tbuckley/cabot-search huggingface dataset:
Improving access to quality medicines in East Africa: An independent perspective on the East African Community Medicines Regulatory Harmonization initiative
Authors: Alexander R. Giaquinto, Alberto Grignolo, Lawrence Liberti, John C. W. Lim, Tomas Salmonson, Fernand Sauer, Henrietta Ukwu
Journal: PLoS Medicine (2020)

The goal of improving access to quality medicines in East Africa has been addressed by the East African Community (EAC) Medicines Regulatory Harmonization (MRH) initiative, which is working to simplify the process of registering medicines and increase the speed at which registration applications are reviewed while ensuring that only highquality medicines are approved.• This article was written by a group of authors with varied expertise in global regulatory affairs but no involvement to date in the EAC MRH initiative.The authors were asked to provide an independent perspective on the initiative's work since its launch in 2012, as well as its plans for the future.• The authors believe that the strengths of the EAC MRH's initiative include its rapid implementation of a joint product assessment process, by which a manufacturer can submit a single marketing authorization application and receive a decision respected by all EAC member states, as well as the creation and use of a common technical document (CTD) for registration applications that is accepted by all member states.In addition, the initiative's twinning program, in which more mature national regulatory authorities carry out joint activities alongside less mature authorities, is an excellent way to build the capacity of all partner states.• The authors believe the EAC MRH initiative may be able to further improve access to essential medicines by increasing transparency, inviting and responding to feedback from industry partners, consistently meeting its advertised assessment and registration timelines, streamlining the joint product assessment process, taking advantage of work done by peer institutions, focusing on the activities most likely to have the greatest public health return, and using metrics and benchmarks to identify opportunities for greater efficiency.
AB0137 Osteoarthritis among german and egyptian patients
Authors: AF El Ghobarey, G Bach, S Mousa, W Kamel
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The aim of the thesis was to study the different clinical features of OA in different ethnic groups of patients. <h3>Methods</h3> One hundred and sixty six Germans and 50 Egyptian patients with OA were studied. Clinical examination, severity index and radiological score (of all body joints) beside a battery of routine blood tests were done for each patient. <h3>Results</h3> There was an increase in the number of joints affected and in total joint lesions among Germans. There was also an increase in age at onset, in disease duration and in family history of OA among Germans. None of the Egyptians had hip affection, while 127 Germans had bilateral or unilateral hip joint affection. Severity index of hips correlated with patients age (p &lt; 0.05) and age at onset (p &lt; 0.05) among Germans. While, severity index of knee joint correlated with age (p &lt; 0.05, p &lt; 0.05) and age at onset (p &lt; 0.05, P -c 0.0 5) among both Egyptians and Germans. While 19 Germans had DISH and 19 Germans had CPPD, none of the Egyptians had neither DISH syndrome nor CPPD. Thirteen Germans but none of the Egyptians had knee effusion. Environmental, habitual and occupational causes, among others, seem to modify the clinical features of OA between ethnic groups of patients. <h3>Conclusion</h3>
The Use of Sacubitril/Valsartan for Hospitalized Heart Failure—Why Do We Care About Cost and Value?
Authors: Clyde W. Yancy, Adrian F. Hernandez, Robert O. Bonow
Journal: JAMA Cardiology (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth
Authors: Ruo-Yu Ma, Hui Zhang, Xue-Feng Li, Cheng-Bin Zhang, Cigdem Selli, Giulia Tagliavini, Alyson D. Lam, Sandrine Prost, Andrew H. Sims, Hai-Yan Hu, Tianlei Ying, Zhan Wang, Zhaoming Ye, Jeffrey W. Pollard, Bin-Zhi Qian
Journal: The Journal of Experimental Medicine (2020)

