tbuckley/cabot-search huggingface dataset:
Antineoplastic Effects of Partially HLA-Matched Irradiated Blood Mononuclear Cells in Patients With Renal Cell Carcinoma
Authors: Roger K. Strair, Dale Schaar, Daniel Medina, Mary B. Todd, Joseph Aisner, Robert S. DiPaola, Jacqueline Manago, Beth Knox, Amanda Jenkinson, Rachelle Senzon, Christina Baker, Liesel Dudek, Marie Ciardella, Mercy Kuriyan, Arnold Rubin, Edmund C. Lattime
Journal: Journal of Clinical Oncology (2003)

Vaccines, cytokines, and other biologic-based therapies are being developed as antineoplastic agents. Many of these agents are designed to induce an autologous immune response directed against the malignancy. In contrast, hematopoietic stem-cell transplantation is being developed as a form of allogeneic immunotherapy. This study tests the tolerance and antineoplastic activity of sequential infusions of partially HLA-matched allogeneic blood mononuclear cells (obtained from relatives) when administered outside of the context of a hematopoietic stem-cell transplantation. The cells are irradiated to prevent graft-versus-host disease.Fifteen patients with relapsed or refractory malignancies for which no standard therapy was available were enrolled onto a clinical trial designed to assess the tolerability and antineoplastic effects of irradiated partially HLA-matched blood mononuclear cells obtained from relatives.There was disease regression in three patients with metastatic renal cell carcinoma during treatment. There was disease progression in six patients with metastatic renal cell carcinoma and two patients with metastatic melanoma during treatment. There was no change in disease state in several other patients.Irradiated allogeneic blood mononuclear cells administered outside the context of hematopoietic stem-cell transplantation may induce disease responses in patients with relapsed or refractory malignancies. Transfusion of irradiated allogeneic blood mononuclear cells should be developed further as a novel therapeutic antineoplastic approach.
Dynamics of Dengue Disease Severity Determined by the Interplay Between Viral Genetics and Serotype-Specific Immunity
Authors: Molly OhAinle, Angel Balmaseda, Alexander R. Macalalad, Yolanda Tellez, Michael C. Zody, Saira Saborío, Andrea Nuñez, Niall J. Lennon, Bruce W. Birren, Aubree Gordon, Matthew R. Henn, Eva Harris
Journal: Science Translational Medicine (2011)

The rapid spread of dengue is a worldwide public health problem. In two clinical studies of dengue in Managua, Nicaragua, we observed an abrupt increase in disease severity across several epidemic seasons of dengue virus serotype 2 (DENV-2) transmission. Waning DENV-1 immunity appeared to increase the risk of severe disease in subsequent DENV-2 infections after a period of cross-protection. The increase in severity coincided with replacement of the Asian/American DENV-2 NI-1 clade with a new virus clade, NI-2B. In vitro analyses of viral isolates from the two clades and analysis of viremia in patient blood samples support the emergence of a fitter virus in later, relative to earlier, epidemic seasons. In addition, the NI-1 clade of viruses was more virulent specifically in children who were immune to DENV-1, whereas DENV-3 immunity was associated with more severe disease among NI-2B infections. Our data demonstrate that the complex interaction between viral genetics and population dynamics of serotype-specific immunity contributes to the risk of severe dengue disease. Furthermore, this work provides insights into viral evolution and the interaction between viral and immunological determinants of viral fitness and virulence.
Pancreatic cancer risk and levels of trace elements
Authors: André F S Amaral, Miquel Porta, Debra T Silverman, Roger L Milne, Manolis Kogevinas, Nathaniel Rothman, Kenneth P Cantor, Brian P Jackson, José A Pumarega, Tomàs López, Alfredo Carrato, Luisa Guarner, Francisco X Real, Núria Malats
Journal: Gut (2011)

