tbuckley/cabot-search huggingface dataset:
B-Cell Depletion — A Frontier in Monoclonal Antibodies for Multiple Sclerosis
Authors: Peter A. Calabresi
Journal: New England Journal of Medicine (2016)

Multiple sclerosis is a disabling autoimmune disease in which immune cells target central nervous system (CNS) antigens, leading to demyelination, glial activation, and subsequent loss of neurons and axons.1 There are three main subtypes of multiple sclerosis: relapsing–remitting, in which patients recover partly or fully from attacks but go on to have others; secondary progressive, in which patients with relapsing–remitting disease have progression of disability between attacks; and primary progressive, in which patients have continual progression from the time of onset of the disease.2 Over the past two decades, a remarkable number of new therapies have been developed that reduce . . .
443. A Comparison of Fetal Gene Therapy Outcomes in Early and Late Gestation
Authors: Citra Mattar, Arijit Biswas, Mahesh Choolani, Nuryanti Johana, Cecilia Rosales, Jenny McKintosh, Yi-Wan Tan, Amit Nathwani, Jerry Chan
Journal: Molecular Therapy (2015)

Fetal gene therapy (FGT) may eliminate clinical disease in monogeneic disorders by correcting aberrant protein production early in development. Early (eFGT) and late (lFGT) intervention suit different therapeutic aims. Critical assessment of long-term outcomes is required for clinical translation, which we have performed in a non-human primate (NHP) model using adeno-associated vector (AAV) expressing human Factor IX. Fetuses received 1-10E+12vg at 0.3-0.5G (eFGT) or 4E+12vg at 0.9G (lFGT). Long-term data is available up to 22 and 62 months for eFGT (n=6) and lFGT infants (n=6) respectively. AAV5 was used if the dam had pre-existing immunity to AAV8. Infants were monitored serially for protein levels and immune toxicity. To boost expression and test tolerance, subjects with protein levels <1% received 2E+11vg/kg of the same AAV serotype in a postnatal challenge. eFGT-AAV5 infants showed stable hFIX activity at 0-15%. AAV8 infants showed significantly higher activity at 10-37% in the first year, (median 15 vs 2%, p<10−3). Initial lFGT expression peaked in the first postnatal month and reached steady-state around day 60. Median expression was higher with AAV8, both during peak (246 vs 33%, p<10−4) and plateau phases (19 vs 8%, p<10−4). Steady-state expression was lower after eFGT with both AAV8 (16 vs 47%, p<10−4) and AAV5 (2 vs 12%, p<10−4). Males had higher expression regardless of serotype (24 vs 2%, p<10−3). eFGT infants showed a mild transient humoral response to AAV capsid while neutralizing antibody and T cell assays were negative. In contrast, lFGT resulted in more robust though transient AAV-IgG levels perinatally. In both groups AAV5 was the more immunogenic vector. Lowest hFIX levels corresponded to prolonged AAV-IgG response. Anti-hFIX IgG was negligible. Most infants maintained transgene expression despite the presence of binding antibodies. VCN in all organs was 1-3 log-folds lower in eFGT infants. Isolated gametes were transduced at a rate of 0.1vg/sperm cell (n=1/2 males) and 0.9vg/oocyte (n=1/3 females), only in lFGT infants. Brief transaminitis occurred without clinical toxicity. Postnatally-treated AAV5-eFGT infants (n=3) demonstrated brief hFIX increases to 3-10% over 60 days. Transient T cell activation occurred but neutralising antibodies were absent. AAV5-lFGT expression was raised to 1-2% without T cell activation. AAV8-lFGT showed no improvement after two postnatal doses; a robust cellular and humoral response was observed and maximum hFIX levels remained <1%. Both lFGT infants showed transient neutralising antibody expression. Outcomes of single-dose FGT thus depend on timing, dose, serotype, gender; immune reactions were not clinically damaging, and tolerance was observed. Germ-line transmission was observed with low frequency. FGT can be tailored to achieve the desired clinical outcomes in the target disease.
