tbuckley/cabot-search huggingface dataset:
Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy
Authors: Hanren Dai, Yao Wang, Xuechun Lu, Weidong Han
Journal: JNCI Journal of the National Cancer Institute (2016)

The genetic modification and characterization of T-cells with chimeric antigen receptors (CARs) allow functionally distinct T-cell subsets to recognize specific tumor cells. The incorporation of costimulatory molecules or cytokines can enable engineered T-cells to eliminate tumor cells. CARs are generated by fusing the antigen-binding region of a monoclonal antibody (mAb) or other ligand to membrane-spanning and intracellular-signaling domains. They have recently shown clinical benefit in patients treated with CD19-directed autologous T-cells. Recent successes suggest that the modification of T-cells with CARs could be a powerful approach for developing safe and effective cancer therapeutics. Here, we briefly review early studies, consider strategies to improve the therapeutic potential and safety, and discuss the challenges and future prospects for CAR T-cells in cancer therapy.
A8.35 Long-lived plasma cell dynamics in autoimmunity: from the homeostasis of the immunological memory to new therapeutic challenges
Authors: Adriano Taddeo, Tobias Alexander, Laleh Khodadadi, Qingyu Cheng, Andreas Radbruch, Falk Hiepe, Bimba F. Hoyer
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> Long-lived plasma cells (LLPC) contribute significantly to the production of pathogenic autoantibodies in Systemic Lupus Erythematosus (SLE), the prototype of systemic autoimmune diseases. These cells are refractory to conventional immunosuppressive therapies and thus represent an unmet therapeutic challenge. In the current view, LLPC are generated early in ontogeny and no longer formed later in disease pathogenesis, when constant generation of short-lived plasma cells is supposed to be a hallmark of pathology. However, the homeostasis of autoreactive LLPC-compartment has not been characterised so far. Therefore, in this study we rigorously analysed the dynamics of generation, maintenance and replacement of LLPC in NZB/W mice, a murine model of SLE. <h3>Materials and Methods</h3> NZB/W mice of different ages (4 to 29 week) were fed with bromodeoxyuridine (BrdU) in their drinking water for two weeks in order to discriminate between cells generated during and before the feeding period and to track the cells and their replacement over time. Next, LLPC were depleted in mice with a stable splenic LLPC-compartment by two injection of bortezomib (0.75 mg/kg BW) in combination or not with a dose of 35 mg/kg BW cyclophosphamide every fourth day. The mice were sacrificed at different time points after BrdU feeding or LLPC-depletion and bone marrow and spleen LLPC were enumerated by FACS and ELISPOT. <h3>Results</h3> Generation of autoreactive LLPC in spleen and bone marrow starts very early in ontogeny before the onset of symptoms. LLPC-generation continues and is maintained throughout life, reaching a plateau in the spleen but showing persistently increasing numbers and replacement in bone marrow. When LLPCs are efficiently depleted by bortezomib, their numbers fully recover within 2 weeks after its withdrawal. After termination of bortezomib, a persistent depletion of LLPC was only maintained if the precursors of the LLPC were continuously targeted e.g. using cyclophosphamide. <h3>Conclusion</h3> Our results provide relevant insights into the disturbed homeostasis of B cell and LLPC showing that, in autoimmunity, the LLPC-compartment manifest an unforeseen dynamism that is related to B cell hyperactivity. Our data disprove the idea of a “therapeutic window of opportunity” as the generation of LLPC starts very early in ontogeny. Moreover, the continuous generation and replacement of autoreactive-LLPC has an impact on the treatment of systemic autoimmune diseases suggesting that the depletion of autoreactive-LLPC has to be connected with the prevention of regeneration of these cells through the targeting of B cell activation and differentiation.
