tbuckley/cabot-search huggingface dataset:
Exploring the utility of exosomal HER receptor dimerization as a resistance mechanism in NSCLC.
Authors: Myria Galazi, Gregory Weitsman, James Monypenny, Oana Coban, Jose Vicencio, Frank McCaughan, Martin David Forster, Tony Ng
Journal: Journal of Clinical Oncology (2016)

e23100 Background: Personalized therapy in lung cancer has improved following the introduction of EGFR tyrosine kinase inhibitors. However, virtually all patients develop resistance leading to disease relapse and decreased patient survival. With the advances in research, several mechanisms have been identified to be involved in the development of resistance, including activation of ErbB3/HER3. HER3 is a key dimerization partner of EGFR and plays an important role in tumorigenesis and cancer progression. As a result, anti-HER3 therapies have been developed and clinical trials with monoclonal antibodies against HER3 are ongoing in NSCLC in combination with other therapies (‘standard of care’). The influence of concomitant therapies such as platinum chemotherapy on EGFR-HER3 heterodimerization remains largely unexplored. We hypothesize that in a subgroup of NSCLC patients, cisplatin treatment will impact on the ‘dependence’ of the tumor on HER3, due to its disruptive effect on the EGFR-HER3 dimer interaction. Methods: We developed a protocol for immunostaining and fluorescence lifetime imaging microscopy (FLIM) of patient-derived exosomes to determine the ability to characterize the EGFR-HER3 dimer from clinical samples of patients with advanced NSCLC. Blood samples were collected prior to initiation of chemotherapy (cisplatin) and 3 weeks after. Biochemical and microscopy analyses were performed on purified exosomes from the paired serum samples of patients. Results: The presence and degree of the EGFR-HER3 dimer in the serum-derived exosomes of NSCLC patients was variable and was significantly reduced in a proportion of patients following treatment with Cisplatin. These results were reproduced in cell-line derived exosomes treated under the same conditions. Conclusions: Our observations may have important clinical implications for the use of anti-HER3 monoclonal antibodies in NSCLC patients, with regard to scheduling of cisplatin treatment. They can also allow the creation of a multivariate predictive model of combining exosomal ErbB receptor activation with other biomarkers of disease to prospectively predict response to chemotherapy and targeted agents as well as time to metastatic relapse.
Response to: ‘Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis’ by Lee and Song
Authors: Yoshikazu Nakaoka
Journal: Annals of the Rheumatic Diseases (2018)

Response to: 'Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis' by Lee and Song I thank Lee and Song 1 for their thoughtful comments on our recent publication. 2The authors state that our study did not examine the steroid-sparing effect of tocilizumab because of mandatory glucocorticoid tapering.Given that the dose reduction rate of glucocorticoid significantly correlates with the relapse rate, 3 this randomised, double-blind, placebo-controlled study was designed with mandatory glucocorticoid tapering to investigate whether tocilizumab treatment enables glucocorticoid tapering without relapse of Takayasu arteritis.Although the primary endpoint, time to relapse of Takayasu arteritis, was not met in our study, the results suggested the effect of tocilizumab as a promising steroid-sparing agent.Moreover, the steroidsparing effect of tocilizumab was observed during an open-label extension period of the study in which the glucocorticoid dose was tapered based on the disease activity of the patient. 4The final results from the long-term extension will be reported in future publications.I concur with Lee and Song that methotrexate and mycophenolate mofetil are commonly used therapeutic agents in patients with refractory Takayasu arteritis.As shown in online supplementary figure S1, 25 of 36 (69.4%) patients in our study had previously received disease-modifying antirheumatic drugs or immunosuppressants.Our study, however, was designed to compare tocilizumab with placebo because the use of immunosuppressive agents had not been found to have a consistent clinical benefit or steroid-sparing effect in a prospective comparative study. 5The findings in our randomised controlled study support the use of tocilizumab as one of the treatment options for patients with Takayasu arteritis who are resistant to glucocorticoid therapy and in whom glucocorticoid withdrawal is difficult.Further discussion of an evidence-based treatment algorithm for patients with Takayasu arteritis is warranted in the future.
The nasal microbiome in patients with chronic rhinosinusitis: Analyzing the effects of atopy and bacterial functional pathways in 111 patients
Authors: Mahboobeh Mahdavinia, Phillip A. Engen, Phillip S. LoSavio, Ankur Naqib, Rafsa J. Khan, Mary C. Tobin, Arpita Mehta, Raj Kota, Nailliw Z. Preite, Christopher D. Codispoti, Bobby A. Tajudeen, Robert P. Schleimer, Stefan J. Green, Ali Keshavarzian, Pete S. Batra
Journal: Journal of Allergy and Clinical Immunology (2018)
High Prevalence of Liver Fibrosis Among European Adults With Unknown Liver Disease: A Population-Based Study
Authors: Llorenç Caballería, Guillem Pera, Ingrid Arteaga, Lluís Rodríguez, Alba Alumà, Rosa Ma Morillas, Napoleón de la Ossa, Alba Díaz, Carmen Expósito, Dolores Miranda, Carmen Sánchez, Rosa Ma Prats, Marta Urquizu, Angels Salgado, Magda Alemany, Alba Martinez, Irfan Majeed, Núria Fabrellas, Isabel Graupera, Ramón Planas, Isabel Ojanguren, Miquel Serra, Pere Torán, Juan Caballería, Pere Ginès
Journal: Clinical Gastroenterology and Hepatology (2018)

