tbuckley/cabot-search huggingface dataset:
Bone turnover and inhaled corticosteroids.
Authors: G E Packe, J G Douglas
Journal: Thorax (1995)

<h3>Objective.</h3> Patients with ANCA-associated vasculitides (AAV) exhibit higher rates of malignancy than the general population. We assessed whether the cancer risk is increased in a well-characterized population-based cohort of AAV in southern Sweden, followed for a median time of 8 years. <h3>Methods.</h3> With case record review, the outcomes and malignancy development in a cohort of 195 patients with AAV [granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and eosinophilic GPA] diagnosed between 1997 and 2010 were assessed. The patients were followed until death or December 31, 2015. The age- and sex-standardized incidence ratios (SIR) were estimated using the Swedish population data as a reference. <h3>Results.</h3> During the observation period of about 1500 person-years, we found 60 cancers in 52 of the 195 patients. SIR (95% CI) was 2.8 (2.1–3.6) for cancers at all sites, 1.8 (1.3–2.5) for all cancers excluding squamous cell carcinoma (SCC), 12.9 (8.4–18.8) for SCC, 4.3 (1.4–10.0) for bladder cancer, and 7.0 (1.4–20.5) for pancreatic cancer. Cumulative doses of cyclophosphamide (CYC) &lt; 10 g were not associated with higher incidence of cancers other than SCC (SIR 1.63, 95% CI 0.8–2.9). <h3>Conclusion.</h3> In contrast to previous publications assessing malignancy risk in patients with AAV, we show in this population-based cohort of patients a persistent increased risk for overall malignancy, bladder cancer, and pancreatic cancer as well as a markedly increased risk for SCC. There was no increase in incidence of cancers other than SCC for those treated with &lt; 10 g CYC.
Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model
Authors: Gwendalyn D. King, A.K.M. Ghulam Muhammad, James F. Curtin, Carlos Barcia, Mariana Puntel, Chunyan Liu, Sarah B. Honig, Marianela Candolfi, Sonali Mondkar, Pedro R. Lowenstein, Maria G. Castro
Journal: Neuro-Oncology (2007)

The disseminated characteristics of human glioblastoma multiforme (GBM) make it a particularly difficult tumor to treat with long-term efficacy. Most preclinical models of GBM involve treatment of a single tumor mass. For therapeutic outcomes to translate from the preclinical to the clinical setting, induction of an antitumor response capable of eliminating multifocal disease is essential. We tested the hypothesis that expression of Flt3L (human soluble FMS-like tyrosine kinase 3 ligand) and TK (herpes simplex virus type 1-thymidine kinase) within brain gliomas would mediate regression of the primary, treated tumor mass and a secondary, untreated tumor growing at a distant site from the primary tumor and the site of therapeutic vector injection. In both the single-GBM and multifocal-GBM models used, all saline-treated control animals succumbed to tumors by day 22. Around 70% of the animals bearing a single GBM mass treated with an adenovirus expressing Flt3L (AdFlt3L) and an adenovirus expressing TK (AdTK + GCV) survived long term. Approximately 50% of animals bearing a large primary GBM that were implanted with a second GBM in the contralateral hemisphere at the same time the primary tumors were being treated with AdFlt3L and AdTK also survived long term. A second multifocal GBM model, in which bilateral GBMs were implanted simultaneously and only the right tumor mass was treated with AdFlt3L and AdTK, also demonstrated long-term survival. While no significant difference in survival was found between unifocal and multifocal GBM-bearing animals treated with AdFlt3L and AdTK, both treatments were statistically different from the saline-treated control group (p < 0.05). Our results demonstrate that combination therapy with AdFlt3L and AdTK can eradicate multifocal brain tumor disease in a syngeneic, intracranial GBM model.
The NHL-15 protocol for aggressive non-Hodgkin's lymphomas: a sequential dose-dense, dose-intense regimen of doxorubicin, vincristine and high-dose cyclophosphamide
Authors: C.S. Portlock, J. Qin, P. Schaindlin, N. Roistacher, J. Myers, D. Filippa, D. Louie, A.D. Zelenetz, J.P. O'Brien, C. Moskowitz, L. Norton, J. Yahalom, D.J. Straus, J.R. Bertino
Journal: Annals of Oncology (2004)
<b> <i>Myh</i> </b> Deficiency Enhances Intestinal Tumorigenesis in Multiple Intestinal Neoplasia (<b> <i>Apc</i> </b> <b> <i>Min</i> </b>/+) Mice
Authors: Oliver M. Sieber, Kimberley M. Howarth, Christina Thirlwell, Andrew Rowan, Nikki Mandir, Robert A. Goodlad, Ashfaq Gilkar, Bradley Spencer-Dene, Gordon Stamp, Victoria Johnson, Andrew Silver, Hanjing Yang, Jeffrey H. Miller, Mohammad Ilyas, Ian P. M. Tomlinson
Journal: Cancer Research (2004)

