tbuckley/cabot-search huggingface dataset:
Mouse Models for Xeroderma Pigmentosum Group A and Group C Show Divergent Cancer Phenotypes
Authors: Joost P.M. Melis, Susan W.P. Wijnhoven, Rudolf B. Beems, Marianne Roodbergen, Jolanda van den Berg, Hojin Moon, Errol Friedberg, Gijsbertus T.J. van der Horst, Jan H.J. Hoeijmakers, Jan Vijg, Harry van Steeg
Journal: Cancer Research (2008)

Abstract The accumulation of DNA damage is a slow but hazardous phenomenon that may lead to cell death, accelerated aging, and cancer. One of the most versatile defense mechanisms against the accumulation of DNA damage is nucleotide excision repair, in which, among others, the Xeroderma pigmentosum group C (XPC) and group A (XPA) proteins are involved. To elucidate differences in the functions of these two proteins, comprehensive survival studies with Xpa−/−, Xpc−/− and wild-type control female mice in a pure C57BL/6J background were done. The median survival of Xpc−/− mice showed a significant decrease, whereas the median survival of Xpa−/− mice did not. Strikingly, Xpa−/− and Xpc−/− mice also showed a phenotypical difference in terms of tumor spectrum. Xpc−/− mice displayed a significant increase in lung tumors and a trend toward increased liver tumors compared with Xpa-deficient or wild-type mice. Xpa−/− mice showed a significant elevation in liver tumors. Additionally, Xpc-deficient mice exhibited a strong increase in mutant frequency in lung compared with Xpa−/− mice, whereas in both models mutant frequency is increased in liver. Our in vitro data displayed an elevated sensitivity to oxygen in Xpc−/− in mouse embryonic fibroblasts (MEF) when compared with Xpa−/− and wild-type fibroblasts. We believe that XPC plays a role in the removal of oxidative DNA damage and that, therefore, Xpc−/− mice display a significant increase in lung tumors and a significant elevation in mutant frequency in lung, and Xpc-deficient MEFs show greater sensitivity to oxygen when compared with Xpa−/− and wild-type mice. [Cancer Res 2008;68(5):1347–53]
The Renin-Angiotensin System in Nonmammalian Vertebrates*
Authors: JOHN X. WILSON
Journal: Endocrine Reviews (1984)

The purpose of this review is to appraise the results of the comparative approach to an endocrine system, the renin-angiotensin system (RAS). Recognizing that animal life is a product of history, comparative endocrinology tries to account for the structure and function of endocrine systems as products of evolution. Its characteristic method is the study of homologies, those resemblances among species resulting from derivation from a common ancestry on which natural selection has operated to produce adaptations. Why the comparative approach to the RAS? In addition to their intrinsic interest, comparative studies are of contextual importance to the understanding of mammalian endocrinology. Insights gained from the study of primitive organisms often are valid even at the level of complexity represented by the most recent vertebrates because animals considered primitive on phylogenetic scales nevertheless possess many of the same components as organisms at higher levels. Furthermore, the comparative approach favors serendipitous discoveries: some physiological relationships are most obvious in primitive animals and yet are fundamental to the lives of all vertebrates. Another advantage is heuristic: some animals, or parts of animals, are more favorable for particular experimental paradigms than are others.
Class-specific rheumatoid factors, DR antigens, and amyloidosis in patients with rheumatoid arthritis.
Authors: C P Maury, A M Teppo, F Wafin, O Wegelius, C Friman, S Koskimies
Journal: Annals of the Rheumatic Diseases (1988)

Class-specific rheumatoid factors (RFs) were measured by enzyme immunoassay in 59 patients with rheumatoid arthritis complicated by systemic amyloidosis (RA+A), 47 patients with rheumatoid arthritis without amyloid (RA), 106 patients with other rheumatic diseases (juvenile rheumatoid arthritis, systemic lupus erythematosus, Sjögren9s syndrome), and 55 blood donors. The patients with RA+A were characterised by a high prevalence of RF negativity; the IgM RF concentration was raised in only 18 of the 59 patients (31%, p less than 0.001 v RA), the IgG RF concentration in 20 of 59 (34%, p less than 0.001 v RA), and the IgA RF concentration in 24 of 59 (41%, p less than 0.001 v RA). A higher prevalence of HLA-DR4 (p less than 0.001) and a lower prevalence of DR2 (p less than 0.05) were found among 48 tested patients with RA+A when compared with a control panel consisting of 500 blood donors. No significant differences in the prevalence of DR1-DR7 or B27 antigens were observed, however, between patients with RA with or without amyloid.
Saddam strikes in the wrong postal district
Authors: C. Anderson
Journal: BMJ (1996)

