tbuckley/cabot-search huggingface dataset:
Synergy of Topical Toll-like Receptor 7 Agonist with Radiation and Low-Dose Cyclophosphamide in a Mouse Model of Cutaneous Breast Cancer
Authors: M. Zahidunnabi Dewan, Claire Vanpouille-Box, Noriko Kawashima, Sara DiNapoli, James S. Babb, Silvia C. Formenti, Sylvia Adams, Sandra Demaria
Journal: Clinical Cancer Research (2012)

This study tested the hypothesis that topical Toll-like receptor (TLR) 7 agonist imiquimod promotes antitumor immunity and synergizes with other treatments in a model of skin-involving breast cancer.TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice. Imiquimod 5% or placebo cream was applied topically on the shaved skin overlying tumors three times/wk. In some experiments, local ionizing radiation therapy (RT) was delivered to the tumor in three fractions of 8 Gy, given on consecutive days. Cyclophosphamide was given intraperitoneally (i.p.) in one dose of 2 mg/mouse. Mice were followed for tumor growth and survival.Treatment with imiquimod significantly inhibited tumor growth, an effect that was associated with increased tumor infiltration by CD11c(+), CD4(+), and CD8(+) cells, and abolished by depletion of CD8(+) cells. Administration of imiquimod in combination with RT enhanced significantly tumor response compared with either treatment alone (P < 0.005), and 11% to 66% of irradiated tumors completely regressed. Importantly, the addition of topical imiquimod also resulted in growth inhibition of a secondary tumor outside of the radiation field. Low-dose cyclophosphamide given before start of treatment with imiquimod and RT further improved tumor inhibition and reduced tumor recurrence. Mice that remained tumor-free rejected a tumorigenic inoculum of TSA cells, showing long-term immunologic memory.Topical imiquimod inhibits tumor growth and synergizes with RT. Addition of cyclophosphamide further increases the therapeutic effect and induces protective immunologic memory, suggesting that this combination is a promising strategy for cutaneous breast cancer metastases.
Intensive Care Unit–acquired Weakness
Authors: Jane Batt, Claudia C. dos Santos, Jill I. Cameron, Margaret S. Herridge
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Intensive care unit-acquired weakness (ICUAW) begins within hours of mechanical ventilation and may not be completely reversible over time. It represents a major functional morbidity of critical illness and is an important patient-centered outcome with clear implications for quality of life and resumption of prior work and lifestyle. There is heterogeneity in functional outcome related to ICUAW across various patient populations after an episode of critical illness. This state-of-the art review argues that this observed heterogeneity may represent a clinical spectrum of disability in which there are recognizable clinical phenotypes for outcome according to age, burden of comorbid illness, and ICU length of stay. It further argues that these functional outcomes are modified by mood, cognition, and caregiver physical and mental health. This proposed construct of clinical phenotypes will be used as a framework for a review of the current literature on the molecular biology of muscle and nerve injury. This translational approach for the development of models pairing clinical phenotypes for different functional outcomes after critical illness with molecular mechanism of injury may offer unique insights into the diagnosis and treatment of muscle and nerve lesions.
An Inflection Point in Gene Discovery Efforts for Neurodegenerative Diseases
Authors: Philip L. De Jager, David A. Bennett
Journal: JAMA Neurology (2013)