Bone metastasis is the major cause of death in breast cancer. The lack of effective treatment suggests that disease mechanisms are still largely unknown. As a key component of the tumor microenvironment, macrophages promote tumor progression and metastasis. In this study, we found that macrophages are abundant in human and mouse breast cancer bone metastases. Macrophage ablation significantly inhibited bone metastasis growth. Lineage tracking experiments indicated that these macrophages largely derive from Ly6C+CCR2+ inflammatory monocytes. Ablation of the chemokine receptor, CCR2, significantly inhibited bone metastasis outgrowth and prolonged survival. Immunophenotyping identified that bone metastasis-associated macrophages express high levels of CD204 and IL4R. Furthermore, monocyte/macrophage-restricted IL4R ablation significantly inhibited bone metastasis growth, and IL4R null mutant monocytes failed to promote bone metastasis outgrowth. Together, this study identified a subset of monocyte-derived macrophages that promote breast cancer bone metastasis in an IL4R-dependent manner. This suggests that IL4R and macrophage inhibition can have potential therapeutic benefit against breast cancer bone disease.
A multitude of signaling pathways associated with Alzheimer's disease and their roles in AD pathogenesis and therapy
Authors: Kundlik Gadhave, Deepak Kumar, Vladimir N. Uversky, Rajanish Giri
Journal: Medicinal Research Reviews (2020)

Abstract The exact molecular mechanisms associated with Alzheimer's disease (AD) pathology continue to represent a mystery. In the past decades, comprehensive data were generated on the involvement of different signaling pathways in the AD pathogenesis. However, the utilization of signaling pathways as potential targets for the development of drugs against AD is rather limited due to the immense complexity of the brain and intricate molecular links between these pathways. Therefore, finding a correlation and cross‐talk between these signaling pathways and establishing different therapeutic targets within and between those pathways are needed for better understanding of the biological events responsible for the AD‐related neurodegeneration. For example, autophagy is a conservative cellular process that shows link with many other AD‐related pathways and is crucial for maintenance of the correct cellular balance by degrading AD‐associated pathogenic proteins. Considering the central role of autophagy in AD and its interplay with many other pathways, the finest therapeutic strategy to fight against AD is the use of autophagy as a target. As an essential step in this direction, this comprehensive review represents recent findings on the individual AD‐related signaling pathways, describes key features of these pathways and their cross‐talk with autophagy, represents current drug development, and introduces some of the multitarget beneficial approaches and strategies for the therapeutic intervention of AD.
17‐Beta Hydroxysteroid Dehydrogenase 13 Deficiency Does Not Protect Mice From Obesogenic Diet Injury
Authors: Yanling Ma, Philip M. Brown, Dennis D. Lin, Jing Ma, Dechun Feng, Olga V. Belyaeva, Maren C. Podszun, Jason Roszik, Joselyn N. Allen, Regina Umarova, David E. Kleiner, Natalia Y. Kedishvili, Oksana Gavrilova, Bin Gao, Yaron Rotman
Journal: Hepatology (2020)

Background and Aims 17‐Beta hydroxysteroid dehydrogenase 13 (HSD17B13) is genetically associated with human nonalcoholic fatty liver disease (NAFLD). Inactivating mutations in HSD17B13 protect humans from NAFLD‐associated and alcohol‐associated liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma, leading to clinical trials of anti‐HSD17B13 therapeutic agents in humans. We aimed to study the in vivo function of HSD17B13 using a mouse model. Approach and Results Single‐cell RNA‐sequencing and quantitative RT‐PCR data revealed that hepatocytes are the main HSD17B13‐expressing cells in mice and humans. We compared Hsd17b13 whole‐body knockout (KO) mice and wild‐type (WT) littermate controls fed regular chow (RC), a high‐fat diet (HFD), a Western diet (WD), or the National Institute on Alcohol Abuse and Alcoholism model of alcohol exposure. HFD and WD induced significant weight gain, hepatic steatosis, and inflammation. However, there was no difference between genotypes with regard to body weight, liver weight, hepatic triglycerides (TG), histological inflammatory scores, expression of inflammation‐related and fibrosis‐related genes, and hepatic retinoid levels. Compared to WT, KO mice on the HFD had hepatic enrichment of most cholesterol esters, monoglycerides, and certain sphingolipid species. Extended feeding with the WD for 10 months led to extensive liver injury, fibrosis, and hepatocellular carcinoma, with no difference between genotypes. Under alcohol exposure, KO and WT mice showed similar hepatic TG and liver enzyme levels. Interestingly, chow‐fed KO mice showed significantly higher body and liver weights compared to WT mice, while KO mice on obesogenic diets had a shift toward larger lipid droplets. Conclusions Extensive evaluation of Hsd17b13 deficiency in mice under several fatty liver–inducing dietary conditions did not reproduce the protective role of HSD17B13 loss‐of‐function mutants in human NAFLD. Moreover, mouse Hsd17b13 deficiency induces weight gain under RC. It is crucial to understand interspecies differences prior to leveraging HSD17B13 therapies.
Social distancing to slow the US COVID-19 epidemic: Longitudinal pretest–posttest comparison group study
Authors: Mark J. Siedner, Guy Harling, Zahra Reynolds, Rebecca F. Gilbert, Sebastien Haneuse, Atheendar S. Venkataramani, Alexander C. Tsai
Journal: PLoS Medicine (2020)

