tbuckley/cabot-search huggingface dataset:
Early detection of lung cancer: role of biomarkers
Authors: C. Brambilla, F. Fievet, M. Jeanmart, F. de Fraipont, S. Lantuejoul, V. Frappat, G. Ferretti, P.Y. Brichon, D. Moro-Sibilot
Journal: European Respiratory Journal (2003)

Early detection of lung cancer requires none or few invasive techniques. Distal lung cancer (40% of the cases in most European countries) can be sensitively detected by spiral computed tomography. Theoretically, in 60% of cases, the proximal lesions (main to segmental bronchi, accessible by bronchoscopy) should be able to be detected by sputum cytology. Unfortunately, this very specific technique has a low sensitivity and is time consuming. Fluorescent bronchoscopy increases the detection rate of early or micro-invasive lesions and may be proposed in highly selected populations, but not as a screening test. Biomarkers in blood and sputum have not yet been clinically validated. However, the amount of data generated from studies first on resected tumours, then on early bronchial lesions and more recently on blood and sputum offer a wide field for investigation. Lung carcinogenesis is a multistep process characterised by the accumulation of successive molecular genetic and epigenetic abnormalities, resulting in selection of clonal cells with uncontrolled growth capacities throughout the whole respiratory tract (field cancerisation). Molecular lesions far precede morphological transformation of preneoplastic bronchial lesions (dysplasia) or alveolar lesions (atypical alveolar hyperplasia). Genetic and epigenetic abnormalities in the genes involved in cell cycle, senescence, apoptosis, repair, differentiation and cell migration control may be detected on bronchial biopsies, on respiratory cells from the sputum and even in the circulating deoxyribonucleic acid (DNA). The key genes involved include those in the P53- retinoblastoma (Rb) pathways. The balance between cyclin-dependent kinases and their inhibitors regulates the level of Rb phosphorylation and its function at G1-S transition; P53 plays at least two functions (cell cycle and apoptosis control). The balance of bax-bcl2 is important in the control of apoptosis as well as loss of fragile histidine triad expression. O(6)-methylguanine-DNA methyltransferase seems to be important in DNA repair control, the RARβ receptor in differentiation, and cadherin H and E and different metalloproteases genes in cell migration. The demonstration of hyperexpression or silencing of these genes needs different validated techniques: immunohistochemistry on biopsies or cytological preparations, molecular biology techniques for mutations, loss of heterozygosity and aberrant methylation abnormalities. Automation and miniaturisation of these techniques will allow early detection and may be widely applied once clinically validated.
RAD marker microarrays enable rapid mapping of zebrafish mutations
Authors: Michael R Miller, Tressa S Atwood, B Frank Eames, Johann K Eberhart, Yi-Lin Yan, John H Postlethwait, Eric A Johnson
Journal: Genome biology (2007)

Abstract We constructed a restriction site associated DNA (RAD) marker microarray to facilitate rapid genetic mapping of zebrafish mutations. Using these microarrays with a bulk segregant approach, we localized previously unmapped mutations to genomic regions just a few centiMorgans in length. Furthermore, we developed an approach to assay individual RAD markers in pooled populations and refined one region. The RAD approach is highly effective for genetic mapping in zebrafish and is an attractive option for mapping in other organisms.
Altered vagal and intestinal mechanosensory function in chronic unexplained dyspepsia
Authors: G Holtmann, H Goebell, F Jockenhoevel, N J Talley
Journal: Gut (1998)