Abstract Monoallelic APC and biallelic MYH (homolog of Escherichia coli mutY) germ-line mutations are independently associated with a strong predisposition to colorectal adenomas and carcinoma in humans. Whereas mice heterozygous for mutant Apc develop intestinal tumors, mice homozygous for mutant Myh do not show increased tumor susceptibility. We analyzed the phenotype of ApcMin/+/Myh−/− mice and found that they developed significantly more adenomas in the small intestine than did ApcMin/+/Myh+/+ or ApcMin/+/Myh+/− mice (median 231 versus 151 versus 152). In the large bowel, ApcMin/+/Myh−/− mice showed significant increases in the number of aberrant crypt foci. In addition, ApcMin/+/Myh−/− mice developed an increased number of mammary tumors. Molecular analyses suggested that at least 19% of intestinal tumors from ApcMin/+/Myh−/− mice had acquired intragenic Apc mutations rather than allelic loss. Consistent with a defect in base excision repair, three intragenic Apc mutations in polyps without allelic loss from ApcMin/+/Myh−/− mice were shown to be G:C to T:A transversions which resulted in termination codons; no such mutations were found in polyps from ApcMin/+/Myh+/+ or ApcMin/+/Myh+/− mice. Tumors from ApcMin/+/Myh+/− mice harbored neither somatic mutations nor allelic loss at Myh. Thus, homozygous, but not heterozygous, Myh deficiency enhanced intestinal tumorigenesis in ApcMin/+ mice. The excess small-bowel adenomas in ApcMin/+/Myh−/− mice, therefore, appear to be a model of MYH-associated polyposis in humans.
FRACTIONATION OF MAMMALIAN LIVER CELLS BY DIFFERENTIAL CENTRIFUGATION: I. PROBLEMS, METHODS, AND PREPARATION OF EXTRACT
Authors: A. Claude
Journal: The Journal of Experimental Medicine (1946)

1. Materials and technical procedures involved in the preparation of liver suspensions have been described and discussed. 2. Liver extracts prepared by the present method appear to contain almost exclusively elements of cytoplasmic origin and can be considered to represent, on a large scale, the cytoplasm of liver cells.
Increased mtDNA mutations with aging promotes amyloid accumulation and brain atrophy in the APP/Ld transgenic mouse model of Alzheimer’s disease
Authors: Lokesh Kukreja, Gregory C Kujoth, Tomas A Prolla, Fred Van Leuven, Robert Vassar
Journal: Molecular Neurodegeneration (2014)

The role of mitochondrial dysfunction has long been implicated in age-related brain pathology, including Alzheimer's disease (AD). However, the mechanism by which mitochondrial dysfunction may cause neurodegeneration in AD is unclear. To model mitochondrial dysfunction in vivo, we utilized mice that harbor a knockin mutation that inactivates the proofreading function of mitochondrial DNA polymerase γ (PolgA D257A), so that these mice accumulate mitochondrial DNA mutations with age. PolgA D257A mice develop a myriad of mitochondrial bioenergetic defects and physical phenotypes that mimic premature ageing, with subsequent death around one year of age. We crossed the D257A mice with a well-established transgenic AD mouse model (APP/Ld) that develops amyloid plaques. We hypothesized that mitochondrial dysfunction would affect Aβ synthesis and/or clearance, thus contributing to amyloidogenesis and triggering neurodegeneration. Initially, we discovered that Aβ42 levels along with Aβ42 plaque density were increased in D257A; APP/Ld bigenic mice compared to APP/Ld monogenic mice. Elevated Aβ production was not responsible for increased amyloid pathology, as levels of BACE1, PS1, C99, and C83 were unchanged in D257A; APP/Ld compared to APP/Ld mice. However, the levels of a major Aβ clearance enzyme, insulin degrading enzyme (IDE), were reduced in mice with the D257A mutation, suggesting this as mechanism for increased amyloid load. In the presence of the APP transgene, D257A mice also exhibited significant brain atrophy with apparent cortical thinning but no frank neuron loss. D257A; APP/Ld mice had increased levels of 17 kDa cleaved caspase-3 and p25, both indicative of neurodegeneration. Moreover, D257A; APP/Ld neurons appeared morphologically disrupted, with swollen and vacuolated nuclei. Overall, our results implicate synergism between the effects of the PolgA D257A mutation and Aβ in causing neurodegeneration. These findings provide insight into mechanisms of mitochondrial dysfunction that may contribute to the pathogenesis of AD via decreased clearance of Aβ.
Joining Chain–Expressing and–Nonexpressing B Cell Populations in the Mouse
Authors: Lena Erlandsson, Peter Akerblad, Carina Vingsbo-Lundberg, Eva Kallberg, Nils Lycke, Tomas Leanderson
Journal: The Journal of Experimental Medicine (2001)

