tbuckley/cabot-search huggingface dataset:
763. HIV-Specific T Cells Can Be Expanded from Virus-Naive Donors to Target a Range of Viral Epitopes: Implications for a Cure Strategy After Allogeneic HSCT
Authors: Shabnum Patel, Sharon Lam, Conrad Russell Cruz, Kaylor Wright, Christina Cochran, Richard Ambinder, Elizabeth Shpall, Catherine Bollard
Journal: Molecular Therapy (2016)

Background: Adoptive T cell therapy has been successful in boosting viral-specific immunity post-hematopoietic stem cell transplant (HSCT), preventing viral rebound of CMV and EBV. However, the therapeutic use of T cells to boost HIV-specific T cell immunity in HIV+ patients has been met with limited success. Despite multiple attempts to eradicate HIV infection with allogeneic HSCT, the Berlin patient remains the only case of functional HIV cure. Previous infusions of HIV-specific T cells have resulted in immune escape from single epitope specificity and limited persistence of the T cell product. Our approach to address these limitations is to expand HIV-specific T cells derived from virus-naïve donors including umbilical cord blood, employing a non-HLA restricted approach for HIV+ patients receiving allogeneic HSCT for HIV-associated hematologic malignancies. Design: We have developed a robust, reproducible platform that can expand HIV-specific T cells (HXTCs) from the naïve pool in the allogeneic setting. Peripheral blood mononuclear cells isolated from virus-naïve donors are used to generate dendritic cells and T cells. T cells are stimulated with antigen presenting cells pulsed with HIV-pepmix and a combination of cytokines that promote proliferation and differentiation. T cells were tested for: (1) specificity against HIV antigens and individual peptides, (2) pro-inflammatory cytokine secretion in response to stimulation with HIV peptides, and (3) ability to suppress HIV replication in vitro. Results: We successfully expanded (75.705 mean fold expansion) HXTCs recognizing HIV antigens from virus naïve donors. IFNg ELISPOT showed HXTCs (n=8) were specific against Gag (mean=331.25 SFC/1e5 cells) and Nef (mean=242.63 SFC/1e5 cells) vs Irrelevant (mean=13 SFC/1e5 cells). HXTCs produced significantly pro-inflammatory responses (p less than 0.05) to stimulation by gag/nef, as determined by levels of TNF-alpha, IL-2, IL-6, IL-8, and perforin (n=3). Importantly, HXTCs (n=4) were able to suppress HIV replication more than non-specific CD8+ T cells when co-cultured with autologous CD4+ T cells infected with HIV SF162 (HXTC 78.62% viral suppression compared to CD8+ T cell 34.19% viral suppression). HXTCs showed both HLA Class I or II specificity for individual HIV epitopes, as determined by HLA blocking and IFNg ELISPOT. Conclusion: This is the first report demonstrating generation of functional, multi-HIV antigen specific T-cells from HIV-negative donors, which has implications for using allogeneic HSCT as a functional HIV cure. The low frequency of circulating HXTCs post-infusion suggests these HXTCs could have a significant effect on preventing viral rebound. The generation of HXTCs from cord blood could provide a further advantage to increase the donor pool.
