tbuckley/cabot-search huggingface dataset:
Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms.
Authors: M R Bristow, W Minobe, R Rasmussen, P Larrabee, L Skerl, J W Klein, F L Anderson, J Murray, L Mestroni, S V Karwande
Journal: Journal of Clinical Investigation (1992)

In order to investigate the general cause of beta-adrenergic receptor neuroeffector abnormalities in the failing human heart, we measured ventricular myocardial adrenergic receptors, adrenergic neurotransmitters, and beta-adrenergic receptor-effector responses in nonfailing and failing hearts taken from nonfailing organ donors, subjects with endstage biventricular failure due to idiopathic dilated cardiomyopathy (IDC), and subjects with primary pulmonary hypertension (PPH) who exhibited isolated right ventricular failure. Relative to nonfailing PPH left ventricles, failing PPH right ventricles exhibited (a) markedly decreased beta 1-adrenergic receptor density, (b) marked depletion of tissue norepinephrine and neuropeptide Y, (c) decreased adenylate cyclase stimulation in response to the beta agonists isoproterenol and zinterol, and (d) decreased adenylate cyclase stimulation in response to Gpp(NH)p and forskolin. These abnormalities were directionally similar to, but generally more pronounced than, corresponding findings in failing IDC right ventricles, whereas values for these parameters in nonfailing left ventricles of PPH subjects were similar to values in the nonfailing left ventricles of organ donors. Additionally, relative to paired nonfailing PPH left ventricles and nonfailing right ventricles from organ donors, failing right ventricles from PPH subjects exhibited decreased adenylate cyclase stimulation by MnCl2. These data indicate that: (a) Adrenergic neuroeffector abnormalities present in the failing human heart are due to local mechanisms; systemic processes do not produce beta-adrenergic neuroeffector abnormalities. (b) Pressure-overloaded failing right ventricles of PPH subjects exhibit decreased activity of the catalytic subunit of adenylate cyclase, an abnormality not previously described in the failing human heart.
Randomized Phase II Trial of Erlotinib Alone or With Carboplatin and Paclitaxel in Patients Who Were Never or Light Former Smokers With Advanced Lung Adenocarcinoma: CALGB 30406 Trial
Authors: Pasi A. Jänne, Xiaofei Wang, Mark A. Socinski, Jeffrey Crawford, Thomas E. Stinchcombe, Lin Gu, Marzia Capelletti, Martin J. Edelman, Miguel A. Villalona-Calero, Robert Kratzke, Everett E. Vokes, Vincent A. Miller
Journal: Journal of Clinical Oncology (2012)

Erlotinib is clinically effective in patients with non-small-cell lung cancer (NSCLC) who have adenocarcinoma, are never or limited former smokers, or have EGFR mutant tumors. We investigated the efficacy of erlotinib alone or in combination with chemotherapy in patients with these characteristics.
In vitro effects of 4-hydroperoxycyclophosphamide on human immunoregulatory T subset function. I. Selective effects on lymphocyte function in T-B cell collaboration.
Authors: H Ozer, J W Cowens, M Colvin, A Nussbaum-Blumenson, D Sheedy
Journal: The Journal of Experimental Medicine (1982)