Background & AimsLiver fibrosis is the main determinant of long-term outcome in chronic liver diseases. Little is known about the prevalence of liver fibrosis in the general population. The aim of the study was to investigate the prevalence of liver fibrosis in the general adult population with unknown liver disease.MethodsThis was a population-based, cross-sectional study performed in the Barcelona metropolitan area. Subjects aged 18 to 75 years old were identified randomly from citizens included in the primary health care registry. Of 4866 subjects invited, 3076 participated (63.2%). Liver fibrosis was estimated by measuring liver stiffness (LS) with transient elastography (TE). Liver histology was assessed in 92 subjects with increased LS.ResultsPrevalence estimates of increased LS (≥6.8, ≥8.0, and ≥9.0 kPa) were 9.0%, 5.8%, and 3.6%, respectively. The etiology of liver disease was mainly nonalcoholic fatty liver disease (NAFLD), followed by alcohol risk consumption (consumption of ≥21 standard drinking units/wk in men and ≥14 standard drinking units/wk in women). Factors independently associated with increased LS were male sex, abdominal obesity, type 2 diabetes, serum glucose, high-density lipoprotein, and triglyceride levels. Subjects without risk factors for NAFLD or without alcohol risk consumption had a very low prevalence of increased LS. The best cut-off value of LS for significant liver fibrosis (F2–F4) was 9.2 kPa, with high sensitivity and specificity. TE was more accurate than alanine aminotransferase, NAFLD fibrosis score, or Fibrosis 4. An algorithm for screening for liver fibrosis using TE in the community setting is proposed.ConclusionsThese findings show a high prevalence of silent liver disease with advanced fibrosis mainly related to NAFLD in adult European subjects without known liver disease. An LS value less than 9.2 kPa predicts the absence of significant liver fibrosis with high accuracy and could be used for screening purposes.
Regulation of 5alpha-reductase type II (SRD5A2) gene expression by phytoestrogens
Authors: Rajasree Solipuram, Srivatcha Naragoni, Wesley G. Gray
Journal: Cancer Research (2006)

142   DHT is the main growth promoting factor in the prostate and is an androgenic stimulus in males. A long period of exposure to androgens has been suggested as one of the causes of prostate cancer in adult life. Thus, inhibition of 5alpha reductase type 2 (SRD5A2) may lower the risk of developing prostate cancer by lowering androgenic stimulation. Epidemiological studies suggest that the incidence of prostate cancer is lower in Eastern men than in Western men, which is attributed to the dietary factors like phytoestrogens (PEs). Extensive research is being conducted on PEs to determine their molecular mechanisms of action in androgen dependent pathways. We investigated the question, does the phytoestrogen, Genistein (GE) regulate SRD5A2 mRNA expression and if so, is the Androgen Receptor (AR) involved. To answer this question, LNCaP cells, an AR-positive cell line, were treated with or without 1 nM DHT, 1 to1000 nM PE for 24 h. RNA was isolated and analyzed by Northern blot and Quantitative Real-Time RT-PCR. Total protein was analyzed for AR expression by Western Blot. Our results demonstrated that SRD5A2 gene expression was stimulated by increasing concentrations of GE when compared to the control. At 100 nM GE, SRD5A2 was up-regulated approximately 2- fold. Western blot indicated that GE, at 100 nM, down-regulated AR protein expression, but with GE at 10 nM a 3-fold up-regulation of AR was observed. To test the binding function of PE, in vitro competitive ligand binding assay was performed using recombinant rat AR Ligand Binding Domain in the presence of 10 nM  3 H-Methyltrienolone ( 3 H-R1881) and increasing concentration (10-10000-fold) of GE. Competitive Ligand Binding Assay data suggests that GE does not bind to AR at concentrations tested. These results suggest that PEs at low concentrations stimulate the SRD5A2 gene expression with out binding to androgen receptor. Thus, PEs may stimulate androgen dependent pathway through stimulation of SRD5A2. Further investigation is needed to elucidate the mechanism of action of phytoestrogens in regulation of SRD5A2 gene expression.
Lung transplantation after allogeneic stem cell transplantation: a pan-European experience
Authors: Mark Greer, Cristina Berastegui, Peter Jaksch, Christian Benden, John Aubert, Antoine Roux, Elodie Lhuillier, Sandrine Hirschi, Martine Reynaud-Gaubert, François Philit, Johanna Claustre, Pierre LePalud, Marc Stern, Christiane Knoop, Robin Vos, Erik Verschuuren, Andrew Fisher, Gerdt Riise, Lennart Hansson, Martin Iversen, Pekka Hämmäinen, Hans Wedel, Jacqueline Smits, Jens Gottlieb, Are M. Holm
Journal: European Respiratory Journal (2018)

