Boric acid treatment caused a significant decrease in proliferation in all of the head and neck cancer cell lines investigated, including UT-SCC 6A, 6B, 9A, 16A, 16B, 24A, 54C, 74A, and 74B. Results from boric acid treatment and untreated controls were analyzed for statistical significance using Mann Whitney U test. The results approached statistical significance with p value of 0.05. After determining the effective doses, cell lines were treated with boric acid and gene expression of P53, RB, ING1 and ING3 were analyzed. All of the genes’ expression were increased in several of the cell lines examined. We couldn't detect the protein expression of ING1 and ING3. But we’ve detected the higher expression of Phospho (PP)-RB and Bax, lower expression of bcl2 protein. In short, our results displayed similar results to prostate cancer reported in literature in terms of inhibition of proliferation. We’ve showed that boric acid has reduced levels of cell proliferation in head and neck cancer cell lines for the first time in our study. Also higher expression of PP-RB indicated that boric acid stopped cell cycle at G1. As a pro-apoptotic Bax expression was up-regulated and anti-apoptotic bcl2 was down-regulated in some of the cell lines showing that boric acid may lead the cells to apoptosis. In the light of these results, boric acid appears to be a candidate alternative therapeutic agent for cancer. Of course, further experiments are necessary in order to strengthen this conclusion. Citation Format: Esra Gunduz, Omer Faruk Hatipoglu, Sadık Cigdem, Kubra Erdogan, Mustafa Semih Elitok, Reidar Grenman, Husamettin Erdamar, Mehmet Gunduz. Boric acid inhibits cell proliferation through RB1 protein in head and neck cancer. [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 1240. doi:10.1158/1538-7445.AM2015-1240
VEGF <sub>165</sub> b Modulates Endothelial VEGFR1–STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease
Authors: Vijay Chaitanya Ganta, Min Choi, Anna Kutateladze, Brian H. Annex
Journal: Circulation Research (2016)

Atherosclerotic-arterial occlusions decrease tissue perfusion causing ischemia to lower limbs in patients with peripheral arterial disease (PAD). Ischemia in muscle induces an angiogenic response, but the magnitude of this response is frequently inadequate to meet tissue perfusion requirements. Alternate splicing in the exon-8 of vascular endothelial growth factor (VEGF)-A results in production of proangiogenic VEGFxxxa isoforms (VEGF165a, 165 for the 165 amino acid product) and antiangiogenic VEGFxxxb (VEGF165b) isoforms.The antiangiogenic VEGFxxxb isoforms are thought to antagonize VEGFxxxa isoforms and decrease activation of VEGF receptor-2 (VEGFR2), hereunto considered the dominant receptor in postnatal angiogenesis in PAD. Our data will show that VEGF165b inhibits VEGFR1 signal transducer and activator of transcription (STAT)-3 signaling to decrease angiogenesis in human and experimental PAD.In human PAD versus control muscle biopsies, VEGF165b: (1) is elevated, (2) is bound higher (versus VEGF165a) to VEGFR1 not VEGFR2, and (3) levels correlated with decreased VEGFR1, not VEGFR2, activation. In experimental PAD, delivery of an isoform-specific monoclonal antibody to VEGF165b versus control antibody enhanced perfusion in animal model of severe PAD (Balb/c strain) without activating VEGFR2 signaling but with increased VEGFR1 activation. Receptor pull-down experiments demonstrate that VEGF165b inhibition versus control increased VEGFR1-STAT3 binding and STAT3 activation, independent of Janus-activated kinase-1)/Janus-activated kinase-2. Using VEGFR1+/- mice that could not increase VEGFR1 after ischemia, we confirm that VEGF165b decreases VEGFR1-STAT3 signaling to decrease perfusion.Our results indicate that VEGF165b prevents activation of VEGFR1-STAT3 signaling by VEGF165a and hence inhibits angiogenesis and perfusion recovery in PAD muscle.
Translational significance of a newly identified hepatocellular carcinoma tumor suppressor gene on chromosome 8p.
Authors: Han Chong Toh, Francis Enane, Marissa Teo, Hideki Makishima, JoAnna Ng, Chit Lai Chee, Soo Fan Ang, Kiat Hon Lim, Yogen Saunthararajah
Journal: Journal of Clinical Oncology (2013)