The alkylating agent cyclophosphamide may suppress or enhance immune responses in vivo but is inactive in vitro unless metabolized by microsomal enzyme activation. 4-hydroperoxycyclophosphamide (4-HC) is a synthetic compound that is spontaneously converted in aqueous solution to the active metabolites. In this report, we examined the in vitro sensitivity of functional human T cell subsets to 4-HC in a polyclonal B cell differentiation assay and in the generation of mitogen-induced suppressor cells for effector B cell function. Con A-induced T suppression of B cell differentiation is completely abrogated by a 1-h pretreatment of T cells at very low concentrations of between 10(-2) and 20 nmol/ml, whereas inducer T cell function is sensitive only to concentrations in greater than 40 nmol/ml. The effects of 4-HC on suppressor T cells appear to occur at concentrations that do not result in DNA cross-linking or decreased blastogenesis. Con A-induced T suppressors are generated from within the OKT4+, OKT8- subset and are sensitive to low-dose 4-HC only before activation, whereas differentiated suppressor cells are resistant to concentrations in greater than 80 nmol/ml. Low-dose 4-HC pretreatment of the B cell population results in abrogation of immunoglobulin secretion when treated B cells are cocultured with unfractionated T cells, however, this effect is completely reversible if pretreated B cells are cocultured with T cells devoid of suppressor activity. These results demonstrate that human presuppressor cells for B-effector function differentiate in response to Con A from the OKT4+, OKT8- subset and are exquisitely sensitive to low concentrations of CYP whereas mature suppressor and inducer functions are resistant to all but very high concentrations in vitro. The differential sensitivity of functional T and B cell subsets to 4-HC in vitro can be a very useful probe in dissecting immunoregulatory interactions with man.
Adjuvant gemcitabine therapy improves survival in a locally induced, R0-resectable model of metastatic intrahepatic cholangiocarcinoma
Authors: Engin Gürlevik, Bettina Fleischmann-Mundt, Nina Armbrecht, Thomas Longerich, Norman Woller, Arnold Kloos, Dirk Hoffmann, Axel Schambach, Thomas C. Wirth, Michael P. Manns, Lars Zender, Stefan Kubicka, Florian Kühnel
Journal: Hepatology (2013)

Complete surgical tumor resection (R0) for treatment of intrahepatic cholangiocarcinoma (ICC) is potentially curative, but the prognosis remains dismal due to frequent tumor recurrence and metastasis after surgery. Adjuvant therapies may improve the outcome, but clinical studies for an adjuvant approach are difficult and time-consuming for rare tumor entities. Therefore, animal models reflecting the clinical situation are urgently needed to investigate novel adjuvant therapies. To establish a mouse model of resectable cholangiocarcinoma including the most frequent genetic alterations of human ICC, we electroporated Sleeping Beauty-based oncogenic transposon plasmids into the left liver lobe of mice. KRas-activation in combination with p53-knockout in hepatocytes resulted in formation of a single ICC nodule within 3-5 weeks. Lineage tracing analyses confirmed the development of ICC by transdifferentiation of hepatocytes. Histologic examination demonstrated that no extrahepatic metastases were detectable during primary tumor progression. However, formation of tumor satellites close to the primary tumor and vascular invasion were observed, indicating early invasion into normal tissue adjacent to the tumor. After R0-resection of the primary tumor, we were able to prolong median survival, thereby observing tumor stage-dependent local recurrence, peritoneal carcinomatosis, and lung metastasis. Adjuvant gemcitabine chemotherapy after R0-resection significantly improved median survival of treated animals.We have developed a murine model of single, R0-resectable ICC with favorable characteristics for the study of recurrence patterns and mechanisms of metastasis after resection. This model holds great promise for preclinical evaluation of novel multimodal or adjuvant therapies to prevent recurrence and metastasis after R0-resection.
Antibody Microarray Profiling Reveals Individual and Combined Serum Proteins Associated with Pancreatic Cancer
Authors: Randal Orchekowski, Darren Hamelinck, Lin Li, Ewa Gliwa, Matt VanBrocklin, Jorge A. Marrero, George F. Vande Woude, Ziding Feng, Randall Brand, Brian B. Haab
Journal: Cancer Research (2005)

Abstract We used antibody microarrays to probe the associations of multiple serum proteins with pancreatic cancer and to explore the use of combined measurements for sample classification. Serum samples from pancreatic cancer patients (n = 61), patients with benign pancreatic disease (n = 31), and healthy control subjects (n = 50) were probed in replicate experiment sets by two-color, rolling circle amplification on microarrays containing 92 antibodies and control proteins. The antibodies that had reproducibly different binding levels between the patient classes revealed different types of alterations, reflecting inflammation (high C-reactive protein, α-1-antitrypsin, and serum amyloid A), immune response (high IgA), leakage of cell breakdown products (low plasma gelsolin), and possibly altered vitamin K usage or glucose regulation (high protein-induced vitamin K antagonist-II). The accuracy of the most significant antibody microarray measurements was confirmed through immunoblot and antigen dilution experiments. A logistic-regression algorithm distinguished the cancer samples from the healthy control samples with a 90% and 93% sensitivity and a 90% and 94% specificity in duplicate experiment sets. The cancer samples were distinguished from the benign disease samples with a 95% and 92% sensitivity and an 88% and 74% specificity in duplicate experiment sets. The classification accuracies were significantly improved over those achieved using individual antibodies. This study furthered the development of antibody microarrays for molecular profiling, provided insights into the nature of serum-protein alterations in pancreatic cancer patients, and showed the potential of combined measurements to improve sample classification accuracy.
Ultrastructural location of human hepatocyte growth factor in human liver
Authors: Hiroki Sakaguchi, Shuichi Seki, Hirohito Tsubouchi, Yasushi Daikuhara, Yoshiyuki Niitani, Kenzo Kobayashi
Journal: Hepatology (1994)

