tbuckley/cabot-search huggingface dataset:
Mapping Sentinel Lymph Node Metastasis by Dual-probe Optical Imaging
Authors: Xiangyu Yang, Zhe Wang, Fuwu Zhang, Guizhi Zhu, Jibin Song, Gao-Jun Teng, Gang Niu, Xiaoyuan Chen
Journal: Theranostics (2016)

Purpose: Sentinel lymph node biopsy (SLNB) has emerged as the preferred standard procedure in patients with breast cancer, melanoma and other types of cancer. Herein, we developed a method to intra-operatively map SLNs and differentiate tumor metastases within SLNs at the same time, with the aim to provide more accurate and real-time intraoperative guidance. Experimental Design: Hyaluronic acid (HA), a ligand of lymphatic vessel endothelial hyaluronan receptor (LYVE)-1, is employed as a SLN mapping agent after being conjugated with a near-infrared fluorophore (Cy5.5). Different sized HAs (5, 10 and 20K) were tested in normal mice and mice with localized inflammation to optimize LN retention time and signal to background ratio. Cetuximab, an antibody against epidermal growth factor receptor (EGFR), and trastuzumab, an antibody against human epidermal growth factor receptor 2 (HER2), were labeled with near-infrared fluorophore (IRDye800) for detecting metastatic tumors. LN metastasis model was developed by hock injection of firefly luciferase engineered human head neck squamous carcinoma cancer UM-SCC-22B cells or human ovarian cancer SKOV-3 cells. The metastases within LNs were confirmed by bioluminescence imaging (BLI). IRDye800-Antibodies were intravenously administered 24 h before local administration of Cy5.5-HA. Optical imaging was then performed to identify nodal metastases. Results: Binding of HA with LYVE-1 was confirmed by ELISA and fluorescence staining. HA with a size of 10K was chosen based on the favorable migration and retention profile. After sequential administration of IRDye800-antibodies intravenously and Cy5.5-HA locally to a mouse model with LN metastases and fluorescence optical imaging, partially metastasized LNs were successfully distinguished from un-metastasized LNs and fully tumor occupied LNs, based on the different signal patterns. Conclusions: Fluorophore conjugated HA is a potential lymphatic mapping agent for SLNB. Dual-tracer imaging with the combination of lymphatic mapping agents and tumor targeting agents can identify tumor metastases within SLNs, thus may provide accurate and real-time intra-operative guidance to spare the time spent waiting for a biopsy result.
Transcatheter Aortic Valve Replacement in Younger Individuals
Authors: Art Sedrakyan, Sanket S. Dhruva, Jeffrey Shuhaiber
Journal: JAMA Internal Medicine (2016)

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The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness
Authors: Tuoqi Wu, Yun Ji, E. Ashley Moseman, Haifeng C. Xu, Monica Manglani, Martha Kirby, Stacie M. Anderson, Robin Handon, Elizabeth Kenyon, Abdel Elkahloun, Weiwei Wu, Philipp A. Lang, Luca Gattinoni, Dorian B. McGavern, Pamela L. Schwartzberg
Journal: Science Immunology (2016)

During chronic viral infections and in cancer, T cells become dysfunctional, a state known as T cell exhaustion. Although it is well recognized that memory CD8 T cells account for the persistence of CD8 T cell immunity after acute infection, how exhausted T cells persist remains less clear. Using chronic infection with lymphocytic choriomeningitis virus clone 13 and tumor samples, we demonstrate that CD8 T cells differentiate into a less exhausted TCF1high and a more exhausted TCF1low population. Virus-specific TCF1high CD8 T cells, which resemble T follicular helper (TFH) cells, persist and recall better than do TCF1low cells and act as progenitor cells to replenish TCF1low cells. We show that TCF1 is both necessary and sufficient to support this progenitor-like CD8 subset, whereas cell-intrinsic type I interferon signaling suppresses their differentiation. Accordingly, cell-intrinsic TCF1 deficiency led to a loss of these progenitor CD8 T cells, sharp contraction of virus-specific T cells, and uncontrolled viremia. Mechanistically, TCF1 repressed several pro-exhaustion factors and induced Bcl6 in CD8 T cells, which promoted the progenitor fate. We propose that the TCF1-Bcl6 axis counteracts type I interferon to repress T cell exhaustion and maintain T cell stemness, which is critical for persistent antiviral CD8 T cell responses in chronic infection. These findings provide insight into the requirements for persistence of T cell immune responses in the face of exhaustion and suggest mechanisms by which effective T cell-mediated immunity may be enhanced during chronic infections and cancer.
Outcome of primary mediastinal large B-cell lymphoma (PMBCL) in the pre- and post-rituximab era: The Stanford University experience.
Authors: L. S. Maeda, R. T. Hoppe, R. R. Balise, S. A. Rosenberg, S. J. Horning, R. Advani
Journal: Journal of Clinical Oncology (2011)

