tbuckley/cabot-search huggingface dataset:
A7.24 The Pentanucleotide Insertion in HSPA1B Gene is Associated with Idiopathic Inflammatory Myopathy
Authors: T Svitalkova, M Remakova, M Faustova, L Plestilova, H Mann, J Vencovsky, P Novota
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and Objectives</h3> The HSPA1B gene is one of the three HSP70 genes located within the Major Histocompatibility Complex (MHC) on chromosome 6p21. The HSP70 molecules in their intracellular form have antiapoptotic function and are responsible for stabilisation of protein structure; in their extracellular form, they act as mediators of immune response. The extracellular HSPs are part of the innate and adaptive immune response and are involved in the process of antigen presentation. The aim of our study was to find out if an association between polymorphisms of MHC located HSP70 genes and subgroups of idiopathic inflammatory myopathy exists. <h3>Materials and Methods</h3> We have analysed 177 patients suffering from idiopathic inflammatory myopathy (82 patients with dermatomyositis – DM, 71 patients with polymyositis – PM, 22 patients with cancer associated myositis, 2 patients with inclusion body myositis) and 59 healthy controls. In total, six genetic polymorphisms located within the three HSP70 genes were analysed by direct genomic DNA sequencing. The statistical analysis was done using Fisher’s exact test with calculated p &lt; 0.05 considered as statistically significant. <h3>Results and Conclusions</h3> The frequency of the “INS” allele of the pentanucleotide insertion polymorphism in HSPA1B (Rs9281590) was increased in patients suffering from myositis (43.79%) in comparison with controls (32.20%; p &lt; 0.05). The Odds Ratio calculated for this polymorphism was 1.64 (CI95% 1.056; 2.545). Its increased frequency was predominantly found in DM patients (p &lt; 0.05); the allele distribution in PM patients did not significantly differ from controls. Presence of INS allele was strongly related to the well described HLA associated risk, the HLA-DRB1*03 allele (p &lt; 0.001), found mostly in PM patients. INS allele is independent on other myositis associated HLA allele, HLA-DRB1*16, found increased in the population of our DM patients. Other polymorphisms analysed in this study did not show any relation to the myositis. Our findings support the hypothesis, that DM and PM have partially different genetic background. <h3>Acknowledgement</h3> This work is supported by Internal Grant Agency of Ministry of Health of the Czech Republic NT/13699.
Successful Adenovirus-Mediated Wild-Type <i>p53</i> Gene Transfer in Patients With Bladder Cancer by Intravesical Vector Instillation
Authors: Jürgen Kuball, Shu Fen Wen, Joachim Leissner, Derek Atkins, Patricia Meinhardt, Erlinda Quijano, Heidrun Engler, Beth Hutchins, Daniel C. Maneval, Michael J. Grace, Mary Ann Fritz, Stefan Störkel, Joachim W. Thüroff, Christoph Huber, Martin Schuler
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To study safety, feasibility, and biologic activity of adenovirus-mediated p53 gene transfer in patients with bladder cancer. PATIENTS AND METHODS: Twelve patients with histologically confirmed bladder cancer scheduled for cystectomy were treated on day 1 with a single intratumoral injection of SCH 58500 (rAd/p53) at cystoscopy at one dose level (7.5 × 10 11 particles) or a single intravesical instillation of SCH 58500 with a transduction-enhancing agent (Big CHAP) at three dose levels (7.5 × 10 11 to 7.5 × 10 13 particles). Cystectomies were performed in 11 patients on day 3, and transgene expression, vector distribution, and biologic markers of transgene activity were assessed by molecular and immunohistochemical methods in tumors and normal bladder samples. RESULTS: Specific transgene expression was detected in tissues from seven of eight assessable patients treated with intravesical instillation of SCH 58500 but in none of three assessable patients treated with intratumoral injection of SCH 58500. Induction of RNA and protein expression of the p53 target gene p21/WAF1 was demonstrated in samples from patients treated with SCH 58500 instillation at higher dose levels. Distribution studies after intravesical instillation of SCH 58500 revealed both high transduction efficacy and vector penetration throughout the whole urothelium and into submucosal tumor cells. No dose-limiting toxicity was observed, and side effects were local and of transient nature. CONCLUSION: Intravesical instillation of SCH 58500 combined with a transduction-enhancing agent is safe, feasible, and biologically active in patients with bladder cancer. Studies to evaluate the clinical efficacy of this treatment in patients with localized high-risk bladder cancer are warranted.
Surveillance With Computed Tomography After Curative Treatment of Early-Stage Lung Cancer
Authors: Sashendra Senthi, Suresh Senan
Journal: Journal of Clinical Oncology (2013)