We are at an inflection point in our study of the human genome as it relates to neurodegenerative disease.The sequencing of the human genome, cataloguing of human genetic variation and rapid technological as well as methodological development, introduced a period of rapid gene discovery over the past decade.These efforts have yielded many new insights and will continue to uncover the genetic architecture of syndromically-defined neurodegenerative diseases in the coming decades.More recently, these successful study designs have been applied to the investigation of intermediate traits that relate to and inform our understanding of clinical syndromes, and the architecture of chromatin (the epigenome), the higher order structure of DNA that dictates the expression of a given genetic risk factor.While still nascent -given the challenges of accumulating large numbers of subjects with detailed phenotypes and technological hurdles in characterizing the state of chromatin -these efforts represent key investments that will enable the characterization of the functional consequences of a genetic risk factor and, eventually, its contribution to the clinical manifestations of a given disease.As a community of investigators, we are therefore at an exciting inflection point at which gene discovery efforts are transitioning towards the functional characterization of implicated genetic variation crucial for understanding the molecular, cellular, and systemic events that lead to a syndromic diagnosis for neurodegenerative diseases.Over the past decade, efforts to catalogue human genetic variation, such as the HapMap 1 and, more recently, the 1000 Genomes project 2 , have synergized with rapidly evolving technologies to yield a wealth of insights into the genetic architecture of many human diseases.We are now at an inflection point where we are shifting from gene discovery for common disease-associated variants to the exploration of the higher-order architecture of the genome, which is captured by the term "epigenome."Neurologic disease research provides a good illustration of this trend.Researchers have successfully exploited the genome-wide association study design, and are now initiating epigenome-wide scans for common diseases.Here, we review our current understanding of the genetic architecture of four common neurodegenerative diseases -Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Parkinson's Disease (PD) -and use them to highlight successful strategies for gene discovery as well as emerging strategies being deployed to
Pulmonary infection with Nocardia species: a report of 10 cases and review
Authors: R Menendez, PJ Cordero, M Santos, M Gobernado, V Marco
Journal: European Respiratory Journal (1997)

Pulmonary nocardiosis (PN) is an infrequent and severe infection due to Nocardia spp., microorganisms that may behave both as opportunists and as primary pathogens. The aim of this study and review was to evaluate the clinical features, evolution and prognostic factors of PN. The study group comprised 10 consecutive patients with pulmonary nocardiosis acquired in a community setting, diagnosed and followed in a tertiary teaching hospital. Chronic obstructive pulmonary disease (COPD), neoplastic disease and human immunodeficiency virus (HIV) infection were the most frequent predisposing factors. Four patients were receiving corticosteroid treatment. Clinical course was chronic and diagnosis was delayed 3 weeks or more in seven of the patients. Lobar or multilobar condensation was the most frequent radiographic pattern. Antimicrobial susceptibility testing showed: 100% sensitivity for amikacin; 83% for imipenem; 71% for cefotaxime; and 71% for trimethoprim-sulphamethoxazole. The disease remained localized in the lung in five cases, with a trend toward chronicity in one with bronchiectasis. In the other five, the disease disseminated, affecting subcutaneous tissue, the central nervous system and the kidney. Three patients died, one with disseminated disease and two who were receiving corticosteroid therapy. The following conclusions were reached: 1) pulmonary nocardiosis is difficult to diagnose, diagnosis is frequently delayed and a high level of suspicion is, thus, required in patients with underlying diseases or chronic corticosteroid therapy; 2) there is frequent dissemination and high mortality; and 3) antimicrobial combinations with proven synergy, such as imipenem and amikacin, are recommended for initial therapy.
Letter concerning: 'Enhanced expression of DYRK1A in cardiomyocytes inhibits acute NFAT activation but does not prevent hypertrophy in vivo'
Authors: P. A. da Costa Martins, L. J. De Windt
Journal: Cardiovascular Research (2011)

One major intracellular signalling pathway involved in heart failure employs the calcium/calmodulin-dependent phosphatase calcineurin and its downstream transcriptional effector nuclear factor of activated T cells (NFAT). A myriad of studies have demonstrated both the sufficiency and requirement of NFAT activation for maladaptive cardiac remodelling,1 and more recent research efforts have started to focus on the identification of the precise intracellular components of calcineurin/NFAT activation. We therefore read the study by Grebe et al. 2 with great interest, as it adds more depth to our understanding of dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1a) function with respect to NFAT homeostasis in the heart muscle. Dyrk1a, a nuclear kinase, has been demonstrated to function as a direct NFAT priming kinase, facilitating subsequent rephosphorylation by alternative kinases such as glycogen synthase kinase-3 (GSK-3); hence, increasing the activity/expression of Dyrk1a may have dampening effects on myocardial calcineurin/NFAT signalling events. Grebe et al. used adenoviral and transgenic overexpression strategies to increase Dyrk1a expression in the heart and used NFAT translocation/activity as a functional readout. Adenoviral expression of Dyrk1a efficiently reduced NFAT activation in cultured myocytes, while siRNA-mediated knockdown potentiated nuclear occupancy of a GFP-tagged …
Insights into the Distinguishing Stress-induced Cytotoxicity of Chiral Gold Nanoclusters and the Relationship with GSTP1
Authors: Chunlei Zhang, Zhijun Zhou, Xiao Zhi, Yue Ma, Kan Wang, Yuxia Wang, Yingge Zhang, Hualin Fu, Weilin Jin, Fei Pan, Daxiang Cui
Journal: Theranostics (2014)