PWE-090 Use of ultrasound scan for diagnosis and monitoring of small bowel Crohn's disease
Authors: S Khalid, S Ramakrishnan, K Gopal
Journal: Gut (2010)

<h3>Introduction</h3> Diagnoses and monitoring of small bowel Crohn9s disease can often present a challenge. Tests for aiding decision making are often not available readily and involve radiation. This can potentially results in uncertainty in diagnosis and reluctance and delay in treatment. We studied the role of ultrasound scan (USS) in diagnosis of small bowel Crohn9s disease. We compared the results of USS with Magnetic Resonant Imaging (MRI). <h3>Methods</h3> This was a prospective study of use of USS followed by a MRI small bowel. Patients who were clinically suspected to have a first diagnosis of small bowel Crohn9s/recurrence after surgery/exacerbation of known Crohn9s disease were referred from Gastroenterology clinics and inpatients. USS were performed by experienced Radiology consultant. All the patients first had an USS performed and reported, followed by MRI scan. <h3>Results</h3> A total of 30 patients were identified for this study. Age range was from 17 to 78 years and median age of 30 years. 50% of patients were males and 50% females. 20% of the patients were known to have Crohn9s disease, 10% had known post surgical recurrence, 17% suspected post surgical recurrence and 53% were clinically suspected to have small bowel Crohn9s. USS was reported as normal or no active disease in 70% of all scans. Out of the remaining 30%, 10% of post resection, 7% of clinically suspected and 13% of the known Crohns disease patients were found to have active disease and stricturing in small bowel on USS. Subsequent MR scans showed very good sensitivity of USS in diagnosis. In 96.2% patients MRI scan showed same or very similar findings as on USS. All Abnormal USS were confirmed with same abnormality on MRI scans (positive predictive value 100%). Of the Normal USS only one MRI scan (3%) showed a stricture in proximal small bowel (Negative predictive value 95.2%). Of the remaining, two MRI scans (7%) could not be performed, as patients were unable to tolerate procedure. One (3%) MRI scan was cancelled after USS, as no longer indicated. One further MRI scan showed a primary small bowel volvulus, but no Crohns disease, where USS was normal. <h3>Conclusion</h3> With emergence of new modalities the role of ultrasound in small bowel disease has diminished. This study shows that ultrasound scan can still play a very important role in monitoring and diagnosis of Crohn9s disease. USS can aid in planning management of patients in acute settings, where other investigations may cause delay. It has the advantages of ready availability, less time to perform, well tolerated and no radiation exposure. In our study it proved to be very sensitive and accurate in comparison to MRI scan and may be usefully employed in assisting clinical decision making before other investigations are performed.
Abstract 1569: Development of a noninvasive and sensitive urine screening test for liver cancer targeting circulation-derived cancer DNA biomarkers
Authors: Surbhi Jain, Sitong Chen, Selena Y. Lin, Adam Clemens, Hei-won L. Hann, Ting-Tsung Chang, Chi-Tan Hu, Shun-Hua Chen, Wei Song, Ying-Hsiu Su
Journal: Cancer Research (2015)

Abstract Hepatocellular carcinoma (HCC), or liver cancer, is an aggressive disease and is regarded as one of the fastest growing cancers in the United States in incidence. The 5-year survival rate of HCC patients drops dramatically from a poor 26%, in early-stage cancer, to a mere 2% in late stages of this disease. The only available early detection biomarker is serum alpha-fetoprotein, which can detect only 40-60% of cases. Our goal is to develop a screening test for early detection of liver cancer, in order to meet this urgent need for new and better biomarkers for HCC. Cancer is a disease of the genome and epigenome, and if we can detect these underlying genetic mutations and epigenetic modifications in the periphery, we can effectively detect cancer early. Hence, we chose a panel of both HCC-associated genetic and DNA methylation biomarkers. We have previously shown that urine contains fragmented cell-free DNA derived from the circulation and that we can detect cancer-related DNA, both mutated and methylated DNA, in the urine of such patients. We have also demonstrated that the concentration of tumor-derived DNA in plasma and in urine is similar in patients with tumors. In order to demonstrate the feasibility of detecting HCC DNA biomarkers in the circulation derived urine DNA, we have developed short amplicon (∼50 bp) PCR-based assays targeting HCC-specific mutations in TP53 and CTNNB1 genes and HCC-specific methylation in GSTP1, RASSF1A and CDKN2A genes. Urine DNA isolated from samples of hepatitis, cirrhosis, and HCC patients were tested in each of the assays and analyzed for individual marker and panel performance. The performance of the markers and our approach towards the development of a targeted next generation urine DNA based HCC screening test is discussed. Citation Format: Surbhi Jain, Sitong Chen, Selena Y. Lin, Adam Clemens, Hei-won L. Hann, Ting-Tsung Chang, Chi-Tan Hu, Shun-Hua Chen, Wei Song, Ying-Hsiu Su. Development of a noninvasive and sensitive urine screening test for liver cancer targeting circulation-derived cancer DNA biomarkers. [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 1569. doi:10.1158/1538-7445.AM2015-1569
Antiproliferative Effects of Tyrosine Kinase (STI 571) and Farnesyl Transferase Inhibitors (R115777 and SCH66336) on Acute Leukemia Human Tumor Cell Lines.