TO THE EDITOR: Furman et al make a persuasive case for limiting intensive follow-up after curative cancer therapy to tumor types for which salvage treatments improve survival. However, their conclusions concerning early-stage non–small-cell lung cancer (NSCLC) disregard the literature that suggests improved outcomes with computed tomography (CT) surveillance may be possible, particularly regarding second primary NSCLC. Using a surveillance program per National Comprehensive Cancer Network recommendations, Lou et al administered postoperative follow-up for 1,294 patients with early-stage NSCLC, using thoracic CT scans every 6 to 12 months for the first 2 years and yearly thereafter. They found a persistent risk of second primary NSCLC of between 3% and 6% per person-years. For patients with early-stage NSCLC treated with stereotactic ablative radiotherapy undergoing the same CT surveillance, second primary NSCLC develops at a similar rate. This reveals that curatively treated survivors of early-stage NSCLC are at a greater risk of lung cancer events than the patients included in the recent National Lung Screening Trial, in which thoracic CT screening improved survival rates by 20% compared with radiographic screenings. Effective surgical salvage for recurrent and second primary NSCLC is possible, with reported 5-year survival rates between 8% and 40% and 25% to 53%, respectively. Although large surgical series have consistently shown that treating recurrences improves survival, this is only feasible in 1% to 4% of patients with isolated local recurrence. This is not the case with CT-detected second primary NSCLC, which are typically small and detected asymptomatically more than 90% of the time. Consequently, such tumors can be resected more than 50% of the time. For patients who are unfit for surgery, stereotactic ablative radiotherapy enables a curative treatment option, achieving 5-year local control rates of approximately 90%, without decreasing patient-reported quality of life. The proponents of intensive surveillance strategies must recognize that the competing risks of death, even in long-term NSCLC survivors, make it difficult to prove improvements in survival. Available literature suggests we should follow surveillance guidelines such as those recommendedbytheAmericanAssociationforThoracicSurgery andsupport ongoing research such as the IFCT-0302 trial in which postsurgical surveillance using radiography is being tested against CT and bronchoscopy, rather than consider NSCLC surveillance futile.
The Stress Kinase Mitogen-Activated Protein Kinase Kinase (Mkk)7 Is a Negative Regulator of Antigen Receptor and Growth Factor Receptor–Induced Proliferation in Hematopoietic Cells
Authors: Takehiko Sasaki, Teiji Wada, Hiroyuki Kishimoto, Junko Irie-Sasaki, Goichi Matsumoto, Takayuki Goto, Zhengbin Yao, Andrew Wakeham, Tak W. Mak, Akira Suzuki, Sarah K. Cho, Juan Carlos Zuniga-Pflucker, Antonio J. Oliveira-dos-Santos, Toshiaki Katada, Hiroshi Nishina, Josef M. Penninger
Journal: The Journal of Experimental Medicine (2001)

The dual specificity kinases mitogen-activated protein kinase (MAPK) kinase (MKK)7 and MKK4 are the only molecules known to directly activate the stress kinases stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) in response to environmental or mitogenic stimuli. To examine the physiological role of MKK7 in hematopoietic cells, we used a gene targeting strategy to mutate MKK7 in murine T and B cells and non-lymphoid mast cells. Loss of MKK7 in thymocytes and mature B cells results in hyperproliferation in response to growth factor and antigen receptor stimulation and increased thymic cellularity. Mutation of mkk7 in mast cells resulted in hyperproliferation in response to the cytokines interleukin (IL)-3 and stem cell factor (SCF). SAPK/JNK activation was completely abolished in the absence of MKK7, even though expression of MKK4 was strongly upregulated in mkk7−/− mast cell lines, and phosphorylation of MKK4 occurred normally in response to multiple stress stimuli. Loss of MKK7 did not affect activation of extracellular signal–regulated kinase (ERK)1/2 or p38 MAPK. mkk7−/− mast cells display reduced expression of JunB and the cell cycle inhibitor p16INK4a and upregulation of cyclinD1. Reexpression of p16INK4a in mkk7−/− mast cells abrogates the hyperproliferative response. Apoptotic responses to a variety of stimuli were not affected. Thus, MKK7 is an essential and specific regulator of stress-induced SAPK/JNK activation in mast cells and MKK7 negatively regulates growth factor and antigen receptor–driven proliferation in hematopoietic cells. These results indicate that the MKK7-regulated stress signaling pathway can function as negative regulator of cell growth in multiple hematopoietic lineages.
Increased Adhesion and Aggregation of Platelets Lacking Cyclic Guanosine 3′,5′-Monophosphate Kinase I
Authors: Steffen Massberg, Matthias Sausbier, Peter Klatt, Markus Bauer, Alexander Pfeifer, Wolfgang Siess, Reinhard Fässler, Peter Ruth, Fritz Krombach, Franz Hofmann
Journal: The Journal of Experimental Medicine (1999)

