tbuckley/cabot-search huggingface dataset:
Pharmaceutical strategies to extend pulmonary exposure of inhaled medicines
Authors: Yi Guo, Hriday Bera, Changzhi Shi, Li Zhang, Dongmei Cun, Mingshi Yang
Journal: Acta Pharmaceutica Sinica B (2021)

Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma, chronic obstructive pulmonary diseases and respiratory infections, and systemic diseases such as diabetes. Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit. The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration, but also enhance the clinical benefits to the patients with improved therapeutic outcomes. This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines. It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure, which is followed by recent advances in various strategies to overcome these barriers. Finally, the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized.
Could Statins Do More Than Lower Cholesterol in Patients With COVID-19?
Authors: Rita Rubin
Journal: JAMA (2021)

INSPIRATION Investigators; Saeideh Mazloomzadeh; Shiva Khaleghparast; Behshid Ghadrdoost; Mostafa Mousavizadeh; Mohammad Reza Baay; Feridoun Noohi; Hamidreza Sharifnia; Arezoo Ahmadi; Sasan Tavan; Nasser Malekpour Alamdari; Mohammad Fathi; Mahshid Soleimanzadeh; Mostafa Mostafa; Navid Davoody; Maryam Zarinsadaf; Sara Tayyebi; Fahimeh Farrokhzadeh; Faeze Nezamabadi; Esmaeil Soomari; Parham Sadeghipour, MD; Azita H. Talasaz, PharmD; Farid Rashidi, MD; Babak Sharif-Kashani, MD; Mohammad Taghi Beigmohammadi, MD; Mohsen Farrokhpour, MD; Seyed Hashem Sezavar, MD; Pooya Payandemehr, MD; Ali Dabbagh, MD; Keivan Gohari Moghadam, MD; Sepehr Jamalkhani, MD ('23); Hossein Khalili, PharmD; Mahdi Yadollahzadeh, MD; Taghi Riahi, MD; Parisa Rezaeifar, MD; Ouria Tahamtan, MD; Samira Matin, MD; Atefeh Abedini, MD; Somayeh Lookzadeh, MD; Hamid Rahmani, PharmD; Elnaz Zoghi, PharmD; Keyhan Mohammadi, PharmD; Pardis Sadeghipour, MD; Homa Abri, MD; Sanaz Tabrizi, MD; Seyed Masoud Mousavian, MD; Shaghayegh Shahmirzaei, MD; Hooman Bakhshandeh, MD, PhD; Ahmad Amin, MD; Farnaz Rafiee, MD; Elahe Baghizadeh, MD; Bahram Mohebbi, MD; Seyed Ehsan Parhizgar, MD; Rasoul Aliannejad, MD; Vahid Eslami, MD; Alireza Kashefizadeh, MD; Hessam Kakavand, PharmD; Seyed Hossein Hosseini, PharmD; Shadi Shafaghi, MD; Samrand Fattah Ghazi, MD; Atabak Najafi, MD; David Jimenez, MD, PhD; Aakriti Gupta, MD, MS; Mahesh V. Madhavan, MD; Sanjum S. Sethi, MD, MPH; Sahil A. Parikh, MD; Manuel Monreal, MD; Naser Hadavand, PharmD; Alireza Hajighasemi, PharmD; Majid Maleki, MD; Saeed Sadeghian, MD; Gregory Piazza, MD, MS; Ajay J. Kirtane, MD, SM; Benjamin W. Van Tassell, PharmD; Paul P. Dobesh, PharmD; Gregg W. Stone, MD; Gregory Y. H. Lip, MD; Harlan M. Krumholz, MD, SM; Samuel Z. Goldhaber, MD; Behnood Bikdeli, MD, MS
The effect of tezepelumab on airway hyperresponsiveness to mannitol in asthma (UPSTREAM)
Authors: Asger Sverrild, Susanne Hansen, Morten Hvidtfeldt, Carl-Magnus Clausson, Olga Cozzolino, Samuel Cerps, Lena Uller, Vibeke Backer, Jonas Erjefält, Celeste Porsbjerg
Journal: European Respiratory Journal (2021)

<b>Blocking TSLP in patients with uncontrolled asthma reduces the proportion of patients with airway hyperresponsiveness and decreases eosinophilic airway inflammation (two key defining features of asthma)</b>https://bit.ly/3yyPxB0
Covid-19: Researchers find higher than expected reinfections with P.1 variant among the Brazilian Amazon
Authors: Luke Taylor
Journal: BMJ (2021)

A study of blood donors in the city of Manaus has found that 1 in 6 of those infected with the coronavirus were reinfected with the P.1 variant.1 The results were higher than researchers anticipated and those found in studies of reinfections conducted elsewhere.

