tbuckley/cabot-search huggingface dataset:
Transcription inhibition of heat shock proteins: A strategy for combination of 17AAG and actinomycin D
Authors: Fabiola Gomez, Ramadevi Nimmanapalli, Varsha Gandhi
Journal: Cancer Research (2007)

5728   Multiple myeloma (MM) is a cancer of the plasma cell that becomes resistant to several chemotherapeutic agents. Recently it has been shown that heat shock proteins (HSPs) are important in the survival of cancer cells. In particular, HSP90 and HSP70 have been linked to chemotherapeutic resistance in hematological malignancies. HSP90 inhibitors such as geldanamycin and its analog, 17AAG, show some antitumor activities in the clinic. However, treatment with these inhibitors results in the elevation of HSP70 antiapoptotic protein levels which may lead to resistance. The increase in HSP70 protein was due to transcription activation of HSP70 mRNA by binding of the transcription factor, HSF-1 to its promoter. We hypothesize that inhibition of HSP70 transcription by transcriptional inhibitors may enhance 17AAG-induced cell death. To test our hypothesis, we used 8226, a MM cell line which expresses high levels of HSP70. Actinomycin D (Act D), already in clinic, was used as a transcription inhibitor. To test the transcriptional inhibitory potency of Act D in 8226 cells, [ 3 H]uridine incorporation assay was conducted. Act D treatment at 0.05 µg/µL for 4h and 8h resulted in 75% decrease in total RNA synthesis. HSP27, 70, and 90 mRNA and protein levels were measured by real time RT-PCR and immunoblot assays. Treatment with HSP90 inhibitor, 17AAG (0.5 μM, 8h), resulted in a 1.5-fold induction in mRNA levels of HSP70 and HSP90 and a 7-fold increase in HSP27 mRNA. Compared to untreated cells, the treatment with Act D alone (0.05 µg/µL, 12h) decreased mRNA levels of all HSPs; there was a 65%, 50%, and 25% reduction in HSP70, HSP90, and HSP27 mRNA, respectively. Combination of Act D with 17AAG attenuated 17AAG-induced increase in transcript levels of HSPs. HSP70 mRNA was reduced to 30% of control, while HSP27 and HSP90 levels were same as the endogenous mRNA levels in untreated control. Consistent with mRNA levels, HSP protein levels were also affected. 17AAG resulted in a 5-fold increase in HSP70 protein levels and 3-fold enhancement of HSP27 and HSP90 protein levels. Compared to untreated control, treatment with the transcription inhibitor Act D did not change protein levels of HSP70, HSP90 and HSP27. However, Act D was able to counter balance 17AAG-induced increase in HSP protein levels as all were back to basal expression levels. Because Act D in combination with 17AAG was able to diminish the effect of 17AAG on both mRNA and protein levels of HSP70, we tested the consequence of these agents on cell death. At this concentration, 17AAG alone did not result in induction of cell death in 8226 cells as measured by annexin binding assay. Treatment with Act D showed 55% cell death while combination of 17AAG and Act D resulted in 80% cell death (more than additive effect). In conclusion, these results indicate that 17AAG-mediated induction of HSP70 and HSP27 mRNAs could be attenuated by Act D resulting in lowering of these HSP proteins and affecting cell death.
Abstract 273: Glycogen Depletion During Hypoxia Results in Enhanced AMPK Phosphorylation and Diminished Smooth Muscle Contractility in Human Saphenous Vein
Authors: Lakshman Segar, Rajkumar Pyla, Prahalathan Pichavaram, Arwa Fairaq, Mark Kozak, Vinayak Kamath, Vijay Patel
Journal: Circulation Research (2014)

