tbuckley/cabot-search huggingface dataset:
Clinical outcomes in patients with locally advanced nasopharyngeal cancer treated with neoadjuvant docetaxel and cisplatin followed by radiation treatment and concomitant cisplatin.
Authors: M. Ekenel, S. Keskin, M. Başsaran, S. E. Bavbek, C. Ozdemir, R. Meral, M. Altun
Journal: Journal of Clinical Oncology (2010)

e16017 Background: Radiation treatment with concomitant chemotherapy has improved the therapeutic outcome of patients with locally advanced nasopharyngeal carcinoma. However, the importance of neoadjuvant chemotherapy before the definitive therapy is still undefined. We report the results of our experience with neoadjuvant chemotherapy. Methods: Between 2004 and 2008, charts of 59 patients with advanced loco regional nasopharyngeal carcinoma treated in our institute were reviewed. They received induction chemotherapy consisting of cisplatin (75mg/m2) on day 1 and docetaxel (75mg/m2) on day 1 every 3 weeks and followed by definitive radiotherapy and concomitant cisplatin (100mg/m2) every 3 weeks or (40mg/m2) weekly during the radiotherapy. Results: The median age was 49 years 18-68y) and median follow up was 29 months (6-56mo). According to the American Joint Committee on Cancer's 2002 stage classification, all patients were stage II (15%), stage III (63%) and stage IV (22%). Fifty eight patients received 3 cycles of chemotherapy. One patient could not take the full dose chemotherapy due to gastrointestinal toxicity. Except for this patient, there was no grade 3 or 4 toxicity after induction chemotherapy. Concomitant cisplatin with radiation therapy was given to forty nine patients (83%). Of those, thirty two patients received more than 1 cycle of concomitant cisplatin. Grade 3 and/or 4 toxicities after cheomoradiation therapy were mucositis (46%), weight loss (10%), skin toxicity (14%), esophagitis (5%), emesis (5%), neutopenia (5%), thrombocytopenia (3%) and anemia (2%). Fifty one patients (87%) and fifty six (95%) patients achieved an objective response (Complete and partial response) after induction chemotherapy and chemoradiotherapy, respectively. One patient had local relapse alone, 2 patients had both local and distant metastases and 4 patients had distant metastases. Three years overall survival (OS) and disease free survival (DFS) rates were 93% and 83%, respectively. Conclusions: Induction chemotherapy with docetaxel and cisplatin is a feasible and tolerable treatment. No significant financial relationships to disclose.
SAMHD1 prevents autoimmunity by maintaining genome stability
Authors: Stefanie Kretschmer, Christine Wolf, Nadja König, Wolfgang Staroske, Jochen Guck, Martin Häusler, Hella Luksch, Laura A Nguyen, Baek Kim, Dimitra Alexopoulou, Andreas Dahl, Alexander Rapp, M Cristina Cardoso, Anna Shevchenko, Min Ae Lee-Kirsch
Journal: Annals of the Rheumatic Diseases (2014)

The HIV restriction factor, SAMHD1 (SAM domain and HD domain-containing protein 1), is a triphosphohydrolase that degrades deoxyribonucleoside triphosphates (dNTPs). Mutations in SAMHD1 cause Aicardi-Goutières syndrome (AGS), an inflammatory disorder that shares phenotypic similarity with systemic lupus erythematosus, including activation of antiviral type 1 interferon (IFN). To further define the pathomechanisms underlying autoimmunity in AGS due to SAMHD1 mutations, we investigated the physiological properties of SAMHD1.
Public Health England has "faltering voice" on key issues, say MPs
Authors: A. O'Dowd
Journal: BMJ (2014)

The agency heading up public health in England is not sufficiently independent of government and has had a “faltering” voice so far in speaking up on public health issues, MPs have said.

MPs on the parliamentary health select committee have levelled several criticisms at Public Health England, the executive agency of the Department of Health that began operating in April last year, in a report published on 26 February.1

The report said that the agency had not yet shown that it was able to be an effective champion of the nation’s public health interests, which is what it was created to do.

