tbuckley/cabot-search huggingface dataset:
Autologous Stem-Cell Transplantation As First-Line Therapy in Peripheral T-Cell Lymphomas: Results of a Prospective Multicenter Study
Authors: Peter Reimer, Thomas Rüdiger, Eva Geissinger, Florian Weissinger, Christoph Nerl, Norbert Schmitz, Andreas Engert, Hermann Einsele, Hans Konrad Müller-Hermelink, Martin Wilhelm
Journal: Journal of Clinical Oncology (2008)

Peripheral T-cell lymphomas (PTCLs) are rare malignancies with poor outcome after conventional chemotherapy. The role of myeloablative therapy and autologous stem-cell transplantation (autoSCT) is still unclear. Therefore, we initiated the first prospective multicenter study on upfront autoSCT in PTCL and recently reported good feasibility and efficacy of this approach. Here, we present the final analysis of the study.The treatment regimen consisted of four to six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by mobilizing therapy with either the dexamethasone, carmustine, melphalan, etoposide, and cytarabine protocol or the etoposide, methylprednisolone, cytarabine, and cisplatin protocol and stem-cell collection. Patients in complete remission (CR) or partial remission (PR) underwent myeloablative chemoradiotherapy (fractionated total-body irradiation and high-dose cyclophosphamide) and autoSCT.From June 2000 to April 2006, 83 patients were enrolled onto the study. Main subgroups were PTCL not specified (n = 32) and angioimmunoblastic T-cell lymphoma (n = 27). Fifty-five (66%) of the 83 patients received transplantation. The main reason for not receiving autoSCT was progressive disease. In an intent-to-treat analysis, the overall response rate after myeloablative therapy was 66% (56% CR and 8% PR). With a median follow-up time of 33 months, 43 patients are alive; the estimated 3-year overall and disease-free survival rates for patients in CR (calculated from CR to the date of relapse) and 3-year progression-free survival rate were 48%, 53%, and 36%, respectively.The results of this prospective study suggest a substantial impact on outcome for upfront autoSCT in PTCL and should be further evaluated in randomized trials. Pretransplantation treatment needs to be improved to increase the transplantation rate.
Membrane and transformation characteristics of lymphocytes isolated from the synovial membrane and paired peripheral blood of patients with rheumatoid arthritis
Authors: C.J.L.M. Meijer, L.B.A. Van De Putte, G.J.M. Lafeber, E. De Haas, A. Cats
Journal: Annals of the Rheumatic Diseases (1980)

Membrane and transformation characteristics of lymphocytes isolated from the synovial membrane and from paired peripheral blood samples, obtained from patients with classical rheumatoid arthritis, were studied. Synovial tissue lymphocytes were isolated by a new technique. Two suspensions of peripheral blood lymphocytes were studied: one isolated by Ficoll-Isopaque density gradient centrifugation, the other enriched in T cells by an additional step of 1 hour nylon wool column filtration. All suspensions were characterised by the percentages of mononuclear phagocytic cells, and T and B lymphocytes. The spontaneous (3)H-thymidine uptake of synovial tissue lymphocyte suspensions always exceeded that of the peripheral blood lymphocyte suspensions. The in-vitro responsiveness of synovial tissue lymphocytes to PHA, Con-A, and PWM, as measured by (3)H-thymidine uptake, was always consistently lower than that of paired peripheral blood lymphocytes whether or not enriched in T cells. The responsiveness to antigens, including PPD, varidase, and an antigen cocktail consisting of varidase, trychophyton, and Staphylococcus aureus antigen, showed the same effect. No dissociation was found between the response to PPD and the other antigens studied. These results suggest that the relative unresponsiveness to mitogens and antigens of synovial tissue lymphocytes in comparison with blood lymphocytes is not caused by mononuclear phagocyte contamination, but either by different subsets of T lymphocytes or by different functional states of T lymphocytes present in the synovial membrane and peripheral blood of patients with rheumatoid arthritis.
Antigenic characterization of human hepatocellular carcinoma. Development of in vitro and in vivo immunoassays that use monoclonal antibodies.
Authors: R I Carlson, E Ben-Porath, D Shouval, W Strauss, K J Isselbacher, J R Wands
Journal: Journal of Clinical Investigation (1985)

