tbuckley/cabot-search huggingface dataset:
Are third-generation cephalosporins associated with a better prognosis than amoxicillin–clavulanate in patients hospitalized in the medical ward for community-onset pneumonia?
Authors: E. Batard, F. Javaudin, E. Kervagoret, E. Caruana, Q. Le Bastard, G. Chapelet, N. Goffinet, E. Montassier
Journal: Clinical Microbiology and Infection (2018)
Abstract 39: LCN2, CD133 expressions in breast cancer spinal bone metastasis and CD151, TWIST1, EPHA2 in lung metastasis: Prognostic value and organ-specific relapse
Authors: Aparna Maiti, Nitai C. Hait
Journal: Cancer Research (2018)

Abstract Purpose: Breast cancer most often recurs and metastasizes to the distal organs that had their primary tumors surgically excised. Due to heterogeneous nature of the breast cancer, metastasis organotropism has poorly understood. In this study, we assessed the specific cancer-related gene expression changes occurring with metastatic breast cancer recurrence to distant organs comparing with non-metastatic breast cancer. Experimental design: We develop a clinically relevant metastatic syngeneic mouse model using two cell lines 4T1-luc2 that can only metastasize to lung and 4T1.2-luc2 metastasized to bone and lung. After the primary mammary tumor surgically excised from mice, we monitor mice using IVIS imaging for metastatic tumor lesion development in the distant organs followed by MRI scan to detect spinal bone metastases. Animals were sacrificed to collect spines, bones, and lung lesions for molecular analysis. We also validate the gene expression data using the RNA-seq cohort data from the Roswell Park Cancer Institute patient samples with advanced breast cancer bone metastases and matched non-metastatic breast cancer. Results: Our cell lines, RNA-seq data analysis suggested that there are at least 50 genes which are statistically highly expressed in 4T1.2-luc2 compared to 4T1-luc2 cells. Out of which only a few genes are well established for cancer metastasis biology, include ANGPTL77, SERPINE2, TSPAN11, ESM1, LCN2 which are expressed more than 8 fold in 4T1.2-luc2 compared to 4T1-luc2 cells. To our surprise, we found that most of these genes are differentially expressed when metastasized to distant organ. Our data revealed that LCN2 (7 fold) and CD133 (above 20 fold) are overexpressed in the spine and bone compared to the primary or lung met lesions formed by 4T1.2-luc2. Conversely, LCN2 and CD133 genes are downregulated in breast cancer lung metastasis tissues, whereas CD151, EPHA2, and TWIST1 genes are highly overexpressed in lung metastatic lesion compared to primary, bone or spine. Further, the RNA-seq data of patient samples explained that LCN2, CD133 expressions are significantly higher (8 out of 10 patients) in advanced breast cancer bone metastases compared with matching non-metastatic breast cancer. Conclusion: Our data suggested that LCN2, CD133 would be a prognostic marker for breast cancer spinal bone metastasis, whereas CD151, TWIST1, EPHA2 would be a prognostic marker for lung metastasis and organ-specific relapse. Citation Format: Aparna Maiti, Nitai C. Hait. LCN2, CD133 expressions in breast cancer spinal bone metastasis and CD151, TWIST1, EPHA2 in lung metastasis: Prognostic value and organ-specific relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 39.
Depression and Suicidal Ideation Among HIV-Infected Adults Receiving Efavirenz Versus Nevirapine in Uganda
Authors: Jonathan L. Chang, Alexander C. Tsai, Nicholas Musinguzi, Jessica E. Haberer, Yap Boum, Conrad Muzoora, Mwebesa Bwana, Jeffrey N. Martin, Peter W. Hunt, David R. Bangsberg, Mark J. Siedner
Journal: Annals of Internal Medicine (2018)