Chiral gold nanoclusters (Au NCs) exhibit attracting properties owing to their unique physical and chemical properties.Herein we report for the first time chiral gold nanoclusters' cytotoxicity and potential molecular mechanism.The L-glutathione (i.e.L-GSH) and D-glutathione (i.e.D-GSH)-capped Au NCs were prepared and characterized by HRTEM, UV-vis, photoluminescence and circular dichroism (CD) spectroscopy.Results showed that the CD spectra of L-glutathione (i.e.L-GSH) and D-glutathione (i.e.D-GSH)-capped Au NCs exhibited multiple bands which were identically mirror-imaged, demonstrating that the chirality of GSH-capped NCs had contributions from both the metal core and the ligand.The effects of AuNCs@L-GSH and AuNCs@D-GSH on cells were similar based on the cell physiology related cytotoxicity, although the effects became more prominent in AuNCs@D-GSH treated cells, including ROS generation, mitochondrial membrane depolarization, cell cycle arrest and apoptosis.Global gene expression and pathway analysis displayed that both AuNCs@L-GSH and AuNCs@D-GSH caused the up-regulation of genes involved in cellular rescue and stress response, while AuNCs@D-GSH individually induced up-regulation of transcripts involved in some metabolic-and biosynthetic-related response.MGC-803 cells were more sensitive to the oxidative stress damage induced by chiral Au NCs than GES-1 cells, which was associated with GSTP1 hypermethylation.In conclusion, chiral gold nanoclusters exhibit this chirality-associated regulation of cytotoxicity, different gene expression profiling and epigenetic changes should be responsible for observed phenomena.Our study highlights the importance of the interplays between chiral materials and biological system at sub-nano level.
Relationship between air pollution and positivity of RA-related autoantibodies in individuals without established RA: a report on SERA
Authors: Ryan W Gan, Kevin D Deane, Gary O Zerbe, M Kristen Demoruelle, Michael H Weisman, Jane H Buckner, Peter K Gregersen, Ted R Mikuls, James R O'Dell, Richard M Keating, V Michael Holers, Jill M Norris
Journal: Annals of the Rheumatic Diseases (2013)

Introduction Studies suggest that respiratory exposures including smoking, proximity to traffic and air pollution might be associated with development of rheumatoid arthritis (RA). RA-related autoantibodies are predictive of the development of RA. Objective We evaluated the relationship between RA-related autoantibodies and exposure to particulate matter (PM), a measure of air pollution of interest to health, in individuals without RA. Methods The Studies of the Etiology of Rheumatoid Arthritis (SERA) is a multicentre study following first-degree relatives (FDRs) of a proband with RA. FDRs are without the 1987 ACR (American College of Rheumatology) classifiable RA at enrolment and are followed for the development of RA-related autoimmunity. RA-related autoantibody outcomes as well as tender and swollen joint outcomes were assessed. Exposure to PM was assigned using ambient air pollution monitoring data and interpolated with inverse distance weighting spatial analyses using Geographic Information Systems. PM exposures were linked to FDR's residential zip codes. Results RA-related autoantibodies as well as tender or swollen joints are not associated with ambient PM concentrations. Discussion While other respiratory exposures may be associated with increased risk of RA, our data suggest that ambient PM is not associated with autoantibodies and joint signs among individuals without RA, but at increased risk of developing RA.
Viral Etiology of Severe Pneumonia Among Kenyan Infants and Children
Authors: James A. Berkley, Patrick Munywoki, Mwanajuma Ngama, Sidi Kazungu, John Abwao, Anne Bett, Ria Lassauniére, Tina Kresfelder, Patricia A. Cane, Marietjie Venter, J. Anthony G. Scott, D. James Nokes
Journal: JAMA (2010)

