Miracle-dz/UniFAR-FTUs huggingface dataset:
Host-Derived Matrix Metalloproteinase-13 Activity Promotes Multiple Myeloma–Induced Osteolysis and Reduces Overall Survival

Genetic and pharmacological approaches show that bone stromal–derived MMP13 catalytic activity is critical for osteoclastogenesis, bone destruction, and disease progression. Multiple myeloma promotes systemic skeletal bone disease that greatly contributes to patient morbidity. Resorption of type I collagen–rich bone matrix by activated osteoclasts results in the release of sequestered growth factors that can drive progression of the disease. Matrix metalloproteinase-13 (MMP13) is a collagenase expressed predominantly in the skeleton by mesenchymal stromal cells (MSC) and MSC-derived osteoblasts. Histochemical analysis of human multiple myeloma specimens also demonstrated that MMP13 largely localizes to the stromal compartment compared with CD138+ myeloma cells. In this study, we further identified that multiple myeloma induces MMP13 expression in bone stromal cells. Because of its ability to degrade type I collagen, we examined whether bone stromal–derived MMP13 contributed to myeloma progression. Multiple myeloma cells were inoculated into wild-type or MMP13–null mice. In independent in vivo studies, MMP13–null mice demonstrated significantly higher overall survival rates and lower levels of bone destruction compared with wild-type controls. Unexpectedly, no differences in type I collagen processing between the groups were observed. Ex vivo stromal coculture assays showed reduced formation and activity in MMP13–null osteoclasts. Analysis of soluble factors from wild-type and MMP13–null MSCs revealed decreased bioavailability of various osteoclastogenic factors including CXCL7. CXCL7 was identified as a novel MMP13 substrate and regulator of osteoclastogenesis. Underscoring the importance of host MMP13 catalytic activity in multiple myeloma progression, we demonstrate the in vivo efficacy of a novel and highly selective MMP13 inhibitor that provides a translational opportunity for the treatment of this incurable disease. Significance: Genetic and pharmacologic approaches show that bone stromal–derived MMP13 catalytic activity is critical for osteoclastogenesis, bone destruction, and disease progression. Graphical Abstract: http://cancerres.aacrjournals. org/content/canres/81/9/2415/F1.large. jpg. Graphical Abstract
The Effect of Antioxidant and Anti-Inflammatory Capacity of Diet on Psoriasis and Psoriatic Arthritis Phenotype: Nutrition as Therapeutic Tool?

Chronic inflammation and increased oxidative stress are contributing factors to many non-communicable diseases. A growing body of evidence indicates that dietary nutrients can activate the immune system and may lead to the overproduction of pro-inflammatory cytokines. Fatty acids as macronutrients are key players for immunomodulation, with n-3 polyunsaturated fatty acids having the most beneficial effect, while polyphenols and carotenoids seem to be the most promising antioxidants. Psoriasis is a chronic, immune-mediated inflammatory disease with multifactorial etiology. Obesity is a major risk factor for psoriasis, which leads to worse clinical outcomes. Weight loss interventions and, generally, dietary regimens such as gluten-free and Mediterranean diet or supplement use may potentially improve psoriasis’ natural course and response to therapy. However, data about more sophisticated nutritional patterns, such as ketogenic, very low-carb or specific macro- and micro-nutrient substitution, are scarce. This review aims to present the effect of strictly structured dietary nutrients, that are known to affect glucose/lipid metabolism and insulin responses, on chronic inflammation and immunity, and to discuss the utility of nutritional regimens as possible therapeutic tools for psoriasis and psoriatic arthritis.
LungINFseg: Segmenting COVID-19 Infected Regions in Lung CT Images Based on a Receptive-Field-Aware Deep Learning Framework

