tbuckley/cabot-search huggingface dataset:
Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness.
Authors: Terhi Jokilehto, Krista Rantanen, Marjaana Luukkaa, Pekka Heikkinen, Reidar Grenman, Heikki Minn, Pauliina Kronqvist, Panu M Jaakkola
Journal: Clinical Cancer Research (2006)

Abstract PURPOSE: Hypoxia in tumors is associated with poor prognosis and resistance to treatment. The outcome of hypoxia is largely regulated by the hypoxia-inducible factors (HIF-1alpha and HIF-2alpha). HIFs in turn are negatively regulated by a family of prolyl hydroxylases (PHD1-3). The PHD2 isoform is the main down-regulator of HIFs in normoxia and mild hypoxia. This study was designed to analyze the correlation of the expression and subcellular localization of PHD2 with the pathologic features of human carcinomas and HIF-1alpha expression. EXPERIMENTAL DESIGN: The expression of PHD2 was studied from paraffin-embedded normal tissue (n = 21) and head and neck squamous cell carcinoma (HNSCC; n = 44) by immunohistochemistry. Further studies included PHD2 mRNA detection and HIF-1alpha immunohistochemistry from HNSCC specimens as well as PHD2 immunocytochemistry from HNSCC-derived cell lines. RESULTS: In noncancerous tissue, PHD2 is robustly expressed by endothelial cells. In epithelium, the basal proliferating layer also shows strong expression, whereas the more differentiated epithelium shows little or no PHD2 expression. In HNSCC, PHD2 shows strongly elevated expression both at the mRNA and protein level. Moreover, PHD2 expression increases in less differentiated phenotypes and partially relocalizes from the cytoplasm into the nucleus. Endogenously high nuclear PHD2 is seen in a subset of HNSCC-derived cell lines. Finally, although most of the tumor regions with high PHD2 expression show down-regulated HIF-1alpha, regions with simultaneous HIF-1alpha and PHD2 expression could be detected. CONCLUSIONS: Our results show that increased levels and nuclear translocation of the cellular oxygen sensor, PHD2, are associated with less differentiated and strongly proliferating tumors. Furthermore, they imply that even the elevated PHD2 levels are not sufficient to down-regulate HIF-1alpha in some tumors.
Management of Postmenopausal Osteoporosis
Authors: Panagiota Andreopoulou, Richard S. Bockman
Journal: Annual Review of Medicine (2014)

A hallmark of menopause, which follows the decline in the ovarian production of estrogen, is the aggressive and persistent loss of bone mineral and structural elements leading to loss of bone strength and increased fracture risk. This review focuses on newer methods of diagnosing osteoporosis and assessing fracture risk, as well as on novel management strategies for prevention and treatment. Fracture-risk prediction has been significantly enhanced by the development of methods such as the trabecular bone score, which helps assess bone microarchitecture and adds value to standard bone densitometry, and the Fracture Risk Assessment Tool (FRAX) algorithm techniques. The treatment of osteoporosis, which has the goals of fracture prevention and risk reduction, is moving beyond traditional monotherapies with antiresorptives and anabolic agents into new combination regimens.
THE BIOSYNTHESIS AND TURNOVER OF OXALATE IN NORMAL AND HYPEROXALURIC SUBJECTS *
Authors: T. David Elder, James B. Wyngaarden
Journal: Journal of Clinical Investigation (1960)

Materials.Glycine I-C14, specific activity 2.2 mc per mmole, and oxalic acid 1,2-C"4, specific activity 2.6 mc per mmole, both of radiopurity > 99 per cent, were pur- chased from Isotopes Specialties Co. Burbank, Calif.Control subjects.Control subj ects were hospitalized
Rapid and slow components of delayed rectifier current in human atrial myocytes
Authors: Z. Wang, B. Fermini, S. Nattel
Journal: Cardiovascular Research (1994)