Social distancing measures to address the US coronavirus disease 2019 (COVID-19) epidemic may have notable health and social impacts.
Substitutions at Nonconserved Rheostat Positions Modulate Function by Rewiring Long-Range, Dynamic Interactions
Authors: Paul Campitelli, Liskin Swint-Kruse, S Banu Ozkan
Journal: Molecular Biology and Evolution (2020)

Amino acid substitutions at nonconserved protein positions can have noncanonical and "long-distance" outcomes on protein function. Such outcomes might arise from changes in the internal protein communication network, which is often accompanied by changes in structural flexibility. To test this, we calculated flexibilities and dynamic coupling for positions in the linker region of the lactose repressor protein. This region contains nonconserved positions for which substitutions alter DNA-binding affinity. We first chose to study 11 substitutions at position 52. In computations, substitutions showed long-range effects on flexibilities of DNA-binding positions, and the degree of flexibility change correlated with experimentally measured changes in DNA binding. Substitutions also altered dynamic coupling to DNA-binding positions in a manner that captured other experimentally determined functional changes. Next, we broadened calculations to consider the dynamic coupling between 17 linker positions and the DNA-binding domain. Experimentally, these linker positions exhibited a wide range of substitution outcomes: Four conserved positions tolerated hardly any substitutions ("toggle"), ten nonconserved positions showed progressive changes from a range of substitutions ("rheostat"), and three nonconserved positions tolerated almost all substitutions ("neutral"). In computations with wild-type lactose repressor protein, the dynamic couplings between the DNA-binding domain and these linker positions showed varied degrees of asymmetry that correlated with the observed toggle/rheostat/neutral substitution outcomes. Thus, we propose that long-range and noncanonical substitutions outcomes at nonconserved positions arise from rewiring long-range communication among functionally important positions. Such calculations might enable predictions for substitution outcomes at a range of nonconserved positions.
Bio-inspired adhesive porous particles with human MSCs encapsulation for systemic lupus erythematosus treatment
Authors: Min Nie, Guopu Chen, Cheng Zhao, Jingjing Gan, Mihribangvl Alip, Yuanjin Zhao, Lingyun Sun
Journal: Bioactive Materials (2020)