The Health Committee’s inquiry that led to the report examined how Public Health England had set about establishing its policy priorities and programme …
<i>MET</i> and <i>KRAS</i> Gene Amplification Mediates Acquired Resistance to MET Tyrosine Kinase Inhibitors
Authors: Virna Cepero, J. Rafael Sierra, Simona Corso, Elena Ghiso, Laura Casorzo, Tim Perera, Paolo Maria Comoglio, Silvia Giordano
Journal: Cancer Research (2010)

The establishment of the role of MET in human cancer has led to the development of small-molecule inhibitors, many of which are currently in clinical trials. Thus far, nothing is known about their therapeutic efficacy and the possible emergence of resistance to treatment, a problem that has been often observed with other receptor tyrosine kinase (RTK) inhibitors. To predict mechanisms of acquired resistance, we generated resistant cells by treating MET-addicted cells with increasing concentrations of the MET small-molecule inhibitors PHA-665752 or JNJ38877605. Resistant cells displayed MET gene amplification, leading to increased expression and constitutive phosphorylation of MET, followed by subsequent amplification and overexpression of wild-type (wt) KRAS. Cells harboring KRAS amplification progressively lost their MET dependence and acquired KRAS dependence. Our results suggest that MET and KRAS amplification is a general mechanism of resistance to specific MET inhibitors given that similar results were observed with two small inhibitors and in different cell lines of different histotypes. To our knowledge, this is the first report showing that overexpression of wt KRAS can overcome the inhibitory effect of a RTK inhibitor. In view of the fact that cellular models of resistance to inhibitors targeting other tyrosine kinases have predicted and corroborated clinical findings, our results provide insights into strategies for preventing and/or overcoming drug resistance.
Long-term efficacy of tiotropium in relation to smoking status in the UPLIFT trial
Authors: D. P. Tashkin, B. Celli, S. Kesten, T. Lystig, S. Mehra, M. Decramer
Journal: European Respiratory Journal (2009)

UPLIFT (Understanding Potential Long-Term Improvements in Function with Tiotropium), a 4-yr trial of tiotropium in chronic obstructive pulmonary disease, allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy. 5,993 patients were randomised (tiotropium/placebo). Lung function, St George's Respiratory Questionnaire, exacerbations and adverse events were followed. Patients were characterised as continuing smokers (CS), continuing ex-smokers (CE), or intermittent smokers (IS) based on self-reporting smoking behaviour. 60%, 14% and 26% of patients were CE, CS and IS, respectively. The rate of forced expiratory volume in 1 s (FEV 1 ) decline for placebo patients was most rapid in CS (-51±4, -36±2 and -23±2 mL·yr −1 in CS, IS, and CE, respectively). Tiotropium did not alter FEV 1 decline, but was associated with significant improvements in pre- and post-bronchodilator FEV 1 over placebo that persisted throughout the 4-yr trial for each smoking status (pre-bronchodilator: 125, 55 and 97 mL at 48 months in CS, IS and CE, respectively; p≤0.0003). Tiotropium reduced exacerbation risk in CS (HR (95%CI) 0.81 (0.68–0.97)), in CE (0.86 (0.79–0.93)) and trended towards significance in IS (0.89 (0.80–1.01)). At 4 yrs, St George’s Respiratory Questionnaire for tiotropium patients improved the most in CS (-4.62 units, p = 0.0006) and the least in IS (-0.54 units, p = 0.55), compared with control. Tiotropium provided long-term benefits irrespective of smoking status, although differences among categories were observed.
Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells
Authors: Abdulkader Azouz, Y-L Wu, J Hillion, I Tarkanyi, A Karniguian, J Aradi, Michele Lanotte, G-Q Chen, M Chehna, E Ségal-Bendirdjian
Journal: Leukemia (2010)
HIV-1 clade promoters strongly influence spatial and temporal dynamics of viral replication in vivo
Authors: Mireille Centlivre, Peter Sommer, Marie Michel, Raphaël Ho Tsong Fang, Sandrine Gofflo, Jenny Valladeau, Nathalie Schmitt, Françoise Thierry, Bruno Hurtrel, Simon Wain-Hobson, Monica Sala
Journal: Journal of Clinical Investigation (2005)

