tbuckley/cabot-search huggingface dataset:
Reasons for a Deficit of Breast Cancer Among HIV-Infected Patients
Authors: Liron Pantanowitz, Bruce J. Dezube
Journal: Journal of Clinical Oncology (2004)

IN REPLY: Dr Dediu raises important issues in his letter.The clinical trials will usually compare a gold standard treatment against the potential new treatment and in the past, such trials were usually sized to look for a 20% improvement in survival.More recently, oncologists have accepted that they are unlikely to reach that end point, and have sized their trials more appropriately for looking at smaller differences.Most recently, quality of life has become an essential component of the assessment of the overall cancer strategy.Response assessment and response duration remain, as we reviewed, a mark of the drug activity and patient outcome measures, just as survival and quality of life are markers of the drug efficacy.A drug becomes registered on the basis of a clinical trial, whereas the outcomes are considered sufficiently important to allow that drug to be marketed.The dose within that trial is the licensed dose.Once a drug is licensed, in every day clinical practice, the dose and schedule are frequently modified.As discussed in our review article, 1 Fossella et al 2 used the well established regimen of cisplatin and vinorelbine as one of their control arms.They based their dosing and schedule of the cisplatin and vinorelbine on four randomized phase III trials, totaling 1,426 patients. [3]4][5][6][7] Phase II trials, looking at other doses and schedules, were not considered as evidence by Fossella et al and we are in agreement with that.We are, as oncologists, also in agreement with Dr Dediu, that the platinum dose at 100 mg/m 2 did contribute to the toxicity of the study, but accept that Fossella et al 2 had no alternative but to use this as the comparator arm, based on the evidence published.
CAR-T Cell Therapy for Lymphoma
Authors: Carlos A. Ramos, Helen E. Heslop, Malcolm K. Brenner
Journal: Annual Review of Medicine (2015)

Lymphomas arise from clonal expansions of B, T, or NK cells at different stages of differentiation. Because they occur in the immunocyte-rich lymphoid tissues, they are easily accessible to antibodies and cell-based immunotherapy. Expressing chimeric antigen receptors (CARs) on T cells is a means of combining the antigen-binding site of a monoclonal antibody with the activating machinery of a T cell, enabling antigen recognition independent of major histocompatibility complex restriction, while retaining the desirable antitumor properties of a T cell. Here, we discuss the basic design of CARs and their potential advantages and disadvantages over other immune therapies for lymphomas. We review current clinical trials in the field and consider strategies to improve the in vivo function and safety of immune cells expressing CARs. The ultimate driver of CAR development and implementation for lymphoma will be the demonstration of their ability to safely and cost-effectively cure these malignancies.
The pathogenesis of pulmonary fibrosis: a moving target
Authors: Wim A. Wuyts, Carlo Agostini, Katerina M. Antoniou, Demosthenes Bouros, Rachel C. Chambers, Vincent Cottin, Jim J. Egan, Bart N. Lambrecht, Rik Lories, Helen Parfrey, Antje Prasse, Carlos Robalo-Cordeiro, Eric Verbeken, Johny A. Verschakelen, Athol U. Wells, Geert M. Verleden
Journal: European Respiratory Journal (2012)

Pulmonary fibrosis is the end stage of many diffuse parenchymal lung diseases. It is characterised by excessive matrix formation leading to destruction of the normal lung architecture and finally death. Despite an exponential increase in our understanding of potentially important mediators and mechanisms, the delineation of primary pathways has proven to be elusive. In this review susceptibility and injurious agents, such as viruses and gastro-oesophageal reflux, and their probable role in initiating disease will be discussed. Further topics that are elaborated are candidate ancillary pathways, including immune mechanisms, oxidative and endoplasmic reticulum stress, activation of the coagulation cascade and the potential role of stem cells. This review will try to provide the reader with an integrated view on the current knowledge and attempts to provide a road map for future research. It is important to explore robust models of overall pathogenesis, reconciling a large number of clinical and scientific observations. We believe that the integration of current data into a “big picture” overview of fibrogenesis is essential for the development of effective antifibrotic strategies. The latter will probably consist of a combination of agents targeting a number of key pathways.
The Future of Drug Development in Urothelial Cancer
Authors: Robert Dreicer
Journal: Journal of Clinical Oncology (2011)

