tbuckley/cabot-search huggingface dataset:
What is the true incidence of COVID-19 in patients with rheumatic diseases?
Authors: Ennio Giulio Favalli, Francesca Ingegnoli, Rolando Cimaz, Roberto Caporali
Journal: Annals of the Rheumatic Diseases (2020)

Scintigraphic evaluation of <sup>123</sup>I-metaiodobenzylguanidine (<sup>123</sup>I-MIBG) in the lungs is considered to recognize endothelial cell lesions. The aim of this study was to clarify the involvement of the pulmonary microvascular injury in the pathogenesis of chronic obstructive pulmonary disease (COPD). <b>Methods:</b> We investigated lung <sup>123</sup>I-MIBG kinetics and clinical indices in 25 COPD patients and 12 control subjects. Mean uptake ratios of lung to mediastinum (L/M) were calculated in anterior planer images at 30 min (early image) and 270 min (delayed image) after intravenous injection of <sup>123</sup>I-MIBG. Pulmonary mean washout rate (WR) of the <sup>123</sup>I-MIBG was also calculated. <b>Results:</b> The L/M ratios in both early and delayed images of COPD patients, as well as its WR, were significantly lower than those of the control subjects (L/M early: 1.26 ± 0.18 vs. 1.54 ± 0.11, <i>P</i> &lt; 0.0001; L/M delayed: 1.20 ± 0.12 vs. 1.33 ± 0.09, <i>P</i> &lt; 0.001; WR: 27.4% ± 5.3% vs. 34.2% ± 5.7%, <i>P</i> &lt; 0.01). There were significant relationships between lung WR of the <sup>123</sup>I-MIBG and other diagnostic tests for the severity of COPD, such as forced expiratory volume in 1 s (% FEV<sub>1.0</sub>: <i>r</i> = 0.386, <i>P</i> &lt; 0.05), carbon monoxide diffusing capacity/alveolar volume (DL<sub>CO</sub>/V<sub>A</sub>: <i>r</i> = 0.449, <i>P</i> &lt; 0.01), arterial blood oxygen pressure (Pao<sub>2</sub>: <i>r</i> = 0.474, <i>P</i> &lt; 0.01), alveolar–arterial oxygen tension gradient [A–a]Do<sub>2</sub> (<i>r</i> = −0.446, <i>P</i> &lt; 0.01), and percentage of low-attenuation area (<i>r</i> = −0.458, <i>P</i> &lt; 0.01) in the study population. <b>Conclusion:</b> Because lung WR of the <sup>123</sup>I-MIBG is considered to be independent of an alteration of the pulmonary vascular surface area, these results suggest that the microvascular endothelial cell injury plays a significant role in the pathogenesis of COPD.
Abstract GMM-039: BUILDING AN ORGANOID-BASED MODEL FOR OVARIAN CANCER
Authors: Kadi Lõhmussaar, Oded Kopper, Hans C. Clevers
Journal: Clinical Cancer Research (2019)