Evidence regarding potential adverse neuropsychiatric effects of efavirenz is conflicting, and data from sub-Saharan Africa, where 70% of persons living with HIV (PLHIV) reside and efavirenz is used as first-line therapy, are limited.To estimate associations between efavirenz use and depression and suicidal ideation among PLHIV in Uganda.Prospective observational cohort study. (ClinicalTrials.gov: NCT01596322).Mbarara, Uganda.Adult PLHIV enrolled at the start of antiretroviral therapy (ART) and observed every 3 to 4 months from 2005 to 2015.The exposure of interest was time-varying efavirenz use, defined as use during the 7 days and in 60 or more of the 90 days before a study visit, compared with nevirapine use. Self-reported outcomes were depression, defined as a mean score greater than 1.75 on the Hopkins Symptom Checklist depression subscale, and suicidal ideation. Multivariable-adjusted generalized estimating equations (GEE) logistic regression, Cox proportional hazards regression, and marginal structural models were fit to estimate the association between efavirenz use and the risk for depression and suicidal ideation.694 participants (median age, 33 years; median pretreatment CD4+ count, 1.8 × 109 cells/L) contributed 1200 person-years of observation (460 person-years receiving efavirenz). No baseline differences in depression or suicidal ideation were found between patients ever exposed to efavirenz and those never exposed to efavirenz and receiving nevirapine (P > 0.80 for both). Of 305 participants ever-exposed to efavirenz, 61 (20.0%) and 19 (6.2%) had depression and suicidal ideation, respectively, on at least 1 follow-up visit, compared with 125 (32.1%) and 47 (12.1%) of the 389 who received nevirapine. In adjusted GEE models, efavirenz use was associated with decreased odds of depression compared with nevirapine use (adjusted odds ratio, 0.62 [95% CI, 0.40 to 0.96]) and was not significantly associated with suicidal ideation (adjusted odds ratio, 0.61 [CI, 0.30 to 1.25]). Time-to-event and marginal structural models yielded similar estimates.Nonrandom assignment to treatment and substantial differences between the efavirenz and nevirapine groups.No evidence was found that use of efavirenz in first-line ART increased the risk for depression or suicidal ideation compared with nevirapine use among PLHIV in Uganda.National Institutes of Health.
Key roles for lipid mediators in the adaptive immune response
Authors: Parker F. Duffney, Megan L. Falsetta, Ashley R. Rackow, Thomas H. Thatcher, Richard P. Phipps, Patricia J. Sime
Journal: Journal of Clinical Investigation (2018)

Chronic inflammation is an underlying feature of many diseases, including chronic obstructive pulmonary disease, rheumatoid arthritis, asthma, and multiple sclerosis. There is an increasing appreciation of the dysregulation of adaptive immunity in chronic inflammatory and allergic diseases. The discovery of specialized pro-resolving lipid mediators (SPMs) that actively promote the resolution of inflammation has opened new avenues for the treatment of chronic inflammatory diseases. Much work has been done focusing on the impact of SPMs on innate immune cells. However, much less is known about the influence of SPMs on the development of antigen-specific adaptive immune responses. This Review highlights the important breakthroughs concerning the effects of SPMs on the key cell types involved in the development of adaptive immunity, namely dendritic cells, T cells, and B cells.
Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: a multisite study
Authors: Marianne S. Muhlebach, Joseph E. Hatch, Gisli G. Einarsson, Stef J. McGrath, Deirdre F. Gilipin, Gillian Lavelle, Bojana Mirkovic, Michelle A. Murray, Paul McNally, Nathan Gotman, Sonia Davis Thomas, Matthew C. Wolfgang, Peter H. Gilligan, Noel G. McElvaney, J. Stuart Elborn, Richard C. Boucher, Michael M. Tunney
Journal: European Respiratory Journal (2018)