COVID-19 is a fast-growing disease all over the world, but facilities in the hospitals are restricted. Due to unavailability of an appropriate vaccine or medicine, early identification of patients suspected to have COVID-19 plays an important role in limiting the extent of disease. Lung computed tomography (CT) imaging is an alternative to the RT-PCR test for diagnosing COVID-19. Manual segmentation of lung CT images is time consuming and has several challenges, such as the high disparities in texture, size, and location of infections. Patchy ground-glass and consolidations, along with pathological changes, limit the accuracy of the existing deep learning-based CT slices segmentation methods. To cope with these issues, in this paper we propose a fully automated and efficient deep learning-based method, called LungINFseg, to segment the COVID-19 infections in lung CT images. Specifically, we propose the receptive-field-aware (RFA) module that can enlarge the receptive field of the segmentation models and increase the learning ability of the model without information loss. RFA includes convolution layers to extract COVID-19 features, dilated convolution consolidated with learnable parallel-group convolution to enlarge the receptive field, frequency domain features obtained by discrete wavelet transform, which also enlarges the receptive field, and an attention mechanism to promote COVID-19-related features. Large receptive fields could help deep learning models to learn contextual information and COVID-19 infection-related features that yield accurate segmentation results. In our experiments, we used a total of 1800+ annotated CT slices to build and test LungINFseg. We also compared LungINFseg with 13 state-of-the-art deep learning-based segmentation methods to demonstrate its effectiveness. LungINFseg achieved a dice score of 80.34% and an intersection-over-union (IoU) score of 68.77%—higher than the ones of the other 13 segmentation methods. Specifically, the dice and IoU scores of LungINFseg were 10% better than those of the popular biomedical segmentation method U-Net.
NEDD9 is a Novel and Modifiable Mediator of Platelet-Endothelial Adhesion in the Pulmonary Circulation.

Rationale: Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. Objectives: Identify a hypoxia-sensitive, modifiable mediator of platelet-pulmonary artery endothelial cell adhesion and thrombotic remodeling. Methods and Measurements: Network medicine was used to profile protein-protein interactions in hypoxia-treated human pulmonary artery endothelial cells. Data from liquid chromatography-mass spectrometry and microscale thermophoresis informed the development of a novel antibody to inhibit platelet-endothelial adhesion, which was tested in cells from chronic thromboembolic pulmonary hypertension (CTEPH) patients and three animal models in vivo. Results: The protein NEDD9 was identified in the hypoxia-thrombosome network in silico. Compared to normoxia, hypoxia (0.2% O2) for 24 hr increased hypoxia inducible factor-1α-dependent NEDD9 upregulation in vitro. Increased NEDD9 was localized to the plasma membrane surface of cells from controls and CTEPH patients. In endarterectomy specimens, NEDD9 co-localized with the platelet surface adhesion molecule P-Selectin. Our custom-made anti-NEDD9 antibody targeted the NEDD9-P-Selectin interaction and inhibited the adhesion of activated platelets to pulmonary artery endothelial cells from controls in vitro and CTEPH patients ex vivo. Compared to controls, platelet-pulmonary endothelial aggregates and pulmonary hypertension induced by adenosine diphosphate were decreased in NEDD9-/- mice or wild type mice treated with the anti-NEDD9 antibody, which also decreased chronic pulmonary thromboembolic remodeling in vivo. Conclusions: InThe NEDD9-P-Selectin protein-protein interaction is a modifiable target by which to inhibit platelet-pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.
Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with anti-fibrotic properties in toxic liver injury models and anti-steatotic functions in non-alcoholic fatty liver disease (NAFLD) attributed to the CD74/AMPK signaling pathway. As NAFLD progression is associated with fibrosis, we studied MIF function during NAFLD-associated liver fibrogenesis in mice and men by molecular, histological and immunological methods in vitro and in vivo. After NASH diet feeding, hepatic Mif expression was strongly induced, an effect which was absent in Mif∆hep mice. In contrast to hepatotoxic fibrosis models, NASH diet-induced fibrogenesis was significantly abrogated in Mif−/− and Mif∆hep mice associated with a reduced accumulation of the pro-fibrotic type-I NKT cell subpopulation. In vitro, MIF skewed the differentiation of NKT cells towards the type-I subtype. In line with the murine results, expression of fibrosis markers strongly correlated with MIF, its receptors, and markers of NKT type-I cells in NASH patients. We conclude that MIF expression is induced during chronic metabolic injury in mice and men with hepatocytes representing the major source. In NAFLD progression, MIF contributes to liver fibrogenesis skewing NKT cell polarization toward a pro-fibrotic phenotype highlighting the complex, context-dependent role of MIF during chronic liver injury.
Fibronectin Extra Domains tune cellular responses and confer topographically distinct features to fibril networks