Late-onset noninfectious pulmonary complications (LONIPCs) affect 6% of allogeneic stem cell transplantation (SCT) recipients within 5 years, conferring subsequent 5-year survival of 50%. Lung transplantation is rarely performed in this setting due to concomitant extrapulmonary morbidity, excessive immunosuppression and concerns about recurring malignancy being considered contraindications. This study assesses survival in highly selected patients undergoing lung transplantation for LONIPCs after SCT. SCT patients undergoing lung transplantation at 20 European centres between 1996 and 2014 were included. Clinical data pre- and post-lung transplantation were reviewed. Propensity score-matched controls were generated from the Eurotransplant and Scandiatransplant registries. Kaplan–Meier survival analysis and Cox proportional hazard regression models evaluating predictors of graft loss were performed. Graft survival at 1, 3 and 5 years of 84%, 72% and 67%, respectively, among the 105 SCT patients proved comparable to controls (p=0.75). Sepsis accounted for 15 out of 37 deaths (41%), with prior mechanical ventilation (HR 6.9, 95% CI 1.0–46.7; p&lt;0.001) the leading risk factor. No SCT-specific risk factors were identified. Recurring malignancy occurred in four patients (4%). Lung transplantation &lt;2 years post-SCT increased all-cause 1-year mortality (HR 7.5, 95% CI 2.3–23.8; p=0.001). Lung transplantation outcomes following SCT were comparable to other end-stage diseases. Lung transplantation should be considered feasible in selected candidates. No SCT-specific factors influencing outcome were identified within this carefully selected patient cohort.
Infectious Scarring: Setting the Trigger for Intestinal Inflammation
Authors: Andrew M.F. Johnson, R. William DePaolo
Journal: Cell Host & Microbe (2018)

The initiating factors that trigger inflammatory bowel disease (IBD) are poorly understood. In a recent paper, Yang et al. (2017) demonstrate that IBD-like syndrome in mice can develop as a consequence of recurrent pathogen infection. Pathogenic triggering of inflammatory disease is a re-emerging concept that has significant therapeutic implications.
IRE1α RNase–dependent lipid homeostasis promotes survival in Myc-transformed cancers
Authors: Hong Xie, Chih-Hang Anthony Tang, Jun H. Song, Anthony Mancuso, Juan R. Del Valle, Jin Cao, Yan Xiang, Chi V. Dang, Roy Lan, Danielle J. Sanchez, Brian Keith, Chih-Chi Andrew Hu, M. Celeste Simon
Journal: Journal of Clinical Investigation (2018)

Myc activation is a primary oncogenic event in many human cancers; however, these transcription factors are difficult to inhibit pharmacologically, suggesting that Myc-dependent downstream effectors may be more tractable therapeutic targets. Here, we show that Myc overexpression induces endoplasmic reticulum (ER) stress and engages the inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP1) pathway through multiple molecular mechanisms in a variety of c-Myc– and N-Myc–dependent cancers. In particular, Myc-overexpressing cells require IRE1α/XBP1 signaling for sustained growth and survival in vitro and in vivo, dependent on elevated stearoyl-CoA-desaturase 1 (SCD1) activity. Pharmacological and genetic XBP1 inhibition induces Myc-dependent apoptosis, which is alleviated by exogenous unsaturated fatty acids. Of note, SCD1 inhibition phenocopies IRE1α RNase activity suppression in vivo. Furthermore, IRE1α inhibition enhances the cytotoxic effects of standard chemotherapy drugs used to treat c-Myc–overexpressing Burkitt's lymphoma, suggesting that inhibiting the IRE1α/XBP1 pathway is a useful general strategy for treatment of Myc-driven cancers.
A new cell line expressing a novel type of TMPRSS2-ERG gene fusion derived from primary tumors of familial prostate cancer patient
Authors: Johng Rhim, Hongzhen Li, Bungo Furusato, Jun Miki, Chen Sun, Taduru Sreenath, Albert Dobi, Gyorgy Petrovics, Bharati Hukku, Isabell Sesterhenn, David McLeod, Shiv Srivastava
Journal: Cancer Research (2008)