Atherosclerotic vascular lesions are considered to be a major cause of ischemic diseases, including myocardial infarction and stroke. Platelet adhesion and aggregation during ischemia–reperfusion are thought to be the initial steps leading to remodeling and reocclusion of the postischemic vasculature. Nitric oxide (NO) inhibits platelet aggregation and smooth muscle proliferation. A major downstream target of NO is cyclic guanosine 3′,5′-monophosphate kinase I (cGKI). To test the intravascular significance of the NO/cGKI signaling pathway in vivo, we have studied platelet–endothelial cell and platelet–platelet interactions during ischemia/reperfusion using cGKI-deficient (cGKI−/−) mice. Platelet cGKI but not endothelial or smooth muscle cGKI is essential to prevent intravascular adhesion and aggregation of platelets after ischemia. The defect in platelet cGKI is not compensated by the cAMP/cAMP kinase pathway supporting the essential role of cGKI in prevention of ischemia-induced platelet adhesion and aggregation.
Quantification of Myocardial Blood Flow With Ultrasound-Induced Destruction of Microbubbles Administered as a Constant Venous Infusion
Authors: Kevin Wei, Ananda R. Jayaweera, Soroosh Firoozan, Andre Linka, Danny M. Skyba, Sanjiv Kaul
Journal: Circulation (1998)

Background —Ultrasound can cause microbubble destruction. If microbubbles are administered as a continuous infusion, then their destruction within the myocardium and measurement of their myocardial reappearance rate at steady state will provide a measure of mean myocardial microbubble velocity. Conversely, measurement of their myocardial concentration at steady state will provide an assessment of microvascular cross-sectional area. Myocardial blood flow (MBF) can then be calculated from the product of the two. Methods and Results —Ex vivo and in vitro experiments were performed in which either flow was held constant and pulsing interval (interval between microbubble destruction and replenishment) was altered, or vice versa. In vivo experiments were performed in 21 dogs. In group 1 dogs (n=7), MBF was mechanically altered in a model in which coronary blood volume was constant. In group 2 dogs (n=5), MBF was altered by direct coronary infusions of vasodilators. In group 3 dogs (n=9), non–flow-limiting coronary stenoses were created, and MBF was measured before and after the venous administration of a coronary vasodilator. In all experiments, microbubbles were delivered as a constant infusion, and myocardial contrast echocardiography was performed using different pulsing intervals. The myocardial video intensity versus pulsing interval plots were fitted to an exponential function: y = A (1− e −β t ), where A is the plateau video intensity reflecting the microvascular cross-sectional area, and β reflects the rate of rise of video intensity and, hence, microbubble velocity. Excellent correlations were found between flow and β, as well as flow and the product of A and β. Conclusions —MBF can be quantified with myocardial contrast echocardiography during a venous infusion of microbubbles. This novel approach has potential for measuring tissue perfusion in any organ accessible to ultrasound.
Noninvasive Molecular Imaging Sheds Light on the Synergy between 5-Fluorouracil and TRAIL/Apo2L for Cancer Therapy
Authors: Kuei C. Lee, Daniel A. Hamstra, Mahaveer S. Bhojani, Amjad P. Khan, Brian D. Ross, Alnawaz Rehemtulla
Journal: Clinical Cancer Research (2007)

