tbuckley/cabot-search huggingface dataset:
Vaccination with Human HER-2/<i>neu</i>(435-443) CTL Peptide Induces Effective Antitumor Immunity against HER-2/<i>neu</i>-Expressing Tumor Cells<i>In vivo</i>
Authors: Angelos D. Gritzapis, Louisa G. Mahaira, Sonia A. Perez, Nike T. Cacoullos, Michael Papamichail, Constantin N. Baxevanis
Journal: Cancer Research (2006)

Abstract HER-2/neu is a self-antigen expressed by tumors and nonmalignant epithelial tissues. The possibility of self-tolerance to HER-2/neu-derived epitopes has raised questions concerning their utility in antitumor immunotherapy. Altered HER-2/neu peptide ligands capable of eliciting enhanced immunity to tumor-associated HER-2/neu epitopes may circumvent this problem. The human CTL peptide HER-2/neu (435-443) [hHER-2(9435)] represents a xenogeneic altered peptide ligand of its mouse homologue, differing by one amino acid residue at position 4. In contrast to mHER-2(9435), vaccination of HLA-A*0201 transgenic (HHD) mice with hHER-2(9435) significantly increased the frequency of mHER-2(9435)-specific CTL and also induced strong protective and therapeutic immunity against the transplantable ALC tumor cell line transfected to coexpress HLA-A*0201 and hHER-2/neu or rHER-2/neu. Similar results were also obtained with wild-type C57BL/6 mice inoculated with HER-2/neu transfectants of ALC. Adoptive transfer of CD8+ CTL from mice immunized with hHER-2(9435) efficiently protected naive syngeneic mice inoculated with ALC tumors. In conclusion, our results show that HER-2(9435) serves as a tumor rejection molecule. They also propose a novel approach for generating enhanced immunity against a self-HER-2/neu CTL epitope by vaccinating with xenogeneic altered peptide ligands and provide useful insights for the design of improved peptide-based vaccines for the treatment of patients with HER-2/neu-overexpressing tumors. (Cancer Res 2006; 66(10): 5452-60)
Rationing Problems and the Aims of Ethical Theory
Authors: Rahul Kumar
Journal: The American Journal of Bioethics (2001)

reasoned assessment of the fairness of a process for rationing healthcare that does not incorporate a substantive preference about the scope of healthcare? Is that any more likely than a reasoned assessment of the fairness of a process for determining how to count votes that does not incorporate a substantive preference about which votes get counted? If Daniels believes it is, he must make that case. To raise this concern is not to refute Daniels’s advocacy of procedural fairness as the best available approach. It does, however, call on him to revisit the potential interaction between his initial construal of what healthcare is and his later call for procedural remedies and to consider more skeptically the prospects for characterizing procedural fairness in a substantively neutral way. One anal point: Daniels, surprisingly, writes of a “surprising convergence between what is needed for our social and political well-being and for our mental and physical health.” He does not say to whom that convergence is surprising. Given that emotional distress is now generally understood to have consequences for health, it should be no surprise to anyone that injustice is unhealthy, and that such a convergence is precisely what one would expect. Reoect on the reaction of young children, even as young as three or four, to physical injury and to perceived injustice. The wailing prompted by the latter abates when the pain subsides; the wailing prompted by the former abates only when the injustice is addressed. (The empirical foundation of this insight was reafarmed here last week with the vigorous assistance of three young grandchildren.)
The HIF-1–Inducible Lysyl Oxidase Activates HIF-1 via the Akt Pathway in a Positive Regulation Loop and Synergizes with HIF-1 in Promoting Tumor Cell Growth
Authors: Floriane Pez, Frédéric Dayan, Jérome Durivault, Bastien Kaniewski, Géraldine Aimond, Gabrielle S. Le Provost, Blandine Deux, Philippe Clézardin, Pascal Sommer, Jacques Pouysségur, Caroline Reynaud
Journal: Cancer Research (2011)