Objective: Previous studies in guinea pig heart cells have shown pharmacologically and kinetically distinct components of the classical delayed rectifier current (IK), generally referred to as IKr (rapid IK) and IKs (slow IK). This study was designed to determine whether the human heart contains corresponding components. Methods: The whole cell voltage clamp technique was used to study IK in single myocytes isolated from human right atrial appendages removed at the time of aortocoronary artery bypass surgery. Results: The activation of IK was best fitted by a biexponential relation, with time constants averaging 204(SEM 20) and 1080(197) ms at +10 mV. IK was inhibited by the specific lKr blocker E-4031 (5 μM), with the drug sensitive and drug resistant components having markedly different kinetic properties. The E-4031 sensitive current activated rapidly, while the drug resistant component activated more slowly, and the activation time courses of E-4031 sensitive and resistant currents paralleled the rapid and slow components of IK between -20 and +50 mV. The E-4031 sensitive component showed strong inward rectification, a half activation voltage (V½ of -14.0(3.3) mV and a slope factor (k) of 6.5(1.5) mV, while the E-4031 resistant current had a linear current-voltage relationship, and values of +19.9(4.2) mV and 12.7(2.5) mV for V½ and k respectively. The envelope of tails analysis showed a time dependent change in IKtail IKstep under control conditions, and E-4031 strongly reduced the time dependent variation, suggesting that the E-4031 resistant current consisted of one dominant component. Conclusions: (1) IK in human atrium shows kinetically distinguishable rapid and slow components. (2) These components correspond to E-4031 sensitive and resistant currents. (3) The kinetics and voltage dependence of the rapid (E-4031 sensitive) and slow (E-4031 resistant) components correspond to properties previously described in guinea pig myocytes. These findings have important potential implications for understanding the mechanisms of human atrial repolarisation and its regulation by the autonomic nervous system and antiarrhythmic drugs. Cardiovascular Research 1994;28:1540-1546
Surgical repair of a chronic rupture of the rectus femoris muscle at the proximal musculotendinous junction in a soccer player
Authors: R Straw, K Colclough, G Geutjens
Journal: British Journal of Sports Medicine (2003)

A rare case is presented of a longstanding rupture of the rectus femoris muscle at the proximal musculotendinous junction in a semiprofessional soccer player. Its different and unique presentation, the surgical repair, and the remarkable functional recovery are discussed.
An 8-year survey of strains identified in blood cultures in a clinical haematology unit
Authors: A. Bousquet, J.-V. Malfuson, N. Sanmartin, J. Konopacki, C. MacNab, B. Souleau, T. de Revel, M. Elouennass, T. Samson, C. Soler, V. Foissaud, C. Martinaud
Journal: Clinical Microbiology and Infection (2013)
Tumor Epidermal Growth Factor Receptor and EGFR PY1068 Are Independent Prognostic Indicators for Head and Neck Squamous Cell Carcinoma
Authors: Sarah Wheeler, Doris R. Siwak, Raymond Chai, Courtney LaValle, Raja R. Seethala, Lin Wang, Kathleen Cieply, Carol Sherer, Corwin Joy, Gordon B. Mills, Athanassios Argiris, Jill M. Siegfried, Jennifer R. Grandis, Ann Marie Egloff
Journal: Clinical Cancer Research (2012)

Abstract Purpose: To assess the prognostic value of epidermal growth factor receptor (EGFR) molecular characteristics of head and neck squamous cell carcinoma (HNSCC). Patients and Methods: HNSCC tumors from patients prospectively enrolled in either an Early Detection Research Network (EDRN) study and treated with surgery without an EGFR-targeted agent (N = 154) or enrolled in a chemoradiation trial involving the EGFR-targeted antibody cetuximab (N = 39) were evaluated for EGFR gene amplification by FISH and EGFR protein by immunohistochemical staining. Fresh-frozen tumors (EDRN) were also evaluated for EGFR protein and site-specific phosphorylation at Y992 and Y1068 using reverse-phase protein array (n = 67). Tumor (n = 50) EGFR and EGFRvIII mRNA levels were quantified using real-time PCR. Results: EGFR expression by immunohistochemistry (IHC) was significantly higher in the EDRN tumors with EGFR gene amplification (P &amp;lt; 0.001), and a similar trend was noted in the cetuximab-treated cohort. In the EDRN and cetuximab-treated cohorts elevated EGFR by IHC was associated with reduced survival (P = 0.019 and P = 0.06, respectively). Elevated expression of total EGFR and EGFR PY1068 were independently significantly associated with reduced progression-free survival in the EDRN cohort [HR = 2.75; 95% confidence interval (CI) = 1.26–6.00 and HR = 3.29; 95% CI = 1.34–8.14, respectively]. Conclusions: In two independent HNSCC cohorts treated with or without cetuximab, tumor EGFR levels were indicative of survival. Tumor EGFR PY1068 levels provided prognostic information independent of total EGFR. Clin Cancer Res; 18(8); 2278–89. ©2012 AACR.
Future therapy of hepatitis C
Authors: John G. McHutchison, Keyur Patel
Journal: Hepatology (2002)