Objectives: Hypoxia promotes vasodilation of coronary arteries as a protective response to improve blood flow to the myocardium. Although diminished formation of ATP and enhanced phosphorylation/activation of AMP-activated protein kinase (AMPK) in vascular smooth muscle are known to mediate hypoxia-induced vasorelaxation, the contribution of glycogen toward AMPK phosphorylation and contractility remains unclear. Methods: Using surgically-removed endothelium-denuded human saphenous vein segments ex vivo, the present study has examined serotonin (5-HT)-induced smooth muscle contractility by isometric tension measurements and AMPK phosphorylation by immunoblot analysis under normoxic (95% O2/5% CO2) and hypoxic conditions (95% N2/5% CO2, 30 min). Results: Under normoxic glycogen-enriched conditions, the maximal contractile response (Emax) and sensitivity (pEC50) to 5-HT-induced contractility were 145 ± 3% and 6.7 ± 0.2, respectively (n = 4). Induction of hypoxia diminished the glycogen content by ~95% (3.7 ± 1 under hypoxia versus 73.6 ± 5 μg/mg protein under normoxia; n = 2). Importantly, glycogen depletion led to diminution in 5-HT-induced maximal contractility to 37 ± 11% with an accompanying exaggerated increase in AMPK phosphorylation, compared with normoxic conditions (n = 4). Inclusion of exogenous D-glucose (5.5 mM) prevented the exaggerated increase in AMPK phosphorylation thereby restoring 5-HT-induced maximal contractility to 125 ± 6% (n = 4). Parallel studies that included either L-glucose or 2-deoxy-D-glucose (non-metabolizable forms of glucose) did not show any changes in contractility or AMPK phosphorylation. Conclusion: The present findings suggest that depletion of smooth muscle glycogen during hypoxia may limit the availability of intracellular glucose in vein grafts, thereby enhancing AMPK phosphorylation to promote vasorelaxation.
HIGH PREVALENCE OF SUBSTANTIAL SHOULDER PROBLEMS AMONG ELITE ADOLESCENT HANDBALL PLAYERS: THE KAROLINSKA HANDBALL STUDY
Authors: Martin Asker, Lena W Holm, Henrik Källberg, Markus Waldén, Eva Skillgate
Journal: British Journal of Sports Medicine (2017)

<h3>Background</h3> Recent studies report a high prevalence of shoulder problems in senior team handball players but studies in adolescent players are lacking. <h3>Objective</h3> To measure the season prevalence of substantial shoulder problems (SSP) in elite adolescent handball players. <h3>Design</h3> Longitudinal cohort study with weekly online follow-ups. <h3>Setting</h3> Elite adolescent male and female handball players at handball-profiled high schools in Sweden. <h3>Participants</h3> 471 (54% females, mean age 16) were recruited from 10 of 15 national handball-profiled high schools. <h3>Assessment of Risk Factors</h3> The prevalence of SSP, stratified by age, was assessed through repeated online questionnaire data. <h3>Main Outcome Measurements</h3> Season prevalence of SSP during the previous handball season was measured during the pre-season (baseline), and was studied prospectively during the current season via weekly reports using the OSTRC Overuse Injury Questionnaire. SSP was defined as problems leading to moderate or severe reductions in handball participation or performance, or to time-loss. <h3>Results</h3> The weekly response rate was 86–96% and 83% of the players responded to at least 90% of the weekly reports. The previous season prevalence measured at baseline was 8% (95% CI 5–11%) among players in the 1st grade and 20% (95% CI (15–26%) in the 2nd and 3rd grades. During the prospective season, 22% (95% CI 17–27%) of players in the 1st grade reported having SSP, and 27% of players in the 2nd and 3rd grades. Of those with SSP at some point during the previous season, 67% (95% CI 54–77%) also reported SSP at least once during the prospective season. <h3>Conclusions</h3> The season prevalence of SSP is high among adolescent handball players and the prevalence increases when the players start high school. A majority of players with previous SSP also report subsequent SSP problems indicating that the pre-high school period is where prevention strategies preferably should be implemented.
Preclinical development of anti B7-H4 therapeutic antibodies
Authors: Jonathan Terrett, Lisheng Lu, Vidusha Devasthali, David King, Mary Huber, Chetana Rao-Naik, Sanjeev Gangwar, Vincent Guerlavais, Allen Zhang, Bilal Sufi, Liang Chen, Pina Cardarelli, James Phillips, Bing Chen, Haichun Huang, Dapeng Yao, Marco Coccia
Journal: Cancer Research (2008)