The preprint, which has not been peer reviewed, was published by the Brazil-UK Center for Arbovirus Discovery, Diagnosis, Genomics, and Epidemiology (CADDE). It is the latest effort from researchers to understand why hospitals in Manaus—which is home to two million in the Brazilian Amazon—collapsed under the weight of coronavirus infections in January 2021 despite antibody levels suggesting that around three quarters of the population had been infected in the first wave.2

The study suggests that reinfections with P.1 are more common than researchers had previously thought and confirms the theory that herd immunity through natural infection is impossible, said Ester Sabino, the study’s lead author …
Re: Scott D. Lundy, Naseer Sangwan, Neel V. Parekh, et al. Functional and Taxonomic Dysbiosis of the Gut, Urine, and Semen Microbiomes in Male Infertility. Eur Urol 2021;79:826-36
Authors: Eugenio Ventimiglia, Edoardo Pozzi, Massimo Alfano, Francesco Montorsi, Andrea Salonia
Journal: European Urology (2021)
AB0876-HPR NEUROFEEDBACK AND TEMPERATURE BIOFEEDBACK TRAINING IMPROVE MIRCOCIRCULATION IN PATIENTS WITH SYSTEMIC SCLEROSIS
Authors: R. Grekhoff
Journal: Annals of the Rheumatic Diseases (2021)

Background: Microcirculatory disorders including Raynaud’s phenomenon are one of the most important clinical symptoms of systemic sclerosis (SS). Objectives: We found it appropriate to evaluate the clinical efficacy of biofeedback (BFB) in the complex therapy of SS patients based on analysis of nailfold capillaroscopy. Methods: The study included 70 SS patients. 94% of patients we examined were women and 6% were men. The average age of the patients = 38±3,3 years, duration of illness = 14±2,6 years. Raynaud’s phenomenon (RP) was observed in all the patients and its severe form was seen in 80% of the patients. The effectiveness of BFB was analyzed by studying the dynamics of the measures from the nailfold capillaroscopy and comparing the data obtained from patients of the main and control groups. Results: Dynamics of capillaroscopic signs of therapy efficiency in main and control groups are summarized in the table: Analized signs Main group (n=40) Control group (n=30) before the therapy after the therapy before the therapy after the therapy Skin score, M±SD 22,56±10,24 14,99±9,44* 21,04±12,01 20,01±9,88 Dilation of the capillaries, % 34 (85) 16 (40)* 24 (80) 17 (56,6) Avascular fields, % 26 (65) 24 (60) 13 (43,3) 17 (56,6) Morphological capillaries’ changes, % 36 (90) 22 (55)* 22 (73,3) 10 (33.3)* Hemorrhage, % 25 (62,5) 10 (25)* 12 (40) 7 (23.3) *- p &lt; 0,05 It was found that patients participated in BFB training, showed significant positive dynamics in the following signs of capillaroscopic picture: dilatation of the capillaries (x 2 = 9,643; p = 0,026), morphological changes of the capillaries (x 2 = 4,90; p = 0,027), and hemorrhage (x 2 = 4,514; p = 0,034). Only one indicator of capillaroscopy showed significant change in the control group of patients, the presence of dilated capillaries (x 2 = 5,833 with p = 0,016). Conclusion: These findings suggest that treatment results were significantly better in the main study group of SS patients. We suggest that biofeedback may be a useful adjunctive treatment for Raynaud’s syndrome in patients with SS. Disclosure of Interests: None declared
Inadequate Dosage of Mycophenolate Mofetil Is Likely to Yield Substandard Trial Results and Substandard Patient Care
Authors: Michiel F. Schreuder, Rasmus Ehren, Lutz T. Weber
Journal: JAMA Pediatrics (2021)

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 Pediatrics 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 Pediatrics journal
Allogeneic haematopoietic cell transplantation for myelofibrosis: proposed definitions and management strategies for graft failure, poor graft function and relapse: best practice recommendations of the EBMT Chronic Malignancies Working Party
Authors: Donal P. McLornan, Juan Carlos Hernandez-Boluda, Tomasz Czerw, Nicholas Cross, H. Joachim Deeg, Marcus Ditschkowski, Mufaddal T. Moonim, Nicola Polverelli, Marie Robin, Mahmoud Aljurf, Eibhlin Conneally, Patrick Hayden, Ibrahim Yakoub-Agha
Journal: Leukemia (2021)
Design, synthesis, and biological evaluation of multiple targeting antimalarials
Authors: Yiqing Yang, Tongke Tang, Xiaolu Li, Thomas Michel, Liqin Ling, Zhenghui Huang, Maruthi Mulaka, Yue Wu, Hongying Gao, Liguo Wang, Jing Zhou, Brigitte Meunier, Hangjun Ke, Lubin Jiang, Yu Rao
Journal: Acta Pharmaceutica Sinica B (2021)