Anaerobic and aerobic bacteria were quantitated in respiratory samples across three cystic fibrosis (CF) centres using extended culture methods. Subjects aged 1-69 years who were clinically stable provided sputum (n=200) or bronchoalveolar lavage (n=55). 18 anaerobic and 39 aerobic genera were cultured from 59% and 95% of samples, respectively; 16 out of 57 genera had a ≥5% prevalence across centres.Analyses of microbial communities using co-occurrence networks in sputum samples showed groupings of oral, including anaerobic, bacteria, whereas typical CF pathogens formed distinct entities. Pseudomonas was associated with worse nutrition and F508del genotype, whereas anaerobe prevalence was positively associated with pancreatic sufficiency, better nutrition and better lung function. A higher total anaerobe/total aerobe CFU ratio was associated with pancreatic sufficiency and better nutrition. Subjects grouped by factor analysis who had relative dominance of anaerobes over aerobes had milder disease compared with a Pseudomonas-dominated group with similar proportions of subjects that were homozygous for F508del.In summary, anaerobic bacteria occurred at an early age. In sputum-producing subjects anaerobic bacteria were associated with milder disease, suggesting that targeted eradication of anaerobes may not be warranted in sputum-producing CF subjects.
<i>IL1RN</i> Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin‐1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis
Authors: Victoria L. Arthur, Emily Shuldiner, Elaine F. Remmers, Anne Hinks, Alexei A. Grom, Dirk Foell, Alberto Martini, Marco Gattorno, Seza Özen, Sampath Prahalad, Andrew S. Zeft, John F. Bohnsack, Norman T. Ilowite, Elizabeth D. Mellins, Ricardo Russo, Claudio Len, Sheila Oliveira, Rae S. M. Yeung, Alan M. Rosenberg, Lucy R. Wedderburn, Jordi Anton, Johannes‐Peter Haas, Angela Rösen‐Wolff, Kirsten Minden, Ann Marie Szymanski, Wendy Thomson, Daniel L. Kastner, Patricia Woo, Michael J. Ombrello
Journal: Arthritis & Rheumatology (2018)

To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date.
Abstract 13944: Right Heart Myocarditis: A Cardiac MRI Perspective
Authors: Brandon M Mikolich, J Ronald Mikolich
Journal: Circulation (2016)

Introduction: In 1961 J. A. Hayes from Boston City Hospital reported in the British Heart Journal a case of myocarditis in a young man who died. Autopsy revealed inflammatory cells confined to the right heart. With the advent of cardiac MRI in the 1990s and its capability of detecting myocardial edema due to inflammation, it became apparent the some cases of arrhythmogenic right ventricular dysplasia (ARVD) were actually myocarditis. Since then, there has been no systematic study of right heart myocarditis. Hypothesis: Myocarditis confined to the right heart is detectable with cardiac MRI. Methods: An institutional cardiac imaging database was queried for all cases of CMR diagnosed myocarditis using published criteria, requiring 2 of the following 3 criteria: Myocardial enhancement on T2 weighted imaging (T2E), “early” myocardial gadolinium uptake (EGE) and standard late gadolinium enhancement (LGE). Patients with CMR evidence of myocarditis confined to the right heart constituted the study population. These patients were also required to have no evidence of left heart myocarditis, ie no T2E, EGE or DHE of LV myocardium. Results: 172 of 3,250 patients (5.3%) had evidence of myocarditis by CMR criteria. Of these 172 patients with myocarditis, 16(9.3%) were confined to the right heart. A typical case of right heart myocarditis is shown below, a T2 weighted 4 chamber CMR image showing myocardial enhancement(edema). All 16 patients complained of fatigue and palpitations. 4 of 16 had mild right heart failure on exam and RV hypokinesis on CMR or 2-D echo. 14 of 16 had documented atrial or ventricular tachy-arrhythmias. 14 of 16 had contiguous focal pericarditis (also confined to the right heart). Conclusions: Myocarditis confined to the right heart is evident in approximately 9% of patients with a CMR diagnosis of myocarditis. Palpitations and fatigue are the most common symptoms. Nearly all have a documentable arrhythmia and evidence of contiguous pericarditis on CMR.
Abstract 18491: BeTACTIC Study: Best Therapy After Cardiac Transplantation, the Italian Challenge
Authors: Fabio M Turazza, Maria Grazia Franzosi, Maria Frigerio, Elena Gardinale, Simona Barlera, Michela Magnoli
Journal: Circulation (2016)