4986  B7-H4 ( O8E ) is a plasma membrane protein and a member of the B7 family of immune system co-stimulatory molecules. Its role and expression in the immune system remains to be fully characterized. However, B7-H4 has been shown to be absent from most normal tissues and highly expressed in multiple malignancies including breast cancer and ovarian cancer. Thus, even though this class of molecules may seem attractive as anti-cancer targets through immune stimulation, B7-H4 may be more tractable as a direct target on cancer cells. Here, we confirm the expression of B7-H4 in breast and ovarian cancer, as well as the limited normal tissue expression. In order to exploit the cancer specific expression of B7-H4 in a therapeutic setting we have developed fully human antibodies targeting B7-H4. These antibodies have high affinity and specificity and show both internalizing and ADCC activity on B7-H4 expressing cell lines. In a therapeutic xenograft model, an anti B7-H4 antibody-drug-conjugate is able to induce long term cures from a single low dose. Furthermore, this anti B7-H4 antibody is cross reactive with the mouse version of the protein, and shows no obvious on target toxicity despite the mouse protein showing similar normal tissue expression to humans. Thus B7-H4 is an attractive target for the development of targeted cytolytic antibodies for multiple cancer types.
Propagation of respiratory viruses in human airway epithelia reveals persistent virus-specific signatures
Authors: Manel Essaidi-Laziosi, Francisco Brito, Sacha Benaoudia, Léna Royston, Valeria Cagno, Mélanie Fernandes-Rocha, Isabelle Piuz, Evgeny Zdobnov, Song Huang, Samuel Constant, Marc-Olivier Boldi, Laurent Kaiser, Caroline Tapparel
Journal: Journal of Allergy and Clinical Immunology (2017)
Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic Stem-Cell Transplantation
Authors: Ifigeneia Tzannou, Anastasia Papadopoulou, Swati Naik, Kathryn Leung, Caridad A. Martinez, Carlos A. Ramos, George Carrum, Ghadir Sasa, Premal Lulla, Ayumi Watanabe, Manik Kuvalekar, Adrian P. Gee, Meng-Fen Wu, Hao Liu, Bambi J. Grilley, Robert A. Krance, Stephen Gottschalk, Malcolm K. Brenner, Cliona M. Rooney, Helen E. Heslop, Ann M. Leen, Bilal Omer
Journal: Journal of Clinical Oncology (2017)

Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available off-the-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.
Immune checkpoint inhibitor-associated interstitial lung diseases: some progress but still many issues
Authors: David Montani, Andrei Seferian, Florence Parent, Marc Humbert
Journal: European Respiratory Journal (2017)

Immunotherapy for cancer management is an old concept in which therapeutic agents are used to modulate immune cells rather than directly target cancer cells. However, it is the recent discovery of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and programmed cell death protein (PD-1) and its ligand PD-L1 that represents the latest major advance in cancer therapy. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies blocking CTLA-4 (ipilimumab and tremelimumab), PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab, durvalumab and avelumab). By unbalancing the immune system, immune checkpoint blockade also has a specific set of toxicities by favouring the development of dysimmune manifestations, also termed immune-related adverse events [1]. Immune checkpoint inhibitor use is increasing so clinicians must be aware of autoimmune complications especially ILD <http://ow.ly/UCQU30dkg2M>
ワクチンアジュバント活性増強の為のアルミニウム・オキシ水酸化物への合成TLR7/8リガンドの吸着;処方手段
Authors: B Fox Christopher, T Orr Mark, Van Hoeven Neal, C Parker Sarah, J T Mikasa Traci, Phan Tony, A Beebe Elyse, I Nana Ghislain, Joshi Sharvari W, A Tomai Mark, Elvecrog James, R Fouts Timothy, G Reed Steven
Journal: Journal of Controlled Release (2016)
05.07 Biomarker discovery in sjögren’s syndrome: database analysis and web interface design
Authors: Jean-Luc Mougeot, Nirav Shah, Aneeta Uppal, Braxton Noll, Mohamed Shehab, Farah Mougeot
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Sjögren's syndrome (SS) is an autoimmune disease with unknown aetiology. SS shares similarity with other autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Our objective was to use bioinformatics tools to identify both unique and common genes involved in the pathogenesis of SS, SLE and RA. <h3>Materials and methods</h3> Literature mining tool PubTator was used to identify genes associated with each disease. Python scripts were used to extract information from PubTator and integrate it into a MySQL database management system. Three salivary glands (SGs) and one peripheral blood mononuclear cells (PBMCs) gene expression datasets (NCBI-GEO) of SS patients were analysed using GEO2R. MySQL tables were joined and organised to retrieve gene sets, which were utilised for molecular network analysis using STRINGdb. A web interface was designed and implemented to provide unique platform for search and retrieval of genes associated with SS. <h3>Results</h3> Text mining yielded 847 genes in common in SS, SLE and RA. A total of 15 990 differentially expressed (DE) genes were represented in at least one dataset, including 683 in common with the 847 previously identified. Of these, 86 genes were differentially expressed in all SGs datasets. To identify DE genes unique to SGs of SS patients, PBMCs dataset was used to subtract DE genes common to SGs and PBMCs from the 86 genes. Remaining 71 genes were integrated into a molecular interaction network including 44 representing 22 SS-related biological processes. The biological processes included cytokine signalling, herpes virus infection, and toll-like receptor signalling. A web interface was established to aggregate and correlate gene expression and text mining data. <h3>Conclusions</h3> By combining text mining and gene expression analysis, we identified a molecular interaction network that contained DE genes representing candidate biomarkers for SS. Previous studies had reported no clear link between some of the identified genes and SS. These genes may be further investigated for their role in the progression of SS in experimental models. Further, the web interface provides dynamic platform to the investigator to correlate different data sources, which may provide additional insights on the development of SS.
L’utilisation de la sécrétine en IRM dans la pathologie pancréatique
Authors: R Ettessami, F Pilleul, T Ponchon, C Partensky, A Crombé, G Gautier, PJ Valette
Journal: Endoscopy (2004)