My fingers suddenly stopped doing what I wanted them to do, my hands were floating aimlessly above the keyboard like two pink fish. To save the computer file I needed to press two keys simultaneously with a practised flick. But now manoeuvring two fingers into the right place at the right time took a couple of minutes. I was worried and got up to go to a telephone. My legs refused commands, they kept splaying sideways. My body had suddenly changed from seamless partner into a spastic encumbrance. My brain remained strangely distant, cranking slowly but clearly. Without warning, in the prime of life, it reasoned, I had been smitten with an advanced motor neuron disease.

While my mind conducted this analysis my body craved air, and it urged me towards the front door. Suddenly the floor tiles appeared in close-up before my nose. I laboured to the door on my elbows, leant up to wrench it open, and fell flat on the threshold in the blast of wintry air. I lost sphincter control, my bowels squirted, and I peed a little too. My mind reasoned that I had to get to a telephone.

My fingers were mittens. It was a modern telephone with push buttons and I realised that I could never have spun a dial correctly. I was calling a close friend, a general practitioner who was on call that night but in a village 65 km away. I could speak only by gasping in short bursts. “I think I'm dying,” I said. She could not diagnose my symptoms, but told me to dial 999.

The doorbell rang almost at once and this time I was able to lumber to the door without crawling. My friend had called my next …
BRAF Inhibition Increases Tumor Infiltration by T cells and Enhances the Antitumor Activity of Adoptive Immunotherapy in Mice
Authors: Chengwen Liu, Weiyi Peng, Chunyu Xu, Yanyan Lou, Minying Zhang, Jennifer A. Wargo, Jie Qing Chen, Haiyan S. Li, Stephanie S. Watowich, Yan Yang, Dennie Tompers Frederick, Zachary A. Cooper, Rina M. Mbofung, Mayra Whittington, Keith T. Flaherty, Scott E. Woodman, Michael A. Davies, Laszlo G. Radvanyi, Willem W. Overwijk, Gregory Lizée, Patrick Hwu
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Treatment of melanoma patients with selective BRAF inhibitors results in objective clinical responses in the majority of patients with BRAF-mutant tumors. However, resistance to these inhibitors develops within a few months. In this study, we test the hypothesis that BRAF inhibition in combination with adoptive T-cell transfer (ACT) will be more effective at inducing long-term clinical regressions of BRAF-mutant tumors. Experimental Design: BRAF-mutated human melanoma tumor cell lines transduced to express gp100 and H-2Db to allow recognition by gp100-specific pmel-1 T cells were used as xenograft models to assess melanocyte differentiation antigen–independent enhancement of immune responses by BRAF inhibitor PLX4720. Luciferase-expressing pmel-1 T cells were generated to monitor T-cell migration in vivo. The expression of VEGF was determined by ELISA, protein array, and immunohistochemistry. Importantly, VEGF expression after BRAF inhibition was tested in a set of patient samples. Results: We found that administration of PLX4720 significantly increased tumor infiltration of adoptively transferred T cells in vivo and enhanced the antitumor activity of ACT. This increased T-cell infiltration was primarily mediated by the ability of PLX4720 to inhibit melanoma tumor cell production of VEGF by reducing the binding of c-myc to the VEGF promoter. Furthermore, analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the preclinical murine model. Conclusion: These findings provide a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell–based immunotherapy for the treatment of patients with melanoma. Clin Cancer Res; 19(2); 393–403. ©2012 AACR.
ONTOGENY OF B-LYMPHOCYTE FUNCTION
Authors: Edmond A. Goidl, Gregory W. Siskind
Journal: The Journal of Experimental Medicine (1974)

