tbuckley/cabot-search huggingface dataset:
In utero CRISPR-mediated therapeutic editing of metabolic genes
Authors: Avery C. Rossidis, John D. Stratigis, Alexandra C. Chadwick, Heather A. Hartman, Nicholas J. Ahn, Haiying Li, Kshitiz Singh, Barbara E. Coons, Li Li, Wenjian Lv, Philip W. Zoltick, Deepthi Alapati, William Zacharias, Rajan Jain, Edward E. Morrisey, Kiran Musunuru, William H. Peranteau
Journal: Nature Medicine (2018)
Benign Esophageal Findings on 68Ga–Prostate-Specific Membrane Antigen PET/CT Scan
Authors: Mads Ryø Jochumsen, Søren Klingenberg, Kirsten Bouchelouche
Journal: Clinical Nuclear Medicine (2018)

In 2 high-risk prostate cancer patients, PET scans revealed focally increased Ga-prostate-specific membrane antigen uptake in the distal esophagus. Both patients had hiatus herniation on gastroscopy, and esophageal biopsies revealed acute and chronic inflammation in both patients and a benign hyperplastic polyp in one of the patients. Recently, reports have demonstrated that inflammation can cause false-positive findings on Ga-prostate-specific membrane antigen PET/CT, and these cases present this phenomenon in the esophagus as well.
Bifunctional PD-1 × αCD3 × αCD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia
Authors: Monika Herrmann, Christina Krupka, Katrin Deiser, Bettina Brauchle, Anetta Marcinek, Ana Ogrinc Wagner, Felicitas Rataj, Ralph Mocikat, Klaus H. Metzeler, Karsten Spiekermann, Sebastian Kobold, Nadja C. Fenn, Karl-Peter Hopfner, Marion Subklewe
Journal: Blood (2018)
Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency
Authors: Coralie Briand, Marie-Louise Frémond, Didier Bessis, Aurélia Carbasse, Gillian I Rice, Vincent Bondet, Darragh Duffy, Lucienne Chatenoud, Stéphane Blanche, Yanick J Crow, Bénédicte Neven
Journal: Annals of the Rheumatic Diseases (2018)

The type I interferonopathies, Mendelian disorders characterised by constitutive upregulation of the type I interferon (IFN) pathway, are associated with a spectrum of phenotypes particularly involving the brain and the skin.1 Mutations in the 3′−5′ DNA exonuclease TREX1 were the first described cause of the severe encephalopathy Aicardi-Goutieres syndrome (AGS),2 of which acral vasculitic lesions are a well-recognised feature. Familial chilblain lupus (FCL) is the name given where such lesions occur in the absence of neurological disease.3 TREX1 dysfunction, due to biallelic loss of function or dominant negative heterozygous mutations, is postulated to lead to aberrant immune recognition of self-nucleic acids inducing the production of type I IFNs. These potent cytokines drive the expression of IFN-stimulated genes (ISGs) through the engagement of a common receptor and the subsequent activation of Janus kinase 1 (JAK1) and tyrosine kinase 2. We describe, to our knowledge for the first time, the efficacy of the JAK1/2 inhibitor ruxolitinib in a patient with TREX1-related skin disease. Parental consent was obtained for the use of ruxolitinib on a compassionate basis.

The patient carried a previously recorded dominant negative heterozygous mutation in TREX1 (c.52G>A, …
ACCURACY OF CONTOURING BY NEURO-ONCOLOGISTS FOR DELIVERY OF FRACTIONATED STEREOTACTIC RADIOTHERAPY (FSRT) AND STEREOTACTIC RADIOSURGERY (SRS) FOR BENIGN INTRACRANIAL CONDITIONS; WHAT DO THE NEURO-RADIOLOGIST AND NEURO-SURGEON ADD?
Authors: Claire Hobbs, Pieter Pretorius, Robin Joseph, Sanjeeva Jeyaretna, Nicola Warner, Sriram Padmanaban, Clare Tunstall, Rhona Watson
Journal: Neuro-Oncology (2018)