<h3>Background and Aims</h3> Knowledge on the aetiology of exocrine pancreatic cancer (EPC) is scant. The best established risk factor for EPC is tobacco smoking. Among other carcinogens, tobacco contains cadmium, a metal previously associated with an increased risk of EPC. This study evaluated the association between concentrations of trace elements in toenails and EPC risk. <h3>Methods</h3> The study included 118 EPC cases and 399 hospital controls from eastern Spain. Levels of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. OR and 95% CI, adjusted for potential confounders, were calculated using logistic regression. <h3>Results</h3> Significantly increased risks of EPC were observed among subjects whose concentrations of cadmium (OR 3.58, 95% CI 1.86 to 6.88; p<sub>trend</sub>=5×10<sup>−6</sup>), arsenic (OR 2.02, 95% CI 1.08 to 3.78; p<sub>trend</sub>=0.009) and lead (OR 6.26, 95% CI 2.71 to 14.47; p<sub>trend</sub>=3×10<sup>−5</sup>) were in the highest quartile. High concentrations of selenium (OR 0.05, 95% CI 0.02 to 0.15; p<sub>trend</sub>=8×10<sup>−11</sup>) and nickel (OR 0.27, 95% CI 0.12 to 0.59; p<sub>trend</sub>=2×10<sup>−4</sup>) were inversely associated with the risk of EPC. <h3>Conclusion</h3> Novel associations are reported of lead, nickel and selenium toenail concentrations with pancreas cancer risk. Furthermore, the results confirm previous associations with cadmium and arsenic. These novel findings, if replicated in independent studies, would point to an important role of trace elements in pancreatic carcinogenesis.
Hepatocyte growth factor gene therapy accelerates regeneration in cirrhotic mouse livers after hepatectomy
Authors: F Xue
Journal: Gut (2003)

Impaired regeneration and dysfunction of the cirrhotic liver following partial hepatectomy (PHx) are the most serious risk factors for postoperative liver failure.Using naked hepatocyte growth factor (HGF) plasmid by the electroporation (EP) in vivo method, we investigated HGF for its role and mechanism of proliferation and restoration of liver mass in cirrhotic mice following PHx.Eight week old female mice were used.HGF plasmid 50 micro g was injected intramuscularly and transferred by EP in vivo once a week for three weeks. After establishment of carbon tetrachloride induced cirrhosis, mice underwent PHx. The HGF treated group was given naked HGF plasmid four days before PHx, and additional HGF was given once a week until they were killed, while a control group was given only empty plasmid. Mice were killed 2, 4, 10, and 14 days after PHx. Morphological and functional restoration of the liver were examined, as well as activation of mitogen activated protein kinase (MAPK) and mRNA levels of HGF activator (HGFA).The HGF treated group demonstrated a continuous threefold increase in HGF levels in plasma. Therapy with HGF in cirrhotic PHx resulted in effective liver regeneration via restoration of HGFA and activation of MAPK p44/p42, accelerated normalisation of liver function, and increased collagen degradation.HGF gene therapy by in vivo EP may be useful for hepatic resection in cirrhotic livers by stimulating liver proliferative and collagenolytic capacities, as well as accelerating functional recovery.
Emerging concepts regarding B cells and autoantibodies in murine lupus nephritis. B cells have multiple roles; all autoantibodies are not equal.
Authors: M P Madaio, M J Shlomchik
Journal: Journal of the American Society of Nephrology (1996)

Despite observations linking the severity of lupus nephritis to the quantity and location of glomerular immune deposits, it had been difficult to decipher the primary role of B cells and autoantibodies in this process. Newer technologies have provided the means to evaluate the roles of whole B cell populations and individual immunoglobulins in lupus lesions. In this review, recent advances in this area are summarized, with particular emphasis on work from the authors' laboratories. The results implicate a primary role for B cells and immunoglobulins in lupus nephritis, including glomerular, interstitial, and vascular lesions. Multiple antibody-ligand interactions participate in glomerular immune deposit formation in individuals with lupus nephritis. Recent evidence suggests that in situ formation of immune deposits by either cross-reactivity of autoantibodies with intrinsic glomerular antigens (i.e., anti-DNA antibodies with laminin) or direct interaction of autoantibodies with circulating autoantigens lodged within glomeruli (i.e., anti-DNA antibodies with histone/DNA). The predominant autoantibody-glomerular antigen interaction(s) in a given individual influences the principal location of immune deposition, which in turn influences the pathologic and clinical expression of disease. It is believed that these phenomena contribute to the phenotypic diversity commonly observed among individuals with lupus nephritis. Furthermore, these consequences are dependent on properties unique to both subsets of lupus autoantibodies and to their target antigen ligands within the glomerulus. Thus, the autoantibody variable or antigen binding region, along with the nature and location of the target glomerular antigen (or site of circulating antigen deposition), are influential in initiating these perturbations.
Pancreatic Stellate Cells: Partners in Crime with Pancreatic Cancer Cells
Authors: Alain Vonlaufen, Swapna Joshi, Changfa Qu, Phoebe A. Phillips, Zhihong Xu, Nicole R. Parker, Cheryl S. Toi, Romano C. Pirola, Jeremy S. Wilson, David Goldstein, Minoti V. Apte
Journal: Cancer Research (2008)