Human hepatocyte growth factor has been purified from the plasma of patients with fulminant liver failure, but where this factor is produced in organs or cells of subjects with liver diseases is unknown. Therefore, we used a monoclonal antibody to human hepatocyte growth factor to stain cells in three normal and 29 diseased liver tissues by immunohistochemical techniques. By light microscopy, the immunostained cells seemed to be polymorphonuclear leukocytes because of their segmented nuclei. Some biliary epithelial cells also were stained. Electron microscopy confirmed that the immunostained cells with segmented nuclei were polymorphonuclear leukocytes and that the stained grains were on the membranes of rough endoplasmic reticulum, around specific or azurophilic granules and in the cell sap. Stained grains in the biliary epithelial cells were found sporadically on the inside and outside of the membranes of rough endoplasmic reticulum near the nuclei. Human hepatocyte growth factor is now known to be the same protein as scatter factor and tumor cytotoxic factor, both of which are produced by human fibroblasts in culture, but our results suggest that polymorphonuclear leukocytes in diseased livers are one cellular source of circulating human hepatocyte growth factor. The immunostaining properties of biliary epithelial cells in diseased livers also suggest that the cells produce and secrete human hepatocyte growth factor.
Prehospital parenteral penicillin for meningitis: Trial in children with suspected meningococcal disease would be useful
Authors: D Graham Mackenzie, Charles J P Saunders, Diptendu N Bhattacharyya, Chris R Steer
Journal: BMJ (2006)

Life without COX 2 inhibitors Risks and benefits are determined by dose and potencyEditor-The paper by Kearney et al on the risk of atherothrombosis with cyclooxygenase-
Endostatin reduces vascularization, blood flow, and growth in a rat gliosarcoma
Authors: D. R. Sorensen, T.-A. Read, T. Porwol, B. R. Olsen, R. Timpl, T. Sasaki, P. O. Iversen, H. B. Benestad, B. K. L. Sim, R. Bjerkvig
Journal: Neuro-Oncology (2002)

Endostatin, the 20-kDa C-terminal fragment of collagen XVIII, has previously been shown to inhibit growth and induce regression of different experimental tumors in rodents. In this study, we show that recombinant murine and human endostatin, produced in 293 EBNA cells and yeast, respectively, inhibit ectotopic as well as orthotopic growing BT4Cn gliosarcomas in BD-IX rats. In rats in which s.c. gliomas were grown for a total of 29 days, systemic treatment with recombinant murine endostatin induced about 50% reduction of intratumoral blood flow and tumor size after only 10 days of therapy. In contrast, the blood flow to irrelevant organs was unaffected by endostatin, indicating its specificity of action. Tumors were not observed to increase in size or regrow after cessation of therapy. Furthermore, endostatin-treated rats with i.c. tumors had significantly longer survival time than did untreated controls. In the treated rats, endostatin therapy resulted in a reduced tumor blood vessel volume and an increased tumor cell density with an increased apoptotic index within a given tumor volume, as verified by flow cytometry and by staining with deoxynucleotidyltransferase-mediated dUTP nick-end labeling. This work verifies the general anti-angiogenic and antitumor effects of endostatin and indicates that the protein may also be considered as a treatment strategy for malignant brain tumors.
The role of H-2-linked genes in helper T cell function. VII. Expression of I region and immune response genes by B cells in bystander help assays.
Authors: P Marrack, J W Kappler
Journal: The Journal of Experimental Medicine (1980)