e15097 Background: After deletion of 17p that removes the tumor suppressor gene (TSG) TP53, deletion of 8p is the next most common chromosome abnormality in hepatocellular carcinoma (HCC). However, 8p TSG are insufficiently defined. Methods: Integrated genomic analysis of HCC and non-malignant liver obtained at therapeutic segmentectomy from the same patients. Results: A minimally deleted region on 8p was identified by SNP array. This incorporated GATA4. Therefore, GATA4 was Sanger sequenced in paired HCC/non-malignant liver: recurrent somatic non-synonymous missense mutations were identified in exon 4 (V267M n=5) or exon 6 (S357T n=6, R362N n=2, T366R n=2). Biallelic abnormalities were deletion and mutation (n=6) or mutation and uniparental disomy (n=4), with mutation or deletion of at least one GATA4 allele in 29/47 (62%) of HCC cases. The other GATA4 exons were mutation free. Although missense mutation is not intrinsically expected to decrease GATA4 expression, GATA4 mRNA was significantly decreased in cases with mutation as well as deletion (p&lt;0.01) compared to non-malignant liver or wild-type GATA4 HCC. GATA4 drives liver differentiation, and the biological significance of GATA4 deficiency was demonstrated by significant enrichment (49%) for liver differentiation genes (p&lt;1.2exp-124, Benjamini corrected) amongst genes with decreased expression in HCC compared to non-malignant liver. From an oncogenesis perspective, the most important of these hepatocyte genes (e.g., HNF4A, CEBPD) antagonize MYC to terminate proliferation: GATA4 introduction (expression vector) into HCC cells containing mutated or deleted GATA4 (HepG2 and PLC respectively) restored HNF4A and CEBPD expression, suppressed MYC protein, upregulated p27/CDKN1B that mediates cell cycle exit by maturation and significantly decreased HCC proliferation without apoptosis. In objectively quantified immunohistochemical analyses (ImageIQ), HCC cases with GATA4 mutation/deletion had significantly increased MYC protein (p&lt;0.05). Conclusions: 8p deletion/GATA4 mutation in HCC suppresses cell cycle exit by maturation, thus complementing 17p deletion that suppresses cell cycle exit by apoptosis.
PWE-044 Do patients presenting with obstructive symptoms, abnormal liver function tests and gallstones on ultrasound scanning require a magnetic resonance cholangiopancreatography before an endoscopic retrograde cholangiopancreatography?
Authors: N Chandra, C Hodgekiss, P Gupta, A Mee
Journal: Gut (2010)

<h3>Introduction</h3> Magnetic resonance cholangiopancreatography (MRCP) is considered the first-line investigation in patients with suspected common bile duct stones after ultrasound scanning (USS). We conducted a study to determine whether MRCP is indeed useful prior to endoscopic retrograde cholangiopancreatography (ERCP) in the management of patients presenting with symptoms of biliary obstruction, abnormal liver function tests (LFTs) and gallstones evident on USS. <h3>Methods</h3> We performed a retrospective casenote analysis for patients presenting with classical symptoms, abnormal LFTs and who had undergone each of the following investigations – USS, MRCP and ERCP – between January 2007 and June 2008. Patients were managed as an inpatient or outpatient depending on their clinical state. <h3>Results</h3> A total of 43 patients (31 female, mean age 63.2 years, 19 as inpatients) were identified. LFTs were abnormal: median bilirubin 8 (3–246); alkaline phophatase 146 (69–1650); alanine transferase 52 (16–752). In 26 patients (group 1), cholelithiasis without extrahepatic duct (EHD) dilatation was evident on USS. Within this group, a subsequent MRCP confirmed EHD stones in 77% of patients, EHD dilatation without stones in 4% and a clear, non-dilated EHD in 19%. Complete correlation between ERCP and MRCP findings occurred in 81% of patients. Three out of 5 patients with clear, non-dilated EHDs on MRCP had EHD stones at ERCP. 17 of the 43 patients had evidence of cholelithiasis and EHD dilatation without EHD stones (group 2). Subsequent MRCP revealed EHD stones in 71% and only EHD dilatation in 29%. Complete correlation between ERCP and MRCP was evident in 52% of cases. In four cases in which only EHD dilatation was noted on MRCP, ERCP revealed EHD stones. In four patients, ERCP failed to identify EHD stones but the median time interval between MRCP and ERCP was 13 days during which time a stone may have passed. ERCP provided identical and additional information when compared to MRCP in 96% and 76% of cases in groups 1 and 2, respectively. 38 out of 43 (88%) patients required therapeutic intervention at ERCP. No complications arose as a result of ERCP. <h3>Conclusion</h3> This observational study demonstrates that ERCP should remain the first-line imaging modality for the investigation and management of suspected EHD stones in the appropriate clinical setting. There is a strong correlation between ERCP and MRCP findings in patients with cholelithiasis, and in particular the cohort without EHD dilatation or stones. MRCP gave false reassurance that the duct was clear in 7 (16%) cases. In addition to therapeutic benefit, the sole use of ERCP will reduce cost by avoiding the need for an expensive investigation and reducing the length of hospital stay and follow-up.
Abstract A50: Genotype tunes PDAC tension to induce matricellular-fibrosis and tumor aggression
Authors: Hanane Laklai, Yekaterina Miroshnikova, Michael Pickup, Eric Collisson, Kim Grace, Alex Barrett, Ryan Hill, Johnathon Lakins, David Schlaepfer, Janna Mouw, Valerie LeBleu, Sergey Novitskiy, Julie Johansen, Valeria Poli, Rahgu Kalluri, Laura Wood, Matthias Hebrok, Kirk Hansen, Harold Moses, Valerie Weaver
Journal: Cancer Research (2016)

