tbuckley/cabot-search huggingface dataset:
Inhibition of Protein arginine methyltransferase 6 reduces reactive oxygen species production and attenuates aminoglycoside- and cisplatin-induced hair cell death
Authors: Yingzi He, Wen Li, Zhiwei Zheng, Liping Zhao, Wenyan Li, Yunfeng Wang, Huawei Li
Journal: Theranostics (2019)

Hair cells in the inner ear have been shown to be susceptible to ototoxicity from some beneficial pharmaceutical drugs, such as aminoglycosides and cisplatin. Thus, there is great interest in discovering new targets or compounds that protect hair cells from these ototoxic drugs. Epigenetic regulation is closely related to inner ear development; however, little is known about epigenetic regulation in the process of ototoxic drugs-induced hearing loss. Methods: In this study, we investigated the role of protein arginine methyltransferase 6 (PRMT6) in aminoglycoside- and cisplatin-induced hair cell loss by using EPZ020411, a selective small molecule PRMT6 inhibitor, in vitro in neonatal mouse cochlear explants and in vivo in C57BL/6 mice. We also took advantage of the HEI-OC1 cell line to evaluate the anti-apoptosis effects of PRMT6 knockdown on cisplatin-induced ototoxicity. Apoptotic cells were identified using cleaved caspase-3 staining and TUNEL assay. The levels of reactive oxygen species (ROS) were evaluated by DCFH-DA and cellROX green staining. The mitochondrial membrane potential (ΔΨm) were determined by JC-1, TMRM, and rhodamine 123 staining. Results: We found that EPZ020411 significantly alleviated neomycin- and cisplatin-induced cell apoptosis and increased hair cell survival. Moreover, pretreatment with EPZ020411 could attenuate neomycin- and cisplatin-induced hearing loss in vivo. Mechanistic studies revealed that inhibition of PRMT6 could reverse the increased expression of caspase-3 and cytochrome c translocation, mitochondrial dysfunction, increased accumulation of ROS, and activation of cell apoptosis after cisplatin injury. Conclusions: Our findings suggested that PRMT6 might serve as a new therapeutic target to prevent hearing loss caused by aminoglycoside- and cisplatin-induced ototoxicity by preventing ROS formation and modulating the mitochondria-related damage and apoptosis.
Mechanistic investigations into the encapsulation and release of small molecules and proteins from a supramolecular nucleoside gel in vitro and in vivo
Authors: Maria Galini Faidra Angelerou, Robert Markus, Vasiliki Paraskevopoulou, Rugerro Foralosso, Philip Clarke, Clara V Alvarez, Miguel Chenlo, Litty Johnson, Catrin Rutland, Stephanie Allen, Christopher Brasnett, Annela Seddon, Mischa Zelzer, Maria Marlow
Journal: Journal of Controlled Release (2019)

Supramolecular gels have recently emerged as promising biomaterials for the delivery of a wide range of bioactive molecules, from small hydrophobic drugs to large biomolecules such as proteins. Although it has been demonstrated that each encapsulated molecule has a different release profile from the hydrogel, so far diffusion and steric impediment have been identified as the only mechanisms for the release of molecules from supramolecular gels. Erosion of a supramolecular gel has not yet been reported to contribute to the release profiles of encapsulated molecules. Here, we use a novel nucleoside-based supramolecular gel as a drug delivery system for proteins with different properties and a hydrophobic dye and describe for the first time how these materials interact, encapsulate and eventually release bioactive molecules through an erosion-based process. Through fluorescence microscopy and spectroscopy as well as small angle X-ray scattering, we show that the encapsulated molecules directly interact with the hydrogel fibres - rather than being physically entrapped in the gel network. The ability of these materials to protect proteins against enzymatic degradation is also demonstrated here for the first time. In addition, the released proteins were proven to be functional in vitro. Real-time fluorescence microscopy together with macroscopic release studies confirm that erosion is the key release mechanism. In vivo, the gel completely degrades after two weeks and no signs of inflammation are detected, demonstrating its in vivo safety. By establishing the contribution of erosion as a key driving force behind the release of bioactive molecules from supramolecular gels, this work provides mechanistic insight into the way molecules with different properties are encapsulated and released from a nucleoside-based supramolecular gel and sets the basis for the design of more tailored supramolecular gels for drug delivery applications.