e18517 Background: For PMBCL the role of radiation therapy (RT) following rituximab (R)-based regimens is unknown. The purpose of this study was to evaluate the outcome of PMBCL according to treatment-specific eras and identify whether RT after R-based therapy improved outcome. Methods: We retrospectively identified patients (pt) with newly diagnosed PMBCL treated at Stanford over two eras: 1975-2002 (pre-R) and 2003-2009 (post-R). Charts were reviewed for pt characteristics, therapy, and outcomes. Freedom from progression (FFP) and overall survival (OS) were estimated by Kaplan Meier methods and differences in strata were compared with log rank tests. Comparisons of treatment regimens were performed using the Freeman-Halton extension of Fisher’s exact tests. Results: 80 pts were identified; pre-R era (n=54) and post-R era (n=26). Median age 33 years (range 19 to 68), 59% females, stage I-II (n=68), stage III-IV (n=9) and unknown (n=3). Pt characteristics were similar in the two eras. Treatment regimens in the pre-R era consisted of RT alone (n=4) or chemotherapy (CT) with CHOP (n=7), CHOP + RT (n=16), MACOP-B/BACOD (n=4), BACOD/MACOP/VACOP-B + RT (n=17), other (n=6), and post-R consisted of R-CHOP + RT (n=5), R-VACOP-B + RT (n=12), dose adjusted (DA) EPOCH-R (n=9). At a median follow-up of 5.3 years (14.5 years pre-R, 2.9 years post-R), the overall FFP and OS were 88% and 81%, respectively. FFP in the pre- and post-R eras was 81% versus 100% (p=0.0376) and OS 72% versus 100% (p=0.0167), respectively. Pts treated with CT + RT versus R-CT+/-RT had a FFP of 85% versus 100% (p=0.122) and OS 80% versus 100% (p=0.058), respectively. The outcome of pts in the R era treated with or without RT was identical with a 100% FFP and OS. Conclusions: Our data confirm improved outcomes for pts with PMBCL treated in the R era. The addition of RT after R-CT did not further benefit the FFP or OS. Our analysis, though limited by small numbers and short follow-up, confirm emerging data that RT may be avoided with the use of regimens like DA-EPOCH-R. Although these results require confirmation in a randomized prospective trial, the elimination of RT is an important consideration in an entity that predominantly affects young women.
460. Purification of AAV8 Using a Prototype Affinity Resin Compatible with cGMP Manufacturing
Authors: Colleen M. Dupuis, Amy A. Medeiros, Samuel C. Wadsworth, K. Reed Clark, Christopher J. Morrison
Journal: Molecular Therapy (2016)

Affinity interaction based resins have long been the foundation for various purification platforms of biological molecules. For the purification of rAAV, the affinity resin AVB Sepharose HP (AVB) has been used to successfully purify a number of different serotypes. However, to date the use of AVB for the purification of the AAV8 serotype has been relatively unsuccessful due in part to modest binding capacity. In this work we investigate the use of a new, prototype affinity resin for the purification of AAV8 from crude feed streams. Performance of the AVB and prototype resins were directly compared for the purification of selected AAV8 feed streams. Differences in capacities, loading steps, wash step tolerances and elution steps will be discussed. In addition, the resulting performance of purifying AAV8 using the prototype resin is directly compared against the best case performance of the AVB resin purifying a different serotype more commonly used on AVB. Finally, the scale-up use of the prototype resin from bench to manufacturing will be discussed. These results demonstrate that the prototype affinity resin is a viable option for the scaleable, chromatographic purification of AAV8 from crude harvest streams.
Treatment of Acute Leukemia During Pregnancy – 20 Years Experience
Authors: Valeri G Savchenko, Elena N Parovichnikova, Valentin G Isaev, Alina V Kokhno, Vera Troitskaya, Andrey N Sokolov, Elena N Ustinova, Galina A Kliasova, Gennadiy M Galstyan, Zoya M Feder
Journal: Blood (2010)
Mirna EXPRESSION SIGNATURES as PROGNOSTIC Markers IN ADVANCED Classical HODGKIN LYMPHOMA
Authors: Beatriz Sanchez-Espiridion, Carlos Montalban ESQ, Pablo Guisado, Maria E. Rodriguez, Miguel Canales, Javier Alves, Francisco Vega, Manuel Morente, José Francisco Tomás, Miguel A. Piris, Juan F. Garcia
Journal: Blood (2010)
149. In Vitro -Synthesized Sendai Virus RNA Fragments Induced Antitumor Immunity and Cancer Cell-Selective Apoptosis
Authors: Tomoyuki Nishikawa, Li-Wen Liu, Yasufumi Kaneda
Journal: Molecular Therapy (2016)

