tbuckley/cabot-search huggingface dataset:
Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound
Authors: Afam A. Okoye, Scott G. Hansen, Mukta Vaidya, Yoshinori Fukazawa, Haesun Park, Derick M. Duell, Richard Lum, Colette M. Hughes, Abigail B. Ventura, Emily Ainslie, Julia C. Ford, David Morrow, Roxanne M. Gilbride, Alfred W. Legasse, Joseph Hesselgesser, Romas Geleziunas, Yuan Li, Kelli Oswald, Rebecca Shoemaker, Randy Fast, William J. Bosche, Bhavesh R. Borate, Paul T. Edlefsen, Michael K. Axthelm, Louis J. Picker, Jeffrey D. Lifson
Journal: Nature Medicine (2018)
Lambert-Eaton Myasthenic Syndrome Associated With Extrapulmonary Small Cell Cancer Detected by 18F-FDG PET/CT
Authors: Guoqian Chen, Zhanli Fu, Xueqi Chen, Qian Li
Journal: Clinical Nuclear Medicine (2018)

A 46-year-old woman suffering from lower extremity weakness, dysarthria, dysphagia, dyspnea, and dry mouth was suspected of having Lambert-Eaton myasthenic syndrome based on the characteristic electromyographic abnormalities of right ulnar nerve, which demonstrated reduced resting compound muscle action potential amplitude and greater than 100% incremental change in high-frequency repetitive nerve stimulation. An F-FDG PET/CT was performed to detect the underlying neoplasm and revealed a retroperitoneal soft tissue mass with high F-FDG avidity in the left iliac fossa. The patient's symptoms were prominently relieved after the tumor resection, and the histopathology indicated a small cell carcinoma.
Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells
Authors: Zahra Kabiri, Gediminas Greicius, Hamed Zaribafzadeh, Amanda Hemmerich, Christopher M Counter, David M Virshup
Journal: Journal of Clinical Investigation (2018)

Intestinal homeostasis depends on a slowly proliferating stem cell compartment in crypt cells, followed by rapid proliferation of committed progenitor cells in the transit amplifying (TA) compartment. The balance between proliferation and differentiation in intestinal stem cells (ISCs) is regulated by Wnt/β-catenin signaling, although the mechanism remains unclear. We previously targeted PORCN, an enzyme essential for all Wnt secretion, and demonstrated that stromal production of Wnts was required for intestinal homeostasis. Here, a PORCN inhibitor was used to acutely suppress Wnt signaling. Unexpectedly, the treatment induced an initial burst of proliferation in the stem cell compartment of the small intestine, due to conversion of ISCs into TA cells with a loss of intrinsic ISC self-renewal. This process involved MAPK pathway activation, as the proliferating cells in the base of the intestinal crypt contained phosphorylated ERK1/2, and a MEK inhibitor attenuated the proliferation of ISCs and their differentiation into TA cells. These findings suggest a role for Wnt signaling in suppressing the MAPK pathway at the crypt base to maintain a pool of ISCs. The interaction between Wnt and MAPK pathways in vivo has potential therapeutic applications in cancer and regenerative medicine.
Noninvasive ventilatory support to reverse weight loss in Duchenne muscular dystrophy: A case series
Authors: P. Deo, J.R. Bach
Journal: Pulmonology (2018)

This case series of five patients with Duchenne muscular dystrophy demonstrates the nutritional advantages of instituting noninvasive intermittent positive pressure ventilatory support via 15 mm angled mouthpieces to relieve tachypnea and provide more time to swallow food safely. In each case weight loss was reversed.
Use of Vascular Assessments and Novel Biomarkers to Predict Cardiovascular Events in Type 2 Diabetes: The SUMMIT VIP Study
Authors: Angela C. Shore, Helen M. Colhoun, Andrea Natali, Carlo Palombo, Faisel Khan, Gerd Östling, Kunihiko Aizawa, Cecilia Kennbäck, Francesco Casanova, Margaretha Persson, Kim Gooding, Phillip E. Gates, Helen Looker, Fiona Dove, Jill Belch, Silvia Pinnola, Elena Venturi, Michaela Kozakova, Isabel Goncalves, Jasmina Kravic, Harry Björkbacka, Jan Nilsson
Journal: Diabetes Care (2018)