Introduction:  Survival after heart transplantation (HTx) has improved, while the attrition rate beyond the 1st year did not change substantially. Cardiac allograft vasculopathy (CAV) and cancer are the leading causes of death late after HTx. Significant morbidity/mortality derive from renal insufficiency and vascular complications.   Hypothesis:  Everolimus (Ev) and Micophenolate (MMF) were adopted due to better efficacy vs Azathioprine in de novo HTx. However, Ev and MMF have not been tested in a head to head comparison late after HTx. We assessed the effect of Ev and MMF on renal function late after HTx.   Methods:  BeTACTIC is a multicenter, randomized, Investigator-driven trial, funded by the National Health Service, comparing efficacy and safety of Ev and MMF in association with Cyclosporine (CyA) in pts with acute multiple/late rejection (3 or more episodes requiring steroids), CAV, worsening renal dysfunction, enrolled at least 1yr after HTx and followed-up for 3 yrs. The primary endpoint was a composite of hierarchical occurrence of death, retransplantation, hospitalization for cardiovascular causes, reduction of EF, progression of CAV detected with coronary angiography/IVUS, renal function worsening and cancer.   Results and Conclusions:  A total of 80 pts with a median age of 60 yrs, 84% men, were randomized in 9 Transplant Centers in Italy. Hypertension was present in 70% of pts, diabetes in 22.5%, CAD history CAD in 6.3%, and CHF in 7.6%. HTx was mainly due to dilated (47.4%) and ischemic (44.7%) cardiomyopathies. At 12 months, patients showing worsening of renal function accounted for the 32.5% of the cumulative incidence of the primary endpoint (53.8%). We evaluated the changes in the estimated glomerular filtration rate (eGFR) at 6 and 12 months from baseline. At 6 months the mean changes in eGFR did not differ between Ev and MMF (+1.25 vs 1.32, p=0.98); at 12 months there was a trend in favor of MMF, even if not statistically significant (+5.25 vs 0.92, p=0.18), stronger in patients assigned to MMF and enrolled in the trial after 5 years or more from HTx. We observed a significant reduction of CyA trough level in patients assigned to Ev. Results will be re-assessed at 3 years follow-up analysis.
Abstract 4152: Synergistic gold nanostar-mediated photothermal and immunotherapy for cancer metastasis treatment
Authors: Yang Liu, Paolo Maccarini, Gregory M. Palmer, Brant A. Inman, Tuan Vo-Dinh
Journal: Cancer Research (2018)