194   Recent studies have established that a high proportion of prostate cancer harbors a gene fusion between the androgen regulated TMPRSS2 gene and the ETS genes ERG, ETV1 or ETV4. However  in vitro  model representing primary tumors to study the molecular mechanisms and functional consequences of this important chromosomal rearrangement are currently limited and are greatly needed. The tumor tissue (RC-123T) used for generating the RC-123T/E cell line with HPV-16 E6E7 genes was obtained from a 57 year old familial prostate cancer patient who had adenocarcinoma with well differentiation (Gleason 3+3). The cell line was characterized phenotypically and cytogenically. Dual color fluorescence in situ hybridization (FISH) assay was used to test for ERG (3’ 5’) break aparts, and for translocation of TMPRSS2 and ERG and ETV1, in both interphase nuclei as well as metaphases. The cells were also characterized for putative stem cell markers CD133, SOX2 and prostate cell markers by immunohistochemistry and RT-PCR.    We have successfully established an immortalized human prostate epithelial cell culture derived from primary tumors of familial prostate cancer patients carrying TMPRSS2-ERG fusion genes with HPV16 E6E7 genes (RC-123T/E). RC-123T/E cells are currently growing well at passage 30, whereas RC-123T cells senesced at passage 5. Expression of an androgen-regulated prostate specific homeobox gene, NKX3.1, the epithelial cell-specific cytokeratin 8 and androgen receptor but not prostate specific antigen, was detected in RC-123T/E cells. TMPRSS2-ERG genes were also expressed in this line. The RC-123T/E cells formed spheres under suspension culture and branched differentiated in matrigel. The RC-123T/E cells also expressed putative stem cell markers CD133 and SOX2. Interestingly, the FISH analysis showed the translocation of chromosome t(7;21)(q21:q21) in the RC-123T/E cell line and also in its primary tumor tissue. We demonstrate that RC-123T/E cell line and its primary tumor tissue possess the translocation of TMPRSS2/ERG to chromosome 7q which adds another class of gene arrangement in prostate cancer. In addition, this cell line expressed putative stem cell markers and TMPRSS2-ERG gene fusion. This model provides a novel tool to study the cellular and molecular mechanisms of TMPRSS2-ETS genes in prostate cancer.
Transcriptional expression of Bcl-2 as predictive of response to neoadjuvant chemotherapy with trastuzumab in HER2-positive ER-positive breast cancer patients.
Authors: Maki Tanioka, Kazuko Sakai, Tamotsu Sudo, Toshiko Sakuma, Kouichi Hirokaga, Shintaro Takao, Hironobu Minami, Shunichi Negoro, Kazuhiko Nakagawa, Kazuto Nishio
Journal: Journal of Clinical Oncology (2014)