Abstract Over the last few years several studies led to a significant change in the field of ovarian cancer and it is currently believed that the fallopian tube and not the ovary surface epithelium (OSE) is the main origin of high-grade serous ovarian cancer (HG-SOC). Nevertheless, due to the lack of unique markers and adequate model systems the relative contribution of each tissue is not yet clear and the notion that OSE has a role in HG-SOC development was not cast aside altogether. In this work we have established novel organoid systems derived from both mouse OSE and oviduct (Ovi, the equivalent of human fallopian tube). These systems recapitulate their tissue of origin and demonstrate differences in medium requirements as well as gene expression. To establish comparable tumor progression models for both OSE and Ovi we used CRISPR-Cas9 technique and targeted commonly mutated genes in ovarian cancer (Trp53, Brca1, Nf1 and Pten). Thus, we were able to establish clones with different combinations of mutations. Histological, metaphase spread and gene expression analysis of the mutated organoid clones from both OSE and Ovi demonstrated different degrees of deviation from their wild type counterpart. This deviation became more evident as the amount of introduced mutations increased. Preliminary transplantation experiments showed that only triple mutants gave rise to tumors (Trp53, Brca1 and Pten or Trp53, Brca1 and Nf1). Moreover, Ovi mutant clones were more prone to grow into tumors in comparison to OSE as no tumors have been detected in mice transplanted with the OSE equivalent clones so far. Taken together, in this study we present the first comparable Ovi/OSE research platform that enables addressing questions related to origin and early stages of HG-SOC development. Citation Format: Kadi Lõhmussaar, Oded Kopper, Hans C. Clevers. BUILDING AN ORGANOID-BASED MODEL FOR OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-039.
Cardiac arrest as a fatal periprocedural complication of peroral endoscopic myotomy (POEM)
Authors: Tomas Hucl, Eva Uchytilova, Jana Markvartova, Petr Tomasek, Eva Kieslichova, Julius Spicak, Jan Martinek
Journal: Endoscopy (2020)

A 66-year-old female with an unremarkable medical history and presenting with a 2-year history of dysphagia, regurgitation, and weight loss was diagnosed with achalasia. Peroral endoscopic myotomy (POEM) was decided upon. Results of the standard pre-anaesthesia evaluation proved unremarkable. Low-flow carbon dioxide was used throughout the procedure. Anterior mucosotomy was performed and a submucosal tunnel created. Percutaneous abdominal needle decompression resulted in normalisation of maximum airway pressure. After the first 3 cm of myotomy had been performed, endoscopically visible movement of the pericardium suddenly stopped ([Video 1]). The knife had not come in contact with, or within the close vicinity of, the pericardium. Although electrocardiographic monitoring showed continuous but slow electrical activity, the central and peripheral pulses were not present. Cardiopulmonary resuscitation was immediately initiated. Bedside examination ruled out the presence of pneumothorax, tamponade, or pulmonary embolism. Despite advanced cardiac life support, the resuscitation was unsuccessful.
Differential expression of RECK and matrix metalloproteinases observed between African American and Caucasian metastatic breast cancer cell lines
Authors: Dayanand Dattatraya Deo, Shirin Sabbaghian, Iris Lindberg, Nicolas G. Bazan, Jay D. Hunt
Journal: Cancer Research (2005)

2978  Platelet-Activating Factor (PAF), an inflammatory bioactive lipid, acts as a mediator of vascularization for tumor growth and metastasis. Invasion of the extracellular matrix by tumor cells requires the activation of the matrix degrading metalloproteinases by intracellular proprotein convertases (PCs) or other metalloproteinases. Furin, a member of the family of subtilisin/kexin-like PCs, is responsible for the activation of precursor pro-proteins to become biologically active. We used the human androgen-insensitive prostate cancer cell line PC-3 as a model system. PAF-induced invasion and migration of PC-3 cells is antagonized upon inhibition of the proprotein convertase furin with its small molecule inhibitor D6R. PAF exposure does not affect the constitutively expressed membrane-bound furin level in PC-3 cells. Furin inhibition has no affect on the expression of PAF-induced TIMP2; however, PAF-stimulated activation of MT1-MMP is antagonized at all time points upon inhibition of furin with D6R. The coordinated PAF-induced expression and activation of TIMP2 and MT1-MMP results in the proteolytic activation of MMP2 in the culture medium, which is attenuated upon inhibition of furin. Our data demonstrate for the first time that PAF-dependent expression and activation of matrix metalloproteinases, resulting in the increased invasion and migration is regulated by furin in human prostatic carcinoma cells.
Mouse Models of Oncoimmunology in Hepatocellular Carcinoma
Authors: Erin Bresnahan, Katherine E. Lindblad, Marina Ruiz de Galarreta, Amaia Lujambio
Journal: Clinical Cancer Research (2020)