Abstract Cancer has become a severe thread to human health resulting in more than eight million deaths each year. Cancer metastasis is the main mechanism in more than 90 percent of cancer deaths. However, current therapeutic options including chemotherapy and radiation therapy have limited therapeutic effects to treat cancer metastasis. Therefore, there is an urgent need to develop novel methods for cancer treatment. Our group has developed a unique method to synthesize star-shaped gold nanoparticles, gold nanostars (GNS), without using toxic surfactant, which is very suitable for in vivo applications. The synthesized GNS has tip-enhanced plasmonics and tunable strong in the near-infrared “tissue optical window”, enabling it a superior photon-to-heat nanotransducer. The GNS nanoparticles accumulate preferably into tumor with enhanced permeability and retention (EPR) effect after intravenous administration. We have applied GNS for photothermal therapy with 808 nm laser to specifically ablate tumor. Here we report a new cancer treatment method by combing nanophotothermal therapy and anti-PD-L1 immunotherapy. Immunogenic cell death is often insufficient to trigger effective anti-cancer immunity due to the presence of immunosuppressive factors occurring in the tumor microenvironment such as hypoxia, impaired leukocyte trafficking and inhibitory immune checkpoint signaling. The GNS-mediated photothermal ablation can reduce hypoxia and improve leukocyte trafficking to the tumor. In addition, the administration of anti-PD-L1 antibody reverses another critical immunosuppression factor. Experiment results using a mouse bladder cancer model demonstrated that the combined photothermal and immunotherapy have synergistic effect and can not only eradicate primary tumors with laser treatment but also distant metastasis without laser treatment. Furthermore, delayed rechallenge in the cured mice didn't result in new tumor generation, indicating that our combined therapy induced memorized immune response against cancer. The combined GNS-mediated photothermal therapy and anti-PD-L1 immunotherapy has promise to improve therapeutic effect on not only primary tumor but also cancer metastasis. Citation Format: Yang Liu, Paolo Maccarini, Gregory M. Palmer, Brant A. Inman, Tuan Vo-Dinh. Synergistic gold nanostar-mediated photothermal and immunotherapy for cancer metastasis treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4152.
Abstract 14624: Are All Diastolic Parameters Equal?
Authors: Leah Wright, Nathan Dwyer, Sudhir Wahi, Thomas Marwick
Journal: Circulation (2016)

Are All Diastolic Parameters Equal? Background:  Recent guidelines propose that diastolic dysfunction may be diagnosed in pts with normal EF if >2 of 4 parameters (average E/e’, annular velocities, TR V max and LAV index) are abnormal. This suggests all diagnostic markers have equivalent diagnostic significance. We hypothesized that markers of chronically elevated LVEDP (LAV, E/e’) would be more specific than TR or e’.   Methods:  We studied 243 pts undergoing investigation of dyspnea, in whom right heart catheterization was performed in close succession to an echo showing EF >50%. PCWP≥15 mmHg was used as a cut off. Pts were 62±14 yrs (75% female) with mPAP 35±13 mmHg & PCWP 13±5 mmHg. Echocardiographic parameters used were; e’ septal  2.8 cm/s, LAVi > 34 ml/m 2 . Bivariate logistic and ROC analysis was used to determine predictive ability of echocardiographic variables. 5 groups were created to show the predictive ability when separate diastolic markers were combined; 1) those with all positive diastolic markers; 2) e’ + TR Vmax+ LAVi; 3)E/e’ + e’ + LAVi; 4)E/e’+ e’ +TR; 5)e’ + TR + LAV.   Results:  Of 188 pts, 76 (40%) had elevated PCWP. Echo was nondiagnostic (2 abnormal) in 122 (35%). The variables showed high specificity and low sensitivity (Table 1). Bivariate logistic regression showed LAV (OR 2.78(1.47;5.3), p=0.002) and E/e’ (OR 6.3(2.1;18.7), p 15 mmHg. ROC showed that LAV (AUC 0.71) and E/e’ (AUC 0.67) to have modest discriminative power for determining PWCP. Combined groups showed that even with all 4 parameters positive (OR 6.8 (1.8;25.6, p=0.005), sensitivity was low for accurately predicting PCWP> 15 mmHg.   Conclusion:  Assessment of evidence regarding prediction of PCWP>15 is discordant with opinions expressed in the guidelines.
Abstract PL01-02: Immune checkpoint therapy: From CTLA-4 to PD-1/PD-L1 and beyond
Authors: Padmanee Sharma
Journal: Cancer Research (2018)