The mode of action by bystander helper T cells was investigated by priming (responder X nonresponder) (B6A)F1 T cells with poly-L-(Tyr, Glu)-poly-D,L-Ala--poly-L-Lys [(TG)-A--L] and titrating the ability of these cells to stimulate an anti-sheep red blood cell (SRBC) response of parental B cells and macrophages in the presence of (TG)-A--L. Under limiting T cell conditions, and in the presence of (TG)-A--L, (TG)-A--L-responsive T cells were able to drive anti-SRBC responses of high-responder C57BL/10.SgSn (B10) B cells and macrophages (M0), but not of low-responder (B10.A) B cells and M0. Surprisingly, the (TG)-A--L-driven anti-SRBC response of B10.A B cells was not restored by addition of high-responder acessory cells, in the form of (B6A)F1 peritoneal or irradiated T cell-depleted spleen cells, or in the form of B10 nonirradiated T cell-depleted spleen cells. These results suggested that (TG)-A--L-specific Ir genes expressed by B cells controlled the ability of these cells to be induced to respond to SRBC by (TG)-A--L-responding T cells, implying that direct contact between the SRBC-binding B cell precursor and the (TG)-A--L-responsive helper T cells was required. Analogous results were obtained for keyhold limpet hemocyanin (KLH)-driven bystander help using KLH-primed F1 T cells restricted to interact with cells on only one of the parental haplotypes by maturing them in parental bone marrow chimeras. It was hypothesized that bystander help was mediated by nonspecific uptake of antigen [(TG)-A--L or KLH] by SRBC-specific b cells and subsequent display of the antigen on the B cell surface in association with Ir of I-region gene products, in a fashion similar to the M0, where it was then recognized by helper T cells. Such an explanation was supported by the observation that high concentrations of antigen were required to elicit bystander help. This hypothesis raises the possibility of B cell processing of antigen bound to its immunoglobulin receptor and subsequent presentation of antigen to helper T cells.
Development of a Clinical Prediction Rule for Risk Stratification of Recurrent Venous Thromboembolism in Patients With Cancer-Associated Venous Thromboembolism
Authors: Martha L. Louzada, Marc Carrier, Alejandro Lazo-Langner, Vi Dao, Michael J. Kovacs, Timothy O. Ramsay, Marc A. Rodger, Jerry Zhang, Agnes Y.Y. Lee, Guy Meyer, Philip S. Wells
Journal: Circulation (2012)

Background— Long-term low-molecular-weight heparin (LMWH) is the current standard for treatment of venous thromboembolism (VTE) in cancer patients. Whether treatment strategies should vary according to individual risk of VTE recurrence remains unknown. We performed a retrospective cohort study and a validation study in patients with cancer-associated VTE to derive a clinical prediction rule that stratifies VTE recurrence risk. Methods and Results— The cohort study of 543 patients determined the model with the best classification performance included 4 independent predictors (sex, primary tumor site, stage, and prior VTE) with 100% sensitivity, a wide separation of recurrence rates, 98.1% negative predictive value, and a negative likelihood ratio of 0.16. In this model, the score sum ranged between −3 and 3 score points. Patients with a score ≤0 had low risk (≤4.5%) for recurrence and patients with a score &gt;1 had a high risk (≥19%) for VTE recurrence. Subsequently, we applied and validated the rule in an independent set of 819 patients from 2 randomized, controlled trials comparing low-molecular-weight heparin to coumarin treatment in cancer patients. Conclusions— By identifying VTE recurrence risk in cancer patients with VTE, we may be able to tailor treatment, improving clinical outcomes while minimizing costs.
Zonisamide reduces obstructive sleep apnoea: a randomised placebo-controlled study
Authors: Davoud Eskandari, Ding Zou, Mahssa Karimi, Kaj Stenlöf, Ludger Grote, Jan Hedner
Journal: European Respiratory Journal (2014)