Abstract 3432: Dietary modifications of rectal cancer survivors to improve bowel function symptoms
Authors: Robert S. Krouse, Christopher S. Wendel, Wendy Demark-Wahnefried, Joanna E. Bulkley, Carmit K. McMullen, Marcia Grant, Mark C. Hornbrook, Andrea Altschuler, Virginia Sun, Lisa J. Herrinton
Journal: Cancer Research (2015)

Abstract Purpose: Rectal cancer (RC) survivors with and without permanent ostomy have similar bowel function challenges, and seek improvement of symptoms through dietary modifications. Identifying patient-reported dietary modifications among survivors with different surgical reconstructions can guide postoperative supportive care and improve health-related quality of life (HRQOL). Methods: We mailed a survey to long-term (≥5 years post-diagnosis) RC survivors enrolled in Kaiser Permanente (Northern California and Northwest). It included a question eliciting foods that were helpful with bowel function and the bowel symptoms that were impacted. Food types were recoded into broader categories based on food families developed around nutrition and common usage patterns and frequencies of food types and symptoms addressed were compared by sex and surgery type (ostomy vs. anastomosis). Results: Of the 577 RC survivors who responded to the survey, 201 (35%) responded to the question related to foods that helped bowel function. Food groups that most commonly were used were fruits other than prunes (16.3%) and vegetables (15.5%). Water was often used (9.2%). The only specific food that was commonly used was prunes (7.6%). Most foods cited were credited with helping prevent the constellation of symptoms and signs of constipation or bloating, followed by predictability. A few foods (e.g., bananas, bread, rice) were more likely to help with diarrhea. Helpful foods addressing constipation/bloating were more likely cited by women than men (55% vs. 44%, p = .007). Vegetables were more likely cited by anastomosis than ostomy subjects (18% vs. 11%, p = .03). Conclusions: Multiple dietary alterations are attempted by RC survivors. It appears very individualized, although multiple strategies can be suggested to improve bowel function. Through this exploratory analysis, strategies can be developed and tested for RC survivors. Citation Format: Robert S. Krouse, Christopher S. Wendel, Wendy Demark-Wahnefried, Joanna E. Bulkley, Carmit K. McMullen, Marcia Grant, Mark C. Hornbrook, Andrea Altschuler, Virginia Sun, Lisa J. Herrinton. Dietary modifications of rectal cancer survivors to improve bowel function symptoms. [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 3432. doi:10.1158/1538-7445.AM2015-3432
Quantitative Assessment of Circulating Clonal IG-VDJ Sequences in Plasma of Follicular Lymphoma at Diagnosis Is Highly Predictive of Progression Free Survival (PFS)
Authors: Clémentine Sarkozy, Sarah Huet, Victoria Carlton, Alain Delmer, Fabrice Jardin, Marie-Helene Delfau-Larue, Malek Faham, Gilles Salles
Journal: Blood (2015)
Problems measuring prostate-related utilities in low-literacy patients
Authors: R. M. Golub, S. J. Knight, S. Pickard, K. Kramer, E. A. Lyons, A. Arseven, M. S. Wolf, K. M. Colella, C. L. Bennett
Journal: Journal of Clinical Oncology (2004)

6129 Background: Measuring patient preferences for health states related to prostate cancer treatment outcomes provides valuable input to help patients make informed treatment decisions. The most accepted method for direct utility assessment is the standard reference gamble (SG). Methods: A pilot study was conducted with 21 newly diagnosed prostate cancer patients at a VA medical center. Each patient completed 6 standard gambles with health states including training exercises with mild and severe arthritis, current health, urinary incontinence, impotence, and both incontinence and impotence. They also rated each state using a visual analogue scale (VAS). The research assistant assessed patient comprehension. Responses were considered invalid if (1) they were inconsistent if combined symptoms were rated as better than either symptom alone, (2) the subject rated all scenarios at 0.5, (3) rank order of states differed from VAS, or (4) the subject rated all scenarios equal to perfect health AND the research assistant judged that there was incomprehension. Literacy was assessed in 19 of the subjects using the Rapid Estimate of Adult Literacy in Medicine (REALM). For comparative purposes, 5 urologists provided preferences for the same scenarios. Results: The mean REALM score (59) corresponded with 7th-8th grade literacy (low literacy is defined as < than 9th grade). Only 57% (12) patients gave potentially valid responses. There was a trend toward better performance in high literacy patients that did not reach statistical significance (χ2 p = 0.37). All urologists gave valid responses. Conclusions: Standard reference gamble assessments of utilities may be difficult to accurately assess in a VA population, particularly in patients with low literacy. Utilities directly elicited from low literacy patients should be done with caution, particularly when used to guide shared clinical decision-making or policy formation. No significant financial relationships to disclose.