Three different clinical trials to treat malignant melanoma, castration-resistant prostate cancer and malignant mesothelioma using inactivated Sendai virus (hemagglutinating virus of Japan; HVJ) particles called HVJ-envelope (HVJ-E) are on-going because of the multiple-anti-cancer activities of HVJ-E. One the activities is the activation of anticancer immunity through inactivation of Treg (regulatory T cell) and promotion of NK cells activation and generation of CTL against cancers by producing interferon (IFN)-β, CXCL10, RANTES and IL-6. Another is the cancer selective apoptosis by induction of proapoptotic genes such as TRAIL and Noxa in various human cancer cells but not in normal cells. Most of these anti-cancer activities are conducted by RNA genome fragments of HVJ-E through RIG-I/MAVS (retinoic-acid inducible gene-I, mitochondrial antiviral signaling protein) signal pathway. Among various Sendai virus strains, Sendai virus Cantell strain showed the highest production of IFN-β in dendritic cells (DCs) and the strongest DC maturaion and we found that DI (defective interfering) particles of Cantell strain resulted in those immunostimulatory activities. Then, we investigated RNA molecules in Cantell HVJ DI particles which have no replication activities. The Cantell stain HVJ DI RNA has complementary termini (approximately 100nt) and exhibits the highest binding affinity to RIG-I. DI RNA genome (544 base) was isolated and transferred to human prostate cancer cell PC3 by lipofection. The DI RNA induced higher expression level of those apoptosis-related proteins such as Noxa and TRAIL and more cancer cell death than whole-genome RNA (approximately 15 kb) of complete Cantell strain without DI particles. Furthermore, we examined whether a specific structure of the DI RNA genome stimulates the RIG-I/MAVS downstream-related cancer suppressive pathways using HVJ-derived in vitro transcribed (IVT) RNAs. IVT-B2 which is derived from Cantell HVJ DI genome has a special secondary structure with a double-stranded RNA terminus and a single-stranded RNA loop. This IVT-B2 strongly stimulated RIG-I dependent proapoptotic proteins induction in prostate cancer cells. Modified IVT-B2 RNAs which had shorter dsRNA stem lost cancer cell killing activity and proapoptotic gene expressions. On the other hand, other modified IVT-RNA which had deleted ssRNA region in loop structure did not induce cancer cell-selective killing. We also found that calf intestinal alkaline-phosphatase-treated IVT-B2 RNA lost capability of inducing RIG-I/MAVS-related downstream Noxa and TRAIL expression. Finally, in vivo electroporation of IVT-B2 RNA induced intra-tumoral apoptosis and tumor suppression in human prostate cancer cell-xenograft mouse model by both direct tumor-cell killing and NK cell activation. These findings provide a novel nucleic acid medicine for the cancer treatment.
PWE-032 Audit of prevention of opportunistic infections in immunosuppressed patients with inflammatory bowel disease: how close are we to the European Crohn's and Colitis Organisation guidelines?: Abstract PWE-032
Authors: T Elliott, J Duncan, P Patel, M Smith, J Sanderson, P M Irving
Journal: Gut (2010)