Several libraries of monoclonal antibodies have been produced by immunization of Balb/c mice with single cell suspensions of nontrypsin-treated human hepatocellular carcinoma cell (HCC) lines in order to study the antigenic properties of transformed hepatocytes. The antibodies were characterized with regards to specificity for hepatoma-associated antigens and their capability for use as reagents in radioimmunoassays (RIAs) and tumor localization in vivo. Three such antibodies namely, P215457, PM4E9917, P232524 of the IgG2a, IgG2a, and IgG1 isotypes, respectively, not only recognized separate and distinct antigenic determinants on four human hepatoma cell lines but also reacted with epitopes present on chemically induced rat hepatoma cell lines. In contrast, only 1 of 38 other human malignant and transformed cell lines demonstrated reactivity with the three antibodies; normal human tissues were also found to be unreactive. Monoclonal antibody P215457 densely stained the plasma membrane by indirect immunofluorescence, showed rapid binding activity to HCC cells in suspension, and precipitated a 50,000-mol wt cell surface protein; antibody PM4E9917 also stained the plasma membrane and precipitated a 65,000-mol wt protein, whereas P232534 recognized cytoplasmic antigenic determinants. With these antibodies "simultaneous sandwich" RIAs were established that detect soluble hepatoma-associated antigens in culture supernatants. Finally, the Fab fragment of P215457 was found to be useful in tumor localization in vivo. This antibody fragment when labeled with 131I was shown to localize by radionuclide-imaging studies in human hepatoma grown in nude mice. Thus, these investigations demonstrate that monoclonal antibodies may be produced against epitopes that reside almost exclusively on transformed hepatocytes and such antibodies may be successfully employed in the development of in vitro and in vivo immunoassays.
The combination of 2% 4-hydroxyanisole (Mequinol) and 0.01% tretinoin is effective in improving the appearance of solar lentigines and related hyperpigmented lesions in two double-blind multicenter clinical studies
Authors: A B Fleischer, E H Schwartzel, S I Colby, D J Altman
Journal: Journal of the American Academy of Dermatology (2000)
Mutations in the D1 domain of von Willebrand factor impair their propeptide-dependent multimerization, intracellular trafficking and secretion
Authors: Jie Yin, Zhenni Ma, Jian Su, Jiong-Wei Wang, Xiaojuan Zhao, Jing Ling, Xia Bai, Wanyan Ouyang, Zhaoyue Wang, Ziqiang Yu, Changgeng Ruan
Journal: Journal of Hematology & Oncology (2015)