Abstract Liver cancer is the fourth leading cause of cancer-related mortality worldwide and incidence is on the rise. Hepatocellular carcinoma (HCC) is the most common form of liver cancer, with a complex etiology and limited treatment options. The standard-of-care treatment for patients with advanced HCC is sorafenib, a tyrosine kinase inhibitor that offers limited survival benefit. In the past years, therapeutic options for the treatment of advanced HCC have increased substantially, including additional multikinase inhibitors as well as immune checkpoint inhibitors. Nivolumab and pembrolizumab were approved in 2017 and 2018, respectively, as second-line treatment in advanced HCC. These drugs, both targeting the programmed death-1 pathway, demonstrate unprecedented results, with objective response rates of approximately 20%. However, the majority of patients do not respond, necessitating the identification of biomarkers of response and resistance to immunotherapy. With the recent success of immunotherapies in oncology, mouse models that better recapitulate the human disease and antitumor immune response are needed. This review lists ongoing clinical trials testing immunotherapy in HCC, briefly discusses the unique immunosuppressive environment of the liver, and then delves into the most applicable current murine model systems to study oncoimmunology within the context of HCC, including syngeneic, genetically engineered, and humanized models.
Could BCG be used to protect against COVID-19?
Authors: Gil Redelman-Sidi
Journal: Nature Reviews Urology (2020)

Nearly 100 years since it was first used in humans as a vaccine for tuberculosis, Bacillus Calmette–Guérin (BCG) has been suggested as a possible agent to prevent coronavirus disease 2019 (COVID-19). A number of studies are underway to investigate this possibility but — even if they prove effective — many questions will remain.
Pharmacokinetics and Pharmacodynamics of Posaconazole
Authors: Lu Chen, Elke H. J. Krekels, Paul. E. Verweij, Jochem B. Buil, Catherijne A. J. Knibbe, Roger J. M. Brüggemann
Journal: Drugs (2020)

Posaconazole is typically used for preventing invasive yeast and mold infections such as invasive aspergillosis in high-risk immunocompromised patients. The oral suspension was the first released formulation and many pharmacokinetic and pharmacodynamic studies of this formulation have been published. Erratic absorption profiles associated with this formulation were widely reported. Posaconazole exposure was found to be significantly influenced by food and many gastrointestinal conditions, including pH and motility. As a result, low posaconazole plasma concentrations were obtained in large groups of patients. These issues of erratic absorption urged the development of the subsequently marketed delayed-release tablet, which proved to be associated with higher and more stable exposure profiles. Shortly thereafter, an intravenous formulation was released for patients who are not able to take oral formulations. Both new formulations require a loading dose on day 1 to achieve high posaconazole concentrations more quickly, which was not possible with the oral suspension. So far, there appears to be no evidence of increased toxicity correlated to the higher posaconazole exposure achieved with the regimen for these formulations. The higher systemic availability of posaconazole for the delayed-release tablet and intravenous formulation have resulted in these two formulations being preferable for both prophylaxis and treatment of invasive fungal disease. This review aimed to integrate the current knowledge on posaconazole pharmacokinetics, pharmacodynamics, major toxicity, existing resistance, clinical experience in special populations, and new therapeutic strategies in order to get a clear understanding of the clinical use of this drug.
Abstract 11395: Percutaneous Pulmonary Valve Implantation in Patients With Right Ventricular Outflow Tract Dysfunction: A Systematic Review and Meta-Analysis
Authors: Liyu Ran, Wuwan Wang, Wei Huang
Journal: Circulation (2018)