Authors: Domenico Russo, Angela Michelutti, Michele Malagola, Tiziana Grafone, Emanuela Ottaviani, Anna Candoni, Cristina Skert, Carla Filì, Maurizio Castelli, Giovanni Martinelli, Daniela Damiani, Michele Baccarani
Journal: Blood (2005)
GENO-25HYPERMUTATION AND MALIGNANT PROGRESSION IN AN EXPANDED COHORT OF TEMOZOLOMIDE-TREATED LOW-GRADE GLIOMA PATIENTS
Authors: Tali Mazor, Brett E. Johnson, Matt Grimmer, Chibo Hong, Emily G. Hamilton, Lindsey E. Jones, Ana Xavier-Magalhães, Ivan V. Smirnov, Henrik Bengtsson, Adam B. Olshen, Kevin Petrecca, Andrew W. Bollen, Mitchel S. Berger, Barry S. Taylor, Sarah J. Nelson, Manish K. Aghi, Jennifer L. Clarke, Joanna J. Phillips, Susan M. Chang, Joseph F. Costello
Journal: Neuro-Oncology (2015)

While patients with primary glioblastoma (GBM) have benefited from increased overall survival due to treatment with the alkylating chemotherapy temozolomide (TMZ), the benefit of TMZ for patients with diffuse low-grade gliomas (LGG) remains unknown. We previously demonstrated that among ten TMZ-treated patients with initial LGG (IDH1 mutant, 1p19q intact), treatment induced hypermutation in the recurrent tumors of six patients, all six of whom underwent malignant progression to secondary GBM (sGBM) (Johnson & Mazor, Science, 2014). To further explore the relationships among TMZ treatment, hypermutation and malignant progression, we studied tumor evolution in an expanded cohort of 35 TMZ-treated patients by exome-sequencing of paired IDH1/2-mutant LGGs and their post-TMZ recurrences. This expanded cohort allowed us to contrast patterns of hypermutation between 1p19q intact versus co-deleted subgroups. Hypermutated recurrences were common in both subgroups and consistently underwent malignant progression to the highest grade while acquiring somatic mutations in mismatch repair (MMR) genes. In contrast to the 1p19q intact subgroup in which TP53 mutations were present at diagnosis, the hypermutated recurrences of the 1p19q co-deleted subgroup frequently acquired TMZ-associated mutations in TP53. This suggests that TP53 mutations may cooperate with MMR mutations to convert TMZ-induced cytotoxicity to mutagenicity. Once hypermutated clones arose, we found that they dominated subsequent recurrences. In one case, a hypermutated sGBM was resected, but soon recurred with leptomeningeal spread, at which point hypermutated clones were found in the spinal cord. We examined the clonality of hypermutated tumors through exome-sequencing of multiple spatially distinct samples, from which we estimate that hypermutated recurrent tumors can originate from a single initiating cell. Together, these findings further our understanding of the molecular features and clinical behavior of hypermutated clones, raising concerns about the potent mutagenic activity of TMZ and other alkylating agents in LGG patients.
25. A Dose Escalation Study of Cyclophophamide (CTX) to Enhance SB-728-T Engraftment
Authors: Dale Ando, Gary Blick, Jay Lalezari, Ricky Hsu, Edwin DeJesus, Trevor Hawkins, David Parks, Shelley Wang, Winson Tang, Ron Mitsuyasu
Journal: Molecular Therapy (2015)

Background: CCR5 modified autologous CD4 cells (SB-728-T) are safe and increases total CD4 counts. The cells traffic to lymphoid tissues and have a selective survival advantage during ART treatment interruption (TI). Additional studies in CCR5 D32 heterozygote HIV subjects showed VL reductions during TI correlated with circulating bi-allelic CCR5-modified CD4 cells supporting the importance of maximizing engraftment. Low dose CTX has been successfully used to increase T cell engraftment. This study examines the effect of escalating doses of CTX on SB-728-T engraftment. Methods: A dose escalation study of IV CTX, with doses ranging from 100 mg/m2 to 2 g/m2 (n=3-6/cohort), administered 1-3 days prior to SB-728-T (>90% CD4, <1% CD8) infusion was performed in 18 aviremic, ART treated HIV subjects with CD4 T cells ≥500/uL. Results: CTX was generally well tolerated with low grade GI side-effects, managed with anti-emetics, at doses up to 1 g/m2. Grade 3 and 4 neutropenia requiring G-CSF developed at 1.5 and 2.0 g/m2 CTX. On Day 7, a dose-related increase in CD4 count and engraftment of bi-allelic CCR5 modified cells was observed with CTX doses up to 1 g/m2 but did not