tbuckley/cabot-search huggingface dataset:
Increased expression of high mobility group box 1 (HMGB1) is associated with an elevated level of the antiapoptotic c-IAP2 protein in human colon carcinomas
Authors: K Volp
Journal: Gut (2005)

High mobility group box 1 (HMGB1) is a non-histone chromosomal protein implicated in a variety of biologically important processes, including transcription, DNA repair, V(D)J recombination, differentiation, and development. Overexpression of HMGB1 inhibits apoptosis, arguing that the molecule may act as an antiapoptotic oncoprotein. Indeed, increased expression of HMGB1 has been reported for several different tumour types. In this study, we analysed human colon carcinoma for HMGB1 as well as for c-IAP2 expression levels. c-IAP2 is an antiapoptotic protein which may be upregulated as a consequence of nuclear factor kappaB (NFkappaB) activation via HMGB1.A comparative genomic hybridisation (CGH) database comprising 1645 cases from different human tumour types was screened to detect cytogenetic changes at the HMGB1 locus. Immunohistochemical staining of human colon tissue microarrays and tumour biopsies, as well as western blot analysis of tumour lysates, were performed to detect elevated HMGB1 and c-IAP2 expression in colon carcinomas. The antiapoptotic potential of HMGB1 was analysed by measuring caspase activities, and luciferase reporter assays and quantitative polymerase chain reaction analysis were employed to confirm NFkappaB activation and c-IAP2 mRNA upregulation on HMGB1 overexpression.According to CGH analysis, the genomic locus containing the HMGB1 gene was overrepresented in one third (35/96) of colon cancers. Correspondingly, HMGB1 protein levels were significantly elevated in 90% of the 60 colon carcinomas tested compared with corresponding normal tissues evaluable from the same patients. HMGB1 increased NFkappaB activity and led to co-overexpression of the antiapoptotic NFkappaB target gene product c-IAP2 in vitro. Furthermore, increased HMGB1 levels correlated with enhanced amounts of c-IAP2 in colon tumours analysed by us. Finally, we demonstrated that HMGB1 overexpression suppressed caspase-9 and caspase-3 activity, suggesting that HMGB1 interferes with the apoptotic machinery at the level of apoptosomal caspase-9 activation.We identified in vitro a molecular pathway triggered by HMGB1 to inhibit apoptosis via c-IAP2 induction. Our data indicate a strong correlation between upregulation of the apoptosis repressing HMGB1 and c-IAP2 proteins in the pathogenesis of colon carcinoma.
Formation of Epidermis After Reimplantation of Pure Primary Epidermal Cell Cultures From Perinatal Mouse Skin 2
Authors: Peter K. M. Worst, Elizabeth A. Valentine, Norbert E. Fusenig
Journal: JNCI Journal of the National Cancer Institute (1974)

Intact cultures of pure epidermal cells, MATERIALS AND METHODS derived as single cell suspensions from perinatal C3H mouse skin, were grafted back onto syngeneic recipients. The cells were grown on collagen gels that formed the bottom of special silicon chambers. The graft bed was a capsule of granulation tissue formed around a glass disc implanted between the back skin and thoracic wall of C3H mice and left in place for 3–4 weeks. Chambers with 1- to 4-day-old epidermal cultures growing as intact cell layers on the collagen were implanted into the capsules after the glass discs were removed. During observation of up to 8 weeks, the implanted cells formed an intact, well-differentiated epidermis in 45 of 47 animals that had retained their chambers among a group of 61 mice grafted initially. Control mice receiving chambers with only collagen and medium never formed new epidermis. The results demonstrated that disintegrated and cultivated epidermal cells could resume normal functioning in vivo, forming a wellorganized epidermis on the artificial graft bed. This experimental technique seems particularly suited for investigation of the function of the epidermis in skin allograft rejection and chemical carcinogenesis in cultured epidermal cells.
Case-control study of salmeterol and near-fatal attacks of asthma
Authors: C. Williams, L. Crossland, J. Finnerty, J. Crane, S. Holgate, N. Pearce, R. Beasley
Journal: Thorax (1998)