Variability exists between clinical oncologists when contouring gross tumour volume (GTV) and normal tissue organs at risk (OAR) volumes. This variability is the ‘weakest link’ in the context of the highly conformal and highly accurate treatment delivery used for SRS and fSRT. In 2016-17NHS England commissioned 17 SRS centres. The service specification mandates “treatment protocols will ensure that target definition is performed by either a sub-specialised neuro-surgeon and / or neuro-oncologist (clinical oncologist) with input from a neuro-radiologist before a treatment plan is created.” To evaluate the additional contribution by the neuro radiologist we analysed contouring conformality for 90 patients with benign conditions treated in our centre (September 2014 – February 2018) using fSRT or SRS. GTV margins contoured by the clinical oncologist were copied and amended with the neuro-radiologist and sometimes neurosurgeon. Clinical target volumes (CTV) were added depending on the tumour type and grade, 1 mm margin was added to CTV for the planning target volume (PTV). The 90 patients included 71 meningioma, 10 pituitary adenoma, 6 craniopharyngioma, 3 other. Doses used were: 45–59.4 Gy in 30–33 fractions for fSRT and 14-16Gy for SRS. We used Eclipse TPS (v13.7) for Varian (Palo Alto, CA) Clinac iX with millennium MLC (5 mm) and Exactrac imaging system (Brainlab, Munich DE). All plans were created either using dynamic conformal arc (DCA) or VMAT RapidArc (RA) techniques with 6 MV photons and calculated using AAA (v10) on a 1 mm dose grid. Values for the final treated GTV and PTV (A) were compared with the GTV and PTV that were generated by the Clinical oncologist alone (B) will be compared using the Conformity analysis consisted of Jaccard coefficient, Dice coefficient, Geographical Miss and Discordance index as defined below. Results will be presented.
Epigenetic adaptation to therapy in glioblastoma: popping the hood on therapeutic resistance
Authors: Mr Seamus Caragher, Mr Jack Shireman, Dr Cheol Hong Park, Prof Atique Ahmed
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, remains one of most intractable diseases. Median survival remains at only 15 months, despite aggressive combination therapy involving surgical resection, radiation, and alkylating chemotherapy. While initially responsive to these therapies, GBM tumors quickly adapt and generate treatment-resistant recurrent growths. We and others have previously shown that the stress induced by standard of care therapies itself activates a remarkable plasticity in GBM cells, converting previously differentiated cells to a therapy-resistant glioma stem cell (GSC) state. The exact processes governing this conversion, however, remain to be fully elucidated. Preliminary investigation revealed that polycomb group protein EZH2, a well-established epigenetic regulator, plays a crucial role in this process. To determine how EZH2 responds to therapy, we performed Genome-wide chromatin immunoprecipitation (ChIP) in parallel with DNA sequencing analyses (ChIP-seq), which identified 1449 distinct regions with elevated EZH2 binding, including critical genes PTPRT, CDK5R2, and Siglec6. Microarray analysis demonstrated subsequent attenuation in their gene expression, leading to heightened activity of STAT3, a critical regulator for promotion of the GSC phenotype. To better understand the epigenetic adaptions occurring during therapeutic stress, we performed ChIP seq analysis for histone 3 lysine 27 acetylation (H3K27ac), a marker for active chromatin. Chemotherapy induces H3K27ac enrichment in 452 unique loci, while radiation caused H3K27ac enrichment at 1029 sites. Comparison of these sites to canonical H3K27me3 sites revealed specific de novo binding in the homeobox transcription factor binding motif (p=0.025). Combination of our epigenomic data from patient-derived xenograft models and GBM patient data with H3K27me3 enrichment profile allowed us to pinpoint several novel homeobox transcription factors potentially linked to GBM plasticity during therapeutic stress. These results provide critical perspective on the global epigenetic changes driving this plasticity occurring during anti-glioma therapy and provide novel avenues for targeting this adaptation therapeutically.
Fighting against depression with TREK-1 blockers: Past and future. A focus on spadin
Authors: Alaeddine Djillani, Mariel Pietri, Jean Mazella, Catherine Heurteaux, Marc Borsotto
Journal: Pharmacology & Therapeutics (2018)

