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Aim. To study the effect of inhalation therapy with an active hydrogen (AH) on the protein composition of exhaled breath condensate (EBC) in patients with post-COVID syndrome (PCS). Material and methods. This randomized controlled parallel prospective study included 60 patients after coronavirus disease 2019 (COVID-19) with PCS during the recovery period and clinical manifestations of chronic fatigue syndrome who received standard therapy according to the protocol for managing patients with chronic fatigue syndrome (CFS). The patients were divided into 2 groups: group 1 (main) - 30 people who received standard therapy and AH inhalations (SUISONIA, Japan) for 10 days, and group 2 (control) - 30 medical workers who received only standard therapy. Patients in both groups were comparable in sex and mean age. All participants in the study were sampled with EBC on days 1 and 10. Samples were subjected to tryptic digestion and high-performance liquid chromatography combined with tandem mass spectrometry analysis using a nanoflow chromatograph (Dionex 3000) in tandem with a high-resolution time-of-flight mass spectrometer (timsTOF Pro). Results. A total of 478 proteins and 1350 peptides were identified using high resolution mass spectrometry. The number of proteins in samples after AH therapy, on average, is 12% more than before treatment. An analysis of the distribution of proteins in different groups of patients showed that only half of these proteins (112) are common for all groups of samples and are detected in EBC before, after, and regardless of hydrogen therapy. In addition to the qualitative difference in the EBC protein compositions in different groups, quantitative changes in the concentration of 36 proteins (mainly structural and protective) were also revealed, which together made it possible to reliably distinguish between subgroups before and after treatment. It is worth noting that among these proteins there are participants of blood coagulation (alpha-1-antitrypsin), chemokine- and cytokine-mediated inflammation, and a number of signaling pathways (cytoplasmic actin 2), response to oxidative stress (thioredoxin), glycolysis (glyceraldehyde-3- phosphate dehydrogenase), etc. Conclusion. The use of hydrogen therapy can contribute to the switching of a number of physiological processes, which may affect the success of recovery in PCS patients. In particular, the obtained results indicate the activation of aerobic synthesis of adenosine triphosphate in mitochondria by hydrogen therapy, which correlates well with the decrease in the blood lactate level detected by laboratory studies. At the same time, this therapy can inhibit pro-inflammatory activity, negatively affecting the coagulation and signaling pathways of integrins and apoptosis, and, in addition, activate protective pathways, tricarboxylic acid cycle, FAS signaling, and purine metabolism, which may be essential for effective recovery after COVID-19.Copyright © 2023 Vserossiiskoe Obshchestvo Kardiologov. All rights reserved.
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Background: The mechanisms driving SARS-CoV-2 susceptibility remain poorly understood, especially the factors determining why a subset of unvaccinated individuals remain uninfected despite high-risk exposures. Method(s): We studied an exceptional group of unvaccinated healthcare workers heavily exposed to SARS-CoV-2 ('nonsusceptible') from April to June 2020, who were compared against 'susceptible' individuals to SARS-CoV-2, including uninfected subjects who became infected during the follow-up, and hospitalized patients with different disease severity providing samples at early disease stages. We analyzed plasma samples using different mass spectrometry technique and obtained metabolites and lipids profiles. Result(s): We found that the metabolite profiles were predictive of the selected study groups and identified lipids profiles and metabolites linked to SARS-CoV-2 susceptibility and COVID-19 severity. More importantly, we showed that non-susceptible individuals exhibited unique metabolomics and lipidomic patterns characterized by upregulation of most lipids -especially ceramides and sphingomyelin-and amino acids related to tricarboxylic acid cycle and mitochondrial metabolism, which could be interpreted as markers of low susceptibility to SARS-CoV-2 infection. Lipids and metabolites pathways analysis revealed that metabolites related to energy production, mitochondrial and tissue dysfunction, and lipids involved in membrane structure and virus infectivity were key markers of SARS-CoV-2 susceptibility. Conclusion(s): Lipid and metabolic profiles differ in 'nonsusceptible' compared to individuals susceptible to SARS-CoV-2. Our study suggests that lipid profiles are relevant actors during SARS-CoV-2 pathogenesis and highlight certain lipids relevant to understand SARS-CoV-2 pathogenesis. (Figure Presented).