and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer. J Clin Oncol 23:8469-8476, 2005 27. Leach MO, Boggis CR, Dixon AK, et al: Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: A prospective multicentre cohort study (MARIBS). Lancet 365: 1769-1778, 2005 28. Trecate G, Vergnaghi D, Bergonzi S, et al: Breast MRI screening in patients with increased familial and/or genetic risk for breast cancer: A preliminary experience. Tumori 89:125-131, 2003 29. Warner E, Hill K, Causer P, et al: Prospective study of breast cancer incidence in women with a BRCA1 or BRCA2 mutation under surveillance with and without magnetic resonance imaging. J Clin Oncol 29:1664-1669, 2011 30. Foulkes WD, Reis-Filho JS, Narod SA: Tumor size and survival in breast cancer: A reappraisal. Nat Rev Clin Oncol 7:348-353, 2010 31. Hagen AI, Tretli S, Maehle L, et al: Survival in Norwegian BRCA1 mutation carriers with breast cancer. Hered Cancer Clin Pract 14;7, 2009 32. Foulkes WD, Grainge MJ, Rakha EA, et al: Tumor size is an unreliable predictor of prognosis in basal-like breast cancers and does not correlate closely with lymph node status. Breast Cancer Res Treat 111:199-204, 2009 33. Robson ME, Chappuis PO, Satagopan J, et al: A combined analysis of outcome following breast cancer: Differences in survival based on BRCA1/ BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res 6:R8-R17, 2004 34. Moller P, Borg A, Evans DG, et al: Survival in prospectively ascertained familial breast cancer: Analysis of a series stratified by tumour characteristics, BRCA mutations and oophorectomy. Int J Cancer 101:555-559, 2002 35. Maurice A, Evans DG, Affen J, et al: Surveillance of women at increased risk of breast cancer using mammography and clinical breast examination: Further evidence of benefit. Int J Cancer [epub ahead of print on August 23, 2011] 36. Evans DG, Gaarenstroom KN, Stirling D, et al: Screening for familial ovarian cancer: Poor survival of BRCA1/2 related cancers. J Med Genet 46:593-597, 2009
Studies on Human Leukemia. I. Spontaneous Lymphoblastoid Transformation of Fibroblastic Bone Marrow Cultures Derived From Leukemic and Nonleukemic Children&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Matilda Benyesh-Melnick, Donald J. Fernbach, Raymond T. Lewis
Journal: JNCI Journal of the National Cancer Institute (1963)

Bone marrow cells from 33 leukemic and 68 nonleukemic children were propagated in long-term tissue culture. Fibroblastic monolayer cultures were obtained from 24 of 43 (56%) specimens taken from the leukemic children when in relapse, from 52 of 79 (66%) specimens taken from the leukemic children when in remission, and from 47 of 71 (66%) specimens from nonleukemic children. Of the 123 fibroblastic cultures obtained, 110 were carried in serial passages and observed for 100 to 300 days. Four fibroblastic cultures, 2 derived from 2 children with acute leukem ia in remission, a culture from a child with infectious mononucleosis, and a culture from a child with hemolytic anemia and thrombocytopenia, showed a spontaneous lymphoblastoid transformation. This usually occurred in secondary (P1) cultures. The spontaneously transformed cultures con sisted of a mixture of fibroblastic and lymphoblastoid cells of various sizes. The latter cells actively multiplied, either free in the supernatant fluid or on the fibroblastic monolayer, forming three-dimensional clusters. Cytologically, the lymphoblastoid cells strongly resembled the immature cells seen in direct smear preparations from bone marrow aspirates of leukemic children during the acute stage of the disease. All transformed cultures were serially propagated for prolonged periods, and they maintained their altered appearance. The phenomenon of “emperipolesis” was observed in all transformed cultures. With the depletion of fibroblastic cells, usually between the 10th and 15th serial transfers, the lymphoblastoid cells ceased multiplying and the cultures degenerated.
Public Health Quality Measurement: Concepts and Challenges
Authors: Stephen F. Derose, Mark A. Schuster, Jonathan E. Fielding, Steven M. Asch
Journal: Annual Review of Public Health (2002)