Introduction The European Crohn's and Colitis Organisation (ECCO) has recently published recommendations on screening and prevention of opportunistic infections in inflammatory bowel disease (IBD) patients. These are based on expert opinion and available evidence, and are more extensive than previous guidelines. The aim of this audit is to compare current practice of screening for, and prevention of, opportunistic infections in our IBD clinic, with these recommendations, and to examine the implications of following the guidelines. Methods IBD patients at risk of opportunistic infections (as defined by ECCO; those treated with thiopurines, methotrexate, anti-TNF or prednisolone>20 mg daily for >2 weeks) were selected consecutively from our IBD clinic and infliximab infusion service from July to November 2009. A data collection sheet was completed for each patient by direct questioning in clinic and by review of patients' records. Information collected included; demographic and clinical details, immunosuppressive medication (IM), screening tests performed (HBsAg, anti-HBs, antiHBc, HCVAb, HIVAb, VZVAb (not applicable (n/a) if history of VZV infection), CXR and cervical smear (females)), and vaccinations given prior to treatment (Hepatits B, VZV (n/a if history of VZV infection), HPV (women<26 years), influenza and Streptococcus pneumoniae). A cost analysis of this screening and vaccination strategy was performed. Results Ninety patients (Crohn's disease (n=70), Ulcerative Colitis (n=19), IBD-unclassified (n=1)) were audited to the time of abstract submission. Of these, 46 were male and 44 female (median age 32 years). Forty-one percent of patients were taking thiopurine monotherapy, 34% concomitant thiopurine and anti-TNF therapy, 14% anti-TNF monotherapy, 6% prednisolone, and 5% methotrexate. The proportion of patients who had recommended screening tests and vaccinations are shown in the table. Patients on anti-TNF therapy were more likely to have undergone CXR, hepatitis B and C screening (p<0.05). The cost of these screening tests and vaccinations (excluding HPV) was GBP£255 per patient (equipment and manpower costs not included) ([Abstract 032][1]). View this table: Abstract PWE-032 Screening tests and vaccinations performed Conclusion Our current practice of screening for and prevention of opportunistic infections in at-risk IBD patients is not in line with recent ECCO recommendations. However, some of the ECCO recommendations are based on limited evidence. Therefore, ongoing audit and research, as well as proof of cost benefit, may be required before they gain widespread acceptance. [1]: #T1
Is There a Clinical Benefit for Less Than a Complete Cytogenetic Response (CCyR) for Patients (Pts) with Chornic Myeloid Leukemia (CML) Receiving Tyrosine Kinase Inhibitors (TKI) as Second or Third Line Therapy?
Authors: Jorge E. Cortes, Alfonso Quintas-Cardama, Elias Jabbour, Elizabeth Burton, Susan O'Brien, Srdan Verstovsek, Marina Konopleva, William G. Wierda, Gautam Borthakur, Farhad Ravandi, Hagop Kantarjian
Journal: Blood (2010)
Interim safety summary of alemtuzumab vs. chlorambucil as front-line therapy for patients with progressive B-cell chronic lymphocytic leukemia (BCLL)
Authors: T. Robak, A. B. Skotnicki, J. Mayer, V. Vukovic, S. Weitman
Journal: Journal of Clinical Oncology (2004)

6563 Background: CAM307, a Phase III, open-label, international, randomized trial compares efficacy and safety of alemtuzumab (CAMPATH, MABCAMPATH® [CAM]) to chlorambucil (CHLO) in B-CLL. Methods: Untreated Rai stage I-IV B-CLL patients are randomized 1:1 to CAM 30 mg IV 3 times a week for a maximum of 12 weeks or CHLO 40 mg/m2 PO once every 28 days, up to a maximum of 12 cycles. Patients with autoimmune thrombocytopenia, prior bone marrow transplant, active infection, positive CMV by quantitative PCR assay, secondary malignancy or CNS involvement are excluded. All CAM patients receive prophylactic antibiotic (trimethoprim/ sulfamethoxazole DS) and antiviral (famciclovir) during treatment and until CD4+ counts are ≥200 cells/μL. The primary endpoint is progression free survival; secondary endpoints include safety, overall survival and response rate. Results: Currently, 174 patients (123 males, 51 females; median age 59 years; 63% Rai I/II; 37% Rai III/IV) have been enrolled. Number and distribution of adverse events (AE) were similar: CAM 142; CHLO 130. CAM patients had more systemic infusion reactions, while CHLO patients had more gastrointestinal AEs. The mean grade for all adverse events was 1.5 for CAM and 1.6 for CHLO. Number and distribution of serious adverse events were similar: CAM 16, CHLO 15. CAM patients had infusion-related events involving fever and chills (none for CHLO) and CHLO patients had nausea/vomiting and thrombocytopenia (none for CAM). CMV infection reactivations occurred in 35 patients (CAM 32; CHLO 3). All 35 CMV reactivation cases resolved and 24 patients completed treatment per protocol. Only 7 of 32 CAM patients with CMV reactivation experienced symptomatic CMV infection, and they were successfully treated with IV ganciclovir or foscarnet. No treatment-related deaths have been reported. Conclusions: Preliminary reports show that therapy-naïve BCLL patients treated with CAM and CHLO have comparable safety profiles. Active screening allows for early diagnosis and effective CMV prophylaxis and CMV infection treatment. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ILEX Products, Inc., an affiliate of ILEX Oncology ILEX Oncology, Inc. ILEX Oncology, Inc. ILEX Oncology ILEX Products, Inc., an affiliate of ILEX Oncology ILEX Products, Inc., an affiliate of ILEX Oncology
Impact of monosomal karyotype and FLT3 status on post-transplant relapse in acute myeloid leukemia (AML).
Authors: Antonio Martin Jimenez, Marcos De Lima, Uday R. Popat, Gautam Borthakur, Lynne Abruzzo, Borje Andersson, Guillermo Garcia-Manero, Elias Jabbour, Julianne Chen, Qaiser Bashir, Stefan O. Ciurea, Partow Kebriaei, Sairah Ahmed, Issa F. Khouri, Piyanuch Kongtim, Muzaffar H. Qazilbash, Gabriela Rondon, Elizabeth J. Shpall, Richard E. Champlin, Betul Oran
Journal: Journal of Clinical Oncology (2013)