<i>Background</i>—Abnormal visceral mechanosensory and vagal function may play a role in the development of functional gastrointestinal disorders. <i>Aims</i>—To assess whether vagal efferent and afferent function is linked with small intestinal mechanosensory function. <i>Methods</i>—In seven patients with functional dyspepsia, six patients with a history of Billroth I gastrectomy and/or vagotomy, and seven healthy controls, intestinal perception thresholds were tested by a randomised ramp distension procedure performed with a barostat device. On a separate day, an insulin hypoglycaemia test was performed to assess the plasma levels of pancreatic polypeptide (PP) in response to hypoglycaemia, as a test of efferent vagal function. <i>Results</i>—First perception of intestinal balloon distension occurred at significantly lower pressures in patients with functional dyspepsia (median 19.3, range 14.7–25.3 mm Hg) compared with healthy controls (median 26.0, range 21.7–43.7 mm Hg, p&lt;0.01). Sensory thresholds were significantly lower in patients after gastrectomy (median 12.2, range 8.0–14.7 mm Hg, p&lt;0.05 versus all others). In healthy controls and patients with functional dyspepsia, insulin hypoglycaemia significantly (p&lt;0.001) increased plasma PP levels. However, only two out of seven patients with functional dyspepsia had a more than twofold increase in PP values whereas all healthy controls had a more than twofold increase in PP levels after insulin hypoglycaemia (p&lt;0.05). In contrast, there was no significant PP response in the gastrectomised patients (median 2%, range −10 to +23%). PP responses and visceral sensory thresholds were significantly correlated (<i>r</i>=0.65, p&lt;0.002). <i>Conclusions</i>—The diminished PP response after insulin hypoglycaemia indicates disturbed efferent vagal function in a subgroup of patients with functional dyspepsia. The data also suggest that the intact vagal nerve may exert an antinociceptive visceral effect.
Why autologous hamstring tendon reconstruction should now be considered the gold standard for anterior cruciate ligament reconstruction in athletes
Authors: L Pinczewski, J Roe, L Salmon
Journal: British Journal of Sports Medicine (2009)

The aim of anterior cruciate ligament (ACL) reconstructive surgery is to provide the patient with a timely return to sport allowing them to participate without any further meniscal damage and having a normal knee function which results in neither clinical nor radiologic evidence of osteoarthritis later in life. Long term study of both endoscopically performed patellar tendon and hamstring tendon graft reconstructions show that this is more likely to be achieved with hamstring tendon graft rather than patellar tendon graft.

ACL reconstruction carried out endoscopically with the patellar tendon graft was popularised last century in the late 1980s and early 1990s due to the advent of easily performed interference screw fixation, and the rapid bone to bone healing of the graft. However donor site morbidity was common, persistent, occasionally severe and particularly disabling in females and trades people who knelt. Longitudinal follow-up demonstrated the development of fixed flexion deformities at the 2 and 5 year post-operative mark associated with the development of Grade B changes in the patellofemoral and medial compartments.1 2 These changes were noted on side to side comparative radiographs. …
Gap junction protein connexin40 is preferentially expressed in vascular endothelium and conductive bundles of rat myocardium and is increased under hypertensive conditions.
Authors: B Bastide, L Neyses, D Ganten, M Paul, K Willecke, O Traub
Journal: Circulation Research (1993)

Gap junction channels consisting of connexin protein mediate electrical coupling between cardiac cells. Expression of two connexins, connexin40 (Cx40) and connexin43 (Cx43), has been studied in ventricular myocytes from normal and hypertensive rats. Polyclonal affinity-purified rabbit antibodies to Cx43 and Cx40 have been used for immunohistochemical analysis on frozen sections from rat heart. These studies revealed coexpression of Cx43 and Cx40 in ventricular myocytes. In addition, Cx40 is preferentially expressed in three distinct regions: first, in the endothelial layer of the heart blood vessels but not in the smooth muscle layer of the arteries; second, in the ventricular conductive myocardium, particularly in the atrioventricular bundle and bundle branches, where Cx43 is not observed; and third, in the myocyte layers close to the ventricular cavities. These results suggest that Cx40 is preferentially expressed in the fast conducting areas of myocardial tissue. Expression of both Cx40 and Cx43 was also found in immunoblots from normal and hypertensive rat myocardiocytes. Under hypertensive conditions (ie, in spontaneous hypertensive rats and in transgenic rats that exhibit hypertension due to expression of an exogenous renin gene), we found a 3.1-fold increase in Cx40 expression, compared with normal myocardium. Furthermore, we detected a 3.3-fold decrease in Cx43 protein level in transgenic hypertensive rats. The coexpression of Cx40 and Cx43 proteins in rat myocytes, their spatial distribution, and the increased amount of Cx40 protein during cardiac hypertrophy suggest that Cx40 may be involved in mediating fast conduction under normal and pathological conditions. The increased expression of Cx40 in hypertrophic heart may be a compensatory mechanism to increase conduction velocity.
Interaction between src family kinases and rho-kinase in agonist-induced Ca2+-sensitization of rat pulmonary artery
Authors: Greg A. Knock, Yasin Shaifta, Vladimir A. Snetkov, Benjamin Vowles, Svetlana Drndarski, Jeremy P.T. Ward, Philip I. Aaronson
Journal: Cardiovascular Research (2007)