Depression is a devastating mood disorder and a leading cause of disability worldwide. Depression affects approximately one in five individuals in the world and represents heavy economic and social burdens. The neurobiological mechanisms of depression are not fully understood, but evidence highlights the role of monoamine neurotransmitter balance. Several antidepressants (ADs) are marketed to treat depression and related mood disorders. However, despite their efficacy, they remain nonspecific and unsafe because they trigger serious adverse effects. Therefore, developing new molecules for new targets in depression has become a real necessity. Eight years ago, spadin was described as a natural peptide with AD properties. This 17-amino acid peptide blocks TREK-1 channels, an original target in depression. Compared to the classical AD drugs such as fluoxetine, which requires 3–4 weeks for the AD effect to manifest, spadin acts rapidly within only 4 days of treatment. The AD properties are associated with increased neurogenesis and synaptogenesis in the brain. Despite the advantages of this fast-acting AD, the in vivo stability is weak and does not last for >7 h. The present review summarizes different strategies such as retro-inverso strategy, cyclization, and shortening the spadin sequence that has led to the development and optimization of spadin as an AD. Shortened spadin analogs present increased inhibition potency for TREK-1, an improved AD activity, and prolonged in vivo bioavailability. Finally, we also discuss about other inhibitors of TREK-1 channels with a proven efficacy in treating depression in the clinic, such as fluoxetine.
Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas
Authors: Irene Scarfò, Maria Ormhøj, Matthew J. Frigault, Ana P. Castano, Selena Lorrey, Amanda A. Bouffard, Alexandria van Scoyk, Scott J. Rodig, Alexandra J. Shay, Jon C. Aster, Frederic I. Preffer, David M. Weinstock, Marcela V. Maus
Journal: Blood (2018)
Sand and Dust Storms: Acute Exposure and Threats to Respiratory Health
Authors: Jane E. Gross, W. Graham Carlos, Charles S. Dela Cruz, Philip Harber, Shazia Jamil
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

"Sand and Dust Storms: Acute Exposure and Threats to Respiratory Health." American Journal of Respiratory and Critical Care Medicine, 198(7), pp. P13–P14
Abstract 18073: Predictors of Reduced Left Ventricular Function in Patients With ST Elevation Myocardial Infarction After Primary Percutaneous Intervention: Propensity Score Matched Analysis
Authors: Jung-Hee Lee, Ung Kim, Chan-Hee Lee, Jang-Won Son, Jong-Seon Park, Dong-Gu Shin, Young-Jo Kim
Journal: Circulation (2016)

Background: There is a paucity of data about factors to predict reduced left ventricular (LV) ejection fraction (EF) after successful primary percutaneous intervention (PCI) in patients with ST-seg...
CD84 regulates PD-1/PD-L1 expression and function in chronic lymphocytic leukemia
Authors: Hadas Lewinsky, Avital F. Barak, Victoria Huber, Matthias P. Kramer, Lihi Radomir, Lital Sever, Irit Orr, Vita Mirkin, Nili Dezorella, Mika Shapiro, Yosef Cohen, Lev Shvidel, Martina Seiffert, Yair Herishanu, Shirly Becker-Herman, Idit Shachar
Journal: Journal of Clinical Investigation (2018)

Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and progressive accumulation of mature B lymphocytes in the peripheral blood, lymphoid tissues, and bone marrow. CLL is characterized by profound immune defects leading to severe infectious complications. T cells are numerically, phenotypically, and functionally highly abnormal in CLL, with only limited ability to exert antitumor immune responses. Exhaustion of T cells has also been suggested to play an important role in antitumor responses. CLL-mediated T cell exhaustion is achieved by the aberrant expression of several inhibitory molecules on CLL cells and their microenvironment, prominently the programmed cell death ligand 1/programmed cell death 1 (PD-L1/PD-1) receptors. Previously, we showed that CD84, a member of the SLAM family of receptors, bridges between CLL cells and their microenvironment. In the current study, we followed CD84 regulation of T cell function. We showed that cell-cell interaction mediated through human and mouse CD84 upregulates PD-L1 expression on CLL cells and in their microenvironment and PD-1 expression on T cells. This resulted in suppression of T cell responses and activity in vitro and in vivo. Thus, our results demonstrate a role for CD84 in the regulation of immune checkpoints by leukemia cells and identify CD84 blockade as a therapeutic strategy to reverse tumor-induced immune suppression.
Abstract 16661: MYH7-R403Q Patient-Derived Induced Pluripotent Stem Cell Cardiomyocytes as a Model of Hypertrophic Cardiomyopathy
Authors: Hannah K Fandl, Theodore J Kaplan, Michael A Dunn, Lori G Morton, Scott M MacDonnell
Journal: Circulation (2017)

Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people worldwide, leading to reduced left ventricle chamber size, impaired relaxation, reduced cardiac output, fibrosis, arrhythmia and failure. U...
Integrating a nationally scaled workforce of community health workers in primary care: a modelling study
Authors: Benedict Hayhoe, Thomas E Cowling, Virimchi Pillutla, Priya Garg, Azeem Majeed, Matthew Harris
Journal: Journal of the Royal Society of Medicine (2018)

Objective To model cost and benefit of a national community health worker workforce. Design Modelling exercise based on all general practices in England. Setting United Kingdom National Health Service Primary Care. Participants Not applicable. Data sources Publicly available data on general practice demographics, population density, household size, salary scales and screening and immunisation uptake. Main outcome measures We estimated numbers of community health workers needed, anticipated workload and likely benefits to patients. Results Conservative modelling suggests that 110,585 community health workers would be needed to cover the general practice registered population in England, costing £2.22bn annually. Assuming community health workerss could engage with and successfully refer 20% of eligible unscreened or unimmunised individuals, an additional 753,592 cervical cancer screenings, 365,166 breast cancer screenings and 482,924 bowel cancer screenings could be expected within respective review periods. A total of 16,398 additional children annually could receive their MMR1 at 12 months and 24,716 their MMR2 at five years of age. Community health workerss would also provide home-based health promotion and lifestyle support to patients with chronic disease. Conclusion A scaled community health worker workforce integrated into primary care may be a valuable policy alternative. Pilot studies are required to establish feasibility and impact in NHS primary care.
Controversies in the Treatment of Classical Hodgkin Lymphoma
Authors: Dennis A. Eichenauer, Marc André, Peter Johnson, Alexander Fossa, Olivier Casasnovas, Andreas Engert
Journal: HemaSphere (2018)

Abstract Hodgkin lymphoma (HL) is a B‐cell‐derived malignancy that mostly affects young adults. Pathologically, HL is divided into classical HL (cHL) and the rare entity of nodular lymphocyte‐predominant HL. Classical HL is characterized by few malignant cells termed Hodgkin and Reed–Sternberg cells embedded in an inflammatory background. The treatment of cHL has consistently improved over the last decades so that current standard approaches result in long‐term remission rates in excess of 80%. However, potentially lethal therapy‐related late complications affect an increasing number of survivors. For this reason, issues regarding the optimal treatment of cHL patients are still fiercely debated. Questions under discussion include how treatment can be guided by interim positron emission tomography, the best initial treatment for advanced‐stage disease and the use of targeted drugs such as the antibody–drug conjugate brentuximab vedotin and the anti‐PD‐1 antibodies nivolumab and pembrolizumab. The identification of patients who should undergo allogeneic stem cell transplantation is another unsolved issue. The present article highlights the most relevant clinical trials and addresses controversial open questions in the treatment of cHL.
Peptide-decorated polymeric nanomedicines for precision cancer therapy
Authors: Huanli Sun, Yangyang Dong, Jan Feijen, Zhiyuan Zhong
Journal: Journal of Controlled Release (2018)