Abstract Pancreatic stellate cells (PSC) produce the stromal reaction in pancreatic cancer, but their role in cancer progression is not fully elucidated. We examined the influence of PSCs on pancreatic cancer growth using (a) an orthotopic model of pancreatic cancer and (b) cultured human PSCs (hPSC) and human pancreatic cancer cell lines MiaPaCa-2 and Panc-1. Athymic mice received an intrapancreatic injection of saline, hPSCs, MiaPaCa-2 cells, or hPSCs + MiaPaCa-2. After 7 weeks, tumor size, metastases, and tumor histology were assessed. In vitro studies assessed the effect of cancer cell secretions on PSC migration and the effect of hPSC secretions on cancer cell proliferation, apoptosis, and migration. Possible mediators of the effects of hPSC secretions on cancer cell proliferation were examined using neutralizing antibodies. Compared with mice receiving MiaPaCa-2 cells alone, mice injected with hPSCs + MiaPaCa-2 exhibited (a) increased tumor size and regional and distant metastasis, (b) fibrotic bands (desmoplasia) containing activated PSCs within tumors, and (c) increased tumor cell numbers. In vitro studies showed that, in the presence of pancreatic cancer cells, PSC migration was significantly increased. Furthermore, hPSC secretions induced the proliferation and migration, but inhibited the apoptosis, of MiaPaCa-2 and Panc-1 cells. The proliferative effect of hPSC secretions on pancreatic cancer cells was inhibited in the presence of neutralizing antibody to platelet-derived growth factor. Our studies indicate a significant interaction between pancreatic cancer cells and stromal cells (PSCs) and imply that pancreatic cancer cells recruit stromal cells to establish an environment that promotes cancer progression. [Cancer Res 2008;68(7):2085–93]
Docetaxel and oxaliplatin in the second-line treatment of platinum-sensitive recurrent ovarian cancer: a phase II study
Authors: G Ferrandina, M Ludovisi, R De Vincenzo, V Salutari, D Lorusso, M Colangelo, T Prantera, M.R. Valerio, G Scambia
Journal: Annals of Oncology (2007)
Noninvasive Ultrasound Imaging of Inflammation Using Microbubbles Targeted to Activated Leukocytes
Authors: Jonathan R. Lindner, Ji Song, Fang Xu, Alexander L. Klibanov, Kai Singbartl, Klaus Ley, Sanjiv Kaul
Journal: Circulation (2000)

Background —Lipid microbubbles used for perfusion imaging with ultrasound are retained within inflamed tissue because of complement-mediated attachment to leukocytes within venules. We hypothesized that incorporation of phosphatidylserine (PS) into the microbubble shell may enhance these interactions by amplifying complement activation and thereby allow ultrasound imaging of inflammation. Methods and Results —In 6 mice, intravital microscopy of tissue necrosis factor-α–treated cremaster muscle was performed to assess the microvascular behavior of fluorescein-labeled lipid microbubbles with and without PS in the shell. Ten minutes after intravenous injection, microbubble attachment to leukocytes within inflamed venules was greater for PS-containing than for standard lipid microbubbles (20±4 versus 10±3 per 20 optical fields, P &lt;0.05). The ultrasound signal from retained microbubbles was assessed in the kidneys of 6 mice undergoing renal ischemia-reperfusion injury and in 6 control kidneys. The signal from retained microbubbles in control kidneys was low (&lt;2.5 video intensity units) for both agents. After ischemia-reperfusion, the signal from retained microbubbles was 2-fold higher for PS-containing than for standard lipid microbubbles (18±6 versus 8±2 video intensity units, P &lt;0.05). An excellent relation was found between the ultrasound signal from retained microbubbles and the degree of renal inflammation, assessed by tissue myeloperoxidase activity. Conclusions —We conclude that noninvasive assessment of inflammation is possible by ultrasound imaging of microbubbles targeted to activated leukocytes by the presence of PS in the lipid shell.
Where does the gene for hemochromatosis lie in relation to HLA-A?
Authors: Elizabeth C. Jazwinska, June W. Halliday, Lawrie W. Powell
Journal: Hepatology (1994)