ABSTRACT Cellular fibronectin (FN; also known as FN1) variants harboring one or two alternatively spliced so-called extra domains (EDB and EDA) play a central bioregulatory role during development, repair processes and fibrosis. Yet, how the extra domains impact fibrillar assembly and function of the molecule remains unclear. Leveraging a unique biological toolset and image analysis pipeline for direct comparison of the variants, we demonstrate that the presence of one or both extra domains impacts FN assembly, function and physical properties of the matrix. When presented to FN-null fibroblasts, extra domain-containing variants differentially regulate pH homeostasis, survival and TGF-β signaling by tuning the magnitude of cellular responses, rather than triggering independent molecular switches. Numerical analyses of fiber topologies highlight significant differences in variant-specific structural features and provide a first step for the development of a generative model of FN networks to unravel assembly mechanisms and investigate the physical and functional versatility of extracellular matrix landscapes. This article has an associated First Person interview with the first author of the paper. Summary: Fibronectin, a major building block of tissues and organs, tunes fibroblast behavior and matrix architecture through the presence of alternatively spliced extra domains.
Comparative Risk Assessment of Three Native Heliotropium Species in Israel

Pyrrolizidine alkaloids (PAs) are genotoxic carcinogenic phytotoxins mostly prevalent in the Boraginaceae, Asteraceae and Fabaceae families. Heliotropium species (Boraginaceae) are PA-producing weeds, widely distributed in the Mediterranean region, that have been implicated with lethal intoxications in livestock and humans. In Israel, H. europaeum, H. rotundifolium and H. suaveolens are the most prevalent species. The toxicity of PA-producing plants depends on the PA concentration and composition. PAs occur in plants as mixtures of dozens of various PA congeners. Hence, the risk arising from simultaneous exposure to different congeners has to be evaluated. The comparative risk evaluation of the three Heliotropium species was based on recently proposed interim relative potency (iREP) factors, which take into account certain structural features as well as in vitro and in vivo toxicity data obtained for several PAs of different classes. The aim of the present study was to determine the PA profile of the major organ parts of H. europaeum, H. rotundifolium and H. suaveolens in order to assess the plants’ relative toxic potential by utilizing the iREP concept. In total, 31 different PAs were found, among which 20 PAs were described for the first time for H. rotundifolium and H. suaveolens. The most prominent PAs were heliotrine-N-oxide, europine-N-oxide and lasiocarpine-N-oxide. Europine-N-oxide displayed significant differences among the three species. The PA levels ranged between 0.5 and 5% of the dry weight. The flowers of the three species were rich in PAs, while the PA content in the root and flowers of H. europaeum was higher than that of the other species. H. europaeum was found to pose a higher risk to mammals than H. rotundifolium, whereas no differences were found between H. europaeum and H. suaveolens as well as H. suaveolens and H. rotundifolium.
Immunophenotypical Characterization of M1/M2 Macrophages and Lymphocytes in Cisplatin-Induced Rat Progressive Renal Fibrosis

Renal fibrosis is regarded as the common final pathway leading to chronic kidney diseases; macrophages and myofibroblasts play important roles in the development of fibrosis. F344 rats were injected once with cisplatin (CDDP; 6 mg/kg BW) for renal lesions. Here, immunophenotypical characteristics of macrophages and lymphocytes in CDDP-induced rat renal lesions were investigated histopathologically; the CDDP-induced renal lesions consisted of tissue damage at the early-stage, worsen the damage and commencement of interstitial fibrosis at the mid-stage, and progressive fibrosis at the late stage; the KIM-1 expression and α-SMA+ myofibroblast area reflected renal tubular damage/abnormal regeneration and renal interstitial fibrosis, respectively. CD68+ M1 macrophages began to increase at the mid-stage, with increased mRNA expressions of M1-related cytokines (INF-γ, TNF-α and IL-6), and then slightly decreased at the late-stage. CD163+ M2 macrophages showed a gradually increased number at the mid- and late-stages, accompanied by increased TGF-β1 mRNA expression (a fibrogenic factor). Double immunofluorescence using fibrotic samples at the late-stage revealed that 62.0–78.0% of CD68+ M1 macrophages co-expressed CD163, indicating that M1/M2 macrophages may contribute to progressive renal fibrosis in cooperation; further, MHC class II-expressing macrophages had a tendency towards M1 polarization, whereas CD204-expressing macrophages towards M2 polarization. In addition, CD4+ and CD8+ T cells were increased at the late-stage. Collectively, progressive renal interstitial fibrosis may be developed by complicated mechanisms that arose via interaction of M1/M2 macrophages (inflammatory for M1 and anti-inflammatory for M2) and T cells reacting to CD4 (for helper) and CD8 (for cytotoxicity). This study would provide some information on the pathogenesis of renal fibrosis based on inflammatory cells.
Targeting AnxA1/Fpr2/ALX Pathway Regulates Neutrophil Function Promoting Thrombo-Inflammation Resolution in Sickle Cell Disease.