increase at 2.0 and 1.5 g/m2. By comparison, there was a progressive decline in CD8 cells with CTX dose escalation. Data is expressed as Mean +/- SE in Table 1.Table 1100 mg/m2500 mg/m21 g/m22 g/m21.5 g/m2ΔCD4 (cells/uL)776±5021695±5182700±9661370±7211396±367ΔCD8 (cells/uL)98±49180±117−210±7−424±63−164±161Bi-allelic (cells/uL)55±42102±24169±67142±30180±25 Open table in a new tab A 1-log VL reduction from peak was seen in 1 subject each at 100 and 500 mg/m2 of CTX while 1 subject each at the 1 and 1.5 g/m2 dose level had a 2-log decline during a TI. At the conclusion of the study, 3 additional subjects were conditioned with 1 g/m2 of CTX and administered CCR5 modified T cells containing 46.9+/-6.4% CD8 cells. CD8 count increased by 2236+/-967/uL (range 1029-4150/uL) with only modest increases in CD4 counts (733+/-233/uL; range 297-1096/uL) at 7 days in the 3 subjects. Two of the three subjects have had modest increases in VL to date during TI (<1000 copies/mL), suggesting an effect on viral control with the added CD8 T cells. Conclusion: CTX conditioning is generally well tolerated and was associated with increased engraftment of CCR5-modified T cells at doses up to 1 g/m2 in HIV subjects. CTX conditioning may be a useful strategy to maximize the engraftment and anti-viral effects of SB-728-T. The effects of co-administering CD8 cells with SB-728-T on VL will be presented.
Abstract 3834: Validation of potential methylation biomarkers in HPV-associated HNSCC
Authors: Kang Mei Chen, Josena K. Stephen, George Divine, Dhananjay Chitale, Tamer Ghanem, Steven Chang, Maria J. Worsham
Journal: Cancer Research (2015)

Abstract Epidemiological and laboratory evidence indicate the human papilloma virus (HPV) as a causative agent for some squamous head and neck cancer (HNSCC). The biologic significance of HPV as independent risk factor is also underscored by the improved prognosis for patients with HPV positive HNSCC relative to HPV negative HNSCC, due in part to a better therapeutic response to chemoradiotherapy. The mechanism for this improved prognosis remains underexplored. To assess the potential of HPV specific methylation biomarkers, we evaluated the status of 10 genes (CDH8, CRMP1, HTRE1, ELMO1, MEI1, MSX2, PCDH10, PCDHB11, C14orf162, and PITX2) in a cohort of 18 HPV positive and 14 HPV negative HNSCC using targeted sequencing (Illumina MiSeq). The genes were previously reported as significantly differentially methylated between HPV positive and HPV negative HNSCC using the Infinium HumanMethylation450 BeadChip (Lechner et al., 2013). In our sample, of the 10 genes, targeted sequencing confirmed significant differential methylation between HPV positive and negative for C14orf162 (p = 0.007), MEI1(p = 0.004), MSX2 (p = 0.002), and PCDHB11(p = 0.002). PCDHB11 and MSX2 were hypermethylated; MEI1 and C14orf162 were hypomethylated, concordant with the Lechner et al., study. In this independent sample set, confirmation of 4 of the 10 genes as differentially methylated in HPV positive vs HPV negative HNSCC with concordance of methylation direction (hypo- vs hypermethylated), validates their potential for differentiating HPV positive and HPV negative HNSCC. Cadherins are implicated in tumor progression and metastasis and are targets of the Polycomb group (PcG) proteins, which form chromatin-modifying complexes that are essential for embryonic development and stem cell renewal and are commonly deregulated in cancer. Our study further supports cadherin PCDHB11, together with C14orf162, MEI1, and MSX2 as likely biomarkers in HPV-associated HNSCC. Support: Komen KG110218 Citation Format: Kang Mei Chen, Josena K. Stephen, George Divine, Dhananjay Chitale, Tamer Ghanem, Steven Chang, Maria J. Worsham. Validation of potential methylation biomarkers in HPV-associated HNSCC. [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 3834. doi:10.1158/1538-7445.AM2015-3834
Plasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker
Authors: Daniel Pietrasz, Nicolas Pécuchet, Fanny Garlan, Audrey Didelot, Olivier Dubreuil, Solène Doat, Francoise Imbert-Bismut, Mehdi Karoui, Jean-Christophe Vaillant, Valérie Taly, Pierre Laurent-Puig, Jean-Baptiste Bachet