Introduction: L’objectif de notre étude a été d’analyser à travers notre expérience, l’apport de l’administration de la sécrétine dans l’amélioration de l’analyse canalaire dans les différentes pathologies canalaires et parenchymateuses pancréatiques, par rapport aux techniques d’imagerie par résonance magnétique (IRM) classique et de la cholangiographie pancréatique rétrograde par voie endoscopique (CPRE). Matériels et Méthodes: Soixante et onze patients répartis en quatre principaux groupes de pancréatite aiguë (n = 13), de pancréatite chronique (n = 32), de tumeur pancréatique (n = 8) et d’anastomose wirsungo gastrique (n = 18) ont été inclus dans l’étude. Des séquences canalaires (RARE) ont été pratiquées avant et après administration intraveineuse de sécrétine. L’analyse quantitative a consisté à mesurer la variation du calibre du canal principal (tête, corps, queue) et à évaluer le remplissage duodénal avant et après stimulation par la sécrétine. L’analyse qualitative a consisté à apprécier la régularité pariétale, à détecter des canaux secondaires dilatés, à dépister des zones de sténose canalaire et de défaut de remplissage endoluminal. Tous les résultats ont été confrontés aux données finales de la CPRE. Concernant les anastomoses wirsungo gastriques, nous avons analysé la visualisation directe de l’anastomose et sa perméabilité avant et après sécrétine. Résultats: Chez les patients sans antécédent de pancréatite chronique, la visualisation de tous les segments du canal pancréatique principal a été améliorée à l’IRM dynamique avec sécrétine (p < 0,001). Chez les patients présentant une pancréatite chronique la visualisation du canal pancréatique principal a été améliorée mais de manière moins significative (p < 0,05). Cependant la visualisation des canaux secondaires n’a été améliorée que chez des patients ne présentant pas de rétrécissement canalaire (p < 0,002) comparée à ceux qui présentaient une sténose canalaire (p > 0,2). L’appréciation de la régularité pariétale et la détection des sténoses canalaires ont également été améliorées chez tous les patients (p < 0,001) avec la même précision qu’à la CPRE (p < 0,01) sauf chez les patients atteints d’une pancréatite chronique sévère (p > 0,6). Une réduction du remplissage duodénal a été détectée chez les patients atteints d’une pancréatite chronique sévère (p < 0,01). Un pancréas divisum a été trouvé chez 7 patients avant et chez 11 patients après administration de la sécrétine. L’évaluation des anastomoses wirsungo gastriques a été améliorée de plus de 50% avec une amélioration significative de la visualisation de l’anastomose (p < 0,004). Conclusion: L’IRM dynamique avec sécrétine permet d’accroître la précision diagnostique en améliorant la visualisation du réseau canalaire pancréatique. Son intérêt est souligné en cas de canal principal non dilaté évitant une CPRE diagnostique.
Immunological response to nitroglycerin-loaded shear-responsive liposomes in vitro and in vivo
Authors: Marzia Buscema, Sofiya Matviykiv, Tamás Mészáros, Gabriela Gerganova, Andreas Weinberger, Ute Mettal, Dennis Mueller, Frederik Neuhaus, Etienne Stalder, Takashi Ishikawa, Rudolf Urbanics, Till Saxer, Thomas Pfohl, János Szebeni, Andreas Zumbuehl, Bert Müller
Journal: Journal of Controlled Release (2017)