Malaria still threatens global health seriously today. While the current discoveries of antimalarials are almost totally focused on single mode-of-action inhibitors, multi-targeting inhibitors are highly desired to overcome the increasingly serious drug resistance. Here, we performed a structure-based drug design on mitochondrial respiratory chain of Plasmodium falciparum and identified an extremely potent molecule, RYL-581, which binds to multiple protein binding sites of P. falciparum simultaneously (allosteric site of type II NADH dehydrogenase, Qo and Qi sites of cytochrome bc1). Antimalarials with such multiple targeting mechanism of action have never been reported before. RYL-581 kills various drug-resistant strains in vitro and shows good solubility as well as in vivo activity. This structure-based strategy for designing RYL-581 from starting compound may be helpful for other medicinal chemistry projects in the future, especially for drug discovery on membrane-associated targets.
POS0469 FALL RISK ASSESSMENT IN RHEUMATOID ARTHRITIS PATIENTS
Authors: O. Jomaa, H. Migaw, I. Loubiri, M. Slama, S. Zrour, I. Bejia, M. Touzi, J. Mahbouba, N. Bergaoui
Journal: Annals of the Rheumatic Diseases (2021)

Background: Rheumatoid arthritis patients may have an increased risk of falls due to changes caused by the disease such as muscle weakness, joint impairment, reduced mobility and postural instability. Objectives: The aim of this study was to analyze the occurrence of falls in RA patients and its risk factors. Methods: Between January2020 and July 2020, 51 patients with RA were included in the study. fall history, and the number of falls within the past 12 month were questioned. All participants were assessed with Timed Up and Go Test (TUGT), One-Leg Stand Test (OLST), Walking and Talking Test (WTT), Sternal Push Test (SPT), Tinetti Test (TT), Four Test Balance Scale (FTBS), The Short Falls Efficacy Scale-International (FES-I), Pain Severity and Patient Global Assessment (PGA) by Visual Analog Scale (VAS), disability by the Health Assessment Questionnaire (HAQ), and disease activity by Disease Activity Score in 28 joints (DAS28) were evaluated in for for each patient. The Kolmogorov-Smirnov, Mann-Whitney and chi-square tests were performed with a significance level of P ≤ 0.05. Results: 22 patients had at least one or more falls. The average age was 54.9±11.5 years with a female predominance (sex ratio = 0.13). Comparing the two groups of patients: those with a history of falls and those without, patients with previous falls were mainly married women (p=0.57), with a low intellectual level (p=0.63). The body mass index in this group was higher (p=0.01) with respectively a higher number of painful and swollen joints (p=0.16, p=0.07); the mean HAQ was higher (p=0.03), and the mean VAS was more important (p=0.05). 12/22 patients had co-morbidities and were poly-medicated.20/22 had joint feet deformities (hallux valgus was the most common deformity). 21/22 were on low dosage corticosteroid therapy. The mean TUGT was 18.5 seconds (&gt;14 seconds). The OLST was less than 5 seconds in 12/22, the sternal push test was positive in 9/22, WTT was positive in 6/22 and the mean tinetti test was 22.4±5.4 suggesting a high risk of falls. The average Short FES-I was 14.6 ±4.4 reflecting a high fear of falls in this group of patients. Conclusion: Knowledge about risk factors can help to identify high-risk patients in order to decrease their risk of falling, thus preventing fall-related injuries. Disclosure of Interests: None declared
Equity and the JAMA Network
Authors: Phil B. Fontanarosa, Annette Flanagin, John Z. Ayanian, Robert O. Bonow, Neil M. Bressler, Dimitri Christakis, Mary L. Disis, S. Andrew Josephson, Melina R. Kibbe, Dost Öngür, Jay F. Piccirillo, Rita F. Redberg, Frederick P. Rivara, Kanade Shinkai, Clyde W. Yancy
Journal: JAMA Pediatrics (2021)
Reply to Fabio C.M. Torricelli and Rafael F. Coelho’s Letter to the Editor re: Sophie Knipper, Luigi Ascalone, Benjamin Ziegler, et al. Salvage Surgery in Patients with Local Recurrence After Radical Prostatectomy. Eur Urol 2021;79:537–44
Authors: Sophie Knipper, Tobias Maurer
Journal: European Urology (2021)
<i>Foxp3</i> enhancers synergize to maximize regulatory T cell suppressive capacity
Authors: Xinying Zong, Xiaolei Hao, Beisi Xu, Jeremy Chase Crawford, Shaela Wright, Jun Li, Yang Zhang, Lu Bai, Minghong He, Menglin Jiang, Yiping Fan, Jon P. Connelly, Shondra M. Pruett-Miller, Hartmut Berns, Laura Janke, Chunliang Li, Yongqiang Feng
Journal: The Journal of Experimental Medicine (2021)

