scholarly journals Effect of the Lymphocyte Activation Gene 3 Polymorphism rs951818 on Mortality and Disease Progression in Patients with Sepsis—A Prospective Genetic Association Study

2021 ◽  
Vol 10 (22) ◽  
pp. 5302
Author(s):  
Caspar Mewes ◽  
Tessa Alexander ◽  
Benedikt Büttner ◽  
José Hinz ◽  
Ayelet Alpert ◽  
...  
Keyword(s):  
Disease Severity ◽  
Molecular Mechanisms ◽  
Medical Center ◽  
Invasive Mechanical Ventilation ◽  
Lymphocyte Activation ◽  
Public Health Problem ◽  
Immune Checkpoints ◽  
Global Public Health ◽  
Genetic Profiling ◽  
Lymphocyte Activation Gene

(1) Background: Sepsis is a leading cause of death and a global public health problem. Accordingly, deciphering the underlying molecular mechanisms of this disease and the determinants of its morbidity and mortality is pivotal. This study examined the effect of the rs951818 SNP of the negative costimulatory lymphocyte-activation gene 3 (LAG-3) on sepsis mortality and disease severity. (2) Methods: 707 consecutive patients with sepsis were prospectively enrolled into the present study from three surgical ICUs at University Medical Center Goettingen. Both 28- and 90-day mortality were analyzed as the primary outcome, while parameters of disease severity served as secondary endpoints. (3) Results: In the Kaplan–Meier analysis LAG-3 rs951818 AA-homozygote patients showed a significantly lower 28-day mortality (17.3%) compared to carriers of the C-allele (23.7%, p = 0.0476). In addition, these patients more often received invasive mechanical ventilation (96%) during the course of disease than C-allele carriers (92%, p = 0.0466). (4) Conclusions: Genetic profiling of LAG-3 genetic variants alone or in combination with other genetic biomarkers may represent a promising approach for risk stratification of patients with sepsis. Patient-individual therapeutic targeting of immune checkpoints, such as LAG-3, may be a future component of sepsis therapy. Further detailed investigations in clinically relevant sepsis models are necessary.

scholarly journals Evaluation of single domain antibodies as nuclear tracers for imaging of the immune checkpoint receptor human lymphocyte activation gene-3 in cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Q. Lecocq ◽  
P. Debie ◽  
J. Puttemans ◽  
R. M. Awad ◽  
L. De Beck ◽  
...  
Keyword(s):  
Human Lymphocyte ◽  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Lymphocyte Activation ◽  
Single Domain ◽  
Whole Body ◽  
Whole Body Imaging ◽  
Single Domain Antibodies ◽  
Immune Oncology ◽  
Lymphocyte Activation Gene

AbstractRecent advancements in the field of immune-oncology have led to a significant increase in life expectancy of patients with diverse forms of cancer, such as hematologic malignancies, melanoma and lung cancer. Unfortunately, these encouraging results are not observed in the majority of patients, who remain unresponsive and/or encounter adverse events. Currently, researchers are collecting more insight into the cellular and molecular mechanisms that underlie these variable responses. As an example, the human lymphocyte activation gene-3 (huLAG-3), an inhibitory immune checkpoint receptor, is increasingly studied as a therapeutic target in immune-oncology. Noninvasive molecular imaging of the immune checkpoint programmed death protein-1 (PD-1) or its ligand PD-L1 has shown its value as a strategy to guide and monitor PD-1/PD-L1-targeted immune checkpoint therapy. Yet, radiotracers that allow dynamic, whole body imaging of huLAG-3 expression are not yet described. We here developed single-domain antibodies (sdAbs) that bind huLAG-3 and showed that these sdAbs can image huLAG-3 in tumors, therefore representing promising tools for further development into clinically applicable radiotracers.

scholarly journals Lymphocyte Activation Gene 3-a Novel Therapeutic Target in Chronic Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2018-2018
Author(s):  
Mika Shapiro ◽  
Ben-Zion Katz ◽  
Chava Perry ◽  
Clare Sun ◽  
Nili Dezorella ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Therapeutic Target ◽  
Research Funding ◽  
Cell Function ◽  
Lymphocyte Activation ◽  
Lymphocytic Leukemia ◽  
Immune Checkpoints ◽  
Tumor Escape ◽  
Lymphocyte Activation Gene ◽  
Novel Therapeutic

