tbuckley/cabot-search huggingface dataset:
Comorbid diseases as predictors of survival of primary total hip and knee replacements: a nationwide register-based study of 96 754 operations on patients with primary osteoarthritis
Authors: Esa Jämsen, Mikko Peltola, Antti Eskelinen, Matti U K Lehto
Journal: Annals of the Rheumatic Diseases (2012)

Objectives To examine how comorbid diseases (cardiovascular diseases, hypertension, diabetes, cancer, pulmonary diseases, depression, psychotic disorders and neurodegenerative diseases) affect survival of hip and knee replacements. Methods Data for this register-based study were collected by combining data from five nationwide health registers. 43 747 primary total hip and 53 007 primary total knee replacements performed for osteoarthritis were included. The independent effects of comorbid diseases on prosthesis survival were analysed using multivariate Cox regression analysis. Results Occurrence of one or more of the diseases analysed was associated with poorer survival of hip (HR for revision 1.16, 95% CI 1.08 to 1.23) and knee replacements (1.23, 1.16 to 1.30). Cardiovascular diseases and psychotic disorders were associated with increased risk of revision after both hip (1.19, 1.06 to 1.34 and 1.41, 1.04 to 1.91, respectively) and knee replacement (1.29, 1.14 to 1.45 and 1.41, 1.07 to 1.86, respectively). Hypertension and diabetes were associated with early revision (0–5 years after primary operation) after knee replacements (1.14, 1.01 to 1.29 and 1.27, 1.08 to 1.50, respectively). Cancer was associated with poorer survival of hip replacements (1.27, 1.05 to 1.54) and late revision (&gt;5 years) of knee replacements (2.21, 1.31 to 3.74). Depression affected the risk of early revision after hip replacement (1.50, 1.02 to 2.21). Neurodegenerative and pulmonary diseases did not affect prosthesis survival. Conclusions Comorbid diseases may play an important role in predicting survival of primary hip and knee replacements. The mechanisms underlying these findings and their effect on cost-effectiveness of joint replacements, merit further research.
Human hair follicle epithelium has an antimicrobial defence system that includes the inducible antimicrobial peptide psoriasin (S100A7) and RNase 7
Authors: K. Reithmayer, K.C. Meyer, P. Kleditzsch, S. Tiede, S.K. Uppalapati, R. Gläser, J. Harder, J.-M. Schröder, R. Paus
Journal: British Journal of Dermatology (2009)

Hair follicle (HF) ostia represent a potential port of microbial entry into the skin. However, they rarely show clinical signs of infection. This suggests the presence of local, efficient, antimicrobial defence systems, which may include antimicrobial peptides (AMPs).We determined the presence and distribution of the major AMPs, RNase 7 and psoriasin (S100A7), in human scalp HFs. We investigated whether HF production of these AMPs was induced by prototypic microbial products and proinflammatory cytokines, i.e. interferon (IFN)-gamma. Finally, we examined whether the classical pathways for AMP induction, such as toll-like receptor (TLR)4 and TLR5 expression, are present in human HFs and up-regulated after stimulation with bacterium-associated ligands.Cryosections from fresh or organ-cultured full-thickness normal human scalp skin treated with lipopolysaccharide (LPS), flagellin, protein A, lipoteichoic acid (LTA) or IFN-gamma were stained for psoriasin and RNase 7 immunoreactivity (IR) as well as for TLR4 and TLR5. In addition, outer root sheath cell culture and semiquantitative analysis of mRNA expression levels of RNase 7 and psoriasin were performed.Specific RNase 7 IR was present throughout the entire HF outer root sheath in situ and in cell culture, whereas psoriasin IR was present only in the most distal compartment and not detectable in cultured ORS cells. Upon treatment with Gram-positive (LTA, protein A) or Gram-negative bacterial (LPS, flagellin) cell wall components, or with the cytokine IFN-gamma, the IR of both psoriasin and RNase 7 was modified. TLR4 and TLR5 IR was detected in the normal HF epithelium and were upregulated after treatment with their respective ligand. The mRNA analysis confirmed the immunohistochemistry results.This pilot study suggests that normal human scalp HF epithelium possesses a functional antimicrobial defence system, which includes the AMPs RNase 7 and psoriasin, and TLRs, and that these are induced by classical microbial products.
Nested PCR in lung tissue for diagnosis of pulmonary tuberculosis
Authors: J. S. Park, Y. A. Kang, S. Y. Kwon, H. I. Yoon, J-H. Chung, C-T. Lee, J. H. Lee
Journal: European Respiratory Journal (2009)