T reg cells bearing a diverse antigen receptor repertoire suppress pathogenic T cells and maintain immune homeostasis during their long lifespan. How their robust function is determined genetically remains elusive. Here, we investigate the regulatory space of the cis-regulatory elements of T reg lineage–specifying factor Foxp3. Foxp3 enhancers are known as distinct readers of environmental cues controlling T reg cell induction or lineage stability. However, their single deficiencies cause mild, if any, immune dysregulation, leaving the key transcriptional mechanisms determining Foxp3 expression and thereby T reg cell suppressive capacity uncertain. We examined the collective activities of Foxp3 enhancers and found that they coordinate to maximize T reg cell induction, Foxp3 expression level, or lineage stability through distinct modes and that ablation of synergistic enhancers leads to lethal autoimmunity in young mice. Thus, the induction and maintenance of a diverse, stable T reg cell repertoire rely on combinatorial Foxp3 enhancers, suggesting broad, stage-specific, synergistic activities of cell-intrinsic factors and cell-extrinsic cues in determining T reg cell suppressive capacity.
National Quality Measure Compliance for Palliative Bone Radiation Among Patients With Metastatic Non–Small Cell Lung Cancer
Authors: Stephen R. Grant, Benjamin D. Smith, Lauren E. Colbert, Qunyh-Nhu Nguyen, James B. Yu, Steven H. Lin, Aileen B. Chen
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: There exists wide practice variability in palliative treatment schedules for bone metastases. In an effort to reduce variation and promote high-quality, cost-conscious care, the National Quality Forum (NQF) endorsed measure 1822 in 2012. This measure recommends the use of 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction for palliative radiation for bone metastases. We report on longitudinal compliance with this measure. Methods: Using the National Cancer Database, patients with metastatic thoracic non–small cell lung cancer diagnosed between 2004 and 2016 who received radiation therapy for bony sites of metastatic disease were identified. Treatment courses fitting 1 of the 4 recommended schedules under NQF 1822 were coded as compliant. Rates of compliance by patient, tumor, and treatment characteristics were analyzed. Results: A total of 42,685 patients met the criteria for inclusion. Among all patients, 60.2% of treatment courses were compliant according to NQF 1822. Compliance increased over time and was highest for treatments to the extremity (69.8%), lowest for treatments to the skull or head (48.8%), and higher for academic practice (67.1%) compared with community (56.0%) or integrated network facilities (61.2%). On multivariable analysis, predictors of NQF 1822 compliance included year of diagnosis after 2011, treatment to an extremity, or treatment at an academic facility. Of noncompliant treatment courses, extended fractionation (≥11 fractions) occurred in 62.6% and was more common before 2012, in community practice, and for treatments of the skull or head. Conclusions: Among patients treated for metastatic non–small cell lung cancer, compliance with NQF 1822 increased over time. Although extended fractionation constituted a majority of noncompliant treatment courses, a substantial proportion also involved shorter courses.
POS0374 SENESCENCE DID NOT ALTER THE CHONDROPROTECTIVE EFFECT OF EXTRACELLULAR VESICLES FROM MESENCHYMAL STROMAL CELLS
Authors: J. Boulestreau, M. Maumus, P. Rozier, C. Jorgensen, D. Noel
Journal: Annals of the Rheumatic Diseases (2021)