Currently available therapies for the treatment of chronic hepatitis C are effective in half of patients, but are expensive, often poorly tolerated, and unsuitable for certain patient populations. The ideal therapy would be highly effective, orally bioavailable, have minimal side effects, be cost effective, and suitable for the majority of patients with hepatitis C. Recent advances in understanding the replication cycle of hepatitis C virus (HCV) and structural, crystallographic definitions of components of the viral polyprotein have improved the prospects for development of novel therapies. The lack of a small animal model of HCV infection continues to hamper progress in the preclinical evaluation of new antivirals and vaccines. Strategies to enhance response to current therapies include the development of novel interferons and delivery systems, nucleoside analogues that have reduced hemolysis compared with ribavirin, inosine 5’ monophosphate dehydrogenase inhibitors, and other immunomodulators that are being evaluated as adjunctive therapy to interferon-based regimens. Compounds in preclinical or early phase human trials include small molecules that inhibit virus specific enzymes (such as the serine proteases, RNA polymerase and helicase), or those that prevent translation initiation (such as antisense molecules and ribozymes). Antifibrotic agents are also being developed in an attempt to prevent disease progression in patients in whom HCV RNA cannot be eradicated. While the advent of these newer compounds represent an exciting phase in the treatment of HCV, their safety and efficacy need to be established. Most of these newer therapies are unlikely to be available for routine clinical use in the next 3 to 5 years.
Superoxide Dismutase 3 Polymorphism Associated with Reduced Lung Function in Two Large Populations
Authors: Morten Dahl, Russell P. Bowler, Klaus Juul, James D. Crapo, Samuel Levy, Børge G. Nordestgaard
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Superoxide dismutase (SOD) 3 inhibits oxidative fragmentation of lung matrix components collagen I, hyaluronan, and heparan sulfate. Inherited change in SOD3 expression or function could affect lung matrix homeostasis and influence pulmonary function.To identify novel SOD3 polymorphisms that are associated with lung function or chronic obstructive pulmonary disease (COPD).Resequencing of 182 individuals identified two novel polymorphisms, E1 (rs8192287) and I1 (rs8192288), in a conserved region of the SOD3 gene of potential relationship to lung function. We next genotyped 9,093 individuals from the Copenhagen City Heart Study for the polymorphisms and recorded spirometry, and admissions and deaths due to COPD during 26-year follow-up. Finally, we validated our findings in a cross-sectional analysis of 35,635 individuals from the Copenhagen General Population Study.Genotyping the Copenhagen City Heart Study identified 35 E1/I1 homozygotes, 1,050 heterozygotes, and 8,008 noncarriers (Hardy-Weinberg equilibrium: P = 0.93). Using quadruple lung function measurements, we found that E1/I1 homozygotes had 7% lower FVC % predicted (P = 0.006) and 4% lower FEV(1) % predicted (P = 0.12) compared with noncarriers. In the Copenhagen General Population Study, E1/I1 homozygotes also had lower FVC % predicted than noncarriers (P = 0.03), confirming an association between E1/I1 genotype and reduced lung function. E1/I1 homozygotes had adjusted hazard ratios for COPD hospitalization and COPD mortality of 2.5 (95% confidence interval, 1.0-5.9) and 3.7 (95% confidence interval, 0.9-15), respectively; the results were independent of influence from the R213G allele of the SOD3 gene.We identified two novel polymorphisms in a conserved region of the SOD3 gene and show that individuals that are homozygous for these polymorphisms have reduced FVC % predicted in two large, population-based studies.
Public Expectations and the Responsiveness of Medical Education
Authors: W. C. Wescoe
Journal: JAMA (1967)

The persistent parade of seconds, minutes, hours, days, weeks, months, and years, the inexorable ticking off of time has brought me now, in this 63rd annual Congress on Medical Education, close to the final moments of a ten-year orbiting journey. In all of that journey, I and my fellow medinauts of the Council have been in constant communication with a host of tracking stations: survey teams, liaison bodies, special interest groups, deans and faculties, chairmen and professors, ad hoc committees, special task forces, public commissions. Not all of the communication was always entirely perfect; some signals were misread. Some signals were so garbled as to be almost indecipherable. A few signals came through loud and continuous. Now I prepare to leave the Council as member and chairman. I prepare for the difficult time of reentry into the earthly atmosphere. I do so fearlessly, and frankly, with a great feeling of
HMGB1 Mediates Endogenous TLR2 Activation and Brain Tumor Regression
Authors: James F Curtin, Naiyou Liu, Marianela Candolfi, Weidong Xiong, Hikmat Assi, Kader Yagiz, Matthew R Edwards, Kathrin S Michelsen, Kurt M Kroeger, Chunyan Liu, A. K. M. Ghulam Muhammad, Mary C Clark, Moshe Arditi, Begonya Comin-Anduix, Antoni Ribas, Pedro R Lowenstein, Maria G Castro
Journal: PLoS Medicine (2009)