PD01.10 Diagnostic Non-Invasive Biopsy Can Substitute Conventional Tissue Dependent Procedures in Suspected Cases of Lung Cancer
Authors: D. Akolkar, R. Patil, D. Patil, P. Fulmali, S. Patil, S. Patel, A. Adhav, P. Fulmali, S. Khan, A. Ranade, A. Srinivasan, R. Datar
Journal: Journal of Thoracic Oncology (2019)
Lenalidomide (Revlimid™), Adriamycin and Dexamethasone Chemotherapy (RAD) Is Safe and Effective in Treatment of Relapsed Multiple Myeloma - First Results of a German Multicenter Phase I/II Trial.
Authors: Stefan Knop, Christian Gerecke, Max S. Topp, Peter Liebisch, Georg Hess, Sandra Kotkiewitz, Hermann Einsele, Ralf Bargou
Journal: Blood (2006)
Direct Current Cardioversion of Atrial Fibrillation in Patients With Left Atrial Appendage Occlusion Devices
Authors: Sharan Prakash Sharma, Mohit K. Turagam, Rakesh Gopinathannair, Vivek Reddy, Saibal Kar, Sangamitra Mohanty, Jie Cheng, David R. Holmes, Lars Sondergaard, Andrea Natale, Dhanunjaya Lakkireddy
Journal: Journal of the American College of Cardiology (2019)
OA01.07 Capmatinib (INC280) in METΔEX14-Mutated Advanced NSCLC: Efficacy Data from the Phase 2 Geometry MONO-1 Study
Authors: R.S. Heist, J. Wolf, T. Seto, J.-Y. Han, N. Reguart, H.J.M. Groen, D.S.W. Tan, T. Hida, M.D. Jonge, S.V. Orlov, E.F. Smit, P.-J. Souquet, J. Vansteenkiste, M. Giovannini, S.L. Mouhaer, A. Robeva, M. Waldron-Lynch, E.B. Garon
Journal: Journal of Thoracic Oncology (2019)
The TNF-like weak inducer of the apoptosis/fibroblast growth factor–inducible molecule 14 axis mediates histamine and platelet-activating factor–induced subcutaneous vascular leakage and anaphylactic shock
Authors: Nerea Mendez-Barbero, Alma Yuste-Montalvo, Emilio Nuñez-Borque, Bettina M. Jensen, Carmen Gutiérrez-Muñoz, Jaime Tome-Amat, María Garrido-Arandia, Araceli Díaz-Perales, Contanza Ballesteros-Martinez, Jose Julio Laguna, J.M. Beitia, Lars K. Poulsen, Javier Cuesta-Herranz, Luis Miguel Blanco-Colio, Vanesa Esteban
Journal: Journal of Allergy and Clinical Immunology (2019)

Anaphylaxis includes mast cell (MC) activation, but less is known about downstream mechanisms (ie, vascular permeability controlled by endothelial cells [ECs]). The TNF-like weak inducer of apoptosis (TWEAK) and its sole receptor, fibroblast growth factor-inducible molecule 14 (Fn14), belong to the TNF superfamily and are involved in proinflammatory responses.We sought to investigate the role of TWEAK/Fn14 axis in anaphylaxis.In vivo vascular permeability and mouse models of passive systemic anaphylaxis (PSA) and active systemic anaphylaxis were applied to wild-type (WT), TWEAK- and Fn14-deficient mice (TWEAK-/- and Fn14-/-, respectively). Primary bone marrow-derived mast cells (BMMCs) and ECs from WT and Fn14-/- or TWEAK-/- mice were studied. The TWEAK/Fn14 axis was also investigated in human samples.Mice with PSA and active systemic anaphylaxis had increased Fn14 and TWEAK expression in lung tissues and increased serum soluble TWEAK concentrations. TWEAK and Fn14 deficiencies prevent PSA-related symptoms, resulting in resistance to decreased body temperature, less severe reactions, and maintained physical activity. Numbers of MCs after PSA are similar between genotypes in different tissue regions, such as ear skin and the trachea, tongue, peritoneum, lungs, and bone marrow. Moreover, in vitro studies revealed no differences in degranulation or mediator release between WT and Fn14-/- BMMCs after IgE-FcεRI stimulation. In vivo and in vitro histamine and platelet-activating factor administration increases Fn14 receptor expression in lungs and ECs. Moreover, Fn14 deficiency in ECs maintained in vitro impermeability when stimulated by mediators or activated BMMCs but not by TWEAK-/- BMMCs, indicating that Fn14 is crucial for endothelial barrier function. TWEAK/Fn14 deletion or TWEAK-blocking antibody prevented histamine/platelet-activating factor-induced vascular subcutaneous permeability. Circulating soluble TWEAK levels were increased in patients with anaphylaxis, and plasma from those patients increased Fn14 expression in ECs.The TWEAK/Fn14 axis participates in anaphylactic reactions. Inhibition of TWEAK/Fn14 interaction could be efficacious in anaphylaxis therapy.