▪ Abstract Public health agencies increasingly are recognizing the need to formally and quantitatively assess and improve the quality of their programs, information, and policies. Measuring quality can help organizations monitor their progress toward public health goals and become more accountable to both the populations they serve and policy makers. Yet quality assessment is a complex task that involves precise determination and specification of useful measures. We discuss a well-established conceptual framework for organizing quality assessment in the context of planning and delivery of programs and services by local health departments, and consider the strengths and limitations of this approach for guiding quality improvement. We review several past and present quality measurement–related initiatives designed for public health department use, and discuss current and future challenges in this evolving area of public health practice.
Direct gene delivery of human tissue kallikrein reduces blood pressure in spontaneously hypertensive rats.
Authors: C Wang, L Chao, J Chao
Journal: Journal of Clinical Investigation (1995)

Hypertension is a multigene and multifactorial disorder af- fecting -25% of the population.To demonstrate potential therapeutic effects of human tissue kallikrein in hyperten- sion, spontaneously hypertensive rats were subjected to so- matic gene therapy.Two human tissue kallikrein DNA con- structs, one under the promoter control of the metallothionein metal response element and the other under the control of the Rous sarcoma virus 3'-LTR, were generated.We delivered naked DNA constructs into spontaneously hyper- tensive rats via intravenous injection.The expression of hu- man tissue kallikrein in rats was identified in the heart, lung, and kidney by reverse transcription polymerase chain reaction followed by Southern blot analysis and an ELISA specific for human tissue kallikrein.A single injection of both human kallikrein plasmid DNA constructs caused a sustained reduction of blood pressure which began 1 wk after injection and continued for 6 wk.A maximal effect of blood pressure reduction of 46 mmHg in rats was observed 2-3 wk after injection with kallikrein DNA as compared to rats with vector DNA (n = 6, P < 0.05).The hypotensive effect caused by somatic gene delivery of human tissue kalli- krein in hypertensive rats is reversed by subcutaneous injection of aprotinin, a potent tissue kallikrein inhibitor.No antibodies to either human tissue kallikrein or kallikrein DNA were detected in rat sera after injection of the human kallikrein gene.These results show that direct gene delivery of human tissue kallikrein causes a sustained reduction in systolic blood pressure in genetically hypertensive rats and indicate that the feasibility of kallikrein gene therapy for treating human hypertension should be studied. (
Distinct endotypes of steroid-resistant asthma characterized by IL-17Ahigh and IFN-γhigh immunophenotypes: Potential benefits of calcitriol
Authors: Emma S. Chambers, Alexandra M. Nanzer, Paul E. Pfeffer, David F. Richards, Peter M. Timms, Adrian R. Martineau, Christopher J. Griffiths, Christopher J. Corrigan, Catherine M. Hawrylowicz
Journal: Journal of Allergy and Clinical Immunology (2015)

BackgroundA small population of patients with severe asthma does not respond to glucocorticoids (steroid resistant [SR]). They have high morbidity, highlighting an urgent need for strategies to enhance glucocorticoid responsiveness.ObjectiveWe investigated the immunologic differences between steroid-sensitive (SS) and SR asthmatic patients and the effect on immunophenotype of oral calcitriol treatment because it has been previously shown to beneficially modulate the clinical response to glucocorticoids in patients with SR asthma.MethodsCD8-depleted PBMCs were isolated from 12 patients with SS and 23 patients with SR asthma and cultured for 7 days with anti-CD3 and IL-2 with or without dexamethasone. Cytokine production was assessed in supernatants by using the Cytometric Bead Array. Patients with SR asthma were subsequently randomized to oral calcitriol or placebo therapy, and identical studies were repeated.ResultsPatients with SR asthma produced significantly increased IL-17A and IFN-γ levels compared with those in patients with SS asthma, although it was evident that cells from individual patients might overproduce one or the other of these cytokines. Production of IL-17A was inversely and production of IL-13 was positively associated with the clinical response to prednisolone. Oral calcitriol, compared with placebo, therapy of the patients with SR asthma significantly improved dexamethasone-induced IL-10 production in vitro while suppressing dexamethasone-induced IL-17A production. This effect mirrored the previously demonstrated improvement in clinical response to oral glucocorticoids in calcitriol-treated patients with SR asthma.ConclusionsIL-17Ahigh and IFN-γhigh immunophenotypes exist in patients with SR asthma. These data identify immunologic pathways that likely underpin the beneficial clinical effects of calcitriol in patients with SR asthma by directing the SR cytokine profile toward a more SS immune phenotype, suggesting strategies for identifying vitamin D responder immunophenotypes.
Beyond tie-ing up endothelial adhesion: new insights into the action of angiopoietin-1 in regulation of microvessel permeability
Authors: P. He
Journal: Cardiovascular Research (2009)