We identified three novel mutations (p.Gly39Arg, p.Lys157Glu, p.Cys379Gly) and one previously known mutation (p.Asp141Asn) in the von Willebrand factor propeptide from three von Willebrand disease patients. All four mutations impaired multimerization of von Willebrand factor, due to reduced oxidoreductase activity of isomeric propeptide. These mutations resulted in the endothelial reticulum retention and impaired basal and stimulated secretions of von Willebrand factor. Our results support that the mutations in the D1 domain lead to defective multimerization, intracellular trafficking, and secretion of von Willebrand factor and result in bleeding of patients.
Lung changes detected by high resolution tomography are present in ACPA positive RA patients already at disease onset
Authors: G Reynisdottir, V Joshua, S Nyren, A Hensvold, R Karimi, A Harju, M Engström, M Sköld, A Eklund, J Grunewald, L Klareskog, A I Catrina
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background/purpose</h3> The authors have previously shown that smoking increases citrullination in the lungs of healthy smokers and hypothesised that this process is an important step in the early development of rheumatoid arthritis (RA). To test this the authors investigated lung function in a cohort of RA patients with very early disease, already at the time of diagnosis and compared it with an aged, smoke and gender matched cohort of individuals without RA. <h3>Methods</h3> 82 patients, 56 female and 26 male, median age 60 (range 22–84) with symptom duration less than 1 year at the time of diagnosis and naive to disease-modifying antirheumatic drug treatment were included in the RA cohort. A second cohort of age, smoking and gender matched non-RA individuals (n=43) were investigated with an identical protocol. Lung function (x-ray, high-resolution CT (HRCT) and dynamic spirometry) was tested in both RA and controls at baseline and repeated after 6 months in the RA group. In a subgroup of patients bronchoscopy was performed at inclusion (n=18) and 6 months later (n=11) and bronchoalveolar lavage samples as well as mucosal large bronchial biopsies were retrieved. Presence of peptydilamino deiminase (PAD) enzymes were evaluated by immunohistochemistry. <h3>Results</h3> 63% of the patients were anticitrullinated protein antibodies (ACPA) positive, 26% were current smokers and 22% have reported a previous lung pathology. All patients had active disease with a mean disease activity score of 5.5±0.1 at inclusion that decreased significantly to 3.3±0.2 after 6 months. A majority of the patients (55%) had any type of changes on HRCT either focal or diffuse. Lung changes of any type were more frequent in RA as compared to non-RA individuals (35%) with a higher prevalence of lung fibrosis (15/82 in the RA cohort and 0/43 in the control cohort). In the RA cohort one patient (1.2%) was diagnosed with lung cancer following HRCT screening while none in the control cohort. ACPA and rheumatoid factor but not smoking status associated with the presence of changes on HRCT. Immunohistochemistry demonstrated a significant increase in expression of both PAD2 and PAD4 in the lungs of current smokers independent of the ACPA status with no significant changes following 6 months of treatment. <h3>Conclusion</h3> Presence of ACPA associates with early lung HRCT changes in RA. The authors suggest that smoking (and other yet unidentified factors) promotes site specific citrullination (such as in lungs) leading to generation of ACPA immunity and lung changes very early in the disease process.
The failing human heart is unable to use the Frank-Starling mechanism.
Authors: R H Schwinger, M Böhm, A Koch, U Schmidt, I Morano, H J Eissner, P Uberfuhr, B Reichart, E Erdmann
Journal: Circulation Research (1994)

There is evidence that the failing human left ventricle in vivo subjected to additional preload is unable to use the Frank-Starling mechanism. The present study compared the force-tension relation in human nonfailing and terminally failing (heart transplants required because of dilated cardiomyopathy) myocardium. Isometric force of contraction of electrically driven left ventricular papillary muscle strips was studied under various preload conditions (2 to 20 mN). To investigate the influence of inotropic stimulation, the force-tension relation was studied in the presence of the cardiac glycoside ouabain. In skinned-fiber preparations of the left ventricle, developed tension was measured after stretching the preparations to 150% of the resting length. To evaluate the length-dependent activation of cardiac myofibrils by Ca2+ in failing and nonfailing myocardium, the tension-Ca2+ relations were also measured. After an increase of preload, the force of contraction gradually increased in nonfailing myocardium but was unchanged in failing myocardium. There were no differences in resting tension, muscle length, or cross-sectional area of the muscles between both groups. Pretreatment with ouabain (0.02 mumol/L) restored the force-tension relation in failing myocardium and preserved the force-tension relation in nonfailing tissue. In skinned-fiber preparations of the same hearts, developed tension increased significantly after stretching only in preparations from nonfailing but not from failing myocardium. The Ca2+ sensitivity of skinned fibers was significantly higher in failing myocardium (EC50, 1.0; 95% confidence limit, 0.88 to 1.21 mumol/L) compared with nonfailing myocardium (EC50, 1.7; 95% confidence limit, 1.55 to 1.86 mumol/L). After increasing the fiber length by stretching, a significant increase in the sensitivity of the myofibrils to Ca2+ was observed in nonfailing but not in failing myocardium. These experiments provide evidence for an impaired force-tension relation in failing human myocardium. On the subcellular level, this phenomenon might be explained by a failure of the myofibrils to increase the Ca2+ sensitivity after an increase of the sarcomere length.
Heart disease and pneumoconiosis
Authors: W. L. Sanders
Journal: Thorax (1970)