Carbonic anhydrase inhibition reduces apnoeic events in sleep disordered breathing. Zonisamide inhibits carbonic anhydrase, and induces weight loss in obese patients. This study explored the relative influence of these two properties, which may both alleviate obstructive sleep apnoea (OSA). Continuous positive airway pressure (CPAP) was used as a standard care comparator. 47 patients with moderate-to-severe OSA and a body mass index of 27–35 kg·m −2 were randomised to receive either zonisamide, placebo or CPAP for 4 weeks. The open extension phase (20 weeks) compared CPAP and zonisamide. Polysomnography, biochemistry and symptoms were evaluated. At 4 weeks, zonisamide reduced apnoea/hypopnoea index (AHI) by a mean± sd 33±39% and oxygen desaturation index by 28±31% (p=0.02 and 0.014, respectively; placebo adjusted). The mean compliance adjusted reduction of AHI after zonisamide and CPAP was 13 and 61%, respectively, (p=0.001) at 24 weeks. Body weight was marginally changed at 4 weeks, but reduced after zonisamide and increased after CPAP at 24 weeks (-2.7±3.0 kg versus 2.3±2.0 kg, p&lt;0.001). Zonisamide decreased bicarbonate at 4 and 24 weeks. Side-effects were more common after zonisamide. Zonisamide reduced OSA independent of body weight potentially by mechanisms related to carbonic anhydrase inhibition. The effect was less pronounced than that obtained by CPAP.
The Inferior Vena Cava Filter
Authors: Myra F. Barginear
Journal: JAMA Internal Medicine (2013)

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Tolerance to histocompatibility determinants in tetraparental bone marrow chimeras.
Authors: H Boehmer, J Sprent, M Nabholz
Journal: The Journal of Experimental Medicine (1975)

Tetraparental bone marrow chimeras were produced by injecting lethally X-irradiated F1 hybrids with relatively high numbers of T-cell-depleted bone marrow cells from both allogeneic parental strains. The mice survival in excellent health and showed a stable, approximately 50:50 (parent:parent), lymphoid cell chimerism lasting for at least 7 mo after irradiation; regeneration of host-type hemopoietic cells was very limited. Thymus, lymph node, and thoracic duct lymphocytes showed specific unresponsiveness to host mixed leukocyte reaction (MLR) determinants. Similarly specific tolerance to H-2 antigens of host type was demonstrated in spleen and lymph node. No suppressor cells could be demonstrated in either system and blocking serum factors could not be found. The results suggest specific deletion of functional T cells reactive to host-type MLR and cell-mediated lympholysis determinants.
Estradiol Inhibits Leukocyte Adhesion and Transendothelial Migration in Rabbits In Vivo
Authors: Lauren Nathan, Shehla Pervin, Rajan Singh, Michael Rosenfeld, Gautam Chaudhuri
Journal: Circulation Research (1999)

Abstract —The mechanism by which estrogens protect against atherosclerosis is not known. We evaluated in vivo whether there is a gender difference in monocyte adhesion and subendothelial migration in hypercholesterolemic rabbits and whether any gender differences observed are due to estradiol. Monocyte adhesion and subendothelial migration were assessed in a blinded fashion by analyzing a standardized segment of aorta using a scanning electron microscope. We also assessed whether estradiol modulates induction of vascular cell adhesion molecule-1 (VCAM-1) protein using Western blot and flow cytometric analyses. We observed that male rabbits develop more monocyte adhesion and subendothelial migration than do female rabbits during hypercholesterolemia. We also observed that oophorectomized rabbits given physiological estradiol supplementation demonstrate fewer adherent and subendothelial monocytes than do oophorectomized rabbits given placebo. VCAM-1 protein expression was increased in aortae obtained from hypercholesterolemic, oophorectomized animals supplemented with placebo, and this increase was attenuated by estradiol. Finally, in cultured rabbit aortic endothelial cells stimulated with lysophosphatidylcholine, we observed an increase in VCAM-1 protein that was inhibited in a concentration-dependent fashion by estradiol. We have demonstrated in vivo that there is a gender difference in monocyte adhesion to endothelial cells and transendothelial migration after hypercholesterolemia and that this gender difference is due in part to estradiol. Our results also suggest that estradiol inhibits monocyte adhesion by inhibiting expression of VCAM-1.