Introduction: Pulmonary valve replacement is required for the patients with right ventricular outflow tract (RVOT) dysfunction, surgical and percutaneous pulmonary valve replacement are the treatme...
The Fully human anti-CD47 antibody SRF231 exerts dual-mechanism antitumor activity via engagement of the activating receptor CD32a
Authors: Marisa O Peluso, Ammar Adam, Caroline M Armet, Li Zhang, Rachel W O’Connor, Benjamin H Lee, Andrew C Lake, Emmanuel Normant, Scott C Chappel, Jonathan A Hill, Vito J Palombella, Pamela M Holland, Alison M Paterson
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background CD47 is a broadly expressed cell surface glycoprotein associated with immune evasion. Interaction with the inhibitory receptor signal regulatory protein alpha (SIRPα), primarily expressed on myeloid cells, normally serves to restrict effector function (eg, phagocytosis and immune cell homeostasis). CD47/SIRPα antagonists, commonly referred to as ‘macrophage checkpoint’ inhibitors, are being developed as cancer interventions. SRF231 is an investigational fully human IgG 4 anti-CD47 antibody that is currently under evaluation in a phase 1 clinical trial. The development and preclinical characterization of SRF231 are reported here. Methods SRF231 was characterized in assays designed to probe CD47/SIRPα blocking potential and effects on red blood cell (RBC) phagocytosis and agglutination. Additionally, SRF231-mediated phagocytosis and cell death were assessed in macrophage:tumor cell in vitro coculture systems. Further mechanistic studies were conducted within these coculture systems to ascertain the dependency of SRF231-mediated antitumor activity on Fc receptor engagement vs CD47/SIRPα blockade. In vivo, SRF231 was evaluated in a variety of hematologic xenograft models, and the mechanism of antitumor activity was assessed using cytokine and macrophage infiltration analyses following SRF231 treatment. Results SRF231 binds CD47 and disrupts the CD47/SIRPα interaction without causing hemagglutination or RBC phagocytosis. SRF231 exerts antitumor activity in vitro through both phagocytosis and cell death in a manner dependent on the activating Fc-gamma receptor (FcγR), CD32a. Through its Fc domain, SRF231 engagement with macrophage-derived CD32a serves dual purposes by eliciting FcγR-mediated phagocytosis of cancer cells and acting as a scaffold to drive CD47-mediated death signaling into tumor cells. Robust antitumor activity occurs across multiple hematologic xenograft models either as a single agent or in combination with rituximab. In tumor-bearing mice, SRF231 increases tumor macrophage infiltration and induction of the macrophage cytokines, mouse chemoattractant protein 1 and macrophage inflammatory protein 1 alpha. Macrophage depletion results in diminished SRF231 antitumor activity, underscoring a mechanistic role for macrophage engagement by SRF231. Conclusion SRF231 elicits antitumor activity via apoptosis and phagocytosis involving macrophage engagement in a manner dependent on the FcγR, CD32a.
Covid-19: BMA demands full death in service benefits for UK doctors
Authors: Abi Rimmer
Journal: BMJ (2020)

The BMA has written to the chancellor of the exchequer calling for all NHS workers to receive full death in service cover.

After an announcement by the Scottish government of a comprehensive death in service package for all NHS workers,1 the BMA is demanding that full protections are put in place in the other UK nations.

In a letter to Rishi Sunak sent on 22 April the BMA council chair, Chaand Nagpaul, called for the benefits to be offered to all staff, including those who would not normally be covered by the scheme. This includes …
Clinical and Public Health Implications of 2019 Endocrine Society Guidelines for Diagnosis of Diabetes in Older Adults
Authors: Michael Fang, Justin B. Echouffo-Tcheugui, Elizabeth Selvin
Journal: Diabetes Care (2020)