Mesenchymal stem cells (MSCs) therapy is a promising treatment for Systemic lupus erythematosus (SLE) patients. However, this method is encumbered by suboptimal phenotype of MSCs used in clinical settings, and a short in vivo persistence time. Herein, inspired by the natural microstructure of the sand tower worm nest, we proposed novel adhesive porous particles with human MSCs encapsulation via microfluidic electrospray technology for SLE treatment. The porous microparticles were formed by immediate gelation reaction between sodium alginate (ALG) and poly-d-lysine (PDL), and then sacrificed polyethylene oxide (PEO) to form the pores. The resultant microparticles could protect MSCs from immune cells while maintain their immune modulating functions, and achieve rapid exchange of nutrients from the body. In addition, owing to the electrostatic adsorption and covalent bonding between PDL and tissues, the porous microparticles could adhere to the bowel surfaces tightly after intraperitoneal injection. Through in vivo imaging system (IVIS) methods and in vivo study, it was demonstrated that the MSCs-encapsulated porous adhesive microparticles could significantly increase the cellular half-life, turn activated inflammatory macrophages into an anti-inflammatory profile, and ameliorate disease progression in MRL/lpr mice. Thus, the MSCs-encapsulated porous microparticles showed distinctive functions in chronic SLE treatment, with additional potential to be used in a variety of biomedical applications.
Mass eradication of<i>Helicobacter pylori</i>to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands
Authors: Tsung-Hsien Chiang, Wei-Jung Chang, Sam Li-Sheng Chen, Amy Ming-Fang Yen, Jean Ching-Yuan Fann, Sherry Yueh-Hsia Chiu, Yi-Ru Chen, Shu-Ling Chuang, Chun-Fu Shieh, Cheng-Ying Liu, Han-Mo Chiu, Hung Chiang, Chia-Tung Shun, Ming-Wei Lin, Ming-Shiang Wu, Jaw-Town Lin, Chang-Chuan Chan, David Y Graham, Hsiu-Hsi Chen, Yi-Chia Lee
Journal: Gut (2020)

Although mass eradication of Helicobacter pylori has been proposed as a means to eliminate gastric cancer, its long-term effects remain unclear.Mass eradication of H. pylori infection was launched in 2004 and continued until 2018 for a high-risk Taiwanese population aged 30 years or older dwelling on Matsu Islands with prevalent H. pylori infection. Test positives for the 13C-urea breath test underwent eradication therapy. We evaluated the effectiveness of the mass eradication in reducing two main outcomes, incidence and mortality rates of gastric cancer, until the end of 2016 and 2018, respectively.After six rounds of mass screening and eradication, the coverage rate reached 85.5% (6512/7616). The referral rate for treatment was 93.5% (4286/4584). The prevalence rates of H. pylori fell from 64.2% to 15.0% with reinfection rates of less than 1% per person-year. The presence and severity of atrophic gastritis and intestinal metaplasia also decreased with time. Compared with the historical control period from 1995 to 2003, the effectiveness in reducing gastric cancer incidence and mortality during the chemoprevention period was 53% (95% CI 30% to 69%, p<0.001) and 25% (95% CI -14% to 51%, p=0.18), respectively. No significant changes were noted in the incidence rates of other digestive tract cancers or the antibiotic resistance rate of H. pylori.Population-based eradication of H. pylori has significantly reduced gastric cancer incidence with no increase in the likelihood of adverse consequences. A significant reduction in mortality is likely to be achieved with a longer follow-up period.NCT00155389.
Abstract 15922: Sensitize Pulmonary Artery Smooth Muscle Cells (PASMC) to Oxidative Stress by 8oxoguanine Hydrolase Nudt1 Inhibition Has a Therapeutic Potential in Pulmonary Arterial Hypertension
Authors: Geraldine Vitry, Marie-Claude Lampron, Alice Bourgeois, Renee Paradis, Valerie Nadeau, Sandra Breuils-Bonnet, Eve Tremblay, Sandra Martineau, Mark Orcholski, Caroline Lambert, Steeve Provencher, Olivier Boucherat, Sebastien Bonnet, Roxane Paulin
Journal: Circulation (2019)

Background: Increased proliferation and apoptosis resistance of PASMC contribute to distal pulmonary arteries (PA) remodeling in pulmonary arterial hypertension (PAH). Despite a sustained stressful...
Physician Orders for Life-Sustaining Treatment and ICU Admission Near the End of Life
Authors: Ambereen K. Mehta, Leslie J. Blackhall
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
In vivo clearance of 19F MRI imaging nanocarriers is strongly influenced by nanoparticle ultrastructure
Authors: Alexander H.J. Staal, Katrin Becker, Oya Tagit, N. Koen van Riessen, Olga Koshkina, Andor Veltien, Pascal Bouvain, Kimberley R.G. Cortenbach, Tom Scheenen, Ulrich Flögel, Sebastian Temme, Mangala Srinivas
Journal: Biomaterials (2020)