Optimized Cyclophosphamide (CY) Dosing in Combination with Fludarabine, TBI and ATG As Conditioning for Unrelated Donor Bone Marrow Transplantation (BMT) in Severe Aplastic Anemia (SAA): A Phase I/II Study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN)
Authors: Paolo Anderlini, Juan Wu, H. Joachim Deeg, Iris Gersten, Marian Ewell, Jakub Tolar, Joseph H. Antin, Sally Arai, Mitchell E. Horwitz, John M. McCarty, Ryotaro Nakamura, Michael A. Pulsipher, Roberta H. Adams, Eric Leifer, Shelly L Carter, Nancy L DiFronzo, Mary M. Horowitz, Dennis L. Confer, Mary Eapen
Journal: Blood (2014)
Pemetrexed versus pemetrexed plus carboplatin in pretreated patients with advanced non-small cell lung cancer (NSCLC): Pooled analysis of two randomized trials.
Authors: A. Ardizzoni, L. Boni, M. Tiseo, A. Vincent, R. Passalacqua, A. Camerini, R. Labianca, G. Genestreti, F. Zanelli, L. Ciuffreda, F. Di Costanzo, F. De Marinis, L. Crinò, A. Santo, A. Pazzola, F. Barbieri, N. Zilembo, I. Colantonio, C. Tibaldi, E. F. Smit
Journal: Journal of Clinical Oncology (2011)

7555 Background: To evaluate the benefit of adding carboplatin (C) to pemetrexed (P) chemotherapy (CT) in 2nd-line therapy of advanced NSCLC, by pooling results of 2 identical randomized phase II trials (GOIRC 02.2006 and NVALT-7) carried out in Italy and The Netherlands, respectively. Methods: Eligibility criteria in both trials included: diagnosis of advanced NSCLC, disease progression after 1st-platinum-based CT and PS 0-2. Patients (pts) were randomized to P 500 mg/m2 alone or combined with C AUC5 every 3 weeks. The pooled analysis was pre-planned and designed to assess the impact of adding C to P in terms of overall survival (OS) in the overall population and in certain subgroups. Results: A total of 479 pts were randomized in the 2 trials. Pts characteristics were: male gender 68%, median age 62 (range 36-84), PS 0/1 45/49%, squamous histology 19%, stage IV 79%, interval from last 1st-line CT ≥ 3 months in 71% of pts, prior response to 1st-line 50%. In the overall population, survival was not improved by the addition of C to P; the HR for death was 0.88 (95%CI: 0.71-1.07; p = 0.202; p for heterogeneity = 0.693). Objective response rate was increased in the C-containing arm with an OR of 1.78 (95%CI: 1.01-3.12; p = 0.046; p for heterogeneity = 0.060). A non-statistically significant increase in PFS favouring combined CT was observed with a HR of 0.85 (95%CI: 0.71-1.02; p = 0.082; p for heterogeneity = 0.019). In the subgroup analyses, there was a statistically significant interaction between histological subtype and treatment: in fact, the addition of C to P in pts with squamous tumours led to a statistically significant improvement of PFS from 2 to 3.2 months (adjusted HR: 0.42; 95%CI 0.27-0.65; p of interaction test = 0.001) and of OS from 5.4 to 9 months (adjusted HR: 0.57; 95%CI 0.36-0.90; p of interaction test = 0.05). Conclusions: Single agent P remains the standard of care 2nd-line CT in pts with relapsed non-squamous lung tumors. Although P has presently no indication in the treatment of squamous subtype NSCLC, the results of this pooled analysis can support further investigation of the carboplatin-pemetrexed regimen in the 2nd-line treatment of this histological subtype.