The diphtheria toxin A chain (DTA) was gene targeted into the Joining chain (J chain) locus to create a mouse strain selecting against J chain–expressing cells, JDTA mice. Serum immunoglobulin (Ig)M and serum IgG were reduced six to eightfold, while serum IgA was elevated 14-fold in these mice. JDTA mice were immune competent although the serum Ig response compared with wild-type mice was reduced sixfold at day 14 but only fourfold at day 45 after immunization. Exchanging the DTA gene with a cDNA for c-myc resulted in mice with a distinct phenotype with increased Ig production and enhanced humoral immune responses. Analysis of single B cells stimulated by lipopolysaccharide in vitro using reverse transcription–polymerase chain reaction showed that J chain–nonexpressing B cells could be detected that had a secretory phenotype as determined by an abundance of transcript for secretory IgM. Finally, limiting dilution analysis of peripheral B cells showed that J chain expression was a clonal property already established in naive, peripheral B lymphocytes.
L'actualite rhumatologique 1966 presentee au praticien
Authors: A. St. J. Dixon
Journal: Annals of the Rheumatic Diseases (1968)

many years of observation, if possible controlled, must pass before any operative procedure in rheuma- toid arthritis can be accepted as of proven value.A few operations, such as osteotomy of the rheumatoid hip, are rightly condemned; time may yet usher others into disrepute.The ingredients for success in this field are correct assessment of the natural history of the disease in the target joint and elsewhere, since deterioration at other sites may compromise an otherwise success- ful result, accurate appraisal of the patient's ability to cooperate in regaining function, selection of the correct operation, and good surgical technique.If Dr. Marmor's excellent descriptions of technique, albeit with less guidance to indications and choice of procedure, are set in this context of other factors, and if, furthermore, many operations are seen as measures still on trial, then his book will give useful service.
Functional Interactions of Neurotrophins and Neurotrophin Receptors
Authors: M Bothwell
Journal: Annual Review of Neuroscience (1995)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome
Authors: Houda Alachkar, Ramasamy Santhanam, Kati Maharry, Klaus H. Metzeler, Xiaomeng Huang, Jessica Kohlschmidt, Jason H. Mendler, Juliana M. Benito, Christopher Hickey, Paolo Neviani, Adrienne M. Dorrance, Mirela Anghelina, Jihane Khalife, Somayeh S. Tarighat, Stefano Volinia, Susan P. Whitman, Peter Paschka, Pia Hoellerbauer, Yue-Zhong Wu, Lina Han, Brad N. Bolon, William Blum, Krzysztof Mrózek, Andrew J. Carroll, Danilo Perrotti, Michael Andreeff, Michael A. Caligiuri, Marina Konopleva, Ramiro Garzon, Clara D. Bloomfield, Guido Marcucci
Journal: Journal of Clinical Investigation (2014)