OBJECTIVE Cardiovascular disease (CVD) risk prediction represents an increasing clinical challenge in the treatment of diabetes. We used a panel of vascular imaging, functional assessments, and biomarkers reflecting different disease mechanisms to identify clinically useful markers of risk for cardiovascular (CV) events in subjects with type 2 diabetes (T2D) with or without manifest CVD. RESEARCH DESIGN AND METHODS The study cohort consisted of 936 subjects with T2D recruited at four European centers. Carotid intima-media thickness and plaque area, ankle-brachial pressure index, arterial stiffness, endothelial function, and circulating biomarkers were analyzed at baseline, and CV events were monitored during a 3-year follow-up period. RESULTS The CV event rate in subjects with T2D was higher in those with (n = 440) than in those without (n = 496) manifest CVD at baseline (5.53 vs. 2.15/100 life-years, P &amp;lt; 0.0001). New CV events in subjects with T2D with manifest CVD were associated with higher baseline levels of inflammatory biomarkers (interleukin 6, chemokine ligand 3, pentraxin 3, and hs-CRP) and endothelial mitogens (hepatocyte growth factor and vascular endothelial growth factor A), whereas CV events in subjects with T2D without manifest CVD were associated with more severe baseline atherosclerosis (median carotid plaque area 30.4 mm2 [16.1–92.2] vs. 19.5 mm2 [9.5–40.5], P = 0.01). Conventional risk factors, as well as measurements of arterial stiffness and endothelial reactivity, were not associated with CV events. CONCLUSIONS Our observations demonstrate that markers of inflammation and endothelial stress reflect CV risk in subjects with T2D with manifest CVD, whereas the risk for CV events in subjects with T2D without manifest CVD is primarily related to the severity of atherosclerosis.
Precisely albumin-hitchhiking tumor cell-activated reduction/oxidation-responsive docetaxel prodrugs for the hyperselective treatment of breast cancer
Authors: Wei Wei, Cong Luo, Jincheng Yang, Bingjun Sun, Dongyang Zhao, Yan Liu, Yingli Wang, Wenqian Yang, Qiming Kan, Jin Sun, Zhonggui He
Journal: Journal of Controlled Release (2018)
Endothelium-Intrinsic Requirement for Hif-2α During Vascular Development
Authors: Li-JuanDuan, YahuiZhang-Benoit, Guo-HuaFong
Journal: Circulation (2005)

Background— The development of the vascular system is a complex process that involves communications among multiple cell types. As such, it is important to understand whether a specific gene regulates vascular development directly from within the vascular system or indirectly from nonvascular cells. Hypoxia-inducible factor-2α (Hif-2α, or endothelial PAS protein-1 [EPAS-1]) is required for vascular development in mice, but it is not clear whether its requirement resides directly in endothelial cells. Methods and Results— To address this issue, we expressed Hif-2α cDNA in the vascular endothelium of Hif-2α−/− embryos by an embryonic stem (ES) cell–mediated transgenic approach and assessed whether endothelium-specific reexpression of Hif-2α could rescue vascular development. Here we report that although ES cell–derived Hif-2α−/− embryos developed severe vascular defects by embryonic day (E) 11.5 and died in utero before E12.5, endothelium-specific expression of Hif-2α cDNA restored normal vascular developme...
Targeted Drug Delivery: Mannose and Mannose-6-Phosphate Receptor-Targeted Drug Delivery Systems and Their Application in Cancer Therapy (Adv. Healthcare Mater. 14/2018)
Authors: Elena Dalle Vedove, Gabriella Costabile, Olivia M. Merkel
Journal: Advanced Healthcare Materials (2018)

In the promising field of targeted nanomedicine, the upregulation of mannose and mannose-6-phosphate receptors expression on the surface of several aggressive tumors not only allows the selective delivery of chemotherapeutics, but pave the way for many other additional applications in cancer treatment such as immunotherapy and cancer prognosis. In article 1701398, a progress report by Olivia M. Merkel and co-workers highlights the latest advances in this area of targeted drug delivery. Image by Christoph Hohmann, Nanosystems Initiative Munich (NIM).
Active Surveillance Magnetic Resonance Imaging Study (ASIST): Results of a Randomized Multicenter Prospective Trial
Authors: Laurence Klotz, Andrew Loblaw, Linda Sugar, Madeline Moussa, David M. Berman, Theo Van der Kwast, Danny Vesprini, Laurent Milot, Marlene Kebabdjian, Neil Fleshner, Sangeet Ghai, Joe Chin, Gregory R. Pond, Masoom Haider
Journal: European Urology (2018)
THO Complex-Dependent Posttranscriptional Control Contributes to Vascular Smooth Muscle Cell Fate Decision
Authors: Xinli Yuan, Tao Zhang, Fang Yao, Yingnan Liao, Fei Liu, Zongna Ren, Leng Han, Lixia Diao, Yankui Li, Bingying Zhou, Fan He, Li Wang
Journal: Circulation Research (2018)