Background Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor that carries a 5-y survival rate of 5%. Attempts at eliciting a clinically relevant anti-GBM immune response in brain tumor patients have met with limited success, which is due to brain immune privilege, tumor immune evasion, and a paucity of dendritic cells (DCs) within the central nervous system. Herein we uncovered a novel pathway for the activation of an effective anti-GBM immune response mediated by high-mobility-group box 1 (HMGB1), an alarmin protein released from dying tumor cells, which acts as an endogenous ligand for Toll-like receptor 2 (TLR2) signaling on bone marrow-derived GBM-infiltrating DCs. Methods and Findings Using a combined immunotherapy/conditional cytotoxic approach that utilizes adenoviral vectors (Ad) expressing Fms-like tyrosine kinase 3 ligand (Flt3L) and thymidine kinase (TK) delivered into the tumor mass, we demonstrated that CD4+ and CD8+ T cells were required for tumor regression and immunological memory. Increased numbers of bone marrow-derived, tumor-infiltrating myeloid DCs (mDCs) were observed in response to the therapy. Infiltration of mDCs into the GBM, clonal expansion of antitumor T cells, and induction of an effective anti-GBM immune response were TLR2 dependent. We then proceeded to identify the endogenous ligand responsible for TLR2 signaling on tumor-infiltrating mDCs. We demonstrated that HMGB1 was released from dying tumor cells, in response to Ad-TK (+ gancyclovir [GCV]) treatment. Increased levels of HMGB1 were also detected in the serum of tumor-bearing Ad-Flt3L/Ad-TK (+GCV)-treated mice. Specific activation of TLR2 signaling was induced by supernatants from Ad-TK (+GCV)-treated GBM cells; this activation was blocked by glycyrrhizin (a specific HMGB1 inhibitor) or with antibodies to HMGB1. HMGB1 was also released from melanoma, small cell lung carcinoma, and glioma cells treated with radiation or temozolomide. Administration of either glycyrrhizin or anti-HMGB1 immunoglobulins to tumor-bearing Ad-Flt3L and Ad-TK treated mice, abolished therapeutic efficacy, highlighting the critical role played by HMGB1-mediated TLR2 signaling to elicit tumor regression. Therapeutic efficacy of Ad-Flt3L and Ad-TK (+GCV) treatment was demonstrated in a second glioma model and in an intracranial melanoma model with concomitant increases in the levels of circulating HMGB1. Conclusions Our data provide evidence for the molecular and cellular mechanisms that support the rationale for the clinical implementation of antibrain cancer immunotherapies in combination with tumor killing approaches in order to elicit effective antitumor immune responses, and thus, will impact clinical neuro-oncology practice.
Intracranial Injection of Recombinant Adeno-associated Virus Improves Cognitive Function in a Murine Model of Mucopolysaccharidosis Type VII
Authors: W.Anthony Frisella, Lynn H. O'Connor, Carole A. Vogler, Marie Roberts, Steve Walkley, Beth Levy, Thomas M. Daly, Mark S. Sands
Journal: Molecular Therapy (2001)

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by the lack of β-glucuronidase (GUSB) activity. GUSB deficiency leads to the progressive accumulation of undegraded glycosaminoglycans (GAGs) in cells of most tissues, including the brain, and is associated with mental retardation. Reduction of lysosomal storage in the central nervous system and prevention of cognitive dysfunction may require intracranial delivery of a therapeutic agent during the newborn period that provides a continuous source of GUSB. Therefore, we injected recombinant adeno-associated virus encoding human GUSB into both the anterior cortex and the hippocampus of newborn MPS VII mice. Total GUSB activity in the brain approached normal levels by 18 weeks. Although GUSB activity was concentrated near the injection sites, lysosomal distension was reduced in most areas of the brain. In addition to histopathologic evidence of GAG reduction, the previously undescribed accumulation of GM2 and GM3 gangliosides in the brain was also prevented. Furthermore, GUSB expression and reduced lysosomal distension correlated with improvements in cognitive function as measured in the Morris Water Maze test. These findings indicate that localized overexpression of GUSB has positive effects on the pathology and cognitive function and does not have overt toxicity.
Safety and Tolerability of Escalating Doses of Microencapsulated Grass (Phleum Pratense) Pollen Extract (MGPE) for Oral Immunotherapy (OIT) in Grass Pollen Allergic Subjects
Authors: J KLEINETEBBE, G KRETSCHMAR, D HEROLD, D MATTHIESEN, P MOLDT, O PEDERSEN, G GOLOR, G KUNKEL
Journal: Journal of Allergy and Clinical Immunology (2008)
Expression of the macrophage-specific antigen F4/80 during differentiation of mouse bone marrow cells in culture.
Authors: S Hirsch, J M Austyn, S Gordon
Journal: The Journal of Experimental Medicine (1981)