BACKGROUND: A case-control study was undertaken to investigate the hypothesis that the use of the long acting beta agonist salmeterol increases the risk of a near-fatal attack of asthma. METHODS: The cases comprised admissions to the intensive care unit (ICU) for asthma in 14 major hospitals within the Wessex region in 1992. For each of the cases four age-matched controls were selected from asthma admissions to the same hospital during the same period. Information on prescribed drug therapy for the 48 cases and 185 controls was collected from the hospital admission records. RESULTS: The patients admitted to the ICU had greater chronic asthma severity and had generally been prescribed more asthma drugs than the control admissions to hospital. The relative risk of a near-fatal attack of asthma in patients prescribed inhaled salmeterol was 2.32 (95% CI 1.05 to 5.16), p = 0.04. However, the salmeterol relative risk decreased to 1.42 (95% CI 0.49 to 4.10), p = 0.52 when the analysis was restricted to the more chronically severe patients (those in the subgroup of patients with a hospital admission for asthma in the previous 12 months). These findings suggest that the increased unadjusted relative risk with salmeterol is predominantly due to confounding by severity--that is, the increased relative risk is due to patients with more severe asthma (at greatest risk of a near-fatal asthma attack) being preferentially prescribed salmeterol. This interpretation is supported by the finding in this study that, within the control group (selected from the population of asthmatics requiring hospital admission), salmeterol was preferentially prescribed to the most severe patients (a threefold greater prescription of salmeterol to control patients if they had been admitted to hospital in the 12 months prior to the index admission). There was no increased risk of a near-fatal attack of asthma in patients prescribed a beta agonist by metered dose inhaler (OR 0.75 (95% CI 0.31 to 1.78), p = 0.51). In contrast, the relative risks for beta agonists delivered by nebulisation (OR 3.86 (95% CI 1.99 to 7.50), p &lt; 0.001) and oral theophylline (OR 2.45 (95% CI 1.26 to 4.78), p &lt; 0.01) were increased and did not markedly decrease when the analysis was restricted to the more severe asthmatic subjects. CONCLUSIONS: Although these findings are not conclusive, particularly because of the small numbers involved in some subgroup analyses, they suggest that the use of salmeterol by patients with chronic severe asthma is not associated with a significantly increased risk of a near-fatal attack of asthma. If a near-fatal asthma attack is considered to be an intermediate step in a process by which a severe attack of asthma may become fatal, these results would suggest that salmeterol is unlikely to be associated with an increased risk of death, at least by this mechanism.
Spanish reform bill looks to prevention to ensure viability of health service
Authors: M. de Lago
Journal: BMJ (2010)

Spain is preparing a reform of its health service that will place greater emphasis on prevention and the cost saving potential of public health policies. 

The goal is not only to improve the general health of the population but to contribute to the economic viability of the national healthcare system—which is more than €7bn (£6bn; $9bn) in debt—and to economic and social sustainability in Spain.

A draft bill from the country’s Ministry of Health and Social Policies, which is expected to enter Congress any day, outlines ways to boost prevention campaigns, promote preventive …
Serum Mesothelin for Diagnosing Malignant Pleural Mesothelioma: An Individual Patient Data Meta-Analysis
Authors: Kevin Hollevoet, Johannes B. Reitsma, Jenette Creaney, Bogdan D. Grigoriu, Bruce W. Robinson, Arnaud Scherpereel, Alfonso Cristaudo, Harvey I. Pass, Kristiaan Nackaerts, José A. Rodríguez Portal, Joachim Schneider, Thomas Muley, Francesca Di Serio, Paul Baas, Marco Tomasetti, Alex J. Rai, Jan P. van Meerbeeck
Journal: Journal of Clinical Oncology (2012)

Mesothelin is currently considered the best available serum biomarker of malignant pleural mesothelioma. To examine the diagnostic accuracy and use of serum mesothelin in early diagnosis, we performed an individual patient data (IPD) meta-analysis.The literature search identified 16 diagnostic studies of serum mesothelin, measured with the Mesomark enzyme-linked immunosorbent assay. IPD of 4,491 individuals were collected, including several control groups and 1,026 patients with malignant pleural mesothelioma. Mesothelin levels were standardized for between-study differences and age, after which the diagnostic accuracy and the factors affecting it were examined with receiver operating characteristic (ROC) regression analysis.At a common diagnostic threshold of 2.00 nmol/L, the sensitivities and specificities of mesothelin in the different studies ranged widely from 19% to 68% and 88% to 100%, respectively. This heterogeneity can be explained by differences in study population, because type of control group, mesothelioma stage, and histologic subtype significantly affected the diagnostic accuracy. The use of mesothelin in early diagnosis was evaluated by differentiating 217 patients with stage I or II epithelioid and biphasic mesothelioma from 1,612 symptomatic or high-risk controls. The resulting area under the ROC curve was 0.77 (95% CI, 0.73 to 0.81). At 95% specificity, mesothelin displayed a sensitivity of 32% (95% CI, 26% to 40%).In patients suspected of having mesothelioma, a positive blood test for mesothelin at a high-specificity threshold is a strong incentive to urge further diagnostic steps. However, the poor sensitivity of mesothelin clearly limits its added value to early diagnosis and emphasizes the need for further biomarker research.
The peptidyl-prolyl isomerase Pin1 determines parathyroid hormone mRNA levels and stability in rat models of secondary hyperparathyroidism
Authors: Morris Nechama, Takafumi Uchida, Irit Mor Yosef-Levi, Justin Silver, Tally Naveh-Many
Journal: Journal of Clinical Investigation (2009)