Abstract Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality. Nevertheless, anti-stromal therapies for pancreatic cancer patients have had mixed results, suggesting there are multifaceted, anti and pro-tumorigenic roles of fibrosis in tumor pathogenesis. We found that human PDACs lacking epithelial TGFβ activity have elevated epithelial Stat3 activity and develop a stiffer, matricellular-enriched fibrosis that associates with high epithelial tension and shorter patient survival. Using several Kras-driven mouse models, we found that both the loss of TGFβ signaling and elevated β1 integrin mechanosignaling engage a positive feedback loop whereby Stat3 signaling modulates pancreatic cancer malignancy by increasing matricellular fibrosis and tissue tension. By contrast, epithelial Stat3 ablation attenuated pancreatic malignancy by reducing the stromal stiffening and epithelial contractility induced by loss of TGFβ signaling. In PDAC patient biopsies, higher matricellular protein and activated Stat3 associated with SMAD4 mutation and shorter survival. The findings implicate epithelial actomyosin tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors, and highlight Stat3 as a key driver of the phenotype. These data illustrate how tumor genotype can directly tune tissue mechanics and support the development of genotype-driven, anti-stromal therapies targeting PDAC. Citation Format: Hanane Laklai, Yekaterina Miroshnikova, Michael Pickup, Eric Collisson, Kim Grace, Alex Barrett, Ryan Hill, Johnathon Lakins, David Schlaepfer, Janna Mouw, Valerie LeBleu, Sergey Novitskiy, Julie Johansen, Valeria Poli, Rahgu Kalluri, Laura Wood, Matthias Hebrok, Kirk Hansen, Harold Moses, Valerie Weaver.{Authors}. Genotype tunes PDAC tension to induce matricellular-fibrosis and tumor aggression. [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 A50.
Characteristics and Outcome of HIV Associated Classical Hodgkin's Lymphoma Among 68 Patients Included in the French ANRS CO16 Lymphovir Cohort Study
Authors: Caroline Besson, Remi Lancar, Sophie Prevot, Pauline Brice, Marie-Caroline Meyohas, Bruno Marchou, Jean Gabarre, Fabrice Bonnet, Cecile Goujard, Olivier Lambotte, Francois Boue, Nicolas Mounier, Marialuisa Partisani, Francois Raffi, Régis T Costello, Herve Ghesquieres, Houria Hendel-Chavez, Michele Genin, Lucie Marchand, Yassine Taoufik, Dominique Costagliola
Journal: Blood (2014)
Abstract 1077: Use of the SVClassify algorithm to classify pediatric solid tumor translocation variant calls as likely true or false positives
Authors: Jo Lynne Harenza, Hemang M. Parikh, Jun S. Wei, Xinyu Wen, Sivasish Sindiri, Rajesh Patidar, Marc Salit, Paul S. Meltzer, Javed Khan, Justin Zook
Journal: Cancer Research (2015)

Abstract With the advent of next-generation sequencing technologies, a variety of structural variant (SV) calling algorithms have been developed. However, these algorithms are generally not sensitive and specific, in part because they are biased toward identification of specific types or lengths of SVs. Thus, concordance among algorithms is often very low. At the National Institute of Standards and Technology (NIST), we have previously rigorously characterized sequencing biases across multiple sequencing platforms for the candidate NIST reference material, RM 8398 (the genome of individual NA12878). This yielded a high-confidence set of SNP and small indel (&amp;lt;40 bp) variant calls. To extend our methods to SVs, we have developed SVClassify, which classifies SVs as likely true or false positive variants by combining evidence from one or more sequencing datasets. For NA12878, we were able to separate a set of validated deletions from random genomic regions with false positive and false negative rates less than 5%. We also found that the set of validated deletions clustered into different categories, including heterozygous Alu deletions, homozygous Alu deletions, and other heterozygous deletions. Until now, SVClassify has only been used for classification of large deletions on the non-cancerous genome, NA12878. In order to assess the sensitivity and specificity of SVClassify for correctly classifying translocations, we are using the RSVSim R package to simulate different numbers of translocations within repeat regions of the human genome. Furthermore, we will investigate the performance of SVClassify on cancer genomes, particularly pediatric solid tumors, which exhibit extensively rearranged genomes compared to their normal counterparts. To do so, pediatric tumor and normal datasets from multiple sequencing technologies will be integrated. To represent a spectrum of translocations, we will assess variant calls from cancer genomes with varying degrees of rearrangements: neuroblastoma, Ewing sarcoma, and osteosarcoma. Finally, we will use SVclassify to classify candidate SV calls made using the Complete Genomics pipeline, as well as those made on Illumina datasets using the recently developed SMUFIN algorithm. Citation Format: Jo Lynne Harenza, Hemang M. Parikh, Jun S. Wei, Xinyu Wen, Sivasish Sindiri, Rajesh Patidar, Marc Salit, Paul S. Meltzer, Javed Khan, Justin Zook. Use of the SVClassify algorithm to classify pediatric solid tumor translocation variant calls as likely true or false positives. [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 1077. doi:10.1158/1538-7445.AM2015-1077