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Despite recent therapeutic advances, prognosis of patients with pancreatic adenocarcinoma remains poor. Analyses from tumor tissues present limitations; identification of informative marker from blood might be a promising alternative. The aim of this study was to assess the feasibility and the prognostic value of circulating tumor DNA (ctDNA) in pancreatic adenocarcinoma. Experimental Design: From 2011 to 2015, blood samples were prospectively collected from all consecutive patients with pancreatic adenocarcinoma treated in our center. Identification of ctDNA was done with next-generation sequencing targeted on referenced mutations in pancreatic adenocarcinoma and with picoliter droplet digital PCR. Results: A total of 135 patients with resectable (n = 31; 23%), locally advanced (n = 36; 27%), or metastatic (n = 68; 50%) pancreatic adenocarcinoma were included. In patients with advanced pancreatic adenocarcinoma (n = 104), 48% (n = 50) had ctDNA detectable with a median mutation allelic frequency (MAF) of 6.1%. The presence of ctDNA was strongly correlated with poor overall survival (OS; 6.5 vs. 19.0 months; P &amp;lt; 0.001) in univariate and multivariate analyses (HR = 1.96; P = 0.007). To evaluate the impact of ctDNA level, patients were grouped according to MAF tertiles: OS were 18.9, 7.8, and 4.9 months (P &amp;lt; 0.001). Among patients who had curative intent resection (n = 31), 6 had ctDNA detectable after surgery, with an MAF of 4.4%. The presence of ctDNA was associated with a shorter disease-free survival (4.6 vs.17.6 months; P = 0.03) and shorter OS (19.3 vs. 32.2 months; P = 0.027). Conclusions: ctDNA is an independent prognostic marker in advanced pancreatic adenocarcinoma. Furthermore, it arises as an indicator of shorter disease-free survival in resected patients when detected after surgery. Clin Cancer Res; 23(1); 116–23. ©2016 AACR.
C-Myb Transactivates the Expression of Erythroid Hsa-miR16-2 Gene,
Authors: Elisa Bianchi, Paola Guglielmelli, Lorenzo Tozzi, Costanza Bogani, Simona Salati, Roberta Zini, Ruggiero Norfo, Valentina Pennucci, Alessandro M. Vannucchi, Rossella Manfredini
Journal: Blood (2011)
Initial and long‐term crestal bone responses to modern dental implants
Authors: Tomas Albrektsson, Bruno Chrcanovic, Per‐Olov Östman, Lars Sennerby
Journal: Periodontology 2000 (2016)

Abstract Successful osseointegration is the result of a controlled foreign body reaction to dental implants. Osseointegrated implants have demonstrated excellent long‐term survivability, although they may be subject to limited marginal bone loss. Marginal bone loss during the first few years after implant placement seldom represents disease, but is instead the result of an adaptive bone response to surgical trauma and implant loading. It is not uncommon for implants with early marginal bone loss to enter a long‐lasting state of bone stability. Extensive bone resorption after the first year is generally due to an exacerbation of adverse body reactions caused by non‐optimal implant components, adverse surgery or prosthodontics and/or compromised patient factors. Disease in the form of peri‐implantitis is a late complication that affects some implants with suppuration and rapid loss of crestal bone, and is probably caused by bacterial pathogens and immunological reactions. Unfortunately, the literature is not consistent with respect to the type or magnitude of clinical implant problems, including how they are defined and diagnosed. If the peri‐implantitis diagnosis is confined to cases with infection, suppuration and significant bone loss, the frequency of the disease is relatively low, which is in sharp contrast to the frequencies reported with unrealistic definitions of peri‐implantitis. We suggest that when modern implants are placed by properly trained individuals, only 1–2% of implants show true peri‐implantitis during follow‐up periods of 10 years or more. Peri‐implantitis must be separated from the initial and self‐limiting marginal bone loss.
A Pilot Study To Test the Efficacy of a Combination of Gleevec with Thalidomide in Patients with Idiopathic Primary Myelofibrosis, Myelofibrosis with Myeloid Metaplasia and Myelodysplastic Syndromes Who Present with Myelofibrosis.
Authors: Marta Batus, Jamile M. Shammo, Parameswaran Venugopal, Stephanie A. Gregory, Azra Raza
Journal: Blood (2006)