The advancement of tissue and cell-specific drug delivery systems is a key to precision cancer therapy. Peptides, with easy synthesis, low immunogenicity and biological functions closely mimicking or surpassing natural proteins, have been actively engineered and explored to provide nanomedicines with the ability to overcome various extracellular and intracellular delivery barriers ranging from phagocytic clearance in the circulation, low tumor penetration, poor cancer cell selectivity, inferior cell penetration, to endosomal entrapment as well as poor blood brain barrier permeation for brain cancer therapy. Anti-tumor studies with peptide-decorated polymeric nanomedicines are currently in the experimental stage. Most of the reported peptide-directed polymeric nanomedicines do have a rather complex design requiring a multi-step reproducible fabrication process. Moreover, many of the proposed peptide-decorated polymeric nanomedicines are still not able to effectively overcome the drug delivery cascade barriers. Consequently, in order to facilitate clinical translation the complexity of the systems has to be reduced, while maintaining the added functions after the introduction of the different peptides and further progress has to be made in passing the various drug delivery barriers. In this review, we give an overview of the rational design, development and preclinical performance of peptide-decorated polymeric nanomedicines, and further discuss their challenges and future perspectives as a next generation cancer treatment modality.
Elevated B cell stimulatory cytokines preceding lymphoma in subjects with acquired immunodeficiency syndrome (AIDS) followed by non-Hodgkin’s B cell lymphoma
Authors: Elizabeth Breen, Larry Magpantay, Malgorzata Grodsky, Roger Detels, Charles Rabkin, Richard Kaslow, Richard Ambinder, Lisa Jacobson, Otoniel Martinez-Maza
Journal: Cancer Research (2007)

4323   Persons with human immunodeficiency virus (HIV) infection are at increased risk of acquired immunodeficiency syndrome-associated non-Hodgkin’s B cell lymphoma (AIDS-NHL). Chronic B cell hyperactivation due to HIV infection and/or disease progression is thought to contribute to this increased risk. Lymphoma can be the initial AIDS-defining condition, but frequently occurs subsequent to some other AIDS-defining condition. In AIDS-NHL cases that follow another AIDS-defining condition, the extent of B cell activation observed prior to the lymphoma diagnosis may be impacted by the prior AIDS diagnosis. In a nested case-control study utilizing samples from participants in the Multicenter AIDS Cohort Study, we assessed serum levels of several B cell stimulatory cytokines and molecules associated with B cell activation. Cases (AIDS+NHL, n=99) were participants who developed AIDS-NHL subsequent to another, non-lymphoma AIDS diagnosis; controls (AIDS, n=99) were participants who developed AIDS, but not lymphoma, matched to cases on time of AIDS diagnosis. Levels of interleukin (IL) 6, IL10, soluble CD23 (sCD23), sCD27, sCD30, C’-reactive protein (CRP), and total IgE were quantified in matched longitudinal serum samples collected at up to three time points prior to lymphoma diagnosis of the case (3-5 years, 1-3 years, and
Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults
Authors: Michael Inouye, Gad Abraham, Christopher P. Nelson, Angela M. Wood, Michael J. Sweeting, Frank Dudbridge, Florence Y. Lai, Stephen Kaptoge, Marta Brozynska, Tingting Wang, Shu Ye, Thomas R. Webb, Martin K. Rutter, Ioanna Tzoulaki, Riyaz S. Patel, Ruth J.F. Loos, Bernard Keavney, Harry Hemingway, John Thompson, Hugh Watkins, Panos Deloukas, Emanuele Di Angelantonio, Adam S. Butterworth, John Danesh, Nilesh J. Samani
Journal: Journal of the American College of Cardiology (2018)

Coronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes. This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention. Using a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank. The hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age. The genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction.
Abstract 20455: Cholesterol Crystal as an Important Contributor to Plaque Instability in Type2 Diabetic Patients With Coronary Artery Disease: Insights From Optical Coherence Tomography Imaging Analysis
Authors: Hiroki Nakano, Yu Kataoka, Shunsuke Usami, Takahiro Nakashima, Shoji Kawakami, Masashi Fujino, Kazuhiro Nakao, Shuichi Yoneda, Fumiyuki Otsuka, Kensaku Nishihira, Yoshio Tahara, Yasuhide Asaumi, Teruo Noguchi, Satoshi Yasuda
Journal: Circulation (2017)

Background: Patients with type 2 diabetes mellitus (DM) exhibit a higher frequency of atherosclerotic cardiovascular events. Their atherosclerotic feature is characterized as the presence of large ...