Diagnosis of pulmonary tuberculosis (TB) is difficult in cases with an unusual presentation and often requires a lung biopsy. The goal of this study was to determine the clinical usefulness of nested PCR on lung tissue for the diagnosis of pulmonary TB. Clinical and laboratory data were reviewed from patients who underwent diagnostic lung biopsies, followed by nested TB PCR on formalin-fixed paraffin-embedded lung tissue specimens. The diagnostic yield and clinical impact of nested PCR were investigated. Of the 223 patients studied, 142 were diagnosed with TB. Microbiologically confirmed TB was identified in 71 patients. Compared to culture results, the sensitivity, specificity, positive predictive value and negative predictive value of nested PCR were 85%, 99%, 98% and 88%, respectively. Nested PCR was more sensitive than acid-fast bacilli smear of respiratory specimens and histopathological findings. The PCR results provided an early diagnosis and initiation of treatment for TB. However, negative PCR results did not lead to discontinuation of unnecessary TB treatment in patients on medication. In conclusion, nested PCR on lung tissue specimens is a useful diagnostic test for pulmonary TB in patients with an unusual presentation.
Do We Still Need Proxies for Quality Control in Rectal Cancer Surgery?
Authors: Łukasz Dziki, Paweł Mroczkowski
Journal: Journal of Clinical Oncology (2015)

TO THE EDITOR: Massarweh et al used the National Cancer Data Base to determine a risk-adjusted margin positivity rate (RAMP) as a quality indicator, stating that patients treated in hospitals that perform better than expected have better outcomes than patients treated in hospitals that perform worse than expected. The analysis concerns 32,354 patients treated within 3 years in 1,349 hospitals resulting in 7.99 resections per hospital per year. The complicated scoring system taken as the basis for the RAMP calculation includes different structure, process, and outcome parameters. Nonoutlier hospitals treated 91.4% of the patients. However, the rationale behind this approach remains unclear. The pathologic margin is determined by only two factors—the ability of the operating surgeon and the local extent of the tumor determined by magnetic resonance imaging (MRI). The determination of margin positivity in patients correctly diagnosed with negative circumferential margin by MRI is not a question of income and social status, it is a surgical error. RAMP, as a quality indicator for margin positivity, encourages acceptance of inferior results for the same tumor condition depending on the place of treatment. In the accompanying editorial, Finlayson states that Europe, with publicly supported quality initiatives, can afford a better system. However, publicly supported programs are available only in a minority of European countries. The rest of Europe conducts voluntary self-financed projects or does not have quality programs at all. However, it is incomprehensible why this most obvious and easiest parameter of quality in rectal cancer surgery cannot be described directly as, for example, a comparison of standardized MRI results with a standardized pathologic report, without any proxies and outliers. From the European perspective, the United States, which has a health system with enormous reach, is a place where this kind of quality control could be implemented without limitations. We agree that economic status and different elements of structure and process quality do have an impact on survival, but we cannot agree that the same rectal cancer with negative mesorectal fascia involvement should have a different probability of negative-margin resection depending, for example, on the income and education of its host. RAMP and outlier status are methods of making a simple thing complicated, but we are not convinced that this is the most effective way to indicate quality and improvement.
Systematic High-Content Proteomic Analysis Reveals Substantial Immunologic Changes in Colorectal Cancer
Authors: Uta Berndt, Lars Philipsen, Sebastian Bartsch, Bertram Wiedenmann, Daniel C. Baumgart, Marcus Hämmerle, Andreas Sturm
Journal: Cancer Research (2008)