OBJECTIVE Screening for diabetes is typically done using hemoglobin A1c (HbA1c) or fasting plasma glucose (FPG). The 2019 Endocrine Society guidelines recommend further testing using an oral glucose tolerance test (OGTT) in older adults with prediabetic HbA1c or FPG. We evaluated the impact of this recommendation on diabetes prevalence, eligibility for glucose-lowering treatment, and estimated cost of implementation in a nationally representative sample. RESEARCH DESIGN AND METHODS We included 2,236 adults aged ≥65 years without known diabetes from the 2005–2016 National Health and Nutrition Examination Survey. Diabetes was defined using: 1) the Endocrine Society approach (HbA1c ≥6.5%, FPG ≥126 mg/dL, or 2-h plasma glucose ≥200 mg/dL among those with HbA1c 5.7–6.4% or FPG 100–125 mg/dL); and 2) a standard approach (HbA1c ≥6.5% or FPG ≥126 mg/dL). Treatment eligibility was defined using HbA1c cut points (≥7% to ≥9%). OGTT screening costs were estimated using Medicare fee schedules. RESULTS Diabetes prevalence was 15.7% (∼5.0 million) using the Endocrine Society’s approach and 7.3% (∼2.3 million) using the standard approach. Treatment eligibility ranged from 5.4% to 0.06% and 11.8% to 1.3% for diabetes cases identified through the Endocrine Society or standard approach, respectively. By definition, diabetes identified exclusively through the Endocrine Society approach had HbA11c &amp;lt;6.5% and would not be recommended for glucose-lowering treatment. Screening all older adults with prediabetic HbA1c/FPG (∼18.3 million) with OGTT could cost between $737 million and $1.7 billion. CONCLUSIONS Adopting the 2019 Endocrine Society guidelines would substantially increase the number of older adults classified as having diabetes, require significant financial resources, but likely offer limited benefits.
A Biomimetic Biphasic Osteochondral Scaffold with Layer‐Specific Release of Stem Cell Differentiation Inducers for the Reconstruction of Osteochondral Defects
Authors: Xuemin Liu, Yingqi Wei, Chengkai Xuan, Lei Liu, Chen Lai, Muyuan Chai, Zhaoguo Zhang, Lin Wang, Xuetao Shi
Journal: Advanced Healthcare Materials (2020)

Abstract There is a great challenge in regenerating osteochondral defects because they involve lesions of both cartilage and subchondral bone, which have remarkable differences in their chemical compositions and biological lineages. Thus, considering the complicated requirements in osteochondral reconstruction, a biomimetic biphasic osteochondral scaffold (BBOS) with the layer‐specific release of stem cell differentiation inducers are developed. The cartilage regeneration layer (cartilage scaffold, CS) in the BBOS contains a hyaluronic acid hydrogel to mimic the composition of cartilage, which is mechanically enhanced by host–guest supramolecular units to control the release of kartogenin (KGN). Additionally, a 3D‐printed hydroxyapatite (HAp) scaffold releasing alendronate (ALN) is employed as the bone‐regeneration layer (bone scaffold, BS). The two layers are bound by semi‐immersion and could regulate the hierarchical targeted differentiation behavior of the stem cells. Compared to the drug‐free scaffold, the MSCs in the BBOS could be promoted to differentiate into both chondrocytes and osteoblasts. The in vivo results demonstrate the strong promotion of cartilage or bone regeneration in their respective layers. It is expected that this BBOS with layer‐specific inducer release can become a new strategy for osteochondral regeneration.
Absorbable Thioether Grafted Hyaluronic Acid Nanofibrous Hydrogel for Synergistic Modulation of Inflammation Microenvironment to Accelerate Chronic Diabetic Wound Healing
Authors: Sha Liu, Qingfei Zhang, Jie Yu, Nannan Shao, Hongtong Lu, Jinshan Guo, Xuepeng Qiu, Dongfang Zhou, Yubin Huang
Journal: Advanced Healthcare Materials (2020)