Liposomes formulated from the 1,3-diamidophospholipid Pad-PC-Pad are shear-responsive and thus promising nano-containers to specifically release a vasodilator at stenotic arteries. The recommended preclinical safety tests for therapeutic liposomes of nanometer size include the in vitro assessment of complement activation and the evaluation of the associated risk of complement activation-related pseudo-allergy (CARPA) in vivo. For this reason, we measured complement activation by Pad-PC-Pad formulations in human and porcine sera, along with the nanopharmaceutical-mediated cardiopulmonary responses in pigs. The evaluated formulations comprised of Pad-PC-Pad liposomes, with and without polyethylene glycol on the surface of the liposomes, and nitroglycerin as a model vasodilator. The nitroglycerin incorporation efficiency ranged from 25% to 50%. In human sera, liposome formulations with 20 mg/mL phospholipid gave rise to complement activation, mainly via the alternative pathway, as reflected by the rises in SC5b-9 and Bb protein complex concentrations. Formulations having a factor of ten lower phospholipid content did not result in measurable complement activation. The weak complement activation induced by Pad-PC-Pad liposomal formulations was confirmed by the results obtained by performing an in vivo study in a porcine model, where hemodynamic parameters were monitored continuously. Our study suggests that, compared to FDA-approved liposomal drugs, Pad-PC-Pad exhibits less or similar risks of CARPA.
Selective suppression of breast cancer aromatase expression and aromatase promoter usage by the DAC inhibitor panobinostat (LBH589)
Authors: Jingjing Ye, Ikuko Kijima, Dean Evans, Shiuan Chen
Journal: Cancer Research (2008)

1576  Aromatase converts androgens to estrogens. Based on results from several major Phase III clinical trials, third-generation aromatase inhibitors (AIs) are now considered to be important drugs for the hormonal therapy of breast cancer in postmenopausal women. While results from clinical trials show efficacy benefits, there are concerns about the side effects associated with estrogen-deprivation achieved with AIs (e.g., bone loss and fractures, joint pain/arthralgia, bone pain/muscle pain). Previous investigations from this and other laboratories have found that expression of aromatase in breast cancer tissue is driven by promoters different from those used in non-cancer tissues. Therefore, the potential for selective suppression of aromatase expression/estrogen biosynthesis in breast cancer tissues through the down-regulation of breast tumor-specific promoters would be a novel approach to reduce side effects associated with whole-body suppression of estrogen biosynthesis achievable with AIs. Our recent research has found that the DAC inhibitor panobinostat is a potent inhibitor of aromatase expression (IC50 = 15 nM; panobinostat is 40 times more potent than SAHA in the suppression of aromatase expression). Panobinostat has been previously found to induce the degradation of proteins driving cancer growth and is currently in Phase II/III clinical development in patients with cutaneous T-cell lymphoma (CTCL). Our results also indicate that panobinostat selectively suppresses the promoters I.3/II of the human aromatase gene, promoters that are preferentially used in breast cancer tissue. Furthermore, using the H295R cell culture model, we observed that to achieve the same degree of inhibition of aromatase activity/estrogen biosynthesis, the needed concentration of letrozole (LET; an AI), in the presence of 25 nM panobinostat, was one fifth that required in the absence of panobinostat. Aromatase expression in H295R cells is selectively driven by promoters I.3/II. In addition, cell culture experiments were performed using a H295R/MCF7 co-culture model that demonstrated the synergistic interaction of panobinostat + LET in suppressing the proliferation of hormone-responsive breast cancer cells. Finally, our preliminary results also indicate that panobinostat down-regulates the activity of aromatase promoters I.3/II through an epigenetic fashion. Experiments are being performed to determine the molecular mechanisms involved. These results demonstrate effects of panobinostat on aromatase promoters utilized in the expression/regulation of aromatase in breast cancers along with synergistic interactions with LET in modifying breast cancer cell proliferation. These initial observations may hold potential value for future clinical evaluation of these agents in combination.