This paper presents an investigation into the relative frequency of deaths from coronary artery disease and from congestive cardiac failure associated with or secondary to chronic lung disease in 367 men with pneumoconiosis. All these men had been receiving a pension for pneumoconiosis and had died in the area served by the Birmingham Pneumoconiosis Medical Panel during 1967 and 1968. Of the total, 76 died from coronary artery disease and 107 from congestive cardiac failure. Thirty-one men had simple pneumoconiosis alone, and of these 87% died from coronary artery disease and 13% from congestive cardiac failure. Sixty-one men had progressive massive fibrosis, and of these 10% died from coronary artery disease and 90% from congestive cardiac failure. Ninety-one men had simple pneumoconiosis with bronchitis and emphysema and in this group death occurred in approximately equal numbers from both causes. It is suggested that the reason for these differences is the variation in the degree of hypoxia present in the different conditions.
Ichthyosis bullosa of Siemens responds well to low-dosage oral retinoids
Authors: P.M. STEIJLEN, R.J. DOORKN-GREEBE, R. HAPPLE, P.C.M. KERKHOF
Journal: British Journal of Dermatology (1991)

Two patients with ichthyosis bullosa of Siemens (IBS) and one patient with bullous ichthyosiform erythroderma of Brocq (BIE) were treated with etretinate. Two additional patients with IBS received acitretin. All the patients had a marked improvement when on retinoids and the maintenance dose required was for IBS 10–25 mg per day. The patient with BIE was on a maintenance dose of 40–60 mg per day.
ATF3-Mediated Epigenetic Regulation Protects against Acute Kidney Injury
Authors: Hsiao-Fen Li, Ching-Feng Cheng, Wei-Ju Liao, Heng Lin, Ruey-Bing Yang
Journal: Journal of the American Society of Nephrology (2010)

A variety of stress stimuli, including ischemia-reperfusion (I/R) injury, induce the transcriptional repressor ATF3 in the kidney. The functional consequences of this upregulation in ATF3 after renal I/R injury are not well understood. Here, we found that ATF3-deficient mice had higher renal I/R-induced mortality, kidney dysfunction, inflammation (number of infiltrating neutrophils, myeloperoxidase activity, and induction of IL-6 and P-selectin), and apoptosis compared with wild-type mice. Furthermore, gene transfer of ATF3 to the kidney rescued the renal I/R-induced injuries in the ATF3-deficient mice. Molecular and biochemical analysis revealed that ATF3 interacted directly with histone deacetylase 1 (HDAC1) and recruited HDAC1 into the ATF/NF-kappaB sites in the IL-6 and IL-12b gene promoters. The ATF3-associated HDAC1 deacetylated histones, which resulted in the condensation of chromatin structure, interference of NF-kappaB binding, and inhibition of inflammatory gene transcription after I/R injury. Taken together, these data demonstrate epigenetic regulation mediated by the stress-inducible gene ATF3 after renal I/R injury and suggest potential targeted approaches for acute kidney injury.
Left Ventricular Ejection Time in Atrial Fibrillation
Authors: MORTON E. TAVEL, DAVID O. BAUGH, HARVEY FEIGENBAUM, WILLIAM K. NASSER, Janie Stewart
Journal: Circulation (1972)

Left ventricular ejection time (LVET; indirect carotid pulse) was studied in 48 patients with atrial fibrillation. In comparison with normal individuals in normal sinus rhythm, ejection times for similar cycle lengths were usually short in patients with atrial fibrillation. Patients without mitral valve disease usually show increasing ejection times following increasing cycle lengths until a certain cycle length is reached (usually around 0.85 sec). Further prolongation of cycle length will not further lengthen the LVET. By contrast, patients with significant mitral stenosis show a continuously sloping curve, i.e. continue to show prolongation of ejection times with progressive lengthening of cycles, eventually reaching ejection times (if cycles are sufficiently long) which exceed those of patients without mitral stenosis. Conversion to normal sinus rhythm (six patients) produced variable results, usually lengthening of ejection time for similar cycle length. Postconversion lengthening of LVET was most pronounced in those cases which lacked progressive increase in LVET with longer cycles during atrial fibrillation. This effect was evident in those patients manifesting relatively slow sinus rates after conversion. Our results indicate that in order to derive information from ejection times in atrial fibrillation one must plot these values against cycle lengths. Moreover, he cannot use data obtained from patients in normal sinus rhythm to interpret ejection times in those manifesting atrial fibrillation.
Origin and Pathogenesis of Pelvic (Ovarian, Tubal, and Primary Peritoneal) Serous Carcinoma
Authors: Niloofar N. Nik, Russell Vang, Ie-Ming Shih, Robert J. Kurman
Journal: Annual Review of Pathology Mechanisms of Disease (2013)