Although the primary determinant of cell tropism is the interaction of viral envelope or capsid proteins with cellular receptors, other viral elements can strongly modulate viral replication. While the HIV-1 promoter is polymorphic for a variety of transcription factor binding sites, the impact of these polymorphisms on viral replication in vivo is not known. To address this issue, we engineered isogenic SIVmac239 chimeras harboring the core promoter/enhancer from HIV-1 clades B, C, and E. Here it is shown that the clade C and E core promoters/enhancers bear a noncanonical activator protein–1 (AP-1) binding site, absent from the corresponding clade B region. Relative ex vivo replication of chimeras was strongly dependent on the tissue culture system used. Notably, in thymic histocultures, replication of the clade C chimera was favored by IL-7 enrichment, which suggests that the clade C polymorphism in the AP-1 and NF-κB binding sites is involved. Simultaneous infection of rhesus macaques with the 3 chimeras revealed a strong predominance of the clade C chimera during primary infection. Thereafter, the B chimera dominated in all tissues. These data show that the clade C promoter is particularly adapted to sustain viral replication in primary viremia and that clade-specific promoter polymorphisms constitute a major determinant for viral replication.
Risk of second cancers in Waldenström macroglobulinemia
Authors: M. Varettoni, A. Tedeschi, L. Arcaini, C. Pascutto, E. Vismara, E. Orlandi, F. Ricci, A. Corso, A. Greco, S. Mangiacavalli, M. Lazzarino, E. Morra
Journal: Annals of Oncology (2011)
Influence of hay and animal feed exposure on respiratory status: a longitudinal study
Authors: I. Thaon, A. Thiebaut, L. Jochault, A. Lefebvre, J.J. Laplante, J.C. Dalphin
Journal: European Respiratory Journal (2010)

Our aim was to study respiratory symptoms and lung function decline in farmers, with particular attention to the influence of handling hay, straw and animal feed. From a cohort recruited in 1993-1994, 219 (82.6%) dairy farmers, 130 (62.5%) nondairy agricultural workers and 99 (66.4%) controls were re-evaluated in 2006. They answered medical and occupational questionnaires, underwent spirometric tests at both evaluations and pulse oximetry in 2006. Dairy and nondairy agricultural workers showed an increased risk for usual morning phlegm (adjusted OR 4.27 (95% CI 1.41-12.95) and 3.59 (95% CI 1.16-11.10), respectively). Animal feed handling was associated with increased risks of wheezing (p = 0.01) and usual morning phlegm (p = 0.04); hay or straw handling was associated with increased risk of wheezing (p = 0.008). Adjusting for smoking, age, height, sex and altitude, dairy farmers had greater declines in forced expiratory volume in 1 s (FEV(1))/forced vital capacity ratio (p = 0.01) than controls. An increased decline in FEV(1) for all agricultural workers was associated with animal feed handling, both measured as a categorical (currently versus never handling; p = 0.05) or quantitative value (years of exposure during the survey period; p = 0.03). Hay, straw or animal feed handling represents a risk factor of bronchial symptoms and, for animal feed only, of accelerated decline in expiratory flows.
Janus-like opposing roles of CD47 in autoimmune brain inflammation in humans and mice
Authors: May H. Han, Deborah H. Lundgren, Siddhartha Jaiswal, Mark Chao, Kareem L. Graham, Christopher S. Garris, Robert C. Axtell, Peggy P. Ho, Christopher B. Lock, Joslyn I. Woodard, Sara E. Brownell, Maria Zoudilova, Jack F.V. Hunt, Sergio E. Baranzini, Eugene C. Butcher, Cedric S. Raine, Raymond A. Sobel, David K. Han, Irving Weissman, Lawrence Steinman
Journal: The Journal of Experimental Medicine (2012)

Comparison of transcriptomic and proteomic data from pathologically similar multiple sclerosis (MS) lesions reveals down-regulation of CD47 at the messenger RNA level and low abundance at the protein level. Immunohistochemical studies demonstrate that CD47 is expressed in normal myelin and in foamy macrophages and reactive astrocytes within active MS lesions. We demonstrate that CD47−/− mice are refractory to experimental autoimmune encephalomyelitis (EAE), primarily as the result of failure of immune cell activation after immunization with myelin antigen. In contrast, blocking with a monoclonal antibody against CD47 in mice at the peak of paralysis worsens EAE severity and enhances immune activation in the peripheral immune system. In vitro assays demonstrate that blocking CD47 also promotes phagocytosis of myelin and that this effect is dependent on signal regulatory protein α (SIRP-α). Immune regulation and phagocytosis are mechanisms for CD47 signaling in autoimmune neuroinflammation. Depending on the cell type, location, and disease stage, CD47 has Janus-like roles, with opposing effects on EAE pathogenesis.
Failure of Talc Pleurodesis Is Associated with Increased Pleural Fibrinolysis
Authors: F. Rodriguez-Panadero, A. Segado, J. Martin Juan, R. Ayerbe, I. Torres Garcia, J. Castillo
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Diffuse pleural inflammation and fibrin deposition following the instillation of the sclerosing agent is considered necessary for a successful pleural symphysis. We hypothesized that an impairment in fibrin formation or an increased endopleural fibrinolysis would lead to failure of pleurodesis. To investigate changes in the pleural coagulation/fibrinolysis balance, we studied 75 consecutive patients who underwent thoracoscopy. Fifty-four of these patients with malignant pleural effusions and four with a benign recurrent effusion underwent thoracoscopic talc pleurodesis. Another four patients with malignancy and 13 with benign effusions had no talc poudrage performed and were included as a control group. Serial determinations of thrombin-antithrombin III complex (TAT), plasminogen activator inhibitor (PAI), and D-dimer were made in pleural fluid samples taken at the beginning of thoracoscopy (baseline), immediately after thoracoscopic biopsies had been done (postbiopsy), 3 h after thoracoscopy--either with talc poudrage or without--and 24 and 48 h after the procedure, as well as in cases of recurrence of effusions (farline). Successful pleurodesis was obtained in 42 of 52 patients who could be evaluated (81%), and failure was seen in 10. Strong activation of coagulation and production of PAI was observed in all groups, including the control (no talc) group. Fibrinolytic activity (as expressed by D-dimer levels) showed a clear decline 24 h after talc poudrage in patients with a good outcome of pleurodesis, as oppossed to those with bad results and to the control group, and returned to the baseline by 15 d. We conclude that increased pleural fibrinolytic activity is associated with failure of pleurodesis, despite significant inhibitory activity of PAI in all groups.
Author’s response to ‘CAP and HCAP are different? An unresolved question’
Authors: Eva Polverino, Antoni Torres
Journal: Thorax (2014)