Evaluation of the Gastrointestinal Tract in Patients with Iron-Deficiency Anemia
Authors: Don C. Rockey, John P. Cello
Journal: New England Journal of Medicine (1993)

Idiopathic iron-deficiency anemia in adults is assumed to be the result of occult chronic blood loss from the gastrointestinal tract. The aim of this study was to determine an effective clinical strategy for managing this common clinical problem.We prospectively studied 100 consecutive patients with iron-deficiency anemia, using colonoscopy and esophagogastroduodenoscopy and, in patients with negative endoscopic studies, enteroclysis (radio-graphic examination of the small intestine).Gastrointestinal endoscopy revealed at least one lesion potentially responsible for blood loss in 62 of the 100 patients. Endoscopic examination of the upper gastrointestinal tract showed a bleeding source in 36 patients, and colonoscopy showed a lesion in 25; 1 patient had lesions in both the upper and lower gastrointestinal tracts. The most common abnormality in the upper gastrointestinal tract was peptic ulceration (duodenal ulcer in 11 patients, gastric ulcer in 5, and anastomotic ulcer in 3). Cancers, detected in 11 patients, were the most common colonic lesions. Enteroclysis was performed in 26 of the 38 patients with negative endoscopic studies, and the results were normal in all instances. Symptoms at a specific site in the gastrointestinal tract were predictive of disease in the corresponding portion of the bowel. In addition, the combination of positive tests for fecal occult blood and symptoms in the lower gastrointestinal tract had a positive predictive value of 86 percent for detecting a lesion in the lower gastrointestinal tract.Gastrointestinal lesions (in both the upper gastrointestinal tract and the colon) are frequently found in patients with iron-deficiency anemia. Since site-specific symptoms are predictive of abnormalities in the corresponding portion of the bowel, the initial evaluation should be directed by the location of the symptoms. Concomitant lesions of the upper and lower gastrointestinal tract are rare; thus, detection of a likely source of blood loss during the initial examination may obviate the need for further procedures.
Immunosuppression and Infection — Progress?
Authors: Myron J. Levin, John A. Zaia
Journal: New England Journal of Medicine (1977)

One characteristic of contemporary physicians is the ease with which they have accepted Shakespeare's tenet that "Diseases desperate grown by desperate appliance are relieved...."1 Oncologists, rheumatologists, tissue transplanters and others are activists. They administer therapy that predictably induces profound suppression of the immune response and often leads to a variety of bacterial and nonbacterial infections that were considered medical curiosities only 20 years ago.2 Implicit in this behavior are several assumptions: the first, of course, is that the frequency of cure and palliation will justify the price of iatrogenic infection; the second is that current therapy will evolve rapidly in . . .
SAT0192 In Vivo Detection of Cortical Micro Channels in Metacarpophalangeal Joints with Xtreme-Ct - A New Instrument to Visualize Communication between the Bone Marrow and the Joint Space
Authors: J. Haschka, D. Simon, J. Rech, A.J. Hueber, G. Schett, A. Kleyer
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Synovitis and osteitis are distinct pathologic findings in patients with rheumatoid arthritis (RA). Their frequent simultaneous occurrence led to the theory of increased communication between the bone marrow and synovial compartments. A widening of pre-existing cortical bone channels, which carry microvessels and penetrate the cortical barrier, has been previously described in animal models as a result of increased osteoclast-mediated bone resorption. To our knowledge these communication channels have not been clearly visualized in humans in vivo. <h3>Objectives</h3> We hypothesised that it is possible to detect cortical channels in human RA patients by high-resolution peripheral quantitative computed tomography (HR-pQCT). <h3>Methods</h3> We used HR-pQCT (XtremeCT, Scanco Medical, Switzerland) with a resolution as low as 82 microns in voxel size to scan the metacarpophalangeal (MCP) joint 2 of 10 patients with early RA (ACPA positive, mean age 36.2±8.2 years, mean disease duration 1.2±0.8 years, 50% female) without concurrent bone erosions and 10 healthy controls of comparable age (mean age 37.9±7.6 years, 70% female). Images were downsized to the minimum of one slice with the 3D evaluation program provided by the