The ontogeny of the ability of B lymphocytes to produce an antihapten response which is heterogeneous with respect to affinity for the antigenic determinant was studied in a cell transfer system. The heterogeneity of affinity of the immune response of lethally irradiated mice reconstituted with syngeneic, adult thymus cells and fetal or neonatal tissues as a source of B lymphocytes was studied. It was found that B cells from 17 day fetal liver or neonatal liver are highly restricted with respect to heterogeneity of affinity as compared with adult spleen or bone marrow. The B-cell population achieves an adult character with respect to heterogeneity of affinity by 2 wk of age. The peripheral lymphoid tissues (spleen) appear to mature in this respect more rapidly than do central lymphoid tissues (bone marrow). Spleens from 10-day old donors behave in an adult, heterogeneous manner while bone marrow from the same donors exhibit a marked restriction in heterogeneity of affinity. Germfree mice produce an immune response which is indistinguishable from conventionally reared adult animals with respect to heterogeneity of affinity. The earlier appearance of the ability to transfer a heterogeneous immune response in spleen as compared with bone marrow suggests that the increasing heterogeneity of the B-lymphocyte population which occurs between birth and 2 wk of age is the result of a differentiation event and not of a somatic mutation or recombination event.
Association of DNA Repair and Steroid Metabolism Gene Polymorphisms with Clinical Late Toxicity in Patients Treated with Conformal Radiotherapy for Prostate Cancer
Authors: Sambasivarao Damaraju, David Murray, Jennifer Dufour, Diana Carandang, Sten Myrehaug, Gino Fallone, Colin Field, Russell Greiner, John Hanson, Carol E. Cass, Matthew Parliament
Journal: Clinical Cancer Research (2006)

Abstract Objective: To explore the possible relationship between single nucleotide polymorphisms (SNP) in candidate genes encoding DNA damage recognition/repair/response and steroid metabolism proteins with respect to clinical radiation toxicity in a retrospective cohort of patients previously treated with three-dimensional conformal radiotherapy (3-DCRT) for prostate cancer. Experimental Design: One hundred twenty-four patients with prostate cancer underwent 3-DCRT at our institution between September 1996 and December 2000. Of these, 83 consented for follow-up of blood sampling and SNP analysis. Twenty-eight patients were documented as having experienced grade ≥2 late bladder or rectal toxicity (scoring system of Radiation Therapy Oncology Group) on at least one follow-up visit. We analyzed 49 SNPs in BRCA1, BRCA2, ESR1, XRCC1, XRCC2, XRCC3, NBN, RAD51, RAD52, LIG4, ATM, BCL2, TGFB1, MSH6, ERCC2, XPF, NR3C1, CYP1A1, CYP2C9, CYP2C19, CYP3A5, CYP2D6, CYP11B2, and CYP17A1 genes using the Pyrosequencing technique. Results: Significant univariate associations with late rectal or bladder toxicity (grade ≥2) were found for XRCC3 (A&amp;gt;G 5′ untranslated region NT 4541), LIG4 (T&amp;gt;C Asp568Asp), MLH1 (C&amp;gt;T, Val219Ile), CYP2D6*4 (G&amp;gt;A splicing defect), mean rectal and bladder dose, dose to 30% of rectum or bladder, and age &amp;lt;60 years. On Cox multivariate analysis, significant associations with toxicity were found for LIG4 (T&amp;gt;C, Asp568Asp), ERCC2 (G&amp;gt;A, Asp711Asp), CYP2D6*4 (G&amp;gt;A, splicing defect), mean bladder dose &amp;gt;60 Gy, and dose to 30% of rectal volume &amp;gt;75 Gy. Conclusions: In this study, we identified SNPs in LIG4, ERCC2, and CYP2D6 genes as putative markers to predict individuals at risk for complications arising from radiation therapy in prostate cancer.
Effect of sulphasalazine on the radiological progression of rheumatoid arthritis.
Authors: T Pullar, J A Hunter, H A Capell
Journal: Annals of the Rheumatic Diseases (1987)

We have investigated the influence of sulphasalazine, a second line antirheumatic drug, on the radiological progression of erosions in rheumatoid arthritis over a two year period in 41 patients. Hand radiograph scores deteriorated significantly over this period, but in a group of 31 patients in whom one year films were also available this deterioration was limited to the first year. This slowing of radiological deterioration was not related to 'normalisation' of the erythrocyte sedimentation rate (ESR). Compared with a 'control' group of 10 patients who had refused offers of second line therapy, sulphasalazine treated patients showed less deterioration over the two year period, and this difference was more marked than in previous studies of gold or penicillamine. No significant change was seen in large joint radiographs in sulphasalazine treated patients over two years, but this probably represents the poor sensitivity of the method of assessment. No significant correlation was seen between changes in inflammatory indices and slowing of radiological deterioration in erosion score. Thus sulphasalazine appears to slow the progression of radiological disease of the hands over the second year of treatment in a representative sample of patients who continue to receive treatment for two years.
Interferon γ and lymphotoxin or tumor necrosis factor act synergistically to induce macrophage killing of tumor cells and schistosomula of schistosoma mansoni
Authors: I Esparza, D Mannel, A Ruppel, W Falk, PH Krammer
Journal: The Journal of Experimental Medicine (1987)