The growth factor angiopoietin-1 (Ang1) has been identified as the primary activating ligand for Tie2, a tyrosine kinase receptor highly expressed in vascular endothelial cells.1 Genetic studies using targeted mutations in mice have demonstrated that Tie2 activation by Ang1 is crucial for angiogenesis, vascular remodelling, and vascular maturation.2 However, the angiogenic functions of Ang1 are distinct from those of vascular endothelial growth factor (VEGF). Transgenic mice studies have revealed that blood vessels induced by VEGF overexpression are leaky, whereas blood vessels induced by Ang1 overexpression are not only non-leaky, but also resistant to vascular leakage during inflammation.3 Previous studies using inflammatory mediator-stimulated animals or cultured endothelial cells have identified the permeability protective effects of Ang1 to be mediated through inhibition of endothelial gap formation4 and strengthening of endothelial adhesion.5 In a new study featured in this issue of Cardiovascular Research , Salmon et al. 6 report the effect of Ang1 on the endothelial glycocalyx and propose a novel mechanism for the permeability protective action of Ang1.

Using individually perfused mesenteric microvessels with the Landis-Michel technique,7,8 Salmon et al. quantified the direct effect of Ang1 on water and albumin permeability in intact microvessels by measuring permeability … 

*Corresponding author. Tel: +1 304 293 1515; fax: +1 304 293 3850. E-mail address : phe{at}hsc.wvu.edu
Phase I/II trial of biweekly paclitaxel and cisplatin in the treatment of metastatic breast cancer.
Authors: K A Gelmon, S E O'Reilly, A W Tolcher, C Campbell, C Bryce, J Ragaz, C Coppin, I H Plenderleith, D Ayers, B McDermott, L Nakashima, D Healey, N Onetto
Journal: Journal of Clinical Oncology (1996)

PURPOSE To determine the maximum-tolerated dose of escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) administered biweekly with a fixed dose of cisplatin, to assess the toxicity, and to evaluate the activity of this combination in a phase I/II trial in metastatic breast cancer. PATIENTS AND METHODS Twenty-nine women with metastatic breast cancer were enrolled; 27 were assessable for response and 29 for toxicity. All but two of the women had received prior adjuvant chemotherapy, with 23 receiving anthracyclines and six previous cisplatin. RESULTS The initial starting dose of paclitxel 90 mg/m2 and cisplatin 60 mg/m2 became the phase II dose due to dose-limiting neutropenia. Responses were seen in 85% of assessable patients, with three patients (11%) achieving a complete response (CR) and 20 patients (14%) a partial response (PR), for an overall response rate of 85% (95% confidence interval [CI], 66% to 96%). The time to disease progression for patients who achieved a CR was 110 to 200 days, and for those with a PR, it was 96 to 377+ days, with a median time to progression of 7.1 months and a median response duration of 7.9 months. Sites of CR were skin, soft tissue, and lung, and all occurred in women with previous exposure to anthracyclines. Septic events were rare, with two grade 3 infections (7%), only one of which required hospital admission. There were no grade 4 nonhematologic toxicity and minimal grade 3 toxicity. A total of 251 chemotherapy cycles were given -- 16 with paclitaxel alone in five patients. Forty-five percent of patients required dose reductions, while 52% had delays due to neutropenia. CONCLUSION Biweekly paclitaxel and cisplatin is an active combination in the treatment of metastatic breast cancer, including for patients with previous exposure to anthracyclines.
Discordance in Perceptions of Barriers to Diabetes Care Between Patients and Primary Care and Secondary Care
Authors: David Simmons, Steven Lillis, Judith Swan, Jarrod Haar
Journal: Diabetes Care (2007)