Abstract The immune system is a significant determinant of epithelial tumorigenesis, but its role in colorectal cancer pathogenesis is not well understood. The function of the immune system depends upon the integrity of the protein network environment, and thus, we performed MELC immunofluorescence microscopy focusing on the lamina propria. By analyzing structurally intact tissues from colorectal cancer, ulcerative colitis, and healthy colonic mucosa, we used this unique and novel highly multiplexed robotic-imaging technology, which allows visualizing dozens of proteins simultaneously, and explored the toponome in colorectal cancer mucosa for the first time. We identified 1,930 motifs that distinguish control from colorectal cancer tissue. In colorectal cancer, the number of activated T cells is increased, explained by a lack of bax, caspase-3, and caspase-8. Whereas CD4+CD25+ T cells are decreased and are, other than in ulcerative colitis, not activated, cytotoxic T cells are significantly increased in colorectal cancer. Furthermore, the number of activated human lymphocyte antigen (HLA)-DR+ T-cells is increased in colorectal cancer, pointing to an altered antigen presentation. In colorectal cancer, CD3+CD29+ expression and assembly of the LFA-1 and LFA-3 receptor are differentially changed, indicating a distinct regulation of T-cell adhesion in colorectal cancer. We also identified increased numbers of natural killer and CD44+ cells in the colorectal cancer mucosa and nuclear factor-κB as regulator of apoptosis in these cell populations. High-content proteomic analysis showed that colorectal cancer induces a tremendous modification of protein expression profiles in the lamina propria. Thus, topological proteomic analysis may help to unravel the role of the adaptive immune system in colorectal cancer and aid the development of new antitumor immunotherapy approaches. [Cancer Res 2008;68(3):880–8]
Mitochondrially Targeted p53 Has Tumor Suppressor Activities <i>In vivo</i>
Authors: Flaminia Talos, Oleksi Petrenko, Patricio Mena, Ute M. Moll
Journal: Cancer Research (2005)

Abstract Complex proapoptotic functions are essential for the tumor suppressor activity of p53. We recently described a novel transcription-independent mechanism that involves a rapid proapoptotic action of p53 at the mitochondria and executes the shortest known circuitry of p53 death signaling. Here, we examine if this p53-dependent mitochondrial program could be exploited for tumor suppression in vivo. To test this, we engage Eμ-Myc transgenic mice, a well-established model of p53-dependent lymphomagenesis. We show that exclusive delivery of p53 to the outer mitochondrial membrane confers a significant growth disadvantage on Eμ-Myc–transformed B-cells of p53-deficient or alternate reading frame–deficient genotypes, resulting in efficient induction of apoptosis and impinged proliferation. Conversely, normal cells from thymus, spleen, and bone marrow showed poor infectivity with these viruses. This proof-of-principle experiment shows that exclusive reliance on the direct mitochondrial program exerts a significant tumor suppressor activity in vivo. Our in vivo data on the direct mitochondrial apoptotic p53 program lays the groundwork to further investigate its efficacy and safety and to address its possible therapeutic value in the future.
TR-15 * USE OF IV N-ACETYLCYSTEINE IN COMBINATION WITH SODIUM THIOSULFATE FOR PREVENTION OF OTOTOXICITY IN PEDIATRIC PATIENTS
Authors: E. Neuwelt, N. Doolittle, K. Knight, S. Lindemulder
Journal: Neuro-Oncology (2015)

Although the childhood cancers medulloblastoma, osteosarcoma, hepatoblastoma, germ cell tumors, and neuroblastoma affect a relatively small number of children, with prevalence under 110,000 in the United States, the impact of these life-threatening illnesses on children and their families is significant. Standard therapy for pediatric cancers typically involves alkylating platinum chemotherapeutics, primarily cisplatin and carboplatin. Platinum chemotherapeutics and other free-radical inducing therapies such as radiotherapy can cause multiple severe systemic and neurological side effects, including permanent ototoxicity. The overall incidence of permanent bilateral hearing loss in children during cisplatin chemotherapy is 60%.(1) Our goal is to decrease the toxic side effects of cisplatin and enhance long-term quality of life by reducing lasting toxicities. Based on our preclinical and clinical studies, we hypothesize that the appropriate timing and dosing of combination chemoprotectants may reduce systemic and neurologic toxicities while maintaining dose intensity, and may even allow for the use of new strategies, such as dose-escalation or chemo-enhancement, for improved cancer control. In particular, our studies have demonstrated that high dose (400 mg/kg) intravenous (IV) N-acetylcysteine (NAC) (Acetadote®) is critical to achieve high plasma concentrations for optimum chemoprotective activity. Recently completed Phase III studies of sodium thiosulfate (STS) otoprotection in children have shown no compromise in efficacy of cisplatin if the tumor is localized (as it is in 50 + % of patients). We have applied for orphan-drug designation of IV NAC in combination with STS for prevention of ototoxicity caused by platinum-based chemotherapeutic agents in children, in addition we are developing a phase I trial of increasing NAC doses in combination with the phase III dose of STS. 1. 1. Brock PR, et al. Platinum-Induced Ototoxicity in Children: A Consensus Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale. J Clin Oncol 30(19), 2408-2417.
Murine Myeloproliferative Virus in Cell Culture&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: H D Soule, W J Arnold
Journal: JNCI Journal of the National Cancer Institute (1970)