Macrophages play a crucial role in the defense against tumors and parasites. Activation of tumoricidal and microbicidal effector mechanisms requires stimulation of macrophages with macrophage-activating factors (MAF). One such MAF is interferon gamma (IFN-gamma). In some assays, substantial activity of IFN-gamma on murine macrophages, however, is only observed in synergy with lipopolysaccharide (LPS) or other cytokines (1). In addition, certain cytokines have been shown to induce monocyte or macrophage activation in the absence of IFN-gamma (2-5). We previously described lymphokines in the supernatant of a murine T cell clone that synergized with IFN-gamma in the induction of tumoricidal and schistosomulicidal murine macrophages (1). We called this lymphokine(s) macrophage cytotoxicityinducing factor 2 (MCIF2)(1). A candidate for MCIF2 was lymphotoxin (LT), because the T cell clone supernatant contained high amounts of LT. LT is functionally homologous and structurally related to the macrophage product tumor necrosis factor (TNF). Therefore, we tested whether recombinant (r) LT or rTNF can function as MAF. We report here that rLT or rTNF synergize with rIFN-gamma in the induction of tumoricidal and schistosomulicidal murine macrophages.
Human Ehrlichiosis in Adults after Tick Exposure: Diagnosis Using Polymerase Chain Reaction
Authors: E. Dale Everett
Journal: Annals of Internal Medicine (1994)

To identify and prospectively follow patients with suspected human ehrlichiosis regarding clinical manifestations, laboratory variables, methods for confirming the diagnosis, and complications.Prospective case study.University and Veterans Affairs hospital and clinics.Observations in 30 adult patients with acute febrile illness or with unexplained fevers and cytopenias or abnormal liver profiles or both.Serial clinical examinations, hematologic profiles, liver profiles, electrolyte determinations, chest radiographs, and response to therapy; other studies appropriate for patient care.Therapy with doxycycline.Thirty cases of ehrlichiosis were identified between 1989 and 1992. Tick exposure was strongly associated with the illness (P = 0.0001). Symptoms were nonspecific; fever, chills, and headache predominated but many other symptoms also occurred. Fever and skin rashes with various morphologic characteristics were the most common physical findings. Laboratory investigations indicate that the hematologic, hepatic, and central nervous systems are commonly involved in human ehrlichiosis. Twenty of 23 patients (87%) tested by the polymerase chain reaction using Ehrlichia chaffeensis sequences and whole blood samples were positive for E. chaffeensis.The syndrome of human ehrlichiosis is not commonly recognized by physicians. Ehrlichiosis should be considered in the differential diagnosis of patients with febrile illness after known or possible tick exposure, particularly if accompanying cytopenias or abnormal liver profiles or both are present. The therapeutic response to doxycycline is prompt, and complications are uncommon in promptly treated patients. The polymerase chain reaction applied to whole blood samples is a promising test for rapid confirmation of the diagnosis within 24 to 48 hours.
Relevance of FDG-PET-CT scan for the evaluation of local pleural invasion assessed by thoracoscopy in malignant pleural mesothelioma
Authors: Valentina Pinelli, Elisa Roca, Sophie Laroumagne, Silvia Lucchini, Gian Franco Tassi, Philippe Astoul
Journal: European Respiratory Journal (2012)

INTRODUCTION: FDG-PET-CT scan(PET) is now widely recognized as an important staging modality in many cancers and PET standard uptake value(SUV) is reported as a prognostic indicator in several malignancies. However only a few previous studies have investigated the utility of PET in malignant pleural mesothelioma(MPM). We hypothesized that pleural assessed by PET might be in accordance to pleural characteristics evaluated by thoracoscopy.

METHODS: 29 patients with a diagnosis of MPM obtained by thoracoscopy were previously evaluated byPET, and considered valuable for this analysis. Among them, 10.34%, 20.69%, 44.83%, 24.14% were assessed as I,II, III, IV stage respectively. There were 10.34% of patients in stage I, 20.69% in stage II, 44.83% in stage III, and 24.14% in stage IV. The histological analysis showed 86.21% epithelioid, 3.45% sarcomatous and 10.34% biphasic types.

RESULTS: At thoracoscopy there were 16 (55.17%) patients with visceral pleural involvement, 21 (72.41%) with diaphragmatic involvement and 2 (6.90%) with mediastinal involvement. All of them had an invasion of the costal parietal pleura. There was a significant difference (<0.05) of the medium SUV between the patients with a visceral pleural involvement and the patients without this feature. Moreover statistically significant differences of the medium SUV was shown between patients with or without pleural nodules.