Abstract Immune checkpoint therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1, have led to significant clinical responses in cancer patients. However, there are still substantial numbers of patients who do not respond to anti-CTLA-4 or anti-PD-1/PD-L1. We and others have demonstrated that treatment of patients with immune checkpoint therapies impacts immune responses to enhance effector T-cell responses but also leads to increased expression of compensatory pathways or development of adaptive resistance mechanisms that act to abrogate antitumor immune responses. Rational combination strategies to address these compensatory pathways and/or adaptive resistance mechanisms, including those that permit blockade of multiple T-cell inhibitory pathways or blockade of inhibitory pathways plus targeting of co-stimulatory pathways or intervention with agents, such as epigenetic agents, to promote differentiation of effector T cells and/or M1 macrophages, are at the forefront of preclinical and clinical studies as the field of immune checkpoint therapy aims to provide benefit to even more patients. Combination therapies with anti-CTLA-4 and anti-PD-1 have already shown improved patient benefit. The next promising combinations include those with ICOS, CD47, VISTA, oncolytic viruses, and EZH2-inhibitors, to name a few. Preclinical and clinical data regarding these targets will be discussed in greater detail. Citation Format: Padmanee Sharma. Immune checkpoint therapy: From CTLA-4 to PD-1/PD-L1 and beyond [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr PL01-02.
Abstract 890: Calmodulin governs nuclear entry of fusion PAX3/FOXO1 oncoprotein, a target in alveolar rhabdomyosarcoma
Authors: Emad Darvishi, Cheryl Lynn Thomas, Berkley Eric Gryder, John Frederick Shern, Javed Khan, Girma M Woldemichael
Journal: Cancer Research (2018)

Abstract Reciprocal chromosomal translocations resulting in the fusion of the DNA binding domain of the transcription factor PAX3 and the transactivational domain of FOXO1 underlie most cases of alveolar rhabdomyosarcoma (aRMS). Testing of compound MTPF63 against a panel of sarcoma cell lines showed that it had an inhibitory effect on proliferation of PAX3-FOXO1 translocation-positive cells. Further evaluation of its activity in Rh4 cells transduced with a PAX3-FOXO1 luciferase reporter showed that it attenuated reporter activity. Additional confirmation for the compound's inhibitory impact on PAX3-FOXO1 activity was obtained by detecting significant attenuation in the levels of Alk1 and MyoD1 proteins whose expression is driven by PAX3-FOXO1 in aRMS cells. Cell viability assays performed under 2D and 3D culturing conditions demonstrated that MTPF63 inhibits cell growth more effectively in translocation-positive alveolar RMS than in translocation-negative embryonal RMS. A hypothesis for MTPF63's mode of action was generated using the complete pool of barcoded essential heterozygous (~1150 strains) and homozygous (~4800 strains) diploid gene deletion mutants of Saccharomyces cerevisiae to identify gene deletions that confer sensitivity to the compound. Gene ontology enrichment analysis of 255 sensitive mutants whose growth rates were significantly inhibited in the presence of the compound compared to control, not only revealed calmodulin as main target of the compound but also illustrated the compound's interference with calmodulin-dependent nuclear protein import pathway, suggesting that it might impact PAX3-FOXO1 nuclear localization. Immunostaining of nuclear-localized PAX3-FOXO1 oncoprotein in two aRMS cell lines revealed cytoplasmic localization. Immunoblot analysis of fractionated cytosolic and nuclear protein lysates for PAX3-FOXO1 in MTPF63 treated cells also showed increased amounts in the cytosolic fractions. Transient overexpression of calmodulin was shown to partially rescue the inhibitory effect of the compound on PAX3-FOXO1-driven luciferase expression in RH4 reporter cells. Taken together, the data demonstrate the involvement of calmodulin in the nuclear import of PAX3-FOXO1 and introduce calmodulin antagonists as potential therapeutics against translocation-positive childhood alveolar rhabdomyosarcoma. Citation Format: Emad Darvishi, Cheryl Lynn Thomas, Berkley Eric Gryder, John Frederick Shern, Javed Khan, Girma M Woldemichael. Calmodulin governs nuclear entry of fusion PAX3/FOXO1 oncoprotein, a target in alveolar rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 890.