Adaptation to hypoxia is a driving force for tumor progression that leads to therapy resistance and poor clinical outcome. Hypoxic responses are mainly mediated by hypoxia-inducible transcription factor-1 (HIF-1). One critical HIF-1 target mediating tumor progression is lysyl oxidase (LOX), which catalyzes cross-linking of collagens and elastin in the extracellular matrix, thereby regulating tissue tensile strength. Paradoxically, LOX has been reported to be both upregulated and downregulated in cancer cells, especially in colorectal cancer. Thus, we hypothesized that LOX might regulate expression of HIF-1 to create a self-timing regulatory circuit. Using human colorectal carcinoma cell lines in which HIF-1 and LOX expression could be modulated, we showed that LOX induction enhanced HIF-1 expression, whereas LOX silencing reduced it. Mechanistic investigations revealed that LOX activated the PI3K (phosphoinositide 3-kinase)-Akt signaling pathway, thereby upregulating HIF-1α protein synthesis in a manner requiring LOX-mediated hydrogen peroxide production. Consistent with these results, cancer cell proliferation was stimulated by secreted and active LOX in an HIF-1α-dependent fashion. Furthermore, nude mice xenograft assays established that HIF-1 potentiated LOX action on tumor growth in vivo. Taken together, these findings provide compelling evidence that LOX and HIF-1 act in synergy to foster tumor formation, and they suggest that HIF-1/LOX mutual regulation is a pivotal mechanism in the adaptation of tumor cells to hypoxia.
A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or without adalimumab effectively reduces MRI synovitis, osteitis and tenosynovitis and halts structural damage progression in early rheumatoid arthritis: results from the OPERA randomised controlled trial
Authors: Mette Bjørndal Axelsen, Iris Eshed, Kim Hørslev-Petersen, Kristian Stengaard-Pedersen, Merete Lund Hetland, Jakob Møller, Peter Junker, Jan Pødenphant, Annette Schlemmer, Torkell Ellingsen, Palle Ahlquist, Hanne Lindegaard, Asta Linauskas, Mette Yde Dam, Ib Hansen, Hans Christian Horn, Christian Gytz Ammitzbøll, Anette Jørgensen, Sophine B Krintel, Johnny Raun, Niels S Krogh, Julia Sidenius Johansen, Mikkel Østergaard
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis (ERA), and whether adalimumab provides an additional effect. <h3>Methods</h3> In a double-blind, placebo-controlled trial, 85 disease-modifying antirheumatic drug-naïve patients with ERA were randomised to receive methotrexate, intra-articular glucocorticosteroid injections and placebo/adalimumab (43/42). Contrast-enhanced MRI of the right hand was performed at months 0, 6 and 12. Synovitis, osteitis, tenosynovitis, MRI bone erosion and joint space narrowing (JSN) were scored with validated methods. Dynamic contrast-enhanced MRI (DCE-MRI) was carried out in 14 patients. <h3>Results</h3> Synovitis, osteitis and tenosynovitis scores decreased highly significantly (p&lt;0.0001) during the 12-months' follow-up, with mean change scores of −3.7 (median −3.0), −2.2 (−1) and −5.3 (−4.0), respectively. No overall change in MRI bone erosion and JSN scores was seen, with change scores of 0.1 (0) and 0.2 (0). The tenosynovitis score at month 6 was significantly lower in the adalimumab group, 1.3 (0), than in the placebo group, 3.9 (2), Mann–Whitney: p&lt;0.035. Furthermore, the osteitis score decreased significantly during the 12-months' follow-up in the adalimumab group, but not in the placebo group, Wilcoxon: p=0.001–0.002 and p=0.062–0.146. DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters. Clinical measures decreased highly significantly during follow-up. <h3>Conclusions</h3> A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis, osteitis and tenosynovitis and halted structural damage progression as judged by MRI. The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis.
Combined Clinical Trial Results of a HER2/<i>neu</i>(E75) Vaccine for the Prevention of Recurrence in High-Risk Breast Cancer Patients: U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02
Authors: George E. Peoples, Jarrod P. Holmes, Matthew T. Hueman, Elizabeth A. Mittendorf, Asna Amin, Steven Khoo, Zia A. Dehqanzada, Jennifer M. Gurney, Michael M. Woll, Gayle B. Ryan, Catherine E. Storrer, Dianna Craig, Constantin G. Ioannides, Sathibalan Ponniah
Journal: Clinical Cancer Research (2008)