A stable cell line, MCF-6, isolated from a leukemic mouse was maintained in culture for more than 28 months with 99 passages and frozen and reactivated 3 times at the most recent completed bioassay without need for animal or embryo passage rejuvenation. Cells or supernatant from MCF-6 produced myeloproliferative disorders when injected into neonatal BALB/c mice, with mortalities of 70–90% and mean latencies of onset of between 100–150 days. Older animals were not susceptible to virus or MCF-6 cells. The culture produced abundant virulent virus with the supernatant, at a dilution of 10−3.1, infecting 50% of the hosts. Electron micrographs of MCF-6 supernatant showed particles similar to published descriptions of murine leukemia-inducing viruses. Cells from the culture did not transplant and, thus, were probably nonmalignant. Spleen cells from infected mice, however, were transplantable and produced malignancy in 92% of young adult animals inoculated, with a mean latency of 31 days.
Effect of Extended-Release Niacin on New-Onset Diabetes Among Hyperlipidemic Patients Treated With Ezetimibe/Simvastatin in a Randomized Controlled Trial
Authors: John R. Guyton, Sergio Fazio, Adeniyi J. Adewale, Erin Jensen, Joanne E. Tomassini, Arvind Shah, Andrew M. Tershakovec
Journal: Diabetes Care (2012)

To determine the effect of niacin on fasting glucose (FG) and new-onset diabetes in statin/ezetimibe-treated patients.This was a prespecified secondary analysis among 942 hyperlipidemic patients randomized to ezetimibe/simvastatin (E/S; 10/20 mg) or E/S + extended-release niacin (N; titrated to 2 g) over 64 weeks.FG levels peaked by 8-12 weeks, then declined even without antidiabetic medication. At 64 weeks, 3.5% taking E/S+N versus 2.6% taking E/S met criteria for new-onset diabetes (P = 0.66). An additional 1.4% taking E/S+N versus 0.4% taking E/S transiently met criteria for diabetes and then remitted (P = 0.46). Of 28 new-diabetes diagnoses in the E/S+N group, 25 occurred by 24 weeks. Among patients with baseline diabetes, 13.9% taking E/S+N and 11.6% taking E/S underwent antidiabetic treatment modification.Increased FG and new-onset diabetes with E/S+N occurred mainly around the time of initial uptitration of N and often improved or remitted without specific treatment.
Electrocardiographic interpretation in athletes: the ‘Seattle Criteria’
Authors: Jonathan A Drezner, Michael John Ackerman, Jeffrey Anderson, Euan Ashley, Chad A Asplund, Aaron L Baggish, Mats Börjesson, Bryan C Cannon, Domenico Corrado, John P DiFiori, Peter Fischbach, Victor Froelicher, Kimberly G Harmon, Hein Heidbuchel, Joseph Marek, David S Owens, Stephen Paul, Antonio Pelliccia, Jordan M Prutkin, Jack C Salerno, Christian M Schmied, Sanjay Sharma, Ricardo Stein, Victoria L Vetter, Mathew G Wilson
Journal: British Journal of Sports Medicine (2013)

Sudden cardiac death (SCD) is the leading cause of death in athletes during sport. Whether obtained for screening or diagnostic purposes, an ECG increases the ability to detect underlying cardiovascular conditions that may increase the risk for SCD. In most countries, there is a shortage of physician expertise in the interpretation of an athlete's ECG. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from abnormal findings suggestive of pathology. On 13-14 February 2012, an international group of experts in sports cardiology and sports medicine convened in Seattle, Washington, to define contemporary standards for ECG interpretation in athletes. The objective of the meeting was to develop a comprehensive training resource to help physicians distinguish normal ECG alterations in athletes from abnormal ECG findings that require additional evaluation for conditions associated with SCD.
EPHB4 and Survival of Colorectal Cancer Patients
Authors: Veronica Davalos, Higinio Dopeso, Julio Castaño, Andrew J. Wilson, Felip Vilardell, Jordi Romero-Gimenez, Eloy Espín, Manel Armengol, Gabriel Capella, John M. Mariadason, Lauri A. Aaltonen, Simo Schwartz, Diego Arango
Journal: Cancer Research (2006)