We sought to compare perceived barriers to diabetes care between people with diabetes and different health professional groups.This was a cross-sectional, postal, open-questionnaire survey conducted in the Waikato district, New Zealand. A total of 3,890 individuals with diabetes participated, as well as 436 primary and secondary health professionals.Barriers were reported in 69.7% of patients. Psychological barriers were most important (55.5%), followed by systems barriers (25.7%), and then knowledge as least important (15.3%). Psychological barriers were ranked first among general practitioners (91.0%), but systems barriers were ranked first by other health professionals (38.8-100%). General practitioner and patient barrier group rankings were similar (r(T) = 0.976, P < 0.05). Of specific barriers among individuals with diabetes, strictness of treatment regimen was the most frequently reported (42.3 vs. 0.1-16.8%) (P < 0.001) and 2.5 (95% CI 2.4-2.7)- to 3.4 (3.2-3.7)-fold more than the 2nd through 4th ranked barriers. Motivation was the most common specific barrier reported by general practitioners (86%), practice nurses (31.5%), and the diabetes team (85.7%). Practice and hospital nurse/dietitian rankings were most comparable with patients (r(T) = 0.457 and 0.466, respectively, both P < 0.05). A major area of patient-health professional discordance was the influence of other health problems, which was ranked 2nd among patients but 10th-18th among health professionals.The most important barriers to diabetes care perceived by patients are psychological and particularly relate to the strictness of the regimen. Discordance between patients and different health professionals exists in the perception of the importance of different barriers to diabetes care.
GAD Antibody in Multiplex Diabetic Pedigrees of Chinese
Authors: Tao Chen, Yan Ren, Yang Long, Xiangxun Zhang, Honglin Yu, Haoming Tian
Journal: Diabetes Care (2007)

ultiplex diabetic families may be caused by mutations in genes of hepatocyte nuclear factors (maturity-onset diabetes of the young [MODY]1, -3, and -5), glucokinase (MODY2), insulin promoter factor-1 (MODY4), NeuroD1 (MODY6), mitochondrion ND1 and tRNA Leu(UUR) , and some other unknown genetic mutations.Recent studies showed that mutations of MODY are not common causes of diabetes in Chinese diabetic families (1-3), indicating that there may be other causes and mechanisms involved.Latent autoimmune diabetes in adults (LADA) shares some similar clinical phenotypes with MODY and is common in phenotypic type 2 diabetes (10 -25%) (4).This study was conducted to investigate the distribution of GAD antibody (GADA) in multiplex diabetic pedigrees from the ChengDu area of China.
Interaction of immune complexes and T suppressor cells in sarcoidosis.
Authors: J D Williams, M D Smith, B H Davies
Journal: Thorax (1982)

Circulating immune complexes were present in half of 31 patients with sarcoidosis and raised levels were associated with low numbers of T suppressor cells (T gamma- and Fc gamma-receptor-positive lymphocytes). Incubation of T cells with trypsin restored the percentage of T gamma cells to within or above the normal range. Incubation of normal lymphocytes with sarcoid immune complexes significantly reduced the number of detectable T gamma cells. Preincubation of normal lymphocytes with circulating immune complexes significantly reduced their blastogenic response to concanavalin A. These studies suggest an interaction between immune complexes and T suppressor cells in sarcoidosis and emphasise the importance of immune complexes in modulating the immune response.
Detection of Subclinical Systemic Disease in Primary CNS Lymphoma by Polymerase Chain Reaction of the Rearranged Immunoglobulin Heavy-Chain Genes
Authors: Kristoph Jahnke, Michael Hummel, Agnieszka Korfel, Thomas Burmeister, Philipp Kiewe, Hermann Ayke Klasen, Hans-Henning Müller, Harald Stein, Eckhard Thiel
Journal: Journal of Clinical Oncology (2006)

To search for subclinical systemic disease in bone marrow and peripheral blood in patients with primary CNS lymphoma (PCNSL) to elucidate whether extracerebral relapse may represent a sequel of initial occult systemic disease rather than true extracerebral spread.Bone marrow and peripheral-blood specimens of 24 PCNSL patients were examined using polymerase chain reaction (PCR) for analysis of clonally rearranged immunoglobulin heavy-chain (IgH) genes.Identical dominant PCR products were found in bone marrow aspirates, blood samples, and tumor biopsy specimens of two patients, indicating that the same tumor cell population is present in the CNS and in extracerebral sites. Follow-up IgH PCR performed in one of these patients in complete remission 24 months after diagnosis yielded a persistent monoclonal product in the blood. An oligoclonal IgH rearrangement pattern was found in the tumor specimen of two other patients, whereas bone marrow and blood samples demonstrated the same dominant PCR products. Follow-up PCR showed a persistent monoclonal amplificate in blood in one of these patients 27 months after diagnosis.It could be demonstrated for the first time that subclinical systemic disease can be present in PCNSL patients at initial diagnosis. Our findings may have an impact on the understanding of PCNSL pathogenesis and the extent of staging and treatment.