CONCLUSIONS: These findings suggest that pleural evaluation by PET should in accordance to the characteristics obtained by thoracoscopy. There is a significant difference between the site of pleural involvement and/or the typology of tumoral lesions and the SUV of PET.
Phenotypic analysis of lymphocytes and monocytes/macrophages in peripheral blood and bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis
Authors: J Wahlstrom, M Berlin, C M Skold, H Wigzell, A Eklund, J Grunewald
Journal: Thorax (1999)

<h3>BACKGROUND</h3> The granulomatous inflammation in sarcoidosis is driven by the interplay between T cells and macrophages. To gain a better understanding of this process the expression by these cells of cell surface activation markers, co-stimulatory molecules, and adhesion molecules was analysed. <h3>METHODS</h3> CD4+ and CD8+ T lymphocytes from peripheral blood (PBL) or bronchoalveolar lavage (BAL) fluid, as well as paired peripheral blood monocytes and alveolar macrophages from 27 patients with sarcoidosis were analysed by flow cytometry. <h3>RESULTS</h3> CD26, CD54, CD69, CD95, and gp240 were all overexpressed in T cells from BAL fluid compared with those from PBL in both the CD4+ and CD8+ subsets, while CD57 was overexpressed only in BAL CD4+ cells. In contrast, CD28 tended to be underexpressed in the BAL T cells. Monocyte/macrophage markers included CD11a, CD11b, CD11c, CD14, CD16, CD54, CD71, CD80 and CD86 and HLA class II. CD11a expression in alveolar macrophages (and peripheral blood monocytes) was increased in patients with active disease and correlated positively with the percentage of BAL lymphocytes. Expression of CD80 in macrophages correlated with the BAL CD4/CD8 ratio. <h3>CONCLUSIONS</h3> Our data indicate substantial activation of both CD4+ and CD8+ lung T cells in sarcoidosis. There were also increased numbers of BAL lymphocytes whose phenotypic characteristics have earlier been associated with clonally expanded, replicatively senescent cells of the Th1 type.
Selective expression of stromal-derived factor-1 in the capillary vascular endothelium plays a role in Kaposi sarcoma pathogenesis
Authors: Lei Yao, Ombretta Salvucci, Adela R. Cardones, Sam T. Hwang, Yoshiyasu Aoki, Maria De La Luz Sierra, Agatha Sajewicz, Stefania Pittaluga, Robert Yarchoan, Giovanna Tosato
Journal: Blood (2003)
Acinar ventilation heterogeneity (Sacin) assessed by nitrogen multiple breath washout is an accurate and sensitive marker of bronchiolitis obliterans (BO)
Authors: Federica De Giacomi, Maria Teresa Lupo-Stanghellini, Alessia Orsini, Fabio Ciceri, George Cremona
Journal: European Respiratory Journal (2014)

BO associated with chronic graft versus host disease (cGVHD) after haematopoietic stem cell transplantation (HSCT) initially affects terminal and respiratory bronchioles which are poorly assessed by spirometry. Impulse Oscillation System (IOS) and the Nitrogen Multiple Breath Washout (N 2 -MBW), more sensitive to peripheral airways, were performed on 41 healthy controls and 78 HSCT recipients along with spirometry, body plethysmography and transfer factor for carbon monoxide (TL CO ).  Compared to controls, recipients without BO (n=40), whether with cGVHD or not, showed increased air trapping, reduced haemoglobin-adjusted TL CO /alveolar ventilation (V A ) ratio and enhanced ventilation inhomogeneity both in conductive and acinar airways.  Patients with BO showed even lower TL CO /V A , increased IOS indices sensible to small airways (DR5-20Hz=1.13±0.97 in BO vs 0.30±0.23 in controls, p=0.001, X5Hz=-1.84±2.26 in BO vs -0.95±0.21 in controls, p=0.023, R peripheral =3.57±2.89 in BO vs 1.74±0.80 in controls, p=0.003) and a three-fold increase in Sacin (551±360% vs 83±28% in controls p  In 9 COPD subjects with the same degree of spirometric obstruction (mean FEV 1= 50%), the increase in Sacin (298%) was 50% less than in recipients with BO (551%, p=0.031).  The ROC curve for Sacin (cut off 321%) showed 89% accuracy, 89% sensitivity and 93% specificity in identifying patients with BO compared to an accuracy of 5% for FEV 1 .  In conclusion, peripheral airway function is altered following HSCT. N 2 -MBW might be useful in the early diagnosis of BO.