Abstract 1048: Chromatin remodelers are frequently disrupted by epigenetic and genetic alterations at an early stage of carcinogenesis
Authors: Hideyuki Takeshima, Tohru Niwa, Takamasa Takahashi, Takayuki Ando, Hirokazu Taniguchi, Hitoshi Katai, Toshiro Sugiyama, Toshikazu Ushijima
Journal: Cancer Research (2015)

Abstract Chromatin remodeling factors (chromatin remodelers), such as SWI/SNF and ISWI complexes, regulate gene transcription by modulating chromatin accessibility. Genes encoding subunits of chromatin remodelers are frequently disrupted by loss of function mutations in various types of cancers. In contrast, inactivation of chromatin remodelers by epigenetic alterations, such as aberrant DNA methylation, is unknown. In this study, we aimed to clarify 1) whether or not chromatin remodelers are inactivated by aberrant DNA methylation, and 2) the timing of this occurrence. DNA methylation statuses of 16 genes encoding chromatin remodelers with promoter CpG islands were analyzed in non-cancerous tissues of male gastric cancer patients using an Infinium HumanMethylation450 BeadChip array. Among the 16 genes, two genes, ACTL6B and SMARCA1, were frequently methylated in non-cancerous gastric tissues. Among these genes, SMARCA1 was expressed at high levels in normal gastric tissues, but ACTL6B was not. In four of 50 primary gastric cancers, SMARCA1 was aberrantly methylated. It was re-expressed after treatment with a DNA demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC), in gastric cancer cell lines, AGS and GC2. Somatic mutations of 18 genes encoding chromatin remodelers were analyzed using a next-generation personal sequencer in the 50 primary gastric cancers. Nine genes, ARID1A, ARID1B, ARID2, SMARCA1, SMARCA2, SMARCA4, SMARCB1, PBRM1, and PHF10, were mutated in one or more of the 50 gastric cancers. The mutant allele frequency was close to the cancer cell content in cancer samples with a specific mutation of a chromatin remodeler. Depletion of a chromatin remodeler, SMARCA1 or SMARCA2, by shRNAs in cancer cell lines promoted their growth. These results showed that epigenetic and genetic alterations of chromatin remodelers are induced at an early stage of carcinogenesis (Takeshima et al., Cancer Letters, in press). Citation Format: Hideyuki Takeshima, Tohru Niwa, Takamasa Takahashi, Takayuki Ando, Hirokazu Taniguchi, Hitoshi Katai, Toshiro Sugiyama, Toshikazu Ushijima. Chromatin remodelers are frequently disrupted by epigenetic and genetic alterations at an early stage of carcinogenesis. [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 1048. doi:10.1158/1538-7445.AM2015-1048
A New Chimeric Antigen Receptor (CAR) Targeting the CD23 Antigen Expressed by Chronic Lymphocytic Leukemia (B-CLL) Cells
Authors: Greta Maria Paola Giordano Attianese, Valentina Hoyos, Virna Marin, Barbara Savoldo, Irene Pizzitola, Valentina Agostoni, Matteo Parma, Maria Teresa Sabrina Bertilaccio, Paolo Ghia, Andrea Biondi, Gianpietro Dotti, Ettore Biagi
Journal: Blood (2010)
A Macromolecular Signaling Complex Formed by CXCR4, VLA4 and hERG1 K+ Channels Mediates Bone Marrow-Induced Chemo-Resistance in Childhood Acute Lymphoblastic Leukemias: Shortcoming Effects of hERG1 Channels Inhibitors.