Abstract A novel therapeutic approach in cancer attempting to stimulate host anti-tumor immunity involves blocking of immune checkpoints. Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor expressed on activated/exhausted T-cells. When engaged by MHC Class II (MHCII) molecules, LAG3 negatively regulates T-cell function thereby contributing to tumor escape. Intriguingly, a soluble LAG3 variant was reported to activate both immune and malignant MHCII-presenting cells. In this study, we examined the role of LAG3 in the pathogenesis of CLL and show that CLL cells express and secrete LAG3. High levels of surface and soluble LAG3 were associated with the unmutated immunoglobulin variable heavy chain CLL and a more aggressive disease. It was evident that recombinant soluble LAG3-Ig fusion protein activated CLL cells, induced increased levels of Bcl-2 and Mcl-1 and protected the cells from spontaneous apoptosis, utilizing a mechanism mediated through MHCII engagement. Our data suggest that autocrine secretion of soluble LAG3 from CLL cells and its subsequent interaction with MHCII on their surface, promotes CLL cell activation and anti-apoptotic effects. Moreover, CLL cells may impose immune exhaustion on their microenvironment by expressing MHCII, thus affecting the surrounding, LAG3-presenting immune cells. Hence, blocking LAG3-MHCII interactions is a potential therapeutic target in CLL. Disclosures Avivi: Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche. Wiestner:Pharmacyclics: Research Funding; Acerta Pharma: Research Funding.

scholarly journals Lymphocyte-Activation Gene 3 (LAG3) Protein as a Possible Therapeutic Target for Parkinson’s Disease: Molecular Mechanisms Connecting Neuroinflammation to α-Synuclein Spreading Pathology

Biology ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 86
Author(s):  
Efthalia Angelopoulou ◽  
Yam Nath Paudel ◽  
Chiara Villa ◽  
Mohd. Farooq Shaikh ◽  
Christina Piperi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Lymphocyte Activation ◽  
Female Population ◽  
Treatment Research ◽  
Lymphocyte Activation Gene

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder without any objective biomarker available to date. Increasing evidence highlights the critical role of neuroinflammation, including T cell responses, and spreading of aggregated α-synuclein in PD progression. Lymphocyte-activation gene 3 (LAG3) belongs to the immunoglobulin (Ig) superfamily expressed by peripheral immune cells, microglia and neurons and plays a key role in T cell regulation. The role of LAG3 has been extensively investigated in several human cancers, whereas until recently, the role of LAG3 in the central nervous system (CNS) has been largely unknown. Accumulating evidence highlights the potential role of LAG3 in PD pathogenesis, mainly by binding to α-synuclein fibrils and affecting its endocytosis and intercellular transmission, which sheds more light on the connection between immune dysregulation and α-synuclein spreading pathology. Serum and cerebrospinal fluid (CSF) soluble LAG3 (sLAG3) levels have been demonstrated to be potentially associated with PD development and clinical phenotype, suggesting that sLAG3 could represent an emerging PD biomarker. Specific single nucleotide polymorphisms (SNPs) of the LAG3 gene have been also related to PD occurrence especially in the female population, enlightening the pathophysiological background of gender-related PD clinical differences. Given also the ongoing clinical trials investigating various LAG3-targeting strategies in human diseases, new opportunities are being developed for PD treatment research. In this review, we discuss recent preclinical and clinical evidence on the role of LAG3 in PD pathogenesis and biomarker potential, aiming to elucidate its underlying molecular mechanisms.

scholarly journals Highly Sensitive Quantification of Plasma Severe Acute Respiratory Syndrome Coronavirus 2 RNA Sheds Light on its Potential Clinical Value

2020 ◽  
Author(s):  
David Veyer ◽  
Solen Kernéis ◽  
Geoffroy Poulet ◽  
Maxime Wack ◽  
Nicolas Robillard ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Disease Severity ◽  
Clinical Manifestations ◽  
Public Health Problem ◽  
Digital Pcr ◽  
Absolute Quantification ◽  
Multiple Organ ◽  
Global Public Health ◽  
Clinical Value ◽  
Pcr Technology

Abstract Background Coronavirus disease 2019 (COVID-19) is a global public health problem that has already caused more than 662 000 deaths worldwide. Although the clinical manifestations of COVID-19 are dominated by respiratory symptoms, some patients present other severe damage such as cardiovascular, renal and liver injury, and/or multiple organ failure, suggesting a spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in blood. Recent ultrasensitive polymerase chain reaction (PCR) technology now allows absolute quantification of nucleic acids in plasma. We intend to use the droplet-based digital PCR technology to obtain sensitive detection and precise quantification of plasma SARS-CoV-2 viral load (SARS-CoV-2 RNAemia) in hospitalized COVID-19 patients. Methods Fifty-eight consecutive COVID-19 patients with pneumonia 8 to 12 days after onset of symptoms and 12 healthy controls were analyzed. Disease severity was categorized as mild to moderate in 17 patients, severe in 16, and critical in 26. Plasma SARS-CoV-2 RNAemia was quantified by droplet digital Crystal Digital PCR next-generation technology (Stilla Technologies, Villejuif, France). Results Overall, SARS-CoV-2 RNAemia was detected in 43 (74.1%) patients. Prevalence of positive SARS-CoV-2 RNAemia correlated with disease severity, ranging from 53% in mild-to-moderate patients to 88% in critically ill patients (P = .036). Levels of SARS-CoV-2 RNAemia were associated with severity (P = .035). Among 9 patients who experienced clinical deterioration during follow-up, 8 had positive SARS-CoV-2 RNAemia at baseline, whereas only 1 critical patient with undetectable SARS-CoV-2 RNAemia at the time of analysis died at day 27. Conclusion SARS-CoV-2 RNAemia measured by droplet-based digital PCR constitutes a promising prognosis biomarker in COVID-19 patients.