A new paradigm for the pathogenesis of female pelvic cancer helps explain persistent problems in describing the development and diverse morphology of these neoplasms. This paradigm incorporates recent advances in the molecular pathogenesis of epithelial ovarian cancer (EOC) with new insights into the origin of these tumors. Correlated clinicopathologic and molecular genetic studies gave rise to a dualistic model that divides the various histologic types of EOCs into two broad categories designated type I and type II. Because serous carcinomas are the most common EOC and account for the vast majority of deaths, they form the subject of this review. Recent studies indicate that the precursor of ovarian high-grade serous carcinoma appears to develop from an occult intraepithelial carcinoma in the fimbria of the fallopian tube and involves the ovary secondarily. Another possible mechanism is implantation of normal fimbrial epithelium on the denuded ovarian surface at the site of rupture when ovulation occurs, causing the development of cortical inclusion cysts. The dualistic model serves as a framework for the study of ovarian cancer and can help investigators organize this complex group of neoplasms. It also facilitates the development of novel approaches to prevention, screening, and treatment of this devastating disease.
MB-33 * THE CRITICAL ROLE OF OLIG2-EXPRESSING PROGENITORS IN THE INITIATION OF G-PROTEIN MEDIATED SONIC HEDGEHOG-DRIVEN MEDULLOBLASTOMA
Authors: X. Lu, R. Lu
Journal: Neuro-Oncology (2015)

Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving medulloblastoma initiation and progression remain poorly understood. Recently we identify GNAS, encoding the G-protein Gsα, as a potent tumor suppressor gene that defines a subset of aggressive Sonic Hedgehog (Shh)-driven human medulloblastomas. Ablation of the single Gnas gene in anatomically-distinct progenitors is sufficient to induce Shh-associated medulloblastomas, which recapitulate their human counterparts. Gsα is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh-signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation of a Gsα effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas mutants. Furthermore, we identify a population of Olig2-expressing progenitor cells are the major source of tumor-propagating cells. Deletion of Olig2 leads to a delay of tumor progression. Eliminating the mitotic Olig2-expression inhibits tumor initiation. Thus, our present studies identify a previously unrecognized tumor suppressor function for Gsα that acts as a molecular link across Shh-group medulloblastomas of disparate cellular and anatomical origins, and reveal that Olig2-expressing progenitors are the critical cell origin of G-protein-mediated SHH subgroup medulloblastoma, illuminating potential therapeutic avenues for SHH medulloblastoma by targeting G-protein and Olig2-expressing glial progenitors.
Renal Replacement Therapy in Patients with Diabetes and End-Stage Renal Disease
Authors: Francesco Locatelli, Pietro Pozzoni, Lucia Del Vecchio
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. The number of patients who have diabetes and ESRD and are being admitted to renal replacement treatment (RRT) is increasing dramatically worldwide, and in many countries, diabetes has become the single most frequent cause of ESRD. Although the prognosis of patients who have diabetes and are receiving RRT has greatly improved, survival and medical rehabilitation rates continue to be significantly worse than those of nondiabetic patients, mainly because of preexisting severely compromised cardiovascular conditions. The most common RRT modality in patients with diabetes is still hemodialysis, but it gives rise to a number of clinical problems, in particular difficulties in the management of the vascular access and high frequency of intradialytic hypotension. However, patients who have diabetes and are on peritoneal dialysis have to face a progressive increase in peritoneal permeability, loss of ultrafiltration, and peritoneal fibrosis, all phenomena being accelerated in patients with diabetes and ultimately leading to an increased technique failure. The results of observational studies and national registries, although conflicting, suggest that these two dialytic modalities are somehow comparable in terms of outcomes, whereas accumulating evidence shows that both survival and medical rehabilitation of patients with diabetes are significantly better after renal transplantation, which should be the first-choice option for patients who have diabetes and reach ESRD but unfortunately still accounts for only a limited proportion of RRT treatments in these patients.