Abstract Purpose: E75 is an immunogenic peptide from the HER2/neu protein, which is overexpressed in many breast cancer patients. We have conducted two overlapping E75 vaccine trials to prevent recurrence in node-positive (NP) and node-negative (NN) breast cancer patients. Experimental Design: E75 (HER2/neu 369-377) + granulocyte macrophage colony-stimulating factor was given intradermally to previously treated, disease-free NP breast cancer patients in a dose escalation safety trial and to NN breast cancer patients in a dose optimization study. Local and systemic toxicity was monitored. Immunologic responses were assessed using in vitro assays and in vivo delayed-type hypersensitivity responses. Clinical recurrences were documented. Results: One hundred and eighty-six patients were enrolled in the two studies (NP, 95; NN, 91). Human leucocyte antigen A2 (HLA-A2) and HLA-A3 patients were vaccinated (n = 101), whereas all others (n = 85) were followed prospectively as controls. Toxicities were minimal, and a dose-dependent immunologic response to the vaccine was shown. Planned primary analysis revealed a recurrence rate of 5.6% in vaccinated patients compared with 14.2% in the controls (P = 0.04) at a median of 20 months follow-up. As vaccine-specific immunity waned over time, the difference in recurrence lost significance at 26 months median follow-up (8.3% versus 14.8%); however, a significant difference in the pattern of recurrence persisted. Conclusions: E75 is safe and effective in raising a dose-dependent HER2/neu immunity in HLA-A2 and HLA-A3 NP and NN breast cancer patients. More importantly, E75 may reduce recurrences in disease-free, conventionally treated, high-risk breast cancer patients. These findings warrant a prospective, randomized phase III trial of the E75 vaccine with periodic booster to prevent breast cancer recurrences.
Adaptive Prediction Model in Prospective Molecular Signature–Based Clinical Studies
Authors: Guanghua Xiao, Shuangge Ma, John Minna, Yang Xie
Journal: Clinical Cancer Research (2013)

Abstract Use of molecular profiles and clinical information can help predict which treatment would give the best outcome and survival for each individual patient, and thus guide optimal therapy, which offers great promise for the future of clinical trials and practice. High prediction accuracy is essential for selecting the best treatment plan. The gold standard for evaluating the prediction models is prospective clinical studies, in which patients are enrolled sequentially. However, there is no statistical method using this sequential feature to adapt the prediction model to the current patient cohort. In this article, we propose a reweighted random forest (RWRF) model, which updates the weight of each decision tree whenever additional patient information is available, to account for the potential heterogeneity between training and testing data. A simulation study and a lung cancer example are used to show that the proposed method can adapt the prediction model to current patients' characteristics, and, therefore, can improve prediction accuracy significantly. We also show that the proposed method can identify important and consistent predictive variables. Compared with rebuilding the prediction model, the RWRF updates a well-tested model gradually, and all of the adaptive procedure/parameters used in the RWRF model are prespecified before patient recruitment, which are important practical advantages for prospective clinical studies. Clin Cancer Res; 20(3); 531–9. ©2013 AACR.
Novel biomarkers in bleomycin-induced pulmonary fibrosis
Authors: Isis Fernandez, Oana Amarie, Önder Yildirim, Melanie Königshoff, Oliver Eickelberg
Journal: European Respiratory Journal (2013)

Idiopathic Pulmonary Fibrosis is a chronic lung disease of unknown etiology, with fatal outcome. Bleomycin model is the most used and known model of lung fibrosis, however a comprehensive compartmental screening of new targets with clinical translational potential is lacking. Extrapolation of novel markers from cellular compartments, i.e. broncho-alveolar lavage (BAL) and peripheral blood, are required to improve the understanding of the pathophysiology and develop an exhaustive assessment of the disease.

Methods

Fibrosis was induced by intratracheal installation of Bleomycin or PBS as control in 8-12 weeks old mice. BAL cell counts; lung function (via FlexiVent) and histology were performed at day 7, 14, 21, 28 and 56 after treatment. ICAM, VCAM, MMP9, E-selectin and PAI-1 were measured in serum via Luminex and MMP7 and WISP-1 via ELISA. Gene screening was performed with RealTime Custom panel by qPCR.

Results

Histology, and lung function parameters confirmed fibrosis. Increase in ICAM-1 levels in serum strongly correlated with a fibrotic phenotype and tissue stiffness (compliance r2= 0.5941, elastance r2=0.7149), MMP9 and MMP7 were significantly elevated in bleomycin-injured animals at day 7 and 14. WISP-1 was significantly elevated in resolution phase of fibrosis(PBS n=20; Bleomycin n=14). Developmental pathway signaling are regulated in alveolar macrophages of bleomycin-treated mice.