Secondary hyperparathyroidism is a major complication of chronic kidney disease (CKD). In experimental models of secondary hyperparathyroidism induced by hypocalcemia or CKD, parathyroid hormone (PTH) mRNA levels increase due to increased PTH mRNA stability. K-homology splicing regulator protein (KSRP) decreases the stability of PTH mRNA upon binding a cis-acting element in the PTH mRNA 3' UTR region. As the peptidyl-prolyl isomerase (PPIase) Pin1 has recently been shown to regulate the turnover of multiple cytokine mRNAs, we investigated the role of Pin1 in regulating PTH mRNA stability in rat parathyroids and transfected cells. The data generated were consistent with Pin1 being a PTH mRNA destabilizing protein. Initial analysis indicated that Pin1 activity was decreased in parathyroid protein extracts from both hypocalcemic and CKD rats and that pharmacologic inhibition of Pin1 increased PTH mRNA levels posttranscriptionally in rat parathyroid and in transfected cells. Pin1 mediated its effects via interaction with KSRP, which led to KSRP dephosphorylation and activation. In the rat parathyroid, Pin1 inhibition decreased KSRP-PTH mRNA interactions, increasing PTH mRNA levels. Furthermore, Pin1-/- mice displayed increased serum PTH and PTH mRNA levels, suggesting that Pin1 determines basal PTH expression in vivo. These results demonstrate that Pin1 is a key mediator of PTH mRNA stability and indicate a role for Pin1 in the pathogenesis of secondary hyperparathyroidism in individuals with CKD.
A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons
Authors: Theron A. Russell, Masafumi Ito, Mika Ito, Richard N. Yu, Fred A. Martinson, Jeffrey Weiss, J. Larry Jameson
Journal: Journal of Clinical Investigation (2003)

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the arginine vasopressin (AVP) precursor. The pathogenesis of FNDI is proposed to involve mutant protein-induced loss of AVP-producing neurons. We established murine knock-in models of two different naturally occurring human mutations that cause FNDI. A mutation in the AVP signal sequence [A(-1)T] is associated with a relatively mild phenotype or delayed presentation in humans. This mutation caused no apparent phenotype in mice. In contrast, heterozygous mice expressing a mutation that truncates the AVP precursor (C67X) exhibited polyuria and polydipsia by 2 months of age and these features of DI progressively worsened with age. Studies of the paraventricular and supraoptic nuclei revealed induction of the chaperone protein BiP and progressive loss of AVP-producing neurons relative to oxytocin-producing neurons. In addition, Avp gene products were not detected in the neuronal projections, suggesting retention of WT and mutant AVP precursors within the cell bodies. In summary, this murine model of FNDI recapitulates many features of the human disorder and demonstrates that expression of the mutant AVP precursor leads to progressive neuronal cell loss.
Implication of ANCA status in Churg-Strauss syndrome
Authors: S Gareeboo
Journal: Thorax (2006)