Pneumonia is the leading cause of childhood death in sub-Saharan Africa. Comparative estimates of the contribution of causative pathogens to the burden of disease are essential for targeted vaccine development.To determine the viral etiology of severe pneumonia among infants and children at a rural Kenyan hospital using comprehensive and sensitive molecular diagnostic techniques.Prospective observational and case-control study during 2007 in a rural Kenyan district hospital. Participants were children aged 1 day to 12 years, residing in a systematically enumerated catchment area, and who either were admitted to Kilifi District Hospital meeting World Health Organization clinical criteria for severe pneumonia or very severe pneumonia; (2) presented with mild upper respiratory tract infection but were not admitted; or (3) were well infants and children attending for immunization.The presence of respiratory viruses and the odds ratio for admission with severe disease.Of 922 eligible admitted patients, 759 were sampled (82% [median age, 9 months]). One or more respiratory viruses were detected in 425 of the 759 sampled (56% [95% confidence interval {CI}, 52%-60%]). Respiratory syncytial virus (RSV) was detected in 260 participants (34% [95% CI, 31%-38%]) and other respiratory viruses were detected in 219 participants (29%; 95% CI, 26%-32%), the most common being Human coronavirus 229E (n = 51 [6.7%]), influenza type A (n = 44 [5.8%]), Parainfluenza type 3 (n = 29 [3.8%]), Human adenovirus (n = 29 [3.8%]), and Human metapneumovirus (n = 23 [3.0%]). Compared with well control participants, detection of RSV was associated with severe disease (5% [corrected] in control participants; adjusted odds ratio, 6.11 [95% CI, 1.65-22.6]) while collectively, other respiratory viruses were not associated with severe disease (23% in control participants; adjusted odds ratio, 1.27 [95% CI, 0.64-2.52]).In a sample of Kenyan infants and children admitted with severe pneumonia to a rural hospital, RSV was the predominant viral pathogen.
Preoperative<i>GNAS</i>and<i>KRAS</i>Testing in the Diagnosis of Pancreatic Mucinous Cysts
Authors: Aatur D. Singhi, Marina N. Nikiforova, Kenneth E. Fasanella, Kevin M. McGrath, Reetesh K. Pai, N. Paul Ohori, Tanner L. Bartholow, Randall E. Brand, Jennifer S. Chennat, Xuong Lu, Georgios I. Papachristou, Adam Slivka, Herbert J. Zeh, Amer H. Zureikat, Kenneth K. Lee, Allan Tsung, Geeta S. Mantha, Asif Khalid
Journal: Clinical Cancer Research (2014)

Management guidelines for pancreatic intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) are based on the assumption that mucinous cysts can be accurately distinguished from other pancreatic cystic lesions. Previous studies using surgical material have identified recurrent mutations in GNAS and KRAS in pancreatic mucinous neoplasms. Yet, the diagnostic utility of testing for both genes in pancreatic cyst fluid obtained by endoscopic ultrasound-fine-needle aspiration (EUS-FNA) remains unclear.GNAS and KRAS testing was performed on EUS-FNA pancreatic cyst fluid from 91 pancreatic cysts: 41 IPMNs, 9 IPMNs with adenocarcinoma, 16 MCNs, 10 cystic pancreatic neuroendocrine tumors (PanNET), 9 serous cystadenomas (SCA), 3 retention cysts, 2 pseudocysts, and 1 lymphoepithelial cyst.Mutations in GNAS were detected in 16 (39%) IPMNs and 2 (22%) IPMNs with adenocarcinoma. KRAS mutations were identified in 28 (68%) IPMNs, 7 (78%) IPMNs with adenocarcinoma, and 1 (6%) MCN. Mutations in either gene were present in 34 (83%) IPMNs, 8 (89%) IPMNs with adenocarcinoma, and 1 (6%) MCN. No mutations were found in cystic PanNETs, SCAs, retention cysts, pseudocysts, and a lymphoepithelial cyst. GNAS and KRAS mutations had 100% specificity [95% confidence interval (CI), 0.83-1.00] but 65% sensitivity (95% CI, 0.52-0.76) for mucinous differentiation. Among IPMNs, mutations in either gene had 98% specificity (95% CI, 0.86-1.00) and 84% sensitivity (95% CI, 0.70-0.92).The combination of GNAS and KRAS testing was highly specific and sensitive for IPMNs; however, the lack of sensitivity for MCNs highlights the need for additional markers to improve the detection of pancreatic mucinous neoplasms.
TCT-712 Better Outcomes with Sapien 3 vsSapien XT balloon-expandable prosthesis in patients undergoing transfemoral aortic valve replacement
Authors: David Jochheim, Magda Zadrozny, Hans Theiss, Moritz Baquet, Martin Greif, Christian Kupatt, Jörg Hausleiter, Steffen Massberg, Julinda Mehilli
Journal: Journal of the American College of Cardiology (2014)
Cancer Incidence in Mormons and Non-Mormons in Utah During 1967–75&lt;xref ref-type="fn" rid="FN1"&gt;1&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J L Lyon, J W Gardner, D W West
Journal: JNCI Journal of the National Cancer Institute (1980)