scholarly journals 279. Clinical Characteristics of Critically Ill Patients with COVID-19 and Invasive Pulmonary Aspergillosis: A Case Series From Mexico City

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S245-S245
Author(s):  
Patricia Galindo-Lopez ◽  
Benjamin Valente-Acosta ◽  
Francisco Moreno-Sanchez ◽  
Luis Espinosa-Aguilar ◽  
Irma Hoyo-Ulloa ◽  
...  
Keyword(s):  
Critically Ill ◽  
Mexico City ◽  
Critically Ill Patients ◽  
Medical Center ◽  
Invasive Mechanical Ventilation ◽  
Invasive Pulmonary Aspergillosis ◽  
Case Series ◽  
Global Public Health ◽  
Pulmonary Aspergillosis ◽  
The Mean

Abstract Background COVID-19 has emerged as a global public health emergency and has been the main cause of intensive care admission during the pandemic. COVID-19-associated pulmonary aspergillosis (CAPA) has been reported in case series of critically ill patients. However, the criteria for CAPA diagnosis has been inconsistent among most of the reports. Mexico has been widely affected by SARS-CoV-2. We present a series of CAPA cases at a teaching hospital in Mexico City. Methods We performed a retrospective analysis of COVID-19 patients admitted to the ABC Medical Center from May 1st, 2020, to May 1st, 2021. Including only those with critical COVID-19 who required invasive mechanical ventilation (IMV). Patients with a diagnosis of CAPA were analyzed. We followed the 2020 ECMM/ISHAM consensus criteria for CAPA diagnosis. Aspergillus antigen testing in tracheal aspirate and serum was done with Aspergillus-specific galactomannoprotein (GP) ELISA (Euroimmun Medizinische Labordiagnostika). Results Among the 230 admitted patients who required IMV, we identified 49 (21.3%) cases of CAPA, 46 probable CAPA and 3 proven CAPA. Nineteen (38%) of those died in the hospital. The mean age was 64.5 ± 12.6 years and 11 were female. Proven CAPA was diagnosed with culture in three cases (one A. niger, one A. terreus and one A. fumigatus). Probable CAPA was diagnosed by a positive serum GP in 27 (55.1%) patients and by a positive bronchoalveolar lavage (BAL) GP in 29 (59.2%) cases. Seven patients had both serum and BAL positive GP. Forty-six (93.9%) patients received corticosteroids, and 22 (49.9%) were treated with tocilizumab before CAPA diagnosis. All but one received isavuconazole as CAPA treatment. We detected 35 (71.4%) patients who had a bacterial co-infection. Eighteen of those died (51.4%) compared to only one dead in the subgroup without coinfections (7.1%). The mean time from hospital admission to CAPA diagnosis was 6.2 days (SD 7.1) among those who survived compared to 13.2 (SD 6.3) days in those who died p< 0.01. Conclusion CAPA had a lower prevalence than previously reported in other series. However, it appears to be linked to high mortality when it occurs with other bacterial coinfections and when it is diagnosed late from admission. Disclosures All Authors: No reported disclosures

scholarly journals Pleiotropic genetic influence on birth weight and childhood obesity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Suvo Chatterjee ◽  
Marion Ouidir ◽  
Fasil Tekola-Ayele
Keyword(s):  
Birth Weight ◽  
Childhood Obesity ◽  
Molecular Mechanisms ◽  
Genetic Correlations ◽  
Public Health Problem ◽  
Genetic Influence ◽  
Global Public Health ◽  
Functional Annotations ◽  
Global Public Health Problem ◽  
Shared Genetic