manufacturer. Transversal (Figure 1), coronal and sagittal images were obtained using the subdim feature of the 3D evaluation program. Transversal planes were projected at the proximal insertion of the capsule of MCP2 head. Sagittal and coronal planes were set exactly into the middle of the MCP2 head. <h3>Results</h3> Cortical bone channels can be clearly visualized with this technique, which mimics a virtual histopathologic slide of the joint (Figure 1). In the transversal view cortical discontinuations (arrows) were observed more frequently (p=0.05) in RA patients (Fig. 1B) compared to healthy controls (Fig. 1A). Due to the small sample size, statistical analysis of the coronal and sagittal view were not performed, though especially in the sagittal view a trend of more cortical bone channels in RA was detected (4.6±3.5 vs.2.3±1.9). <h3>Conclusions</h3> In summary, we show that in vivo visualization of cortical bone channels in humans is feasible and that early RA patients exhibit a significantly higher number of such channels in the area of the proximal insertion site of the capsule compared to controls. These changes may represent key communication pathways between the bone marrow and the joint and the place where inflammation starts in RA patients. These changes cannot be seen by conventional X-ray or MRI. Systematic evaluation of cortical bone channels will be necessary to define the extent of these lesions in inflammatory joint diseases as well as their longitudinal dynamics in larger cohorts. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4395
THU0391 Efficacy of TOCILIZUMAB in Patients with Refractory Uveitis to Other Biologic Therapy. Multicenter Study of 20 Cases
Authors: F.M. Ortiz Sanjuán, E. Beltrán-Catalán, V. Calvo-Río, R. Blanco, I. Calvo, M. Hernández-Garfella, A. Atanes, L. Linares, O. Maíz, B. Bravo, G. Díaz, J. Loricera, T. Pina, M.A. González-Gay
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> To evaluate Tocilizumab (TCZ) in uveitis refractory to other biologic drugs. <h3>Methods</h3> Multicenter study of 20 patients from 11 hospitals. All patients presented inadequate response to at least other biologic drug. The degree of ocular inflammation was evaluated according to SUN-2005. Macular thickness was defined by OCT. Comparisons were made between baseline and 1st week, 1st month, 6th month, 1st year. (Wilcoxon test) <h3>Results</h3> We studied 20 patients/37 affected eyes (5 men/15 women); mean age, 27.4±16 years (range 8-67). The main underlying diseases were: Juvenile Idiopathic Arthritis (n=9), Behçet disease (n=3), spondyloarthritis (n=2), rheumatoid arthritis (n=1), and idiopathic uveitis (n=5). Besides oral steroids and before TCZ onset they had received: intraocular corticosteroids (n=13), methylprednisolone i.v. boluses (n=7), methotrexate (n=19), cyclosporine A (n=13), azathioprine (n=3), adalimumab (n=15), infliximab (n=9), abatacept (n=5) and golimumab (n=1). TCZ was started because inefficacy (n=20) and/or toxicity (n=3) to other biologics. TCZ was used as monotherapy (n=4) or in combination with methotrexate (n=11), leflunomide (n=2), cyclosporine A (n=2) and mycophenolate (n=1). There was a rapid (from 1st week) and maintained (1st year) improvement of visual acuity, anterior chamber inflammation, vitritis and OCT. The mean OCT in 5 cases (8 eyes) of macular thickness (OCT&gt;250 μm) improved from 325±54.2 (baseline) to 264.3±22 μm (1st month) (p=0.03). After a mean follow-up of 13.7±10.2 months the more important side-effects observed were bullous impetigo (n=1) and mild thrombocytopenia (n=1). <h3>Conclusions</h3> Tocilizumab seems effective and safe for patients with refractory uveitis to other biologic treatments. <h3>Acknowledgements</h3> This study was supported by a grant from “Fondo de Investigaciones Sanitarias” PI12/00193 (Spain). This work was also partially supported by RETICS Programs, RD08/0075 (RIER) and RD12/0009/0013 from “Instituto de Salud Carlos III” (ISCIII) (Spain). <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4475
Endoscopic Biliary Drainage for Severe Acute Cholangitis
Authors: Edward C.S. Lai, Francis P.T. Mok, Eliza S.Y. Tan, Chung-mau Lo, Sheung-tat Fan, Kok-tjang You, John Wong
Journal: New England Journal of Medicine (1992)

Emergency surgery for patients with severe acute cholangitis due to choledocholithiasis is associated with substantial morbidity and mortality. Because recent results suggested that emergency endoscopic drainage could improve the outcome of such patients, we undertook a prospective study to determine the role of this procedure as initial treatment.