We investigated the role of src family kinases (srcFK) in agonist-mediated Ca2+-sensitization in pulmonary artery and whether this involves interaction with the rho/rho-kinase pathway. Intra-pulmonary arteries (IPAs) and cultured pulmonary artery smooth muscle cells (PASMC) were obtained from rat. Expression of srcFK was determined at the mRNA and protein levels. Ca2+-sensitization was induced by prostaglandin F2α (PGF2α) in α-toxin-permeabilized IPAs. Phosphorylation of the regulatory subunit of myosin phosphatase (MYPT-1) and of myosin light-chain-20 (MLC20) and translocation of rho-kinase in response to PGF2α were also determined. Nine srcFK were expressed at the mRNA level, including src, fyn, and yes, and PGF2α enhanced phosphorylation of three srcFK proteins at tyr-416. In α-toxin-permeabilized IPAs, PGF2α enhanced the Ca2+-induced contraction (pCa 6.9) approximately three-fold. This enhancement was inhibited by the srcFK blockers SU6656 and PP2 and by the rho-kinase inhibitor Y27632. Y27632, but not SU6656 or PP2, also inhibited the underlying pCa 6.9 contraction. PGF2α enhanced phosphorylation of MYPT-1 at thr-697 and thr-855 and of MLC20 at ser-19. This enhancement, but not the underlying basal phosphorylation, was inhibited by SU6656. Y27632 suppressed both basal and PGF2α-mediated phosphorylation. The effects of SU6656 and Y27632, on both contraction and MYPT-1 and MLC20 phosphorylation, were not additive. PGF2α triggered translocation of rho-kinase in PASMC, and this was inhibited by SU6656. srcFK are activated by PGF2α in the rat pulmonary artery and may contribute to Ca2+-sensitization and contraction via rho-kinase translocation and phosphorylation of MYPT-1.
Suppression of T cells specific for the nonthymic parental H-2 haplotype in thymus-grafted chimeras.
Authors: F I Smith, J F Miller
Journal: The Journal of Experimental Medicine (1980)

The mechanism of restriction of T-cell specificity by the genotype of the thymus in allogeneic and semiallogeneic chimeras was investigated. Lack of induction of delayed-type hypersensitivity (DTH) directed against antigen in association with the nonthymic parental haplotype in naive cells adoptively transferred into chimeras suggests the existence of an in vivo suppressive mechanism. However, it was not possible to suppress the expression of DTH in sensitized cells transferred into chimeras, or to transfer this suppression to normal naive recipients.
Activity of the Epipodophyllotoxin VP‐16 in the Treatment of Combination Chemotherapy‐Resistant Non‐Hodgkin Lymphoma
Authors: Richard A. Bender, Tom Anderson, Richard I. Fisher, Robert C. Young
Journal: American Journal of Hematology (1978)

Abstract Twenty patients with several histologic subtypes of non‐Hodgkin lymphoma who had become resistant to combination chemotherapy were treated with a five‐day course of the epipodophyllotoxin VP‐16. Of 19 evaluable patients, 8 (42%) responded to treatment with 1 complete response and 7 partial responses. The median duration of response was 5.5 months. Seven of the responders had a diffuse lymphoma and 1 had a nodular lymphoma. Of the responders who had diffuse histiocytic lymphoma (DHL), diffuse mixed lymphoma (DML), and diffuse undifferentiated lymphoma (DUL)–the more aggressive histologies in the Rappaport classification–6 of 13 (46%) evaluable patients responded to therapy. Responses were seen in node‐dominant, skin‐dominant, and marrow‐dominant disease. Toxicity was mainly hematopoietic, 53% of patients experiencing leukopenia (&lt;2, 000 cells per cu mm) and 68% of patients experiencing thrombocytopenia (&lt;100, 000 platelets per cu mm). There were two deaths attributable to profound leukopenia with sepsis. The activity of VP‐16 in patients who have previously been extensively treated with multiple drugs including vincristine supports its activity in the lymphomas and suggests its lack of cross‐resistance with vincristine. The inclusion of VP‐16 in primary treatment protocols in the diffuse lymphomas should be considered.
Negative Regulation of β4 Integrin Transcription by Homeodomain-Interacting Protein Kinase 2 and p53 Impairs Tumor Progression
Authors: Giulia Bon, Selene E. Di Carlo, Valentina Folgiero, Paolo Avetrani, Chiara Lazzari, Gabriella D'Orazi, Maria Felice Brizzi, Ada Sacchi, Silvia Soddu, Giovanni Blandino, Marcella Mottolese, Rita Falcioni
Journal: Cancer Research (2009)