Conclusion

We identified novel discovery of disease regulators in different compartments (e.g. alveolar macrophages, BAL, serum) from bleomycin model and further correlation with fibrotic patients are critical to broaden the understanding, ultimately leading to detection accuracy, modify outcomes, and predict prognosis in IPF patients.
Comparative mycobacterial genomics as a tool for drug target and antigen discovery
Authors: S.T. Cole
Journal: European Respiratory Journal (2002)

Genomics and the associated downstream technologies are generating vast data sets that provide new opportunities for understanding and combating both infectious and genetic diseases in humans. The genomic approach has been applied to tuberculosis, a major cause of transmissible morbidity and mortality, with notable success. Complete genome sequences are now available for three members of the Mycobacterium tuberculosis complex and the related intracellular pathogen M. leprae . Many of the predictions generated in silico by genomics have been validated through functional analysis, including studies of the transcriptome and proteome, and led to the identification of essential genes. Knowledge of the latter defines potential targets for new and existing drugs and their specificity can be assessed by comparative genomics with the host or other pathogens. Genomics is also furthering tuberculosis vaccine development by pinpointing potentially antigenic proteins as well as providing better diagnostic tools to detect infection.
A Randomized Phase III Study of Doxorubicin Versus Cisplatin/Interferon α-2b/Doxorubicin/Fluorouracil (PIAF) Combination Chemotherapy for Unresectable Hepatocellular Carcinoma
Authors: Winnie Yeo, Tony S. Mok, Benny Zee, Thomas W. T. Leung, Paul B. S. Lai, Wan Y. Lau, Jane Koh, Frankie K. F. Mo, Simon C. H. Yu, Anthony T. Chan, Pun Hui, Brigette Ma, Kwok C. Lam, Wing M. Ho, Herman T. Wong, Amanda Tang, Philip J. Johnson
Journal: JNCI Journal of the National Cancer Institute (2005)

Single-agent doxorubicin has been widely used to treat unresectable hepatocellular carcinoma (HCC), but the response rate is low (< 20%) and there is no convincing evidence for improved survival. Cisplatin, interferon, doxorubicin, and fluorouracil (PIAF) used in combination, by contrast, has shown promise in a phase II study. We compared doxorubicin to PIAF in patients with unresectable HCC in a phase III trial.Patients with histologically confirmed unresectable HCC were randomly assigned to receive either doxorubicin or PIAF every 3 weeks, for up to six cycles. The primary endpoint was overall survival, and secondary endpoints were response rate and toxicity. Survival differences were calculated using the Kaplan-Meier method. Treatment groups were compared for differences in the incidence of adverse events using chi-square tests. All statistical tests were two-sided.The median survival of the doxorubicin and PIAF groups was 6.83 months (95% confidence [CI] = 4.80 to 9.56) and 8.67 months (95% CI = 6.36 to 12.00), respectively (P = 0.83). The hazard ratio for death from any cause in the PIAF compared with the doxorubicin groups was 0.97 (95% CI = 0.71 to 1.32). Eighty-six of the 94 patients receiving doxorubicin and 91 of the 94 receiving PIAF were assessable for response. The overall response rates in the doxorubicin and PIAF groups were 10.5% (95% CI = 3.9% to 16.9%) and 20.9% (95% CI = 12.5% to 29.2%), respectively. Neutropenia, thrombocytopenia, and hypokalemia were statistically significantly more common in patients treated with PIAF than in patients treated with doxorubicin.Although patients on PIAF had a higher overall response rate and better survival than patients on doxorubicin, the differences were not statistically significant. PIAF was also associated with increased treatment-related toxicity. The prognosis of patients with unresectable HCC remains poor.
Epigenetic Modulation of Retinoic Acid Receptor β2 by the Histone Deacetylase Inhibitor MS-275 in Human Renal Cell Carcinoma
Authors: Xiao-fei Wang, David Z. Qian, Mingqiang Ren, Yukihiko Kato, Yongfeng Wei, Lu Zhang, Zoya Fansler, Doug Clark, Osamu Nakanishi, Roberto Pili
Journal: Clinical Cancer Research (2005)