In a previous report, a recombinant luciferase reporter, activated during apoptosis via caspase-3 cleavage, was developed for imaging of apoptosis using bioluminescence. The ability to noninvasively image apoptosis in vivo could dramatically benefit the preclinical development of therapeutics targeting the apoptotic pathway. In this study, we examined the use of 5-fluorouracil (5-FU) for sensitizing D54 tumors to tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) therapy by monitoring apoptotic activity in vivo using bioluminescence imaging.Using our apoptosis imaging platform and diffusion magnetic resonance imaging (MRI), we monitored the antitumor effects of 5-FU, TRAIL, and 5-FU + TRAIL using D54 xenografts. Additionally, volumetric and histologic analyses were done for correlation with findings from bioluminescence imaging and diffusion MRI.Bioluminescence imaging showed that therapy with TRAIL alone produced an initial 400% increase in apoptotic activity that rapidly diminished during the 10-day treatment period despite continued therapy. In contrast, concomitant 5-FU and TRAIL therapy elicited an apoptotic response that was sustained throughout the entire therapeutic course. Using diffusion MRI, an enhanced tumor response was detected when concomitant therapy was given versus TRAIL-alone therapy. Last, concomitant therapy resulted in a prolonged growth delay ( approximately 9 days) compared with TRAIL alone ( approximately 4 days).We showed that concomitant 5-FU and TRAIL therapy indeed enhanced apoptotic activity in vivo, which translated into greater tumor control. Moreover, this technique sheds light on the synergy of 5-FU and TRAIL as evidenced by differences in the temporal activation of caspase-3 resulting from the different therapeutic regimens.
Serotonin Toxicity in a CYP2D6 Poor Metabolizer, Initially Diagnosed As a Drug-Resistant Major Depression
Authors: Florence Gressier, Pierre Ellul, Céline Dutech, Abd El Kader Ait Tayeb, Joel Monfort, Emmanuelle Corruble, Laurent Becquemont, Patrick Hardy, Céline Verstuyft
Journal: American Journal of Psychiatry (2014)
Immunomodulator FTY720 Induces eNOS-Dependent Arterial Vasodilatation via the Lysophospholipid Receptor S1P <sub>3</sub>
Authors: Markus Tölle, Bodo Levkau, Petra Keul, Volker Brinkmann, Günter Giebing, Gilbert Schönfelder, Michael Schäfers, Karin von Wnuck Lipinski, Joachim Jankowski, Vera Jankowski, Jerold Chun, Walter Zidek, Markus Van der Giet
Journal: Circulation Research (2005)

The novel immunomodulator FTY720 is effective in experimental models of transplantation and autoimmunity, and is currently undergoing Phase III clinical trials for prevention of kidney graft rejection. FTY720 is a structural analogue of sphingosine-1-phosphate (S1P) and activates several of the S1P receptors. We show that FTY720 induces endothelium-dependent arterial vasodilation in phenylephrine precontracted mouse aortae. Vasodilation did not occur in thoracic aortic rings from eNOS-deficient mice, implicating and effect dependent of activation of the eNOS/NO pathway. Accordingly, FTY720 induced NO release, Akt-dependent eNOS phosphorylation and activation in human endothelial cells. For biological efficacy, FTY720 required endogenous phosphorylation, since addition of the sphingosine kinase antagonist N',N-dimethylsphingosine (DMS) prevented activation of eNOS in vitro and inhibited vasodilation in isolated arteries. The endothelial phosphorylation of FTY720 was extremely rapid with almost complete conversion after 10 minutes as determined by mass spectrometry. Finally, we identified the lysophospholipid receptor S1P3 as the S1P receptor responsible for arterial vasodilation by FTY720, as the effect was completely abolished in arteries from S1P3-deficient mice. In summary, we have identified FTY720 as the first immunomodulator for prevention of organ graft rejection in clinical development that, in addition, positively affects the endothelium by stimulating NO production, and thus potentially displaying beneficial effects on transplant survival beyond classical T cell immunosuppression.
MicroRNAs Associated With HBV Infection And HBV-related HCC
Authors: Kun-Lin Xie, Yan-Ge Zhang, Jun Liu, Yong Zeng, Hong Wu
Journal: Theranostics (2014)

Hepatitis B virus (HBV) infection is a global problem and a major risk factor for hepatocellular carcinoma (HCC).microRNAs (miRNAs) comprise a group of small noncoding RNAs regulating gene expression at the posttranslational level, thereby participating in fundamental biological processes, including cell proliferation, differentiation, and apoptosis.In this review, we summarize the roles of miRNAs in HBV infection, the recently identified mechanism underlying dysregulation of miRNAs in HBV-associated HCC, and their association with hepatocarcinogenesis.Moreover, we discuss the recent advances in the use of circulating miRNAs in the early diagnosis of HCC as well as therapies based on these aberrantly expressed miRNAs.
Evolutionary Origin and Diversification of Epidermal Barrier Proteins in Amniotes
Authors: Bettina Strasser, Veronika Mlitz, Marcela Hermann, Robert H. Rice, Richard A. Eigenheer, Lorenzo Alibardi, Erwin Tschachler, Leopold Eckhart
Journal: Molecular Biology and Evolution (2014)