Aberrant expression of the secreted protein, acidic, cysteine-rich (osteonectin) (SPARC) gene, which encodes a matricellular protein that participates in normal tissue remodeling, is associated with a variety of diseases including cancer, but the contribution of SPARC to malignant growth remains controversial. We previously reported that SPARC was among the most upregulated genes in cytogenetically normal acute myeloid leukemia (CN-AML) patients with gene-expression profiles predictive of unfavorable outcome, such as mutations in isocitrate dehydrogenase 2 (IDH2-R172) and overexpression of the oncogenes brain and acute leukemia, cytoplasmic (BAALC) and v-ets erythroblastosis virus E26 oncogene homolog (ERG). In contrast, SPARC was downregulated in CN-AML patients harboring mutations in nucleophosmin (NPM1) that are associated with favorable prognosis. Based on these observations, we hypothesized that SPARC expression is clinically relevant in AML. Here, we found that SPARC overexpression is associated with adverse outcome in CN-AML patients and promotes aggressive leukemia growth in murine models of AML. In leukemia cells, SPARC expression was mediated by the SP1/NF-κB transactivation complex. Furthermore, secreted SPARC activated the integrin-linked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent β-catenin signaling, which is involved in leukemia cell self-renewal. Pharmacologic inhibition of the SP1/NF-κB complex resulted in SPARC downregulation and leukemia growth inhibition. Together, our data indicate that evaluation of SPARC expression has prognosticative value and SPARC is a potential therapeutic target for AML.
2B4 (CD244) Signaling by Recombinant Antigen-specific Chimeric Receptors Costimulates Natural Killer Cell Activation to Leukemia and Neuroblastoma Cells
Authors: Bianca Altvater, Silke Landmeier, Sibylle Pscherer, Jaane Temme, Katharina Schweer, Sareetha Kailayangiri, Dario Campana, Heribert Juergens, Martin Pule, Claudia Rossig
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Novel natural killer (NK) cell–directed strategies in cancer immunotherapy aim at specifically modulating the balance between NK cell receptor signals toward tumor-specific activation. The signaling lymphocyte activation molecule–related receptor 2B4 (CD244) is an important regulator of NK cell activation. We investigated whether 2B4-enhanced activation signals can redirect the cytolytic function of human NK cells to NK cell–resistant and autologous leukemia and tumor targets. Experimental Design: In vitro–stimulated NK cells from healthy donors and pediatric leukemia patients were gene modified with CD19 or GD2-specific chimeric receptors containing either the T-cell receptor ζ or 2B4 endodomain alone or combined. Results: Chimeric 2B4 signaling alone failed to induce interleukin-2 receptor up-regulation and cytokine secretion but triggered a specific degranulation response. Integration of the 2B4 endodomain into T-cell receptor ζ chimeric receptors significantly enhanced all aspects of the NK cell activation response to antigen-expressing leukemia or neuroblastoma cells, including CD25 up-regulation, secretion of IFN-γ and tumor necrosis factor-α, release of cytolytic granules, and growth inhibition, and overcame NK cell resistance of autologous leukemia cells while maintaining antigen specificity. Conclusion: These data indicate that the 2B4 receptor has a potent costimulatory effect in NK cells. Antigen-specific 2B4ζ-expressing NK cells may be a powerful new tool for adoptive immunotherapy of leukemia and other malignancies.
Bevacizumab plus Fotemustine as First-line Treatment in Metastatic Melanoma Patients: Clinical Activity and Modulation of Angiogenesis and Lymphangiogenesis Factors
Authors: Michele Del Vecchio, Roberta Mortarini, Stefania Canova, Lorenza Di Guardo, Nicola Pimpinelli, Mario R. Sertoli, Davide Bedognetti, Paola Queirolo, Paola Morosini, Tania Perrone, Emilio Bajetta, Andrea Anichini
Journal: Clinical Cancer Research (2010)

To assess the clinical and biological activity of the association of bevacizumab and fotemustine as first-line treatment in advanced melanoma patients.Previously untreated, metastatic melanoma patients (n = 20) received bevacizumab (at 15 mg/kg every 3 weeks) and fotemustine (100 mg/m² by intravenous administration on days 1, 8, and 15, repeated after 4 weeks) in a multicenter, single-arm, open-label, phase II study. Primary endpoint was the best overall response rate; other endpoints were toxicity, time to progression (TTP), and overall survival (OS). Serum cytokines, angiogenesis, and lymphangiogenesis factors were monitored by multiplex arrays and by in vitro angiogenesis assays. Effects of fotemustine on melanoma cells, in vitro, on vascular endothelial growth factor (VEGF)-C release and apoptosis were assessed by ELISA and flow cytometry, respectively.One complete response, 2 partial responses (PR), and 10 patients with stable disease were observed. TTP and OS were 8.3 and 20.5 months, respectively. Fourteen patients experienced adverse events of toxicity grade 3-4. Serum VEGF-A levels in evaluated patients (n = 15) and overall serum proangiogenic activity were significantly inhibited. A significant reduction in VEGF-C levels was found in several post-versus pretherapy serum samples. In vitro, fotemustine inhibited VEGF-C release by melanoma cells without inducing significant cell death. Serum levels of interleukin (IL)-10 and IL-12p70 showed the highest levels in sera of PR patients, compared with patients with stable or progressive disease whereas IL-23 showed the opposite pattern.The combination of bevacizumab plus fotemustine has clinical activity in advanced melanoma and promotes systemic modulation of angiogenesis and lymphangiogenesis factors.
Frequency of hereditary non-polyposis colorectal cancer in Danish colorectal cancer patients
Authors: N Katballe
Journal: Gut (2002)