▴ Sable-Fourtassou R, Cohen P, Mahr A, et al . Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med2005;143:632–8 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Churg-Strauss syndrome is a small vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA) in a significant proportion of patients. In this study a cross sectional analysis was performed of the clinical and histological features of patients with Churg-Strauss syndrome in relation to their ANCA status. A cohort of … [1]: {openurl}?query=rft.jtitle%253DAnnals%2Bof%2BInternal%2BMedicine%26rft.stitle%253DANN%2BINTERN%2BMED%26rft.issn%253D0003-4819%26rft.aulast%253DSable-Fourtassou%26rft.auinit1%253DR.%26rft.volume%253D143%26rft.issue%253D9%26rft.spage%253D632%26rft.epage%253D638%26rft.atitle%253DAntineutrophil%2BCytoplasmic%2BAntibodies%2Band%2Bthe%2BChurg-Strauss%2BSyndrome%26rft_id%253Dinfo%253Adoi%252F10.7326%252F0003-4819-143-9-200511010-00006%26rft_id%253Dinfo%253Apmid%252F16263885%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.7326/0003-4819-143-9-200511010-00006&link_type=DOI [3]: /lookup/external-ref?access_num=16263885&link_type=MED&atom=%2Fthoraxjnl%2F61%2F3%2F270.atom [4]: /lookup/external-ref?access_num=000233030600002&link_type=ISI
Role of Redox Signaling in the Autonomous Proliferative Response of Endothelial Cells to Hypoxia
Authors: M. Schäfer, C. Schäfer, N. Ewald, H.M. Piper, Th. Noll
Journal: Circulation Research (2003)

Endothelial cells exhibit an autonomous proliferative response to hypoxia, independent of paracrine effectors. In cultured endothelial cells of porcine aorta, we analyzed the signaling of this response, with a focus on the roles of redox signaling and the MEK/ERK pathway. Transient hypoxia (1 hour) stimulated proliferation by 61+/-4% (n=16; P<0.05 versus control), quantified after 24 hours normoxic postincubation. Hypoxia induced an activation of ERK2 and of NAD(P)H oxidase and a burst of reactive oxygen species (ROS), determined by DCF fluorescence. To inhibit the MEK/ERK pathway, we used PD 98059 (PD, 20 micromol/L); to downregulate NAD(P)H oxidase, we applied p22phox antisense oligonucleotides; and to inhibit mitochondrial ROS generation, we used the ubiquinone derivate mitoQ (MQ, 10 micromol/L). All three inhibitions suppressed the proliferative response: PD inhibited NAD(P)H oxidase activation; p22phox antisense transfection did not inhibit ERK2 activation, but suppressed ROS production; and MQ inhibited ERK2 activation and ROS production. The autonomous proliferative response depends on the MEK/ERK pathway and redox signaling steps upstream and downstream of ERK. Located upstream is ROS generation by mitochondria, downstream is NAD(P)H oxidase.
Pneumonia in the context of severe sepsis: a significant diagnostic problem
Authors: T. Bewick, M. Simmonds, M. Chikhani, J. Meyer, W. S. Lim
Journal: European Respiratory Journal (2008)

plasma D-dimer level was low (282 mg?L -1 ).Chest radiography showed multiple ill-defined increased densities in both lower lung fields.High-resolution computed tomography was then performed and showed ill-defined, wedge-shaped increased densities with patent airways in the posterior subpleural regions of both lower lobes.The computed tomography differential diagnosis was organising pneumonia, bronchopneumonia, Churg-Strauss syndrome, Wegener granulomatosis, pulmonary haemorrhage, or vasculitis of various causes.Transbronchial lung biopsy was performed in the right lower lobe.Microscopic examination showed alveolar haemorrhage without evidence of vasculitis, eosinophilic infiltration or organising pneumonia.Serum circulating antiphospholipid antibodies were eventually found.Therefore, pulmonary angiography was performed and an intra-arterial low density was found in the right main pulmonary artery.This finding was believed to be compatible with pulmonary thromboembolism; however, it didn't exclude a possible right pulmonary artery sarcoma.In this case, the only procedure that would rule out the presence of a right pulmonary artery sarcoma (without delays in diagnosis) with any reasonable certainty was surgery.
The Price of Growth in the Medical-Device Industry
Authors: Alan M Garber
Journal: New England Journal of Medicine (2006)

In one of the most dramatic corporate acquisitions in recent memory, Boston Scientific, a large manufacturer of medical devices, outbid industry giant Johnson & Johnson to purchase Guidant Corporation earlier this year. Joining Boston Scientific in this effort was Abbott Laboratories, which paid $5 billion for Guidant's endovascular-device business. The outcome could hardly have been anticipated when Johnson & Johnson agreed to purchase Guidant for $25 billion in December 2004. In the wake of disclosures of lawsuits over allegedly defective Guidant devices, Guidant agreed to reduce the purchase price to $21.5 billion. Then Boston Scientific stepped in with a higher . . .
Response of Small-Cell Lung Cancer Xenografts to Chemotherapy: Multidrug Resistance and Direct Clinical Correlates
Authors: M. F. Poupon, F. Arvelo, A. F. Goguel, Y. Bourgeois, M. Jacrot, N. Hanania, R. Arriagada, T. L. Chevalier
Journal: JNCI Journal of the National Cancer Institute (1993)