602 Background: Several trials have confirmed that pathologic complete response (pCR) rates after neoadjuvant chemotherapy (NAC) are significantly lower in HER2+/ER+ patients (pts) than in HER2+/ER− pts. To elucidate this phenomenon, we investigated the association of anti-apoptotic Bcl-2, which is frequently overexpressed in ER+ tumors, with to NAC resistance. Methods: Pretreatment formalin-fixed tumor tissues were collected from 75 HER2+ pts receiving NAC comprising anthracyclines, taxanes, and trastuzumab. mRNA expression was detected by PCR amplificationand quantitative primer extension using MassARRAY (Sequenom, CA). The panel of 15 genes comprised EGFR, HER2, HER3, IGF1R, FGFR, PTEN, INPP4B, SRC-1, DUSP4, ESR1, PgR, FOXA1, PDL1, CTLA-4, and Bcl-2, whose expressions were dichotomized according to median values. PIK3CA mutations were detected using MassARRAY genotyping. ER, PTEN, and Bcl-2 protein expressions were scored from 0 to 3 according to the frequency and intensity by immunohistochemisty (IHC). The relationship between variables was assessed by Spearman's correlation. Logistic regression analysis was performed to detect predictors of pCR, which was defined as no invasive tumor in the breast or axilla. Results: Median age was 58 years; 97% were stage II–III, 47% were ER+, and 52% (40%/ 63% in ER+/ ER−) achieved pCR. Bcl-2 mRNA and protein expression were correlated (r=0.66, p=.001). In univariate analysis, pCR was associated with high mRNA levels of ESR1, PgR, IGF1R, HER2, CTLA4, PDL-1, and Bcl-2 (p≤.05), but not with PIK3A mutations or PTEN loss by IHC. Bcl-2 expression was significantly correlated with ESR1 (r=0.74), PgR (r=0.74), and IGF1R (r=0.68); thus, PDL-1, CTLA4, HER2, and Bcl-2 were tested in the multivariate model. Bcl-2 retained the predictive value for pCR [p=.022; odds ratio (OR), 0.28 (0.10–0.84)]. In ER+ pts, median Bcl-2 levels were 2.2 times higher than in ER− pts, and pCR rates were 17% and 65% in pts with high and low Bcl-2 expression, respectively (p=.006; OR, 0.11). Conclusions: Our data suggests Bcl-2 expression is predictive of pCR and provides a rationale for the evaluation of Bcl-2 inhibitors in HER2+/ER+ BC pts.
Recent Insights into the Pathogenesis of Nonalcoholic Fatty Liver Disease
Authors: Juan Pablo Arab, Marco Arrese, Michael Trauner
Journal: Annual Review of Pathology Mechanisms of Disease (2018)

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches based on a profound understanding of its pathogenesis to halt disease progression to advanced fibrosis or cirrhosis and cancer. The pathogenesis of NAFLD involves a complex interaction among environmental factors (i.e., Western diet), obesity, changes in microbiota, and predisposing genetic variants resulting in a disturbed lipid homeostasis and an excessive accumulation of triglycerides and other lipid species in hepatocytes. Insulin resistance is a central mechanism that leads to lipotoxicity, endoplasmic reticulum stress, disturbed autophagy, and, ultimately, hepatocyte injury and death that triggers hepatic inflammation, hepatic stellate cell activation, and progressive fibrogenesis, thus driving disease progression. In the present review, we summarize the currently available data on the pathogenesis of NAFLD, emphasizing the most recent advances. A better understanding of NAFLD/NASH pathogenesis is crucial for the design of new and efficient therapeutic interventions.
Ultra-Slow Single-Vessel BOLD and CBV-Based fMRI Spatiotemporal Dynamics and Their Correlation with Neuronal Intracellular Calcium Signals
Authors: Yi He, Maosen Wang, Xuming Chen, Rolf Pohmann, Jonathan R. Polimeni, Klaus Scheffler, Bruce R. Rosen, David Kleinfeld, Xin Yu
Journal: Neuron (2018)
Remote Ischemic Preconditioning with - but not Without - Metabolic Support Protects Against Ischemia-Reperfusion Injury in the Newborn Piglet In-vivo
Authors: M R Schmidt, N B Stoettrup, M M Michelsen, R Birkler, M Johannesen, R K Kharbanda, A N Redington, H E Botker
Journal: Circulation (2012)
Evolution of Continuing Medical Education
Authors: Graham T. McMahon, Susan E. Skochelak
Journal: JAMA (2018)

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GPs in Scotland vote to accept new contract
Authors: Bryan Christie
Journal: BMJ (2018)

Scotland’s family doctors have voted by a large majority to accept a new contract that will radically change the way they work.

It will see GPs develop a new role as “expert medical generalists” working at the head of primary care teams to deliver integrated community services. It offers a guaranteed minimum income of just over £80 000 for GP partners, the end of GP responsibility for some services such as vaccinations, and a new funding formula that gives greater resources to practices with large numbers of elderly patients.

Although …
Safety of rAAV2/2-ND4 Gene Therapy for Leber Hereditary Optic Neuropathy
Authors: Catherine Vignal, Scott Uretsky, Serge Fitoussi, Anne Galy, Laure Blouin, Jean-François Girmens, Samuel Bidot, Nitza Thomasson, Céline Bouquet, Sonia Valero, Sandrine Meunier, Jean-Philippe Combal, Bernard Gilly, Barrett Katz, José-Alain Sahel
Journal: Ophthalmology (2018)

Leber hereditary optic neuropathy (LHON) is the most commonly recognized mitochondrial disease. It typically occurs in young male adults, causing painless, acute, and profound vision loss. It presents asynchronously with the second eye almost always involved within weeks or months, a phenotypic declaration nearly pathognomonic for LHON. Visual prognosis is poor and therapy wanting.1