Background: Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant cancer syndrome, characterised by familial aggregation of HNPCC related cancers, germline mutations in mismatch repair genes, and/or microsatellite instability (MSI) in tumour tissue. Aim: To estimate the frequency of HNPCC among non-selected Danish patients with colorectal cancer (CRC), and to evaluate the value of MSI analysis as a pre-screen test. Methods: This was a prospective population based study on consecutive CRC patients. A family history of malignancy was obtained and suspected HNPCC cases were screened for hMLH1/hMSH2 mutations and subjected to MSI analysis. Patients with germline mutations and/or those with Amsterdam criteria I or II families were categorised as HNPCC patients. Results: Among 1328 eligible CRC patients, 1200 (90.4%) completed a questionnaire. A total of 1.7% (95% confidence interval (CI) 1.0–2.4) (20 cases) were categorised as HNPCC patients. Amsterdam criteria I or II were met in 18 cases (1.5%), and in another two cases (0.2%) pathogenic hMLH1/hMSH2 mutations were detected without fulfilment of the Amsterdam criteria I or II. Among 77 patients younger than 50 years of age, 11 cases (14.3%) were categorised as HNPCC. The Amsterdam criteria I or II were met in eight of 10 gene carriers (80%). The MSI-high phenotype was demonstrated in all 10 gene carriers. Conclusion: The frequency of HNPCC was approximately 1.7% among all CRC cases and 14.3% among patients younger than 50 years of age. MSI analysis is a reliable pre-screen test for hMLH1/hMSH2 mutations in families suspected of having HNPCC.
Synergistic Antipancreatic Tumor Effect by Simultaneously Targeting Hypoxic Cancer Cells With HSP90 Inhibitor and Glycolysis Inhibitor
Authors: Xianhua Cao, Mark Bloomston, Tao Zhang, Wendy L. Frankel, Guang Jia, Bing Wang, Nathan C. Hall, Regina M. Koch, Hao Cheng, Michael V. Knopp, Duxin Sun
Journal: Clinical Cancer Research (2008)

Abstract Purpose: We sought to examine the synergistic antipancreatic cancer effect by simultaneously targeting hypoxic cancer cells with heat-shock protein 90 (HSP90) inhibitor and blockade of energy production. Experimental Design: The anticancer effects of an HSP90 inhibitor (geldanamycin) in pancreatic cells were investigated in hypoxia and normoxia. A hexokinase II inhibitor, 3-broma-pyruvate (3BrPA), was evaluated for selective glycolysis inhibition in hypoxia as a sensitizer of HSP90 inhibitor against pancreatic cancer. The HSP90 client protein degradation was monitored by Western blot. The synergistic antitumor effect of geldanamycin and 3BrPA was evaluated in a xenograft pancreatic cancer model and monitored by a noninvasive dynamic contrast-enhanced magnetic resonance imaging. Results: Hypoxia enhanced HIF-1α expression by 11-fold in pancreatic cancer cells, and HSP90 inhibitor exhibited a seven- to eightfold higher anticancer effect in hypoxia compared with normoxia via HSP90 client protein degradation. 3BrPA selectively inhibited glycolysis and sensitized geldanamycin against pancreatic cancer cells by 17- to 400-fold through HSP90 client protein degradation. The synergistic anticancer effect of reduced doses of geldanamycin and 3-BrPA was confirmed in xenograft models in vivo by more than 75% tumor growth inhibition. Conclusions: The combination of HSP90 inhibitors and glycolysis inhibitors provides preferential inhibition of cancer cells in hypoxia through HSP90 client protein degradation and selective glycolysis inhibition. This may provide a new therapeutic regimen to battle chemotherapy-resistant pancreatic cancers, by enhancing the synergistic therapeutic efficacy and reducing dose-limiting toxicity.
eHealth: Extending, Enhancing, and Evolving Health Care
Authors: Carlos A. Meier, Maria C. Fitzgerald, Joseph M. Smith
Journal: Annual Review of Biomedical Engineering (2013)

eHealth holds the promise of revolutionizing health care by improving its efficiency; extending and enhancing its reach; energizing and engaging its practitioners and their patients; and in the process, democratizing, decentralizing, and even partially demystifying the practice of medicine. In emerging and developing countries, the use of eHealth and smart health-care planning has the potential to expand access to necessary treatments and prevention services that can serve as underpinnings of rapid economic development. In developed countries, the application of eHealth promises to restructure the business model of health-care delivery, while at the same time improving and personalizing the quality of care received. This article reviews the past, present, and future of eHealth in an effort to illuminate the potential of its impact.