Neutrophils plays a crucial role in the intertwined processes of thrombosis and inflammation. Altered neutrophil phenotype may contribute to inadequate resolution which is known to be a major pathophysiological contributor of thrombo-inflammatory conditions such as Sickle Cell Disease (SCD). The endogenous protein Annexin A1 (AnxA1) facilitates inflammation resolution via Formyl Peptide Receptors (FPRs). We sought to comprehensively elucidate the functional significance of targeting neutrophil dependent AnxA1/FPR2/ALX pathway in SCD. Administration of AnxA1 mimetic peptide AnxA1Ac2-26 ameliorated cerebral thrombotic responses in Sickle transgenic mice via regulation of FPR2/ALX (a fundamental receptor involved in resolution) pathway. We demonstrated direct evidence that neutrophils with SCD phenotype play a key role in contributing to thrombo-inflammation. In addition, AnxA1Ac2-26 regulated activated SCD neutrophils through protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2) to enable resolution. Herein, we present compelling conceptual evidence that targeting the AnxA1/FPR2/ALX pathway may provide new therapeutic possibilities against thrombo-inflammatory conditions such as SCD.
Neurological risks and benefits of cytokine‐based treatments in coronavirus disease 2019: from preclinical to clinical evidence

Immunodeficiency and hyperinflammation are responsible for the most frequent and life‐threatening forms of coronavirus disease 2019 (COVID‐19). Therefore, cytokine‐based treatments targeting immuno‐inflammatory mechanisms are currently undergoing clinical scrutiny in COVID‐19‐affected patients. In addition, COVID‐19 patients also exhibit a wide range of neurological manifestations (neuro‐COVID), which may also benefit from cytokine‐based treatments. In fact, such drugs have shown some clinical efficacy also in neuroinflammatory diseases. On the other hand, anti‐cytokine drugs are endowed with significant neurological risks, mainly attributable to their immunodepressant effects. Therefore, the aim of the present manuscript is to briefly describe the role of specific cytokines in neuroinflammation, to summarize the efficacy in preclinical models of neuroinflammatory diseases of drugs targeting these cytokines and to review the clinical data regarding the neurological effects of these drugs currently being investigated against COVID‐19, in order to raise awareness about their potentially beneficial and/or detrimental neurological consequences.
A Novel Soluble ACE2 Variant with Prolonged Duration of Action Neutralizes SARS-CoV-2 Infection in Human Kidney Organoids.

BACKGROUND There is an urgent need for approaches to prevent and treat SARS-CoV-2 infection. Administration of soluble ACE2 protein acting as a decoy to bind to SARS-CoV-2 should limit viral uptake mediated by binding to membrane-bound full-length ACE2, and further therapeutic benefit should result from ensuring enzymatic ACE2 activity to affected organs in patients with COVID-19. METHODS A short variant of human soluble ACE2 protein consisting of 618 amino acids (hACE2 1-618) was generated and fused with an albumin binding domain (ABD) using an artificial gene encoding ABDCon, with improved albumin binding affinity. Human kidney organoids were used for infectivity studies of SARS-CoV-2 in a BSL-3 facility to examine the neutralizing effect of these novel ACE2 variants. RESULTS Whereas plasma ACE2 activity of the naked ACE2 1-618 and ACE2 1-740 lasted about 8 hours, the ACE2 1-618-ABD resulted in substantial activity at 96 hours, and it was still biologically active 3 days after injection. Human kidney organoids express ACE2 and TMPRSS2, and when infected with SARS-CoV-2, our modified long-acting ACE2 variant neutralized infection. CONCLUSIONS This novel ACE2 1-618-ABD can neutralize SARS-CoV-2 infectivity in human kidney organoids, and its prolonged duration of action should ensure improved efficacy to prevent viral escape and dosing convenience.
COVID‐19 deaths by occupation, Massachusetts, March 1–July 31, 2020