Dear Editor,

We thank the authors for the interest in our recent publication and for their useful comments.

Unfortunately we consider the comparison with the publication from Giannella et al 1 poorly appropriate in many aspects. The main strength of our work is the multicentre prospective case–control study design (match by age, gender and period of hospitalisation). Although severity scores were not used for matching, we considered this design the most appropriate to describe healthcare-associated pneumonia (HCAP) features. In fact, the Giannella group performed an observational prospective study only on patients admitted to internal medicine departments: these elements (study design and patients) could justify a different population composition and, consequently, …
A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2
Authors: Kai B. Kaufmann, Albert Gründer, Tobias Hadlich, Julius Wehrle, Monika Gothwal, Ruzhica Bogeska, Thalia S. Seeger, Sarah Kayser, Kien-Binh Pham, Jonas S. Jutzi, Lucas Ganzenmüller, Doris Steinemann, Brigitte Schlegelberger, Julia M. Wagner, Manfred Jung, Britta Will, Ulrich Steidl, Konrad Aumann, Martin Werner, Thomas Günther, Roland Schüle, Alessandro Rambaldi, Heike L. Pahl
Journal: The Journal of Experimental Medicine (2012)

The molecular pathophysiology of myeloproliferative neoplasms (MPNs) remains poorly understood. Based on the observation that the transcription factor NF-E2 is often overexpressed in MPN patients, independent of the presence of other molecular aberrations, we generated mice expressing an NF-E2 transgene in hematopoietic cells. These mice exhibit many features of MPNs, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. The MPN phenotype is transplantable to secondary recipient mice. NF-E2 can alter histone modifications, and NF-E2 transgenic mice show hypoacetylation of histone H3. Treatment of mice with the histone deacetylase inhibitor (HDAC-I) vorinostat restored physiological levels of histone H3 acetylation, decreased NF-E2 expression, and normalized platelet numbers. Similarly, MPN patients treated with an HDAC-I exhibited a decrease in NF-E2 expression. These data establish a role for NF-E2 in the pathophysiology of MPNs and provide a molecular rationale for investigating epigenetic alterations as novel targets for rationally designed MPN therapies.
Galanin Receptor Subtype 2 Suppresses Cell Proliferation and Induces Apoptosis in <i>p53</i> Mutant Head and Neck Cancer Cells
Authors: Takeharu Kanazawa, Pavan K. Kommareddi, Toshihide Iwashita, Bhavna Kumar, Kiyoshi Misawa, Yuki Misawa, Ilwhan Jang, Thankam S. Nair, Yukiko Iino, Thomas E. Carey
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Galanin and its three receptors (GALR1-3) are expressed in many normal tissues, but silenced in some tumors. Contradictory roles for galanin and its receptors in various tumors have been reported. To understand their function, investigations of individual galanin receptors are necessary. In head and neck squamous carcinoma cells (HNSCC) with silenced GALR1 and GALR2, we showed that reexpressed GALR1 suppresses tumor cell proliferation via Erk1/2-mediated effects on cdk inhibitors and cyclin D1. Others showed that GALR2 could induce apoptosis in neuroblastoma cells with wild-type p53, whereas GALR2 stimulated proliferation in small cell lung cancer. In this study, we investigated the role of GALR2 in HNSCC cells that have mutant p53 and do not express GALR1. Experimental Design: UM-SCC-1, a human oral carcinoma cell line with a splice site mutation causing a 46-bp p53 off-frame deletion, was stably transfected to express GALR2 (UM-SCC-1-GALR2). Results: Galanin treatment of UM-SCC-1-GALR2 caused morphologic changes and a marked decrease in cell number that were not observed in UM-SCC-1-mock cells. Galanin and GALR2 resulted in decreased bromodeoxyuridine incorporation, p27Kip1 and p57Kip2 up-regulation, and decreased cyclin D1 expression. These effects were similar to GALR1 signaling in HNSCC, but GALR2 also induced caspase-3–dependent apoptosis, which was confirmed by Annexin-V staining and DNA fragmentation analysis. These were not observed with GALR1. Conclusion: This study shows that GALR2 reexpression can inhibit cell proliferation and induce apoptosis in HNSCC cells with mutant p53. GALR2 may be a feasible target for HNSCC therapy.
Identification of S664 TSC2 Phosphorylation as a Marker for Extracellular Signal-Regulated Kinase–Mediated mTOR Activation in Tuberous Sclerosis and Human Cancer
Authors: Li Ma, Julie Teruya-Feldstein, Pauline Bonner, Rosa Bernardi, David Neal Franz, David Witte, Carlos Cordon-Cardo, Pier Paolo Pandolfi
Journal: Cancer Research (2007)