Background: Patients with small-cell lung carcinomas (SCLCs) initially respond to combination chemotherapy. Only a few benefit in terms of long-term survival because most relapse. Such outcome may be attributable to development of multi-drug resistance. Purpose : The response of SCLC to chemotherapy was examined in terms of ( a ) patient survival, ( b ) drug sensitivity of tumors in patients and of tumor xenografts in nude mice, and ( c ) expression of multidrug resistance gene MDR1 and GST-π gene. Methods : Tumor samples obtained from seven untreated patients and from one patient both before and after chemotherapy were transplanted into nude mice. The patients were treated with a combination of cyclophosphamide (C'), cisplatin (C), doxorubicin (A), and etoposide (V) (C'CAV) or C'AV and radiotherapy. Drug sensitivity of SCLCs was tested in nude mice that had received tumor xenografts from these seven patients. The expression of MDR1 and GST-π genes was assessed in the mRNA extracted from xenografts by Northern blot analysis. P-glycoprotein was quantified by enzyme immunoassay. Results : The patients' responses to C'CAV closely correlated with those of the corresponding xenografts. The tumors of the two patients who showed long-term survival after C'CAV completely regressed when they were transplanted into nude mice and subsequently treated with C'CAV. Despite initial complete response, the remaining five patients died during year 1. A high percentage of mice receiving the tumor grafts from these five patients showed only partial tumor regression after C'CAV treatment. The MDR1 transcript was detected in all five of these xenografts. Four of five xenografts were from untreated patients, and the fifth was from a treated patient. MDR1 mRNA expression was absent in the tumor of this fifth patient before chemotherapy, but both the mice receiving the corresponding xenograft and the patient showed expression of MDR1 after C'CAV treatment. MDR1 mRNA expression was absent in the tumor xenografts obtained from two patients with long-term survival. Expression of P-glycoprotein correlated with MDR1 mRNA expression. All xenografts except one expressed the GST-π gene. Conclusions : The absence of MDR1 gene expression during chemotherapy for SCLC indicates a favorable prognosis, gene expression is often coincident with ineffective chemotherapy, and tumor xenografts can be appropriately used to predict response to chemotherapy. Implications : Failure of chemotherapy to control SCLC seems to be related to an acquired multidrug resistance involving the MDR1-mediated mechanism. Therapeutic benefit could therefore be expected from chemotherapy combined with inhibitors of MDR1. [J Natl Cancer Inst 85:2023–2029, 1993]
A TRiP to heart failure
Authors: R. Vennekens
Journal: Cardiovascular Research (2013)

This editorial refers to ‘Blockade of sarcolemmal TRPV2 accumulation inhibits progression of dilated cardiomyopathy’ by Y. Iwata et al ., pp. 757–765, this issue. 

Transient receptor potential (TRP) channels constitute a somewhat eclectic family of ion channels that share structural similarities and some functional properties, especially cation permeability and weak voltage sensitivity. TRP channels are expressed in virtually every cell type present in the heart, including cardiomyocytes, fibroblasts, endothelial cells and vascular smooth muscle cells.1

In the current issue of Cardiovascular Research , Iwata et al .2 describe a potential role for TRPV2 in the progression of dilated cardiomyopathy (DCM). TRPV2 is a Ca2+ permeable cation channel which is activated by temperatures >50°C, and might also function as a mechanosensitive channel.3 Both in sensory neurons and atrial myocytes, TRPV2 has been proposed to function as a stretch-activated channel. However, it seems now relatively established that TRPV2 has no physiological role in sensing of physical stimuli such as pressure or temperature, since thermal and mechanical responses of the Trpv2 −/− mouse are identical to those of WT mice. Notably, a cardiac phenotype of Trpv2 −/− mice has not been reported yet.4 Chemical agonists of the channel include endocannabinoids, 2-APB, and probenecid, but caution should be taken. It is a common theme in the TRP channel field that pharmacological agents are notoriously non-selective. Thus, the response of Trpv2 −/− neurons to …