Data from the Utah Cancer Registry were used to compare cancer incidence in Mormons and non-Mormons in Utah for the period 1967--75. Church membership was identified for 97.8% of the 20,379 cases in Utah by a search of the central membership files of the Church of Jesus Christ of Latter-Day Saints (or Mormon Church). Sites associated with smoking (lung, larynx, pharynx, oral cavity, esophagus, and urinary bladder) showed an incidence in Mormons at about one-half that of non-Mormons. Rates of cancers of the breast, cervix, and ovary were low in Mormon women; the rate for cervical cancer was about one-half of that observed in non-Mormons. Cancers of the stomach, colon-rectum, and pancreas were about one-third lower in Mormons than in others who are not members of this religious group. Most of the differences seen in cancer incidence can be explained by Mormon teachings regarding sexual activity and alcohol and tobacco use, but some differences (e.g., colon and stomach) remain unexplained.
The Efficacy, Sensitivity, and Specificity of In Vivo Laser Confocal Microscopy in the Diagnosis of Meibomian Gland Dysfunction
Authors: Osama M.A. Ibrahim, Yukihiro Matsumoto, Murat Dogru, Enrique Sato Adan, Tais Hitomi Wakamatsu, Tateki Goto, Kazuno Negishi, Kazuo Tsubota
Journal: Ophthalmology (2010)
An evolved ribosome-inactivating protein targets and kills human melanoma cells in vitro and in vivo
Authors: Melissa C Cheung, Leigh Revers, Subodini Perampalam, Xin Wei, Reza Kiarash, David E Green, Aws Abdul-Wahid, Jean Gariépy
Journal: Molecular Cancer (2010)

Abstract Background Few treatment options exist for patients with metastatic melanoma, resulting in poor prognosis. One standard treatment, dacarbazine (DTIC), shows low response rates ranging from 15 to 25 percent with an 8-month median survival time. The development of targeted therapeutics with novel mechanisms of action may improve patient outcome. Ribosome-inactivating proteins (RIPs) such as Shiga-like Toxin 1 (SLT-1) represent powerful scaffolds for developing selective anticancer agents. Here we report the discovery and properties of a single chain ribosome-inactivating protein (scRIP) derived from the cytotoxic A subunit of SLT-1 (SLT-1A), harboring the 7-amino acid peptide insertion IYSNKLM (termed SLT-1A IYSNKLM ) allowing the toxin variant to selectively target and kill human melanoma cells. Results SLT-1A IYSNKLM was able to kill 7 of 8 human melanoma cell lines. This scRIP binds to 518-A2 human melanoma cells with a dissociation constant of 18 nM, resulting in the blockage of protein synthesis and apoptosis in such cells. Biodistribution and imaging studies of radiolabeled SLT-1A IYSNKLM administered intravenously into SCID mice bearing a human melanoma xenograft indicate that SLT-1A IYSNKLM readily accumulates at the tumor site as opposed to non-target tissues. Furthermore, the co-administration of SLT-1A IYSNKLM with DTIC resulted in tumor regression and greatly increased survival in this mouse xenograft model in comparison to DTIC or SLT-1A IYSNKLM treatment alone (115 day median survival versus 46 and 47 days respectively; P values &lt; 0.001). SLT-1A IYSNKLM is stable in serum and its intravenous administration resulted in modest immune responses following repeated injections in CD1 mice. Conclusions These results demonstrate that the evolution of a scRIP template can lead to the discovery of novel cancer cell-targeted compounds and in the case of SLT-1A IYSNKLM can specifically kill human melanoma cells in vitro and in vivo .