Rationale: Modulation of vascular smooth muscle cell (VSMC) phenotype plays a fundamental role in vascular development and diseases. Although extensive studies uncovered the roles of transcriptional regulation in VSMC-specific gene expression, how posttranscriptional regulation contributes to VSMC fate decisions remains to be determined. Objective: To establish THO complex-dependent VSMC gene expression as a novel regulatory basis controlling VSMC phenotypes. Methods and Results: Immunohistochemical staining against THOC2 and THOC5, 2 components of the THO complex, revealed a dramatic reduction in their expression in human arteries undergoing carotid endarterectomy compared with normal internal mammary arteries. Silencing of THOC2 or THOC5 led to dedifferentiation of VSMCs in vitro, characterized by decreased VSMC marker gene expression and increased migration and proliferation. Furthermore, RNA high-throughput sequencing (Seq) revealed that THOC5 silencing closely resembled the gene expression changes induced on PDGF (platelet-derived growth factor)-BB/PDGF-DD treatments in cultured VSMCs. Mechanistically, THOC2 and THOC5 physically interacted with and functionally relied on each other to bind to specific motifs on VSMC marker gene mRNAs. Interestingly, mRNAs that lost THOC2 or THOC5 binding during VSMC dedifferentiation were enriched for genes important for the differentiated VSMC phenotype. Last, THOC5 overexpression in injured rat carotid arteries significantly repressed loss of VSMC marker gene expression and neointima formation. Conclusions: Our data introduce dynamic binding of THO to VSMC marker gene mRNAs as a novel mechanism contributing to VSMC phenotypic switching and imply THOC5 as a potential intervention node for vascular diseases.
THU0186 Rheumatoid arthritis and interstitial lung disease. multicentric retrospective study of 118 patients treated with biological no anti tnf
Authors: C. Fernández-Díaz, S. Castañeda, B. Garcia-Magallon, J. Narvaez-García, M. Retuerto, T. Perez-Sandoval, M. Martin-Lopez, P. Rubio-muñoz, M. Carrasco-Cubero, D. Reina-Sainz, A. Urruticoechea, C. Ojeda-Garcia, S. Rodriguez-Muguruza, P. Carreira, L. Belmar-Vega, E. Cervantes, B. Robles-flores, L. Arboleya, G. Bonilla, I. Hernandez-Rodriguez, O. Maiz-Alonso, D. Palma, C. Delgado, R. Expósito-Molinero, F. Ortiz-Sanjuan, A. Ruibal-Escribano, S. Ordoñez, M. Moreno, I. Villa blanco, C. Fito, J. Blanco-Madrigal, J. Bernal, S. Romero, N. Mena-Vazquez, M. Lopez-corbeto, T.J. Mas, T.R. Vazqzez, M.A. Gonzalez-Gay, R. Blanco, H. Macarena, Sevill J. Bernal
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Interstitial lung disease (ILD) associated with Rheumatoid Arthritis (RA) has a poor prognosis. Treatments such as anti-TNF, have been implicated in the exacerbation of an ILD. <h3>Objectives</h3> Our objective is to evaluate and compare the evolution of ILD in patients with RA treated with Abatacept (ABA), Rituximab (RTX) and Tocilizumab (TCZ) after 1 year of treatment. <h3>Methods</h3> Retrospective multicentre study of patients with ILD and AR treated with ABA, RTX and TCZ at standard doses. The ILD was diagnosed by CT. The efficacy was evaluated whith the following measures: i) Dyspnea by modified scale of the Medical Research Council (mMRC); considering variations of 1 point. ii) Respiratory function tests; considering variations in FVC and DLCO ≥10%. iii) Imaging test (CT). <h3>Results</h3> We included 118 (72 women/46 men) patients, mean age of 62.27±10.55 years. The ILD had a median evolution of 12 12–37 months. The RA was ACPA+in 102 cases (86.4%). At diagnosis, the mean DLCO onset of biological treatment was 65.63±19.38. Table 1 shows the characteristics by subgroups. The Figure expresses the evolution in the cases available at 12 months. There is an improvement in CT in 36.4% of patients with ABA, 28.6% of patients with RTX and only 8.3% of patients with TCZ. <h3>Conclusions</h3> There seems to be a trend towards a better radiological response in patients treated with RTX and ABA. It would be necessary prospective studies. <h3>Disclosure of Interest</h3> None declared
Abstract 17049: Computer Simulation to Study the Effect of Structural Remodeling on Atrial Fibrillation Using Clinically-obtained Cardiac MRIs
Authors: Jason Ng, Justin K Ng, Paras Parikh, Jeffrey J Goldberger, Michael Markl, James Carr, Wenjia Bai, Prapa Kanagaratnam, Phang B Lim, Louisa C Malcolme-Lawes, Norman A Qureshi, Nicholas S Peters
Journal: Circulation (2015)