Hereditary Hemochromatosis (HFE) is one of the most common inherited disorders with an estimated frequency of homozygous patients of 0.002-0.0045. The disease is characterized by increased intestinal iron absorption and progressive iron overload. Affected subjects show clinical symptoms of parenchymal organ damage after the third-fourth decade of life and have a 200-fold increased risk of developing hepatocellular carcinoma. Early diagnosis and treatment prevent complications and may normalize life expectancy of patients. The biochemical and genetic defects leading to progressive iron accumulation are still unknown, but the HFE gene is tightly linked to HLA complex on the short arm of chromosome 6. Utilizing HLA serotypes and the study of several polymorphic markers of 6p21, a linkage analysis of the disease locus was performed in a series of Italian hemochromatosis families. The data obtained by linkage analysis and the study of a family with a double recombinant allowed us to better define the HFE gene location with respect to HLA-class I A and F loci.
Remarks ON THE ETIOLOGY OF DIABETES MELLITUS AND THE DIET AND CONDITIONS OF LIFE DURING THE WAR
Authors: R. T. Williamson
Journal: BMJ (1918)

WHATEVER may be the exact patlhology of diabetes mellitus, certain etiological relations are of much interest and of some iimiportance with respect to the prevention of the disease in England during this period of overstrain through the war.Diabetes mellitaLs has been steadily becoming more frequent for many years.The deatlh-rate from the disease has increased in England and Wales from 59 per million living in 1886, to 97 in 1906, and to 130 in 1915.The larger portion of the increased mortality rate may be clearly attributed to the increased frequency of tlle disease.In 1908 I collected all tlle information I could obtain respecting the frequency of diabetes in various countries, and obtained information from all quarters of the world.Some was reliable, some unsatisfactory.1My conclusions were:The mortality from diabetes is much greater than in England anid London, in tlle following towns and countries:In Malta, in many of the large towns of the United States (Worcester, Syracuse, Rochester, New York, Boston, Wash- ington), in Bordeaux (France), in Berlin, Paris, Frankfort (am Maini).Also experience indicates that diabetes is especially comilmon.in Bengal, Ceylon, Siam, and Tunis.Certain races are especially liable to suffer: Jews, Hindus, and Maltese.In 1907, the year when my statistics were collected, tlhe mortality for diabetes per 100,000 living in Malta and Gozo was four times that in England and Wales.
Prognostic significance of telomerase-associated parameters in glioblastoma: effect of patient age
Authors: Daniela Lötsch, Bahil Ghanim, Magdalena Laaber, Gabriele Wurm, Serge Weis, Stefan Lenz, Gerald Webersinke, Josef Pichler, Walter Berger, Sabine Spiegl-Kreinecker
Journal: Neuro-Oncology (2013)