Abstract Constitutive activation of extracellular signal-regulated kinases (Erk1/2) is frequently implicated in human cancers. Recently, aberrantly activated Erk was also found in brain lesions associated with tuberous sclerosis (TSC). We reported previously that Erk might contribute to tumorigenesis by phosphorylating TSC2 at specific residues, particularly S664. In our present study, 25 TSC-related cortical tubers or subependymal giant cell astrocytomas, as well as tissue microarrays of six types of human cancers, were analyzed for the expression of phospho-Erk (pErk) 1/2, S664-phospho-TSC2 (pTSC2), and phospho-S6 (pS6) by immunohistochemistry. We found that Erk-mediated TSC2 phosphorylation occurred at a high incidence and positively correlated with mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) activation in TSC-associated brain lesions as well as in various cancers. Interestingly, in certain types of cancers (e.g., breast carcinoma and colon carcinoma), S664-pTSC2 seemed to be a more sensitive marker than pErk. Furthermore, most of the pTSC2-positive samples (∼75%) were positive for pS6, but only 40% to 55% of the pS6-positive tumors exhibited TSC2 phosphorylation. Our results show that S664 TSC2 phosphorylation is a marker for Erk-mediated (as opposed to Akt-mediated) mTOR activation in TSC and human cancer. On the basis of these findings, TSC2 phosphorylation at S664 can be used to identify patients that may benefit from antitumor therapy with MAPK and mTOR inhibitors. Importantly, our results indicate that Erk-mediated phosphorylation and inactivation of TSC2 can be critical in development of hamartomatous lesions in TSC and cancer pathogenesis. [Cancer Res 2007;67(15):7106–12]
Which antibiotic for hospital acquired pneumonia caused by MRSA?
Authors: J. Muscedere
Journal: BMJ (2014)

Vancomycin is as safe and effective as newer alternatives

Hospital acquired pneumonia is associated with increased patient morbidity, mortality, and healthcare costs. Outcome is greatly influenced by aspects of antibiotic treatment including the agent chosen, the timing of initiation, adequacy, and duration.1 Gram negative organisms were traditionally thought to be the causal pathogens, but there has been an increasing shift towards Gram positive organisms, particularly Staphylococcus aureus . Surveillance studies have found that 50–60% are meticillin resistant S aureus (MRSA).2 Clinicians treating hospital acquired pneumonia, which is known or suspected to be secondary to MRSA, need to know which antimicrobial agent works best and is least harmful.

Vancomycin was traditionally considered the mainstay of treatment for MRSA, but in the past few years the number of available antimicrobials active against MRSA has increased substantially. Newly available drugs include linezolid, telavancin, tigecycline, quinupristin-dalfopristin, daptomycin, and ceftaroline. Given these available alternatives, how can we optimise the treatment of hospital acquired pneumonia caused by MRSA? Or, to paraphrase, are the newer antibiotics any better or any safer than the old standby vancomycin? 

For hospital acquired pneumonia, the seemingly large number of options is quickly reduced because of the pharmacology, inadequate evaluation, possible harm, …