AB1019 Osteoporotic fracture incidence reduction in hepatic transplanted patients:
Authors: J.L. Valero Sanz, E. Grau García, I. Chalmeta Verdejo, M.D. García Armario, C. Molina Almela, I. Martinez Cordellat, M.L. Muñoz Guillem, L. Gonzalez Puig, R. Negueroles Albuixech, C. Nuñez-Cornejo Piquer, C. Alcañiz Escandell, J. Ivorra Cortes, J.A. Roman Ivorra
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Osteoporosis in transplanted patients is a well-documented event, and shows a multifactorial etiology. Intervention and prevention in these patients could be related to a secondary osteoporotic effect decreasing (as a reduced fracture incidence), as well as a reduced sanitary cost associated to fracture treatment and intervention. <h3>Objectives</h3> The identification of osteoporotic fracture incidence reduction in hepatic transplanted patients with preventive osteoporotic treatment. <h3>Methods</h3> We considered 142 hepatic transplanted patients (that had undergone surgery at the reference hospital) immediately after the transplantation and at one-year after monitoring. Demographic and clinical data about symptomatic fractures and radiological fracture diagnosis where collected. All patients were administered 1000 mg Ca daily, 5600 IU vitD weekly and 200 IU calcitonin nasally during the first three months followed by oral Bophosphonates (as is described on bibliography). <h3>Results</h3> Our samples series consists of 76% of men and 24% of women. The average transplant age is 53.61 years, and no significant variations of this variable in both sexes were observed. The clinical diagnosis on which the transplant is based is shown in the following table: Mainly, transplants are due to VHC and chronic enolism. In 23 patients basal fractures were observed (all vertebral), and after treatment 9 new fractures (8 vertebrals and 1 in ankle) were observed. In this way, fracture rate decreases from 13.38% at trasplant to 7.9% at annual monitoring, with a relative decrease of the fracture risk in 40.95%, even in HCV patients a decrease from 17.34% to 5.79% 1 year later was observed (relative risk of decrease 66.6%). <h3>Conclusions</h3> Preventive osteoporosis treatment in hepatic transplanted patients leads to a decreasing on osteoporotic fracture risk, as is shown on control results and the monitoring of clinical results in these patients. Thus, it is possible to reach an osteoporotic post-transplant event decrease, as well as the decrease of the sanitary derived-cost. <h3>Disclosure of Interest</h3> None Declared
Evaluation of Drug Efficacy by a Preference Technic
Authors: Hershel Jick, Dennis Slone, Barbara Dinan, Hugo Muench
Journal: New England Journal of Medicine (1966)

INCREASED awareness of the importance of properly controlled drug evaluations has brought with it a need for the development of experimental technics that can provide essential information about drug effects. Since an enormous number of drugs are available for therapeutic use, and the relative efficacy of most has not been fully evaluated, an important element to consider in designing such studies is simplicity. Studies that involve the accumulation of large quantities of data obtained at frequent intervals require numerous personnel. Furthermore, since a large proportion of their time is spent in the frequent collection of information, relatively few studies can . . .