Glioblastoma multiforme (GBM) is a heterogeneous, highly aggressive primary brain tumor with strongly variable patient survival. Because reliable prognostic biomarkers are lacking, we investigated the relation between telomerase-associated parameters and the disease course.Telomerase-associated parameters were determined in 100 GBM tissues and associated with clinical characteristics and overall survival. Expressions of telomere length, telomerase activity (TA), and human telomerase reverse transcriptase (hTERT) were analyzed by quantitative PCR, telomeric repeat amplification protocol assay, and reverse transcriptase-PCR, respectively. Mutation status of isocitrate dehydrogenase (IDH)1 was determined by direct sequencing, and O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation by methylation-specific PCR.Of 100 GBM tissues, 61 were positive for both hTERT mRNA and TA, with a highly significant correlation between both parameters (linear regression, P < .0001). Telomere length determination revealed a significant difference between the hTERT/TA-positive and -negative subgroups, with markedly longer telomeres in the hTERT/TA-negative cohort (unpaired Student's t-test, P = .0001). Accordingly, significantly shorter telomeres were detected in GBM tissues derived from older patients (>60 y at diagnosis, P < .0001). While no association of telomere parameters with MGMT promoter status was found, all tumors with IDH1 mutation (6/100) were negative for both hTERT expression and TA and harbored significantly longer telomeres. Patients with tumors lacking hTERT expression/TA showed a significant survival benefit (Kaplan-Meier test, both P < .01), which, however, was based exclusively on the younger patient subgroup (≤60 y, both P < .005; >60 y, both ns).Telomerase activation is not an independent prognostic parameter in GBM but predicts aggressive tumor behavior solely in a younger patient cohort.
The Intermediate-Term Outcome of Chinese Patients With Anorexia Nervosa in Hong Kong
Authors: Sing Lee, Y.Y. Lydia Chan, L.K. George Hsu
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: The authors determined the intermediate-term outcome of anorexia nervosa for Chinese patients in Hong Kong. METHOD: A consecutive series of 88 patients who fulfilled DSM-III-R criteria for typical (i.e., fat phobic [N=63]) and atypical (i.e., no fat phobia [N=25]) anorexia nervosa were contacted at least 4 years after onset of their illness for semistructured and self-rated assessments of outcome. RESULTS: Three patients (3.4%) died; the mortality ratio for this group against the expected standard for subjects of similar age and gender was 10.5 to 1. Eighty (94.1%) of the remaining 85 patients were successfully traced 9.0 years after onset of their illness. Good, intermediate, and poor outcomes were seen in 61.8%, 32.9%, and 5.3% of the subjects, respectively. Anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified was exhibited by 55.0% of the subjects (N=44). Lifetime depressive (81.6%) and anxiety (27.6%) disorders were common. Older age at onset and the presence of fat phobia independently predicted poor outcome. Patients with atypical anorexia nervosa were symptomatically stable, less likely to demonstrate bulimia, and had a better eating disorder outcome than patients with typical anorexia nervosa. CONCLUSIONS: The outcome profile of Chinese patients supported the cross-cultural disease validity of anorexia nervosa. The cultural fear of fatness not only shaped the manifest content but also added to the chronicity of the illness.
An interaction between the human cholesteryl ester transfer protein (CETP) and apolipoprotein A-I genes in transgenic mice results in a profound CETP-mediated depression of high density lipoprotein cholesterol levels.
Authors: T Hayek, T Chajek-Shaul, A Walsh, L B Agellon, P Moulin, A R Tall, J L Breslow
Journal: Journal of Clinical Investigation (1992)

We have previously described two transgenic mouse lines, one heterozygous for the human apo A-I gene and the other heterozygous for a human cholesteryl ester transfer protein (CETP) minigene driven by the mouse metallothionein-I gene promoter. In the current study, these two lines were crossed producing control, HuCETPTg, HuAITg, and HuAICETPTg mice to study the influence of CETP on HDL cholesterol levels, particle size distribution, and metabolism in animals with mouse and human-like HDL. In the HuCETPTg and HuAICETPTg animals, zinc induction approximately doubled plasma CETP activity, with no activity in plasma from the control and HuAITg animals. The only significant effect of CETP on lipoprotein subfraction cholesterol concentrations was for HDL-C. Compared to control animals, HuCETPTg animals had lower HDL-C, 20% before and 35% after Zn induction, and compared to HuAITg animals, HuAICETPTg animals had lower HDL-C, 35% before and 66% after Zn induction. Control and HuCETPTg HDL consist primarily of a single size population with a mean diameter of 10.00 +/- 0.10 nm and 9.71 +/- 0.05 nm, respectively. HuAITg HDL consists primarily of three distinct HDL size subpopulations with peak diameters of 10.35 +/- 0.08 nm, 8.80 +/- 0.06 nm, 7.40 +/- 0.10 nm, and HuAICETPTg HDL also consists primarily of three distinct HDL size subpopulations with peak diameters of 9.87 +/- 0.05 nm, 8.60 +/- 0.10 nm, 7.30 +/- 0.15 nm before, and 9.71 +/- 0.08 nm, 8.50 +/- 0.11 nm, 7.27 +/- 0.15 nm after zinc induction, respectively. Western blotting analysis of nondenaturing gradient gels of plasma with a monoclonal antibody to CETP indicated that in HuCETPTg and HuAICETPTg mice, 22 and 100%, respectively, of the CETP was HDL associated. Turnover studies with HDL doubly labeled with 125I apo A-I and 3H cholesteryl linoleate indicated that the CETP-induced fall in HDL-C was associated with increased HDL-cholesterol ester fractional catabolic rate in both the absence and presence of human apo A-I, suggesting CETP-mediated transfer of HDL-cholesterol ester to apo B-containing lipoproteins. In summary, these studies suggest that CETP has a much more profound effect on HDL cholesterol levels in transgenic animals expressing human apo A-I. This may be due to an enhanced interaction of CETP with human compared to mouse apo A-I or to the HDL particles they produce.