Perfluorocarbons hold great promise both as imaging agents, particularly for 19F MRI, and in therapy, such as oxygen delivery. 19F MRI is unique in its ability to unambiguously track and quantify a tracer while maintaining anatomic context, and without the use of ionizing radiation. This is particularly well-suited for inflammation imaging and quantitative cell tracking. However, perfluorocarbons, which are best suited for imaging - like perfluoro-15-crown-5 ether (PFCE) - tend to have extremely long biological retention. Here, we showed that the use of a multi-core PLGA nanoparticle entrapping PFCE allows for a 15-fold reduction of half-life in vivo compared to what is reported in literature. This unexpected rapid decrease in 19F signal was observed in liver, spleen and within the infarcted region after myocardial infarction and was confirmed by whole body NMR spectroscopy. We demonstrate that the fast clearance is due to disassembly of the ~200 nm nanoparticle into ~30 nm domains that remain soluble and are cleared quickly. We show here that the nanoparticle ultrastructure has a direct impact on in vivo clearance of its cargo i.e. allowing fast release of PFCE, and therefore also bringing the possibility of multifunctional nanoparticle-based imaging to translational imaging, therapy and diagnostics.
Reelin depletion protects against autoimmune encephalomyelitis by decreasing vascular adhesion of leukocytes
Authors: Laurent Calvier, Guillaume Demuth, Navid Manouchehri, Connie Wong, Anastasia Sacharidou, Chieko Mineo, Philip W. Shaul, Nancy L. Monson, Maria Z. Kounnas, Olaf Stüve, Joachim Herz
Journal: Science Translational Medicine (2020)

Anti-Reelin is a therapeutic approach that selectively targets endothelial adhesion of leukocytes, blocking neuroinflammation and demyelination.
Arsenic Metabolism in Mice Carrying a <i>BORCS7/AS3MT</i> Locus Humanized by Syntenic Replacement
Authors: Beverly H. Koller, John N. Snouwaert, Christelle Douillet, Leigh A. Jania, Hisham El-Masri, David J. Thomas, Miroslav Stýblo
Journal: Environmental Health Perspectives (2020)

Background: Chronic exposure to inorganic arsenic (iAs) is a significant public health problem. Methylation of iAs by arsenic methyltransferase (AS3MT) controls iAs detoxification and modifies risks of iAs-induced diseases. Mechanisms underlying these diseases have been extensively studied using animal models. However, substantive differences between humans and laboratory animals in efficiency of iAs methylation have hindered the translational potential of the laboratory studies. Objectives: The goal of this study was to determine whether humanization of the As3mt gene confers a human-like pattern of iAs metabolism in mice. Methods: We generated a mouse strain in which the As3mt gene along with the adjacent Borcs7 gene was humanized by syntenic replacement. We compared expression of the mouse As3mt and the human AS3MT and the rate and pattern of iAs metabolism in the wild-type and humanized mice. Results: AS3MT expression in mouse tissues closely modeled that of human and differed substantially from expression of As3mt. Detoxification of iAs was much less efficient in the humanized mice than in wild-type mice. Profiles for iAs and its methylated metabolites in tissues and excreta of the humanized mice were consistent with those reported in humans. Notably, the humanized mice expressed both the full-length AS3MT that catalyzes iAs methylation and the human-specific AS3MTd2d3 splicing variant that has been linked to schizophrenia. Conclusions: These results suggest that AS3MT is the primary genetic locus responsible for the unique pattern of iAs metabolism in humans. Thus, the humanized mouse strain can be used to study the role of iAs methylation in the pathogenesis of iAs-induced diseases, as well as to evaluate the role of AS3MTd2d3 in schizophrenia. https://doi.org/10.1289/EHP6943