Longitudinal oncology registry of head and neck carcinoma (LORHAN): First report of outcomes
Authors: W. J. Curran, A. Y. Chen, A. S. Garden, P. Harari, B. A. Murphy, S. Wong, L. A. Bellm, M. Schwartz, D. Dawson, K. K. Ang
Journal: Journal of Clinical Oncology (2009)

6071 Background: Registries can be invaluable for describing patterns of care and outcomes for a population of patients (pts). We report the initial survival findings from LORHAN, a prospective, longitudinal, observational national registry of head and neck carcinoma (HNC) pts. Methods: Pts are eligible for LORHAN if they have newly diagnosed HNC, are scheduled to receive radiotherapy (RT) or drug therapy, are ≥18 years of age and have provided written informed consent. Data are entered in the registry electronically and transferred via Secure HTTP protocols. Patient confidentiality is strictly maintained. Pts are followed from time of initial diagnosis and for a minimum of 2 and up to 10 years. When information is complete and has been verified and signed off by the investigator, a record is locked. Only locked records are summarized and reported. Results: 2,354 pts have been enrolled in LORHAN since Dec. 2005. Of these, 1,326 pts have completed initial cancer treatment and have locked records. 1- and 2-year follow-up data are available for 583 and 56 pts, respectively. Baseline characteristics were similar between settings, except that pts treated at academic centers were significantly younger (58 vs. 62 years of age), had poorer performance status (mean Zubrod: 0.9 vs. 0.7), had fewer laryngeal tumors (17% vs. 27% of pts) but more oropharyngeal tumors (42% vs. 37% of pts) and presented with more advanced disease (stage IV: 70% vs. 48% of pts) compared to pts treated in community. Treatment did not differ by setting. Treatment and survival data are shown below. Conclusions: LORHAN demonstrates it is feasible to collect more detailed information about patient and tumor features and treatment other than surgery. Changes in the pattern of care and survival findings are expected to emerge as newer regimens, including IC and targeted agents, are incorporated more broadly into clinical practice, and data in LORHAN matures. [Table: see text] [Table: see text]
Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach
Authors: Yacine Bareche, Laurence Buisseret, Tina Gruosso, Edwina Girard, David Venet, Floriane Dupont, Christine Desmedt, Denis Larsimont, Morag Park, Françoise Rothé, John Stagg, Christos Sotiriou
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background Recent efforts of gene expression profiling analyses recognized at least four different triple-negative breast cancer (TNBC) molecular subtypes. However, little is known regarding their tumor microenvironment (TME) heterogeneity. Methods Here, we investigated TME heterogeneity within each TNBC molecular subtype, including immune infiltrate localization and composition together with expression of targetable immune pathways, using publicly available transcriptomic and genomic datasets from a large TNBC series totaling 1512 samples. Associations between molecular subtypes and specific features were assessed using logistic regression models. All statistical tests were two-sided. Results We demonstrated that each TNBC molecular subtype exhibits distinct TME profiles associated with specific immune, vascularization, stroma, and metabolism biological processes together with specific immune composition and localization. The immunomodulatory subtype was associated with