Increased expression of alpha(6)beta(4) integrin in several epithelial cancers promotes tumor progression; however, the mechanism underlying its transcriptional regulation remains unclear. Here, we show that depletion of homeodomain-interacting protein kinase 2 (HIPK2) activates beta(4) transcription that results in a strong increase of beta(4)-dependent mitogen-activated protein kinase and Akt phosphorylation, anchorage-independent growth, and invasion. In contrast, stabilization of HIPK2 represses beta(4) expression in wild-type p53 (wtp53)-expressing cells but not in p53-null cells or cells expressing mutant p53, indicating that HIPK2 requires a wtp53 to inhibit beta(4) transcription. Consistent with our in vitro findings, a strong correlation between beta(4) overexpression and HIPK2 inactivation by cytoplasmic relocalization was observed in wtp53-expressing human breast carcinomas. Under loss of function of HIPK2 or p53, the p53 family members TAp63 and TAp73 strongly activate beta(4) transcription. These data, by revealing that beta(4) expression is transcriptionally repressed in tumors by HIPK2 and p53 to impair beta(4)-dependent tumor progression, suggest that loss of p53 function favors the formation of coactivator complex with the TA members of the p53 family to allow beta(4) transcription.
Nek2 as an Effective Target for Inhibition of Tumorigenic Growth and Peritoneal Dissemination of Cholangiocarcinoma
Authors: Toshio Kokuryo, Takeshi Senga, Yukihiro Yokoyama, Masato Nagino, Yuji Nimura, Michinari Hamaguchi
Journal: Cancer Research (2007)

We investigated the role of Nek2, a member of the serine/threonine kinase family, Nek, in the tumorigenic growth of cholangiocarcinoma cells. Expression of Nek2 is elevated in cholangiocarcinoma in a tumor-specific manner as compared with that of normal fibroblast cells. Expression of exogenous Nek2 did not perturb the growth of cholangiocarcinoma cells, whereas suppression of the Nek2 expression with siRNA resulted in the inhibition of cell proliferation and induced cell death. In xenograft-nude mouse model, s.c. injection of Nek2 siRNA around the tumor nodules resulted in reduction of tumor size as compared with those of control siRNA injection. In peritoneal dissemination model, Nek2 siRNA-treated mice showed statistically longer survival periods in comparison with those of the control siRNA-treated mice. Taken together, our data indicate a pivotal role of Nek2 in tumorigenic growth of cholangiocarcinoma.
Inhibition of MTOR Disrupts Autophagic Flux in Podocytes
Authors: Davide P. Cinà, Tuncer Onay, Aarti Paltoo, Chengjin Li, Yoshiro Maezawa, Javier De Arteaga, Andrea Jurisicova, Susan E. Quaggin
Journal: Journal of the American Society of Nephrology (2011)