PTH-065 Impact Of A Standardised Clinical Management Network For Complex Polyps Within The Bowel Cancer Screening Programme (bcsp)
Authors: R Ramaraj, M Davies, M Morgan, A Maw, N Williams, G Tudor, H Heard, S Dolwani
Journal: Gut (2014)

<h3>Introduction</h3> Initial data from the UK BCSP demonstrated variation in referrals to surgery and management for complex polyps encountered in colonoscopy. Associated factors included local availability of operator skills and expertise with endoscopic resection, lack of a structure for discussion and standardised management at the Local assessment centres (LAC). Inappropriately high incomplete resection rates at colonoscopy was noted for such polyps at local units. We hence established a National Clinical Network of specialist expert advisors, meeting every fortnight via videoconference to review endoscopy, radiology, pathology and clinical data of cases referred through specific criteria for complex lesions. We also established a National referral centre (NRC) at Llandough with the requisite skills and expertise in complex Endoscopic Mucosal Resection and Dissection (EMR, ESD) where appropriate polyps that met the referral criteria after a Network Multidisciplinary Team meeting discussion (NMDT) could undergo advanced therapy. An NMDT and NRC pilot was established in Oct 2011 to offer the opportunity to access expert opinion and discussion of therapeutic options for Welsh participants of the BCSP. We present our preliminary results. <h3>Methods</h3> Referral criteria for complex polyps were agreed based on a composite of site, size, morphology and accessibility. Polyps satisfying the criteria were referred to the NMDT electronically along with relevant images and video. Depending on outcomes of NMDT discussion participants were given the option of accessing local surgery or travelling to the NRC for therapeutic endoscopy. Over a 2 year period, 140 referrals were made from 14 different welsh BCS centres to the NMDT. <h3>Results</h3> The various management decisions taken in 126 benign complex polyps and the 14 cancers detected is illustrated in fig 1. Polyps that had incomplete resection (22) often had piecemeal EMR or repeated attempts at EMR at LAC causing failure of lifting in polyps. It is noteworthy that in the first 1 year of NMDT and NRC establishment;16 such cases were referred in contrast to 6 in the subsequent year with most cases in the 1st year needing surgery. This is an encouraging trend as awareness through discussion in the NMDT has streamlined management and decreased the incidence of incomplete resections allowing definitive management in the first instance and reduction in inappropriate referral to surgery for benign disease. <h3>Conclusion</h3> Establishing a clinical network for standardised decision making for complex polyps appears to have a significant effect on clinical outcomes. <h3>Disclosure of Interest</h3> None Declared.
Non-Hodgkin's Lymphoma Rate Climbed Rapidly
Authors: T. Reynolds
Journal: JNCI Journal of the National Cancer Institute (1991)

Journal Article Non-Hodgkin's Lymphoma Rate Climbed Rapidly Get access Tom Reynolds Tom Reynolds Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 83, Issue 4, 20 February 1991, Pages 232–233, https://doi.org/10.1093/jnci/83.4.232 Published: 20 February 1991
Abstract 2904: Docking-based virtual screening of Chk1 inhibitors
Authors: Yan Li, Dong Joon Kim, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2011)

Abstract Checkpoint 1 (Chk1), which is required for checkpoint arrest, is activated in response to DNA damage through the ATM/ATR pathway, and plays an essential role in the regulation of the G2/M checkpoint. Inhibition of Chk1 should abrogate this checkpoint in a manner relevant to the treatment of cancer, and may also induce apoptosis. Selective Chk1 inhibitors should also prove useful to study the regulation of the G2/M checkpoint. Several Chk1 inhibitors are already known, including natural products. UCN-01, a Chk1 inhibitor and staurosporine derivative, is undergoing clinical trials as an anticancer agent. A limited number of additional Chk1 inhibitors have been reported; however, a need to identify more drug-like Chk1 inhibitors is clear. This should be facilitated by the structural information available for the Chk1 kinase domain. The first crystal structure of the kinase domain of human Chk1 has been reported at 1.7Å resolution in 2000. After that, 46 co-crystal structures of Chk1 and inhibitors have also been solved. This puts docking-based virtual screening of Chk1 inhibitors on firm footing. Molecular docking is a very popular method employed to investigate molecular associations and is particularly useful in the drug discovery arena to study the binding of small molecules (ligands) to macromolecules (receptors). To deal with the binding event in a realistic manner, we took into account the conformational flexibility of the ligand and the flexibility of the receptor. In this work, a large collection of crystallographic structures of Chk1 was employed to determine if multiple-structure docking performs better than single-structure docking. Known ligands were used to test the success of docking in binding mode prediction and virtual screening enrichment factors. A chemical library with more than 60,000 compounds was docked into the selected Chk1 structures, and the top-ranked compounds were then tested in experiments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2904. doi:10.1158/1538-7445.AM2011-2904