the highest expression of adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check point inhibitors. In contrast, most mesenchymal stem-like and luminal androgen receptor tumors showed an immunosuppressive phenotype as witnessed by high expression levels of stromal signatures. Basal-like, luminal androgen receptor, and mesenchymal subtypes exhibited an immune cold phenotype associated with stromal and metabolism TME signatures and enriched in margin-restricted spatial pattern. Tumors with high chromosomal instability and copy number loss in the chromosome 5q and 15q regions, including genomic loss of major histocompatibility complex related genes, showed reduced cytotoxic activity as a plausible immune escape mechanism. Conclusions Our results demonstrate that each TNBC subtype is associated with specific TME profiles, setting the ground for a rationale tailoring of immunotherapy in TNBC patients.
Interventions to Improve Informed Consent
Authors: Peter Angelos
Journal: JAMA Surgery (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Logistical Challenges Associated With Implementing Precision Medicine—Reply
Authors: Thomas J. Povsic, E. Magnus Ohman, C. Michael Gibson
Journal: JAMA Cardiology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
<i>MUC5B</i> promoter variant: genomic fingerprint for early identification of undiagnosed pulmonary fibrosis
Authors: Ayodeji Adegunsoye
Journal: Thorax (2019)

The rising prevalence of pulmonary fibrosis and its attendant morbidity and mortality burden have spurred a renewed interest in the search for radiographical biomarkers predictive of early and clinically inconspicuous disease.1 The pressing need to identify such biomarkers becomes increasingly important as these abnormalities may herald the onset of pulmonary fibrosis, which could be rapidly progressive, necessitating clinical intervention. Antifibrotic therapies have been recently demonstrated to slow the progression of pulmonary fibrosis across diverse forms of interstitial lung disease (ILD), providing some hope in those individuals shown to be at risk.2 In this regard, high-resolution CT (HRCT) scans of the chest hold a broad appeal as a non-invasive radiological tool that is clinically accessible and rapidly performed with near-instantaneous results. Thus, a great deal of emphasis is currently placed on the recognition of radiological abnormalities that possibly signify pulmonary fibrosis in its early stages.3 These subclinical bilateral interstitial densities, often termed interstitial lung abnormalities (ILAs) or early ILD, are frequently observed on chest HRCTs and are associated with increased risk of hospitalisation and death.3 4 However, substantial inter-reader variability in radiologist interpretations of these fibrotic indices has led to increased reliance on deep learning algorithms and artificial intelligence to identify and accurately quantify the extent of lung parenchymal fibrosis in a more objective manner.5 

In tandem with the rapid pace of radiological biomarker advancements is the increasing recognition of the predictive and prognostic value of genomic biomarkers associated with pulmonary fibrosis.6 Of prime importance among the genomic biomarkers that predict risk of pulmonary fibrosis are the polymorphisms in the promoter region of the gene encoding mucin 5B ( MUC5B ) ( rs35705950 ) and gene variants in the …
The effect of an antimicrobial stewardship programme in two intensive care units of a teaching hospital: an interrupted time series analysis
Authors: L. Onorato, M. Macera, F. Calò, C. Monari, F. Russo, M.R. Iovene, G. Signoriello, R. Annibale, M.C. Pace, C. Aurilio, G.B. Gaeta, N. Coppola
Journal: Clinical Microbiology and Infection (2019)
Ovarian cancer cell-secreted exosomal miR-205 promotes metastasis by inducing angiogenesis
Authors: Liuqing He, Wei Zhu, Quan Chen, Yishu Yuan, Yixuan Wang, Junpu Wang, Xiaoying Wu