Introduction: Structural remodeling of the atria in the form of fibrosis is known to be a contributing factor for the initiation and maintenance of atrial fibrillation (AF). Hypothesis: Using computer simulation based on clinically-obtained MRIs, we tested the hypothesis that both dense and diffuse fibrosis play significant roles in the inducibility of AF and the effectiveness of pulmonary vein (PV) ablation. Methods: Magnetic resonance angiograms and delayed enhancement MRIs (DEMRIs) of the left atrium from 34 AF patients were used to construct the models for the computer simulations. Using the Fenton-Karma action potential model, three conditions were tested for AF inducibility: 1) no fibrosis, 2) diffuse fibrosis, and 3) diffuse and dense fibrosis. AF induction was attempted at each of the four PVs and episodes lasting &gt;30 s were considered sustained. Wide area PV ablation was simulated on all sustained episodes. Results: With no fibrosis, sustained AF was achieved in 55.9±32.0% of induction attempts. This percentage was significantly increased to 92.6±15.7% and 93.4±12.8% with diffuse fibrosis and combined dense and diffuse fibrosis, respectively (p&lt;0.0001 for both). PV ablation terminated 75% of episodes induced with no fibrosis, 62% with diffuse fibrosis and 60% with combined dense and diffuse fibrosis. Organized reentry usually formed after ablation with dense scar providing an anchor for reentry in episodes where dense scar is present. Conclusions: Both diffuse and dense fibrosis significantly increases the likelihood for AF induction and maintenance in the computer model with dense fibrosis providing additional anchor points in the left atrium for reentrant circuits.
Application of a Tool to Identify Undiagnosed Hypertension — United States, 2016
Authors: Elizabeth L. Ciemins, Matthew D. Ritchey, Vaishali V. Joshi, Fleetwood Loustalot, Judy Hannan, John K. Cuddeback
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Approximately 11 million U.S. adults with a usual source of health care have undiagnosed hypertension, placing them at increased risk for cardiovascular events (1-3). Using data from the National Health and Nutrition Examination Survey (NHANES), CDC developed the Million Hearts Hypertension Prevalence Estimator Tool, which allows health care delivery organizations (organizations) to predict their patient population's hypertension prevalence based on demographic and comorbidity characteristics (2). Organizations can use this tool to compare predicted prevalence with their observed prevalence to identify potential underdiagnosed hypertension. This study applied the tool using medical billing data alone and in combination with clinical data collected among 8.92 million patients from 25 organizations participating in American Medical Group Association (AMGA) national learning collaborative* to calculate and compare predicted and observed adult hypertension prevalence. Using billing data alone revealed that up to one in eight cases of hypertension might be undiagnosed. However, estimates varied when clinical data were included to identify comorbidities used to predict hypertension prevalence or describe observed hypertension prevalence. These findings demonstrate the tool's potential use in improving identification of hypertension and the likely importance of using both billing and clinical data to establish hypertension and comorbidity prevalence estimates and to support clinical quality improvement efforts.
US drugs were granted breakthrough approval on weak evidence, study finds
Authors: Jacqui Wise
Journal: BMJ (2018)

Promising new drugs that were granted “breakthrough therapy” status in the United States were often approved on the basis of very little strong evidence, according to a research letter published in JAMA .1

The study of all Food and Drug Administration (FDA) approvals between 2012 and 2017 found that the trials supporting these approvals commonly lacked randomisation, double blinding and control …
Serum free light chain measurements to reduce 24‐h urine monitoring in patients with multiple myeloma with measurable urine monoclonal protein
Authors: Marcella Tschautscher, Vincent Rajkumar, Angela Dispenzieri, Martha Lacy, Morie Gertz, Francis Buadi, David Dingli, Lisa Hwa, Amie Fonder, Miriam Hobbs, Suzanne Hayman, Stephen Zeldenrust, John Lust, Stephen Russell, Nelson Leung, Pranshant Kapoor, Ronald Go, Yi Lin, Wilson Gonsalves, Taxiarchis Kourelis, Rahma Warsame, Robert Kyle, Shaji Kumar
Journal: American Journal of Hematology (2018)