Background: Age is the most important risk factor in degenerative osteoarthritis (OA) and is associated with the accumulation of senescent cells that contribute to functional decline of joint. We previously demonstrated that extracellular vesicles (EVs) from mesenchymal stromal cells (MSCs) largely mediate the therapeutic effect of parental cells in OA. Objectives: Here, we assessed the impact of senescence on the characteristics of EVs from adipose tissue-derived MSCs (ASC-EVs) and their properties in an in vitro model of OA Methods: ASCs were induced to senescence using 25µM etoposide for 24 hours. Senescence was assessed by quantifying proliferation rate, SA-βGal activity, nuclear γH2AX foci number, phalloidin staining and expression of cyclin dependent kinase inhibitors (CDKI) (RT-qPCR). ASC-EVs were isolated by differential ultracentrifugation and characterized by size, concentration, total protein content, structure (cryo-TEM) and immunophenotype. In vitro OA model used chondrocytes isolated from OA patients, which were stimulated with IL1β for 48h before culture with ASCs or ASC-EVs for 7 days. Expression of chondrocytic and inflammatory markers was quantified by RT-qPCR and SASP factors were quantified by ELISA in supernatants. Results: Senescence-induced ASCs experienced growth arrest and increase of SA-βGal staining, of p21 CDKI expression, of nuclear γH2AX foci, of stress fibers and of several SASP factors (IL6, IL8, MMP3) confirming the expression of main senescence features. Senescent ASCs produced 4-fold more EVs than healthy ASCs and senescent ASC-EVs were larger. In vitro, both healthy and senescent ASCs decreased fibrotic markers ( type III COLLAGEN ), catabolic and hypertrophic markers ( MMP3, MMP13, AP ) and increased COX2 expression in OA chondrocytes. By contrast, healthy ASCs decreased the expression of IL6 while senescent ASCs highly increased IL6 . Looking at the role of ASC-EVs on OA chondrocytes, we found out that both healthy and senescent ASC-EVs were able to increase the expression of AGG and type II COLLAGEN while they decreased the expression of MMP13, AP, type X COLLAGEN, HMOX1 and IL6 . Finally, healthy and senescent ASC-EVs decreased the number of SA-βGal positive chondrocytes but did not impact the expression of p21 in IL1β-induced chondrocytes. Conclusion: Our results indicated a chondroprotective effect of ASC-EVs, independently of the senescent state of parental cells and suggested that EVs might act through different mechanisms than ASCs, which warrants further investigation Disclosure of Interests: Jérémy Boulestreau: None declared, Marie Maumus Employee of: Bauerfeind France, Pauline Rozier: None declared, Christian Jorgensen Shareholder of: Medxcell sciences, Consultant of: Medxcell sciences, Daniele Noel Shareholder of: Medxcell sciences, Consultant of: Medxcell sciences
OP0019 DEFINING SYSTEMIC LUPUS ERYTHEMATOSUS MOLECULAR TAXONOMY THROUGH DATA-DRIVEN RESTRATIFICATION AND IDENTIFICATION OF CLUSTER-TAILORED DRUGS FOR A PERSONALIZED MEDICINE APPROACH
Authors: P. Garantziotis, D. Nikolakis, S. Doumas, E. Fragou, A. Fanouriakis, A. Filia, T. Witte, G. Bertsias, D. Boumpas
Journal: Annals of the Rheumatic Diseases (2021)

Background: Systemic Lupus Erythematosus (SLE) is characterized by lack of treatment diversity, largely empirical treatment decisions, and paucity of novel compound development. Objectives: We sought to stratify SLE patients based on their molecular phenotype and predict personalized therapeutic compounds, tailored to the molecular fingerprint of each subgroup. Methods: We performed a co-expression analysis using our publicly available whole blood RNA-seq data of 120 SLE patients. Modules of commonly regulated genes were established and used to re-stratify patients through hierarchical clustering, in a data-driven, clinically independent, manner. Next, we established an in silico, subgroup signature-based, drug prediction pipeline. Investigated drugs included both those currently in practice and those who have been tested in SLE clinical trials and are listed in the iLINCS prediction databases. Finally, drug repurposing analysis was performed, to identify novel perturbagens that counteract group-specific SLE signatures. Results: Molecular taxonomy identified five distinct lupus molecular endotypes, each characterized by a unique gene module enrichment pattern. A group defined by strong neutrophilic signature encompassed almost exclusively patients with active nephritis, while a B-cell expression group included patients with severe lupus phenotype. Metabolic processes enrichment defined a group of patients with disease of moderate severity and serologic activity. Finally, patients with mild lupus features were distributed in two groups, which demonstrated enhanced basic cellular functions, myelopoiesis, and autophagy. The ability of different compounds to reverse the transcriptomic aberrancies observed in each patient group was examined. Bortezomib efficiently reversed disturbances in the “neutrophilic” cluster. Azathioprine and ixazomib might be a reasonable option for patients of the “B-cell” cluster, whereas fostamatinib appeared efficacious for the “Metabolism” patient subgroup. Conclusion: The clinical spectrum of SLE encompasses distinct molecular endotypes, each defined by unique pathophysiologic aberrancies, which can be utilized to guide personalized care and direct novel compound development. Acknowledgements: This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 742390). Disclosure of Interests: None declared