Abstract Background Exposure to COVID‐19 is more likely among certain occupations compared with others. This descriptive study seeks to explore occupational differences in mortality due to COVID‐19 among workers in Massachusetts. Methods Death certificates of those who died from COVID‐19 in Massachusetts between March 1 and July 31, 2020 were collected. Occupational information was coded and age‐adjusted mortality rates were calculated according to occupation. Results There were 555 deaths among MA residents of age 16–64, with usable occupation information, resulting in an age‐adjusted mortality rate of 16.4 per 100,000 workers. Workers in 11 occupational groups including healthcare support and transportation and material moving had mortality rates higher than that for workers overall. Hispanic and Black workers had age‐adjusted mortality rates more than four times higher than that for White workers overall and also had higher rates than Whites within high‐risk occupation groups. Conclusion Efforts should be made to protect workers in high‐risk occupations identified in this report from COVID‐19 exposure.
Nitrous anhydrase activity of carbonic anhydrase II: cysteine is required for nitric oxide (NO) dependent phosphorylation of VASP in human platelets

Abstract The carbonic anhydrase (CA) family does not only catalyse the reversible hydration of CO2 to bicarbonate, but it also possesses esterase and phosphatase activity. Recently, bovine CA II and human CA II have been reported to convert inorganic nitrite (O=N-O−) to nitric oxide (NO) and nitrous anhydride (N2O3). Given the ability of NO to mediate vasodilation and inhibit platelet aggregation, this CA II activity would represent a bioactivation of nitrite. There are contradictory reports in the literature and the physiological role of CA II nitrite bioactivation is still disputed. Here, we provide new experimental data in support of the nitrous anhydrase activity of CA II and the key role L-cysteine in the bioactivation of nitrite by CA II. Using washed human platelets and by measuring VASP phosphorylation we provide evidence that exogenous nitrite (10 µM) is bioactivated to NO in a manner strongly depending on L-cysteine (100 and 200 µM). The process is not inhibitable by acetazolamide, a potent CA inhibitor. The contradictory results of recently published studies in this area are thoroughly discussed.
Recognition of Diagnostic Gaps for Laboratory Diagnosis of Fungal Diseases: Expert Opinion from the Fungal Diagnostics Laboratories Consortium (FDLC)

Fungal infections are a rising threat to our immunocompromised patient population, as well as other nonimmunocompromised patients with various medical conditions. However, little progress has been made in the past decade to improve fungal diagnostics. ABSTRACT Fungal infections are a rising threat to our immunocompromised patient population, as well as other nonimmunocompromised patients with various medical conditions. However, little progress has been made in the past decade to improve fungal diagnostics. To jointly address this diagnostic challenge, the Fungal Diagnostics Laboratory Consortium (FDLC) was recently created. The FDLC consists of 26 laboratories from the United States and Canada that routinely provide fungal diagnostic services for patient care. A survey of fungal diagnostic capacity among the 26 members of the FDLC was recently completed, identifying the following diagnostic gaps: lack of molecular detection of mucormycosis; lack of an optimal diagnostic algorithm incorporating fungal biomarkers and molecular tools for early and accurate diagnosis of Pneumocystis pneumonia, aspergillosis, candidemia, and endemic mycoses; lack of a standardized molecular approach to identify fungal pathogens directly in formalin-fixed paraffin-embedded tissues; lack of robust databases to enhance mold identification with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; suboptimal diagnostic approaches for mold blood cultures, tissue culture processing for Mucorales, and fungal respiratory cultures for cystic fibrosis patients; inadequate capacity for fungal point-of-care testing to detect and identify new, emerging or underrecognized, rare, or uncommon fungal pathogens; and performance of antifungal susceptibility testing. In this commentary, the FDLC delineates the most pressing unmet diagnostic needs and provides expert opinion on how to fulfill them. Most importantly, the FDLC provides a robust laboratory network to tackle these diagnostic gaps and ultimately to improve and enhance the clinical laboratory’s capability to rapidly and accurately diagnose fungal infections.