Abstract Detection of myeloma progression (PD) relies on serial 24‐h urinary M protein measurements in patients without measurable serum M spike. We examined whether serial difference free light chain (dFLC) levels could be used as a surrogate for serial 24‐h urine M protein measurements in monitoring for PD in patients with baseline measurable urine M protein. We studied 122 patients who had serial measurement of urine M protein and serum FLC and had demonstrated PD. The median increase in dFLC with progression as defined by urine M spike was 110% (IQR: 55‐312) and median absolute increase was 74 mg/dL; while 89% of patients had dFLC increase ≥ 25%, 94% had absolute increase in dFLC &gt; 10 mg/dL, and 98% met at least 1 of these 2 criteria at PD. In patients with baseline measurable serum FLC ( n = 118), 89% had increase in dFLC ≥ 25%, 97% had dFLC increase of &gt; 10 mg/dL, and 98% had 1 of the 2. We conclude that serial dFLC assessments can be used in place of serial 24‐h urine protein assessments during myeloma surveillance to monitor for PD. Once patients have an absolute increase in dFLC of &gt;10 mg/dL from the nadir, a 24‐h urine collection can then be assessed to document PD as per the International Myeloma Working Group criteria.
Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1β/VEGFA signalling
Authors: Fuqing Hu, Haijie Li, Lu Liu, Feng Xu, Senyan Lai, Xuelai Luo, Junbo Hu, Xi Yang
Journal: Molecular Cancer (2018)

Gastrointestinal stromal tumour (GIST) is the most common soft tissue sarcoma. The identification of the molecular mechanisms regulating GIST progression is vital for its treatment and prevention. Increasing reports have demonstrated that epigenetic alterations play critical roles in GIST development. However, the role of the histone demethylase KDM4D in GIST progression is poorly understood.In clinically matched GIST tissues, KDM4D protein levels were measured by Western blot and immunohistochemical (IHC) staining. KDM4D mRNA levels were examined by quantitative real-time PCR (qRT-PCR). Bioinformatics analysis was used to examine KDM4D expression. The biological effects of KDM4D were investigated in vitro using CCK-8, BrdU/PI, wound healing, colony formation, tube formation and Transwell assays and in vivo using a xenograft mice model. Luciferase assays were used to assess regulation of HIF1β gene promoter activity by KDM4D. ChIP assays were performed to assess KDM4D, H3K36me3 and H3K9me3 occupancy on the HIF1β gene promoter.We observed a significant upregulation of KDM4D in GIST tissue compared with matched normal tissue and further explored the oncogenic function of KDM4D both in vitro and in vivo. Furthermore, we demonstrated that KDM4D directly interacted with the HIF1β gene promoter and regulated its activity, promoting tumour angiogenesis and GIST progression both in vitro and in vivo. Finally, we demonstrated that KDM4D transcriptionally activates HIF1β expression via H3K9me3 and H3K36me3 demethylation at the promoter region.Our findings reveal the important roles of the KDM4D/HIF1β/VEGFA signalling pathway in GIST progression, and this pathway may act as a potential therapeutic target for GIST patients.
Abstract 19236: No Difference in Composite of Patency and Rutherford Class in Patients Receiving Drug Eluting Stents vs. Bare Metal Stents in Peripheral Vascular Interventions
Authors: Perwaiz M Meraj, Rajkumar Doshi, Pavitra Vijayaraghavan, Daniel Helfgott
Journal: Circulation (2015)

Background: The presence of peripheral arterial disease (PAD) results in limitation of physical activity due to claudication, and when left untreated, develops into limb ischemia followed by limb loss. The use of drug eluting stents (DES) in peripheral vascular interventions (PVI) has been shown to improve patency over angioplasty (PTA) and bare metal stents (BMS), however this was in a cohort of patients with short lesion lengths. Clinical trials comparing the efficacy of the DES in long lesion lengths are not well described, neither in patency or continued symptom relief at 6 months. Here, we compare the a composite endpoint of patency and Rutherford Class in patients receiving DES. Methods: 277 patients underwent PVI with either DES or BMS from January 2011 to January 2015 for claudication and/or limb ischemia. The primary end point was patency (either ABI improvement above 0.9 or US velocity &lt;250 m/s) and Rutherford class (Class I to VI) at follow up. A Pearson chi-square analysis and multivariate analysis were used to determine results. Results: A total of 20 patients underwent DES placement and 257 underwent BMS placement. Baseline differences existed between the two groups, particularly stent length. No difference in patency or Rutherford class was observed after correcting for all baseline differences in a multivariate analysis. Conclusion: After correcting for stent length and baseline characteristics, no significant differences in patency and Rutherford Class was observed. More data is needed in this real world use of DES as the current clinical trials only define very short lesion length, which defines a small subset of the patients treated in modern day practice.