We have defined the expression of the macrophages (m phi)-specific antigen (Ag) F4/80 during differentiation in culture. The progenitor cells-the colony-forming unit in culture and cluster-forming cell-lacked Ag F4/80 but gave rise to colonies of F4/80-positive adherent m phi, as shown by fluorescence-activated cell sorting and clonal assays with L cell-conditioned medium as the source of growth factor. Ag F4/80 first appeared on a nonadherent precursor found in mass liquid BM cultures after 3 d. Once adherent, m phi expressed high levels of Ag F4/80 and other markers. The role of L cell-conditioned medium and of adherence on expression of Ag F4/80 was also examined. Clonal analysis of F4/80 and other Ag, Mac-1, and 2.4G2 (FcR) showed that all cells in all independent colonies come to express these markers. These studies establish that F4/80 is a marker for the more mature stages of m phi development and that Ag expression increases progressively during maturation in vitro. Heterogeneity of Ag expression can be ascribed to variation in development and not to independent subsets of the m phi.
Small intestinal permeability in patients with eosinophilic oesophagitis during active phase and remission
Authors: David A Katzka, Debra M Geno, Hilary E Blair, Jesse L Lamsam, Jeffrey A Alexander, Michael Camilleri
Journal: Gut (2014)

Eosinophilic oesophagitis (EoE) is presumed to be an isolated oesophageal disease; yet other allergic diseases associated with eosinophilic infiltration of target tissues, such as asthma and eczema, show perturbed functions of other sites that may be involved in the diathesis of allergy modulation.To analyse small intestinal permeability in patients with active EoE and in a separate group of patients in remission.Small bowel permeability was determined using a dual sugar method by calculating lactulose:mannitol (L:M) ratio in 17 patients who met consensus criteria for active EoE (>15 eos/HPF) and 8 patients in remission (<5 eos/HPF). Data from 28 healthy controls was used for comparison.Patients with active EoE had significantly higher L:M ratios when compared to controls (0.045 vs. 0.033, p<0.001) and to EoE in remission (0.041 vs. 0.027, p<.001). There was no significant difference in L:M between the group with EoEin remission and healthy controls. The current data show that L:M ratio of 0.033 also provides a reasonable cut-off that defined the active EoE group compared to patients in remission. The main component explaining the change in L:M ratio was increased absorption (and excretion) of lactulose ((1601 ± 106 ug) when compared to the EoE remission (969 ± 91 ug) and control (1043 ± 92 ug, p<.001) groups.Small bowel permeability is overall increased in patients with active EoE, and is normal in patients with EoE in remission when compared to healthy controls. The role of the small bowel in active EoE deserves further investigation.
High Risk for Ovarian Cancer in a Prospective Series Is Restricted to BRCA1/2 Mutation Carriers
Authors: Lovise Mæhle, Jaran Apold, Torbjørn Paulsen, Bjørn Hagen, Kjell Løvslett, Bent Fiane, Marijke Van Ghelue, Neal Clark, Pål Møller
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Inherited ovarian cancer carries a serious prognosis. Prophylactic oophorectomy has been advocated. The degree to which inherited ovarian cancer is restricted to BRCA mutation carriers is not fully known. We wanted to determine the prevalence of BRCA mutation carriers in women at high risk from ovarian cancer. Experimental Design: Healthy women who were found to be at increased risk judged by family history were followed prospectively. Full BRCA1/2 mutation analysis was conducted on all patients who contracted pelvic cancer. Results: We identified 1,582 women at risk during 5,674 person-years. Forty infiltrating epithelial ovarian cancers, six peritoneal cancers, and one fallopian tube cancer were diagnosed. All but one of these patients (98%) had a BRCA mutation, a frequency that was significantly higher than for the 3 patients with borderline ovarian cancers, who were all mutation negative (P = 0.0002). Eighty-two percent of the detected mutations belonged to one of the 10 Norwegian founder mutations previously reported. At prophylactic bilateral salpingo-oophorectomy, cancer was found in 18 of 345 (5.2%) of mutation carriers compared with none in the 446 mutation negative (P = 0.0000). Conclusions: In healthy women with a family history of ovarian cancer, high risk for ovarian cancer was restricted to BRCA1/2 mutation carriers. A woman at risk for ovarian cancer according to her family history should have access to full BRCA1/2 mutation testing before deciding on prophylactic bilateral salpingo-oophorectomy.