The evolution of amniotes has involved major molecular innovations in the epidermis. In particular, distinct structural proteins that undergo covalent cross-linking during cornification of keratinocytes facilitate the formation of mechanically resilient superficial cell layers and help to limit water loss to the environment. Special modes of cornification generate amniote-specific skin appendages such as claws, feathers, and hair. In mammals, many protein substrates of cornification are encoded by a cluster of genes, termed the epidermal differentiation complex (EDC). To provide a basis for hypotheses about the evolution of cornification proteins, we screened for homologs of the EDC in non-mammalian vertebrates. By comparative genomics, de novo gene prediction and gene expression analyses, we show that, in contrast to fish and amphibians, the chicken and the green anole lizard have EDC homologs comprising genes that are specifically expressed in the epidermis and in skin appendages. Our data suggest that an important component of the cornified protein envelope of mammalian keratinocytes, that is, loricrin, has originated in a common ancestor of modern amniotes, perhaps during the acquisition of a fully terrestrial lifestyle. Moreover, we provide evidence that the sauropsid-specific beta-keratins have evolved as a subclass of EDC genes. Based on the comprehensive characterization of the arrangement, exon–intron structures and conserved sequence elements of EDC genes, we propose new scenarios for the evolutionary origin of epidermal barrier proteins via fusion of neighboring S100A and peptidoglycan recognition protein genes, subsequent loss of exons and highly divergent sequence evolution.
Tissue-Specific Promoters Active in CD44+CD24−/low Breast Cancer Cells
Authors: Gerd J. Bauerschmitz, Tuuli Ranki, Lotta Kangasniemi, Camilla Ribacka, Minna Eriksson, Marius Porten, Isabell Herrmann, Ari Ristimäki, Pekka Virkkunen, Maija Tarkkanen, Tanja Hakkarainen, Anna Kanerva, Daniel Rein, Sari Pesonen, Akseli Hemminki
Journal: Cancer Research (2008)

Abstract It has been proposed that human tumors contain stem cells that have a central role in tumor initiation and posttreatment relapse. Putative breast cancer stem cells may reside in the CD44+CD24−/low population. Oncolytic adenoviruses are attractive for killing of these cells because they enter through infection and are therefore not susceptible to active and passive mechanisms that render stem cells resistant to many drugs. Although adenoviruses have been quite safe in cancer trials, preclinical work suggests that toxicity may eventually be possible with more active agents. Therefore, restriction of virus replication to target tissues with tissues-specific promoters is appealing for improving safety and can be achieved without loss of efficacy. We extracted CD44+CD24−/low cells from pleural effusions of breast cancer patients and found that modification of adenovirus type 5 tropism with the serotype 3 knob increased gene delivery to CD44+CD24−/low cells. α-Lactalbumin, cyclo-oxygenase 2, telomerase, and multidrug resistance protein promoters were studied for activity in CD44+CD24−/low cells, and a panel of oncolytic viruses was subsequently constructed. Each virus featured 5/3 chimerism of the fiber and a promoter controlling expression of E1A, which was also deleted in the Rb binding domain for additional tumor selectivity. Cell killing assays identified Ad5/3-cox2L-d24 and Ad5/3-mdr-d24 as the most active agents, and these viruses were able to completely eradicate CD44+CD24−/low cells in vitro. In vivo, these viruses had significant antitumor activity in CD44+CD24−/low–derived tumors. These findings may have relevance for elimination of cancer stem cells in humans. [Cancer Res 2008;68(14):5533–9]
Can rock climbing lead to Dupuytren’s disease?
Authors: A J Logan, G Mason, J Dias, N Makwana
Journal: British Journal of Sports Medicine (2005)

To determine if rock climbing is a significant factor in the development of Dupuytren's disease in men, and, if so, what is the most likely related factor.Questionnaires were distributed to all 1100 members of the Climbers' Club of Great Britain. These detailed basic information about the climber, the presence of Dupuytren's disease, and any known risk factors for its development.About half (51%) of the questionnaires were returned. The respondents were almost entirely male. It was revealed that 19.5% of male climbers had developed Dupuytren's disease. There was a significantly higher life time intensity of climbing activity in those with the disease. An earlier age of onset of the disease was found in climbers compared with the general population.This study further strengthens the hypothesis that repetitive trauma to the palmar fascia predisposes to the development of Dupuytren's disease in men.
Response to Letter Regarding Article, “Signature MicroRNA Expression Profile of Essential Hypertension and Its Novel Link to Human Cytomegalovirus Infection”
Authors: Shuqiang Li, Jianguo Zhu, Mingming Zhang, Shuyan Wang, Liping Yu, Xinchun Yang, Jun Cai, Weili Zhang, Youren Chen, Ke Zhang, Laurentiu M. Popescu, Xinliang Ma, Wayne Bond Lau, Rong Rong, Xueqing Yu, Bingbing Wang, Yafeng Li, Chuanshi Xiao, Alex F. Chen
Journal: Circulation (2012)