Journal: Theranostics (2019)

Background: By providing oxygen, nutrients and metastatic conduits, tumour angiogenesis is essential for cancer metastasis. Cancer cell-secreted microRNAs can be packaged into exosomes and are implicated in different aspects of tumour angiogenesis. However, the underlying mechanisms are incompletely understood. Methods: The GEPIA database and in situ hybridization assay were used to analyse expression of miR-205 in ovarian tissues. Immunohistochemistry was performed to examine the relationship between miR-205 and microvessel density. Expression of circulating miR-205 was evaluated by RT-PCR and GEO database analysis. Co-culture and exosome labelling experiments were performed to assess exosomal miR-205 transfer from ovarian cancer (OC) cells to endothelial cells ECs. Exosome uptake assays were employed to define the cellular pathways associated with the endocytic uptake of exosomal miR-205. The role of exosomal miR-205 in angiogenesis was further investigated in vivo and in vitro. Western blotting and rescue experiments were applied to detect regulation of the PTEN-AKT pathway by exosomal miR-205 in ECs. Results: miR-205 was up-regulated in OC tissues, and high expression of miR-205 was associated with metastatic progression in OC patients. Moreover, miR-205 was highly enriched in cancer-adjacent ECs, and up-regulation of miR-205 correlated positively with high microvessel density in OC patients. Importantly, miR-205 was markedly enriched in the serum of OC patients, and a high level of miR-205 in circulating exosomes was associated with OC metastasis. In addition, OC-derived miR-205 was secreted into the extracellular space and efficiently transferred to adjacent ECs in an exosome-dependent manner, and the lipid raft-associated pathway plays an important role in regulating uptake of exosomal miR-205. Exosomal miR-205 from OC cells significantly promoted in vitro angiogenesis and accelerated angiogenesis and tumour growth in a mouse model. Furthermore, we found that exosomal miR-205 induces angiogenesis via the PTEN-AKT pathway. Conclusion: These findings demonstrate an exosome-dependent mechanism by which miR-205 derived from cancer cells regulates tumour angiogenesis and implicate exosomal miR-205 as a potential therapeutic target for OC.
Long-Term Results of Aortic-Pulmonary Anastomosis for Tetralogy of Fallot
Authors: MILTON H. PAUL, ROBERT A. MILLER, WILLIS J. POTTS
Journal: Circulation (1961)

The first 100 consecutive patients with a diagnosis of tetralogy of Fallot upon whom an aortic-pulmonary anastomosis could be performed were subjected to a clinical and physiologic evaluation 11 to 13 years after operation. At this long-term follow-up 92 patients were traced. Nine patients died at the time of surgery and, in the period from 1946 to 1959, 10 patients died, most often from congestive heart failure. To our knowledge only three patients have required a second shunt operation to relieve recurrent cyanosis. The clinical results were considered good or excellent in 68 per cent of the survivors, fair in 30 per cent, and poor in 2 per cent. The long-term poor results and mortality were usually associated with too large an initial anastomosis leading to either left ventricular overwork and congestive heart failure or severe pulmonary hypertension and progressive pulmonary vascular obstruction. Right heart catheterization studies indicated that in a group of 18 patients in whom the pulmonary vascular bed could be evaluated, 15 patients had a normal pulmonary vascular resistance after 11 to 13 years of a clinically adequate aortic-pulmonary shunt. The role of the shunt procedures as a valuable salvage operation at the present time for a select segment of patients with tetralogy of Fallot and certain other complex cyanotic lesions is reemphasized.