Inhibitors of the mammalian target of rapamycin (MTOR) belong to a family of drugs with potent immunosuppressive, antiangiogenic, and antiproliferative properties. De novo or worsening proteinuria can occur during treatment with these agents, but the mechanism by which this occurs is unknown. We generated and characterized mice carrying a podocyte-selective knockout of the Mtor gene. Although Mtor was dispensable in developing podocytes, these mice developed proteinuria at 3 weeks and end stage renal failure by 5 weeks after birth. Podocytes from these mice exhibited an accumulation of the autophagosome marker LC3 (rat microtubule-associated protein 1 light chain 3), autophagosomes, autophagolysosomal vesicles, and damaged mitochondria. Similarly, human podocytes treated with the MTOR inhibitor rapamycin accumulated autophagosomes and autophagolysosomes. Taken together, these results suggest that disruption of the autophagic pathway may play a role in the pathogenesis of proteinuria in patients treated with MTOR inhibitors.
Prognostic Significance of <i>p53</i> Codon 72 Polymorphism Differs with Race in Colorectal Adenocarcinoma
Authors: Venkat R. Katkoori, Xu Jia, Chandrakumar Shanmugam, Wen Wan, Sreelatha Meleth, Harvey Bumpers, William E. Grizzle, Upender Manne
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Several studies have examined the prognostic value of the codon 72 polymorphism of the p53 gene in colorectal adenocarcinoma, but none have addressed patient race/ethnicity. Therefore, this study assessed the prognostic value of this polymorphism in African American and Caucasian colorectal adenocarcinoma patients separately. Experimental Design: Colorectal adenocarcinomas from 137 African Americans and 236 non-Hispanic Caucasians were assessed for p53 mutations and genotyped for the codon 72 polymorphism. The phenotypes were correlated with p53 mutational status, clinicopathologic features, and patient survival using the χ2 test and Kaplan-Meier and Cox regression models. Results: The incidence of p53 mutations was similar in African American and Caucasian patients (50% versus 54%, respectively); however, the homozygous Pro72 allele frequency was higher in African Americans (17%) as compared with Caucasians (7%). In contrast, the homozygous Arg72 allele frequency was higher in Caucasians (36%) than in African Americans (19%). In African Americans but not Caucasians, the Pro/Pro phenotype significantly correlated with a higher incidence of missense p53 mutations and with nodal metastasis. African Americans, but not Caucasians, with the Pro/Pro phenotype had significantly higher mortality (log-rank P = 0.005 versus. P = 0.886) and risk of death due to colorectal adenocarcinoma (hazard ratio, 2.15; 95% confidence interval, 1.02-4.53 versus hazard ratio, 1.60; 95% confidence interval, 0.69-3.18) than those with the phenotype Arg/Arg or Arg/Pro. Conclusions: The higher frequency of the Pro/Pro phenotype of p53 in African American patients with colorectal adenocarcinoma is associated with an increased incidence of p53 mutations, with advanced tumor stage, and with short survival.
Follicular regulatory T cells control humoral autoimmunity via NFAT2-regulated CXCR5 expression
Authors: Martin Vaeth, Gerd Müller, Dennis Stauss, Lena Dietz, Stefan Klein-Hessling, Edgar Serfling, Martin Lipp, Ingolf Berberich, Friederike Berberich-Siebelt
Journal: The Journal of Experimental Medicine (2014)

Maturation of high-affinity B lymphocytes is precisely controlled during the germinal center reaction. This is dependent on CD4+CXCR5+ follicular helper T cells (TFH) and inhibited by CD4+CXCR5+Foxp3+ follicular regulatory T cells (TFR). Because NFAT2 was found to be highly expressed and activated in follicular T cells, we addressed its function herein. Unexpectedly, ablation of NFAT2 in T cells caused an augmented GC reaction upon immunization. Consistently, however, TFR cells were clearly reduced in the follicular T cell population due to impaired homing to B cell follicles. This was TFR-intrinsic because only in these cells NFAT2 was essential to up-regulate CXCR5. The physiological relevance for humoral (auto-)immunity was corroborated by exacerbated lupuslike disease in the presence of NFAT2-deficient TFR cells.
Evolution of Hox Gene Clusters in Gnathostomes: Insights from a Survey of a Shark (Scyliorhinus canicula) Transcriptome
Authors: S. Oulion, M. Debiais-Thibaud, Y. d'Aubenton-Carafa, C. Thermes, C. Da Silva, S. Bernard-Samain, F. Gavory, P. Wincker, S. Mazan, D. Casane
Journal: Molecular Biology and Evolution (2010)

It is now well established that there were four Hox gene clusters in the genome of the last common ancestor of extant gnathostomes. To better understand the evolution of the organization and expression of these genomic regions, we have studied the Hox gene clusters of a shark (Scyliorhinus canicula). We sequenced 225,580 expressed sequence tags from several embryonic cDNA libraries. Blast searches identified corresponding transcripts to almost all the HoxA, HoxB, and HoxD cluster genes. No HoxC transcript was identified, suggesting that this cluster is absent or highly degenerate. Using Hox gene sequences as probes, we selected and sequenced seven clones from a bacterial artificial chromosome library covering the complete region of the three gene clusters. Mapping of cDNAs to these genomic sequences showed extensive alternative splicing and untranslated exon sharing between neighboring Hox genes. Homologous noncoding exons could not be identified in transcripts from other species using sequence similarity. However, by comparing conserved noncoding sequences upstream of these exons in different species, we were able to identify homology between some exons. Some alternative splicing variants are probably very ancient and were already coded for by the ancestral Hox gene cluster. We also identified several transcripts that do not code for Hox proteins, are probably not translated, and all but one are in the reverse orientation to the Hox genes. This survey of the transcriptome of the Hox gene clusters of a shark shows that the high complexity observed in mammals is a gnathostome ancestral feature.