Abstract Current standard of care dressings are unsatisfactorily inefficacious for the treatment of chronic wounds. Chronic inflammation is the primary cause of the long‐term incurable nature of chronic wounds. Herein, an absorbable nanofibrous hydrogel is developed for synergistic modulation of the inflammation microenvironment to accelerate chronic diabetic wound healing. The electrospun thioether grafted hyaluronic acid nanofibers (FHHA‐S/Fe) are able to form a nanofibrous hydrogel in situ on the wound bed. This hydrogel degrades and is absorbed gradually within 3 days. The grafted thioethers on HHA can scavenge the reactive oxygen species quickly in the early inflammation phase to relieve the inflammation reactions. Additionally, the HHA itself is able to promote the transformation of the gathered M1 macrophages to the M2 phenotype, thus synergistically accelerating the wound healing phase transition from inflammation to proliferation and remodeling. On the chronic diabetic wound model, the average remaining wound area after FHHA‐S/Fe treatment is much smaller than both that of FHHA/Fe without grafted thioethers and the control group, especially in the early wound healing stage. Therefore, this facile dressing strategy with intrinsic dual modulation mechanisms of the wound inflammation microenvironment may act as an effective and safe treatment strategy for chronic wound management.
Home Monitoring in Patients with Idiopathic Pulmonary Fibrosis. A Randomized Controlled Trial
Authors: Catharina C. Moor, Rémy L. M. Mostard, Jan C. Grutters, Paul Bresser, Joachim G. J. V. Aerts, Niels H. Chavannes, Marlies S. Wijsenbeek
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Idiopathic pulmonary fibrosis (IPF) is a deadly disease with increasingly impaired health-related quality of life (HRQOL). eHealth technologies facilitate collection of physiological outcomes and patient-reported outcomes at home, but randomized controlled trials (RCTs) on the effects of eHealth are scarce.Objectives: To investigate whether a home monitoring program improves HRQOL and medication use for patients with IPF.Methods: We performed a multicenter RCT in newly treated patients with IPF. Patients were randomly assigned to standard care or a home monitoring program on top of standard care for 24 weeks. The home monitoring program included home spirometry, reporting of symptoms and side effects, patient-reported outcomes, information, a medication coach, and eConsultations. The primary endpoint was between-group difference in change in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) score at 24 weeks.Measurements and Main Results: A total of 90 patients were randomized (46 assigned to the home monitoring group and 44 to the standard care group). After 24 weeks, no statistically significant difference was found in K-BILD total score, with a 2.70-point increase in the home monitoring group (SD = 9.5) and a 0.03-point increase in the standard care group (SD = 10.4); between-group difference was 2.67 points (95% confidence interval [CI], -1.85 to 7.17; P = 0.24). Between-group difference in psychological domain score was 5.6 points (95% CI, -1.13 to 12.3; P = 0.10), with an increase of 5.12 points in the home monitoring group (SD = 15.8) and a decline of 0.48 points in the standard care group (SD = 13.3). In the home monitoring group, medication was more often adjusted (1 vs. 0.3 adjustments per patient; 95% CI, 0.2 to 1.3; P = 0.027). Patient satisfaction with the home monitoring program was high. Home-based spirometry was highly correlated with hospital-based spirometry over time.Conclusions: The results of this first-ever eHealth RCT in IPF showed that a comprehensive home monitoring program did not improve overall HRQOL measured with K-BILD but tended to improve psychological well-being. Home monitoring was greatly appreciated by patients and allowed for individually tailored medication adjustments.Clinical trial registered with www.clinicaltrials.gov (NCT03420235).
Major Concerns Over Improving Measurement of Inflammation Remain—Reply
Authors: Line Jee Hartmann Rasmussen, Terrie E. Moffitt, Avshalom Caspi
Journal: JAMA Pediatrics (2020)

In Reply We thank Luo et al for their interest in soluble urokinase plasminogen activator receptor (suPAR), as discussed in our article.1 Soluble urokinase plasminogen activator receptor is associated with chronic conditions, as revealed in many prior reports of midlife to older adults.2-6
Limiting the spread of COVID-19 in Africa: one size mitigation strategies do not fit all countries
Authors: Shaheen Mehtar, Wolfgang Preiser, Ndèye Aissatou Lakhe, Abdoulaye Bousso, Jean-Jacques Muyembe TamFum, Oscar Kallay, Moussa Seydi, Alimuddin Zumla, Jean B Nachega
Journal: The Lancet Global Health (2020)