Histone deacetylase (HDAC) inhibitors have been shown to reverse epigenetic repression of certain genes, including retinoic acid receptor beta2 (RARbeta2). In this study, we examined whether RARbeta2 expression is repressed in human renal cell carcinoma (RCC) and whether the HDAC inhibitor MS-275 may revert its epigenetic repression.Six human tumor RCC cell lines were analyzed for RARbeta2 gene expression and for methylation and acetylation status at the promoter level. Modulation of RARbeta2 expression and correlation with antitumor activity by combination of MS-275 with 13-cis-retinoic acid (CRA) was assessed in a RARbeta2-negative RCC cell line.RARbeta2 expression was either strongly present, weakly expressed, or absent in the RCC cell lines analyzed. Methylation-specific PCR indicated that the RARbeta2 promoter was partially methylated in three of the cell lines. CRA treatment did not inhibit clonogenic growth in the RARbeta2-negative cell line RCC1.18, whereas MS-275 induced a dose-dependent inhibitory effect. A greater inhibitory effect was observed with combination treatment (MS-275 + CRA). Treatment with MS-275 was associated with histone acetylation at the promoter level and synergistic gene reexpression of RARbeta2 in combination with CRA. RARbeta2 reexpression was associated with synergistic induction of the retinoid-responsive gene HOXA5. In vivo, single-agent CRA treatment showed no significant effect, whereas MS-275 and the combination induced a regression of RCC1.18 tumor xenografts. Discontinuation of treatment produced tumor recurrence in MS-275-treated mice, whereas animals treated with the combination remained tumor free.The HDAC inhibitor MS-275 seems to revert retinoid resistance due to epigenetic silencing of RARbeta2 in a human RCC model and has greater antitumor activity in combination with CRA compared with single agents. Thus, the combination of HDAC inhibitors and retinoids may represent a novel therapeutic approach in patients with RCC.
Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial
Authors: Harry LA Janssen, Monika van Zonneveld, Hakan Senturk, Stefan Zeuzem, Ulus S Akarca, Yilmaz Cakaloglu, Christopher Simon, Thomas MK So, Guido Gerken, Robert A de Man, Hubert GM Niesters, Pieter Zondervan, Bettina Hansen, Solko W Schalm
Journal: The Lancet (2005)
REPETITIVE MOTION INJURIES
Authors: Philip E. Higgs, M.D, Susan E. Mackinnon, M.D
Journal: Annual Review of Medicine (1995)

▪ Abstract Repetitive motion injuries have presented clinicians with a significant challenge over the past two and a half decades. Acceptable treatment of inflammatory disorders is well established, but compressive neuropathies and nonspecific complaints of numbness, tingling, and discomfort in the upper extremity present vexing dilemmas. Current research and experience point to multilevel problems, including posturally induced muscular imbalance. Although surgical solutions to these problems are sometimes indicated, conservative approaches successfully treat many individuals and have narrowed the scope and indications for surgical intervention. These approaches include ergonomic changes at the workstation, postural changes, and muscle stretching and strengthening to correct imbalance.
Circulation and migration of small blood lymphocytes in the rat: II. Study of the lymphocyte selective migration by light and electron microscopic autoradiography
Authors: N. D. Schnuda
Journal: American Journal of Hematology (1979)

Fourteen male Wistar rats were the recipients of labeled small lymphocytes (1.5 x 10(7) each) collected from the peripheral blood of syngeneic donors. The migrating labeled lymphocytes were traced in the various organs from one to 60 minutes following their transfusion. Sections from the lymph nodes, bone marrow, spleen, thymus, ileum, liver, lung, and kidney were analyzed morphologically by autoradiographic studies. The results showed that some of the labeled small blood lymphocytes migrate to the lymph node and bone marrow as early as one minute following transfusion; their exodus from these two organs occurs within three minutes. In the case of the spleen, the lymphocytes did not migrate selectively to the marginal zone of the lymphoid follicles until ten minutes following transfusion. The electron microscopic study of the spleen and lymph node showed that the labeled lymphocytes selectively migrate to certain areas which consist of reticulum cells, macrophages, unlabeled lymphocytes, and plasma cells. The term "immunocompetent zones" is proposed for these areas because of the biological significance of this selective migration with reference to immunity.