Authors: Serena Pillozzi, Marika Masselli, Amedeo Amedei, Giuseppe Gaipa, Andrea Biondi, Dario Campana, Andrea Becchetti, Annarosa Arcangeli
Journal: Blood (2008)
Quantitative and Qualitative Analysis of Regulatory T Cells (Tregs) in B Cell Chronic Lymphocytic Leukemia (B-CLL)
Authors: Vassiliki Mpakou, Dikea-Eleni Ioannidou, Myrofora Vikentiou, Eugenia Konsta, Aris Spathis, Frieda Kontsioti, Christos Kontos, Diamantina Vasilatou, Anthi Bouchla, Kostas Gontopoulos, Christoforos Roubakis, Georgia Stavroulaki, Nikos Papanikolaou, Maria Atta, Sotiris Papageorgiou, Efi Bazani, Christina Economopoulou, Stela Kokkori, Elias Kyriakou, George Dimitriadis, Vassiliki Pappa
Journal: Blood (2015)
Contralateral Prophylactic Mastectomy Decisions in a Population-Based Sample of Patients With Early-Stage Breast Cancer
Authors: Reshma Jagsi, Sarah T. Hawley, Kent A. Griffith, Nancy K. Janz, Allison W. Kurian, Kevin C. Ward, Ann S. Hamilton, Monica Morrow, Steven J. Katz
Journal: JAMA Surgery (2016)

Contralateral prophylactic mastectomy (CPM) use is increasing among women with unilateral breast cancer, but little is known about treatment decision making or physician interactions in diverse patient populations.
Fludarabine Busulfan Compared to Fludarabine Melphalan Is Associated with Increased Relapse Risk in Reduced Intensity Conditioning Transplant Despite Pharmacokinetic Dosing
Authors: Moussab Damlaj, Hassan B Alkhateeb, Daniel K. Partain, Jehad Almasri, Mehrdad Hefazi, Shahrukh K. Hashmi, Dennis A. Gastineau, Aref Al-Kali, Robert C Wolf, Naseema Gangat, Mark R Litzow, William J Hogan, Mrinal M Patnaik
Journal: Blood (2015)
Abstract 176: MicroRNA-122 is a potential regulator of DNA methylation partly by affecting the global level profile of 5hmC
Authors: Ann-Ping Tsou, Kuan-Hua Wang, Hsi-Yuan Huang, Li-Jung Chen, Tze-Tze Liu
Journal: Cancer Research (2015)

Abstract MicroRNA-122 is a liver specific microRNA. Previously, we demonstrated that Mir122a-/- mice developed steatohepatitis, fibrosis and HCC which recapitulates the multistep hepatocarcinogenesis found in human. In addition, we detected a global change of gene expression involving upregulation of 606 genes and downregulation of 280 genes. Among the genes highly differentially expressed in Mir122a-/- livers are several classic imprinted genes H19/Igf2, Meg3, Mirg, Gdf10 and Rian. Imprinting of both H19/Igf2 and Mirg loci is controlled by CTCF, which is a direct target of miR-122. These earlier findings imply that miR-122 may have a role in epigenetic regulation. Recently, the active demethylation pathway involving 5-hydroxymethylcytosine (5hmC) and TET (tet methylcytosine dioxygenase) enzymes are found to regulate the genome epigenetically. 5hmC epigenetic mark was found to associate with human cancer development with frequent downregulation in cancers, including HCC. We detected a progressive loss of 5hmC in liver, the tumor-adjacent tissues and liver tumors of Mir122a-/- mice similar to that of human HCC. Loss of 5hmC is accompanied with downregulation of DNA dioxygenase (Tet1 and Tet3), and upregulation of DNA deaminases (Apobec1 and Apobec3) as well as DNA glycosyalse (Smug1) in Mir122a-/- tumors. A genome-wide profiling of 5hmC was performed to delineate the dynamic changes of DNA methylation. The 5hmC-containing genomic DNA fragments were collected and sequenced. Our preliminary results showed that Mir122a-/- livers appear to have significantly fewer 5hmC peaks and covered smaller portion of the genome than that of WT. Even fewer 5hmC peaks covering small portion of the genome were detected for the Mir122a-/- liver tumor samples. The number