AbstractChildhood obesity is a global public health problem. Understanding the molecular mechanisms that underlie early origins of childhood obesity can facilitate interventions. Consistent phenotypic and genetic correlations have been found between childhood obesity traits and birth weight (a proxy for in-utero growth), suggesting shared genetic influences (pleiotropy). We aimed to (1) investigate whether there is significant shared genetic influence between birth weight and childhood obesity traits, and (2) to identify genetic loci with shared effects. Using a statistical approach that integrates summary statistics and functional annotations for paired traits, we found strong evidence of pleiotropy (P < 3.53 × 10–127) and enrichment of functional annotations (P < 1.62 × 10–39) between birth weight and childhood body mass index (BMI)/obesity. The pleiotropic loci were enriched for regulatory features in skeletal muscle, adipose and brain tissues and in cell lines derived from blood lymphocytes. At 5% false discovery rate, 6 loci were associated with birth weight and childhood BMI and 13 loci were associated with birth weight and childhood obesity. Out of these 19 loci, one locus (EBF1) was novel to childhood obesity and one locus (LMBR1L) was novel to both birth weight and childhood BMI/obesity. These findings give evidence of substantial shared genetic effects in the regulation of both fetal growth and childhood obesity.

Modulation of the drug resistance by Platonia insignis Mart. extract, ethyl acetate fraction and Morelloflavone/Volkensiflavone (biflavonoids) in Staphylococcus aureus strains overexpressing efflux pump genes

2020 ◽  
Vol 21 ◽  
Author(s):  
Andressa Kelly Ferreira e Silva ◽  
Antonielly Campinho dos Reis ◽  
Emanuelly Elanny Andrade Pinheiroc ◽  
Jonas Nascimento de Sousa ◽  
Felipe Araújo de Alcântara Oliveira ◽  
...  
Keyword(s):  
Natural Products ◽  
Ethyl Acetate ◽  
Native Species ◽  
Efflux Pump ◽  
Public Health Problem ◽  
Ethyl Acetate Fraction ◽  
Multidrug Resistant ◽  
Global Public Health ◽  
Minimal Inhibitory Concentrations ◽  
Subinhibitory Concentrations

Background: Microbial resistance to antibiotics is a global public health problem, which requires urgent attention. Platonia insignis is a native species from the eastern Brazilian Amazon, used in the treatment of burns and wounds. Objectives: To evaluate the antimicrobial activity of the hydroalcoholic extract of P. insignis (PIHA), the ethyl acetate fraction (PIAE), and its subfraction containing a mixture of biflavonoids (BF). Moreover, the effect of these natural products on the antibiotic activity against S. aureus strains overexpressing efflux pump genes was also evaluated. Methods: Minimal inhibitory concentrations were determined against different species of microorganisms. To evaluate the modulatory effect on the Norfloxacin-resistance, the MIC of this antibiotic was determined in the absence and presence of the natural products at subinhibitory concentrations. Inhibition of the EtBr efflux assays were conducted in the absence or presence of the natural products. Results: PIHA showed a microbicidal effect against S. aureus and C. albicans, while PIAE was bacteriosctatic for S. aureus. PIAE and BF at subinhibitory concentrations were able to reduce the MIC of Norfloxacin acting as modulating agents. BF was able to inhibit the efflux of EtBr efflux in S. aureus strains overexpressing specific efflux pump genes. Conclusion: P. inignisis a source of efflux pump inhibitors, including volkensiflavone and morelloflavone which were able to potentiate the Norfloxacin activity by NorA inhibition, being also able to inhibit QacA/B, TetK and MsrA. Volkensiflavone and morelloflavone could be used as adjuvant in the antibiotic therapy of multidrug resistant S. aureus strains overexpressing efflux pumps.

4H-1,3-Benzothiazin-4-one a Promising Class Against MDR/XDR-TB

2019 ◽  
Vol 19 (8) ◽  
pp. 567-578 ◽  
Author(s):  
Marcus Vinicius Nora de Souza ◽  
Thais Cristina Mendonça Nogueira
Keyword(s):  
Treatment Time ◽  
Public Health Problem ◽  
New Drugs ◽  
Global Public Health ◽  
Synthesis Mechanism ◽  
Highly Active ◽  
Latent Disease ◽  
Resistant Strains ◽  
Chemical Class ◽  
Global Public Health Problem

Nowadays, tuberculosis (TB) is an important global public health problem, being responsible for millions of TB-related deaths worldwide. Due to the increased number of cases and resistance of Mycobacterium tuberculosis to all drugs used for the treatment of this disease, we desperately need new drugs and strategies that could reduce treatment time with fewer side effects, reduced cost and highly active drugs against resistant strains and latent disease. Considering that, 4H-1,3-benzothiazin-4-one is a promising class of antimycobacterial agents in special against TB-resistant strains being the aim of this review the discussion of different aspects of this chemical class such as synthesis, mechanism of action, medicinal chemistry and combination with other drugs.

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