Abstract The family of receptor tyrosine kinases EPH and their Ephrin ligands regulate cell proliferation, migration, and attachment. An important role in colorectal carcinogenesis is emerging for some of its members. In this study, we evaluate the role of EPHB4 in colorectal cancer and its value as a prognostic marker. EPHB4 levels were assessed by immunohistochemical staining of tissue microarrays of 137 colorectal tumors and aberrant hypermethylation of the EPHB4 promoter was investigated using methylation-specific PCR. We found that EPHB4 expression is frequently reduced or lost in colorectal tumors. Patients with low EPHB4 tumor levels had significantly shorter survival than patients in the high EPHB4 group (median survival, 1.8 and &amp;gt;9 years, respectively; P &amp;lt; 0.01, log-rank test), and this finding was validated using an independent set of 125 tumor samples. In addition, we show that EPHB4 promoter hypermethylation is a common mechanism of EPHB4 inactivation. Moreover, reintroduction of EPHB4 resulted in a significant reduction in the clonogenic potential of EPHB4-deficient cells, whereas abrogation of EPHB4 in cells with high levels of this receptor lead to a significant increase in clonogenicity. In summary, we identified EPHB4 as a useful prognostic marker for colorectal cancer. In addition, we provide mechanistic evidence showing that promoter methylation regulates EPHB4 transcription and functional evidence that EPHB4 can regulate the long-term clonogenic potential of colorectal tumor cells, revealing EPHB4 as a potential new tumor suppressor gene in colorectal cancer. (Cancer Res 2006; 66(18): 8943-8)
The Promyelocytic Leukemia Zinc Finger–MicroRNA-221/-222 Pathway Controls Melanoma Progression through Multiple Oncogenic Mechanisms
Authors: Federica Felicetti, M. Cristina Errico, Lisabianca Bottero, Patrizia Segnalini, Antonella Stoppacciaro, Mauro Biffoni, Nadia Felli, Gianfranco Mattia, Marina Petrini, Mario P. Colombo, Cesare Peschle, Alessandra Carè
Journal: Cancer Research (2008)

Abstract The incidence of cutaneous melanoma is steadily increasing. Although several molecular abnormalities have been associated with melanoma progression, the mechanisms underlying the differential gene expression are still largely unknown and targeted therapies are not yet available. Noncoding small RNAs, termed microRNAs (miR), have been recently reported to play important roles in major cellular processes, including those involved in cancer development and progression. We have identified the promyelocytic leukemia zinc finger (PLZF) transcription factor as a repressor of miR-221 and miR-222 by direct binding to their putative regulatory region. Specifically, PLZF silencing in melanomas unblocks miR-221 and miR-222, which in turn controls the progression of the neoplasia through down-modulation of p27Kip1/CDKN1B and c-KIT receptor, leading to enhanced proliferation and differentiation blockade of the melanoma cells, respectively. In vitro and in vivo functional studies, including the use of antisense “antagomir” oligonucleotides, confirmed the key role of miR-221/-222 in regulating the progression of human melanoma; this suggests that targeted therapies suppressing miR-221/-222 may prove beneficial in advanced melanoma. [Cancer Res 2008;68(8):2745–10]
Effects of Ouabain on Insulin Secretion in the Dog
Authors: L. TRINER, J. PAPAYOANOU, P. KILLIAN, Y. VULLIEMOZ, R. CASTANY, G. G. NAHAS
Journal: Circulation Research (1969)

The mechanism of the previously reported hypoglycemic effect of ouabain was studied in dogs. Ouabain (1.0 µg/kg/min infused intravenously for 60 minutes) combined with insulin or propranolol caused a greater and more prolonged decrease in blood glucose than either of the drugs administered separately. In intact dogs, ouabain changed significantly portohepatic venous differences in plasma glucose from +6.6 to -13.6 mg/100 ml and in K + from -0.03 to -0.4 mEq/liter. In pancreatectomized animals, ouabain did not cause any significant decrease in peripheral glucose level, and the portohepatic differences in plasma glucose changed from +5.3 to +30.2 mg/100 ml and the differences in K + from -0.01 to +0.2 mEq/liter. These changes, indicating an increased release of glucose and K + by the liver in the pancreatectomized dog, were also observed in isolated rat liver perfused with ouabain 10 -6 M. Glucose uptake of the hindlimb increased significantly during the infusion of ouabain in normal dogs, but did not change in pancreatectomized dogs. Ouabain caused a significant increase in plasma insulin in portal blood (+155%). These results demonstrate that the observed metabolic effects of ouabain in the dog are mainly mediated by insulin and that ouabain increases the secretion of insulin in intact dogs.