of identified 5hmC peaks follows the order of WT &amp;gt; Mir122a-/- (2-month) &amp;gt; tumor-adjacent liver tissue &amp;gt; tumor of Mir122a-/-, a trend that is in agreement with quantification of 5hmC by both IHC and DNA dot blotting. The preliminary finding that aberrant DNA demethylation was initiated in young Mir122a-/- mice suggests that active demethylation is likely an early event of hepatocarcinogenesis. Note: This abstract was not presented at the meeting. Citation Format: Ann-Ping Tsou, Kuan-Hua Wang, Hsi-Yuan Huang, Li-Jung Chen, Tze-Tze Liu. MicroRNA-122 is a potential regulator of DNA methylation partly by affecting the global level profile of 5hmC. [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 176. doi:10.1158/1538-7445.AM2015-176
Abstract 699: PIK3CA/BRAF mutations negatively affect outcome of patients with KRAS wild-type metastatic colorectal cancer treated with front line anti-EGFR monoclonal antibodies: Meta-analysis results
Authors: Amr Mohamed, Kelly Schrapp, Taraq Attumi, Nabil F. Saba, Bassel F. El-Rayes
Journal: Cancer Research (2015)

Abstract BACKGROUND:The aim of this meta-analysis is to evaluate the effect of PIK3CA and BRAF mutations in patients with KRAS wild-type metastatic colorectal cancer receiving an EGFR monoclonal antibody (anti-EGFR) inhibitor in the first line therapy. METHODS:literature search was performed to identify studies exploring the association between PIK3CA/BRAF mutations and clinical outcomes of KRAS wild mCRC patients treated with anti-EGFR as a first line therapy. The primary clinical outcome is response rate (RR). The secondary outcomes include progression-free survival (PFS), and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed effect model or random effect model according to heterogeneity between studies. RESULTS:Ten studies with 1,470 mCRC patients (357 for PI3K studies and 1,113 from BRAF studies) met selection criteria. We observed a trend towards lower RR in patients with PIK3CA mutations (2 studies, 137 patients; RR = 14.3% versus 52.4%; 95% confidence interval (CI) -0.12-0.02; P = 0.13). Patients with mutant-type PI3K have significant shorter PFS (3.8 vs 4.15 mos, HR = 1.36; 95% CI 1.04-1.77; P = 0.02), and OS (14.17 Vs 16.3 mos., HR = 1.50; 95% CI 1.14-1.97; P = 0.004) compared to those with wild PI3K. For BRAF, patients with mutant type have significant lower RR [4 studies, 416 patients; RR = 33% versus 39%; 95% confidence interval (CI) -0.16- 0.01; P = 0.03], shorter PFS (6 studies, 893 pts., 3.9 Vs 5.7 mos., HR = 1.72; 95% CI 1.47- 2.01; P = 0.00001), and shorter OS (6 studies, 1065 pts., 9.1 Vs 18.9 mos., HR = 1.22; 95% CI 1.04-1.44; P = 0.01) compared to those with wild type. CONCLUSION:These analyses suggest that patients with colorectal cancer and either PIK3CA or BRAF mutation have worse outcome when treated with anti-EGFR in the first line. Given their worse outcome, trials evaluating novel agents are needed in this group of patients. Meta-analyses on BRAFF and PIK3CA mutations in KRAS wild mCRCBRAF WildBRAF MutantHR (95% CI)p-valuePI3K WildPI3K MutantHR (95% CI)p-valueRR (%)39%33%-0.16 - 0.010.0352.4%14.3%-0.12 - 0.020.13PFS (mos)5.73.91.47 - 2.010.000014.153.81.04 - 1.770.02OS (mos)18.99.11.04 - 1.440.0116.314.71.14 - 1.970.004 Citation Format: Amr Mohamed, Kelly Schrapp, Taraq Attumi, Nabil F. Saba, Bassel F. El-Rayes. PIK3CA/BRAF mutations negatively affect outcome of patients with KRAS wild-type metastatic colorectal cancer treated with front line anti-EGFR monoclonal antibodies: Meta-analysis results. [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 699. doi:10.1158/1538-7445.AM2015-699