7010 Background: Relapse remains the major cause of treatment failure in AML patients (pts) undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). We aimed to identify prognostic factors for relapse and leukemia free survival (LFS) after allo-HCT in AML pts. Methods: We retrospectively analyzed 987 consecutive pts who underwent their first allo-HCT for AML between January 2001 and June 2012. 124 pts had monosomal karyotype (MK+), 440 had other cytogenetic abnormalities (core-binding factor [CBF] n=67; MK-, n=373). 113 pts had diploid cytogenetics and FLT3 mutations (CN-FLT3+), 235 were diploid without FLT3 mutations (CN-FLT3-); FLT3 data was unavailable for 75 CN pts. Pts were stratified based on disease status at HCT: complete remission (CR, n=627) and active disease (n=360). Results: In this cohort, median age was 52 years (range: 19 – 76) and 191 pts (20%) had secondary AML (sAML). Conditioning intensity was non-myeloablative in 230 pts (23%). On multivariate analysis in pts with CR at HCT (adjusted for age, donor type and conditioning intensity) factors that predicted inferior LFS included: sAML (HR=1.5, 95% CI=1.1-2.2, p=0.009), &gt;=CR2 vs. CR1 (HR=1.6, 95% CI=1.2-2.1, p=0.002), CN-FLT3+ (HR=1.7, 95% CI=1.1-2.5, p=0.02), MK- (HR=1.4, 95% CI=1.1-2.0, p=0.04) and MK+ disease (HR=2.1, 95% CI=1.4-3.2, p &lt;0.001). Three-year LFS rates for CN-FLT3+ and MK+ were 45.3% and 34% vs. 53.3% for CN-FLT3- pts. For pts with active disease; CN-FLT3+ (HR=2.6, 95% CI= 1.5-4.2, p&lt;0.001) and MK+ (HR=2.3, 95% CI= 1.5-3.5, p&lt;0.001) predicted worse 3-year LFS: 10% and 6% vs. 30.8% in pts with CN-FLT3- . For CR pts, cumulative incidence of relapse (CIR) was higher for those with CN–FLT3+ (HR=1.9, 95% CI=1.1-3.1, p=0.01) and MK+ disease (HR=2.1, 95% CI=1.2-3.5, p=0.005). Among active disease pts, CN-FLT3+ (HR=2.5, 95% CI=1.4-4.3, p=0.002) and MK+ (HR=1.9, 95% CI=1.2-3.0, p=0.009) also predicted for higher CIR. Conclusions: Although pts with CN-FLT3+ and MK+ represent a high risk group for decreased LFS with increased relapse incidence after allo-HCT, they may still enjoy LFS of 30% - 45% if transplanted in CR. Post-transplant strategies to minimize the risk of relapse should be investigated in this setting.
VPS33B, a Member of the Sec1/Munc18 Protein Family, Binds to Integrin Beta Subunits and Is Required for αIIbβ3 Outside-in Signaling
Authors: Binggang Xiang, Guoying Zhang, Shaojing Ye, Cai Huang, Jun Liu, Changgeng Ruan, Susan S. Smyth, Sidney W. Whiteheart, Zhenyu Li
Journal: Blood (2014)
Pharmacokinetics of RO5072759 (GA101) In Patients with Relapsed/Refractory CD20+ Malignant Disease (Phase I/II Study BO20999)
Authors: Georgina Meneses-Lorente, David Carlile, Joe Birkett, Michael K. Wenger, Guillaume Cartron, Franck Morschhauser, Gilles Andre Salles
Journal: Blood (2010)