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Social isolation is associated with increased risk and mortality from many diseases, such as breast cancer. Socially isolated breast cancer survivors have a 43% higher risk of recurrence and a 64% higher risk of breast cancer-specific mortality than socially integrated survivors. Since Covid-19 has dramatically increased the incidence of social isolation, it is important to determine if social isolation affects the response to endocrine therapy and/or recurrence after the therapy is completed. Since previous studies indicate that social isolation increases circulating inflammatory cytokines, we investigated if an anti-inflammatory herbal mixture Jaeumkanghwa-tang (JGT) prevents the adverse effects of social isolation on breast cancer mortality. Estrogen receptor positive mammary tumors were initiated with 7,12-dimethylbenz[a]anthracene. When a rat developed a palpable mammary tumor, it was either socially isolated (SI) by housing it singly or a rat was allowed to remain group-housed (GH). Tamoxifen (340ppm via diet) or tamoxifen + JGT (500ppm via drinking water) started when the first mammary tumor reached a size of 11 mm in diameter. Tamoxifen administration ended when a complete response to this therapy had lasted for 9 weeks (corresponds to 5 years in women). During tamoxifen therapy, social isolation non-significantly reduced the rate of complete responses to 21%, from 31% in GH group (p>0.05). After the therapy was completed, SI significantly increased local mammary tumor recurrence (p<0.001;45% GH vs 75% SI). RNAseq analysis was performed in the mammary glands. Gene set enrichment analysis (GSEA) of transcriptome showed that the increased recurrence risk in socially isolated rats was associated with an enrichment of IL6/JAK/STAT3 signaling: this result was confirmed in the tumors. In addition, oxidative phosphorylation (OXPHOS) pathway was suppressed: the suppressed genes included those involved in mitochondrial pyruvate transport and conversion of pyruvate to acetyl CoA as well as genes in the TCA cycle and mediating electron transport in mitochondrial complexes I-IV. Social isolation also increased the expression of inflammatory receptor for advanced glycation end-products (RAGE) (p≤0.05). Consumption of an anti-inflammatory JGT inhibited IL6/JAK/STAT3 signaling, upregulated OXPHOS signaling and prevented the increased risk of mammary cancer recurrence in socially isolated animals. The percentage of recurrences in the SI rats dropped from 75% without JGT to 22% with JGT (p<0.001). Breast cancer mortality among socially isolated survivors may be most effectively prevented by focusing on the period following endocrine therapy using tools that inhibit IL6/JAK/STAT3 inflammatory cytokine signaling and correct disrupted OXPHOS and mitochondrial dysfunction.
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RATIONALE: Long-term quality of life is a significant concern for survivors of sepsis and acute respiratory failure (ARF). Financial burdens await as many patients never return to work. Notably, the duration of the ICU stay significantly correlates with the severity of physical impairment and up to 25% of skeletal muscle is lost within one week in the ICU. The recent pandemic due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) is likely to exacerbate these issues. We have previously reported that metabolites related to mitochondrial bioenergetics status can predict acute patient outcomes. Here, we propose that these same metabolomic and mitochondrial biomarkers of mortality also predict physical function in survivors. METHODS: To test this hypothesis, we performed a retrospective analysis of metabolomic changes in ARF survivors using ultrahigh performance liquid chromatography mass spectrometry. Six months after ICU admission, physical function was determined by the short physical performance battery (SPPB), an objective physical function measurement assessing gait speed, balance and lower extremity strength. A total of 70 consecutively enrolled patients were selected, of which 35 had good physical function (SPPB ≥ 7) and 35 had poor physical function (SPPB ≤6). The patients were matched for age, race and sex. Metabolomic analysis of patient's serum was measured at ICU admittance (n=70), 5d-post admittance (n=20) and discharge (n=20). RESULTS: More than 1250 named compounds were identified. There were only 19 metabolites that were significantly different at admittance (ANOVA;p < 0.05), of which seven were bile acids. However at discharge, despite less patient samples tested, 151 metabolites were significantly different (ANOVA;p < 0.05). Specifically, we found that 10 lysophospholipids, eight bile acids, three TCA cycle metabolites, eight kynurenine-related metabolites and nine urea cycle metabolites were significantly different. Many of these pathways have previously been shown to be altered in nonsurvivors of sepsis and ARF. CONCLUSIONS: Findings suggest that bioenergetic abnormalities arising during the acute phase of recovery may be persistent and predict longer-term decrements of physical function in survivors of ARF. Larger retrospective and prospective studies are needed to confirm these preliminary findings;however, predicting poor physical function in survivors as well as identifying the affected metabolic pathways may lead to improved therapies and long-term patient outcomes.
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Background: Understanding the role of crucial biomolecules and mechanistic pathways supporting coronavirus disease 2019 (COVID-19) pathophysiology is essential to handle the immune dysregulation and complications driven by uncontrolled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Thus, we evaluated the proteomics, metabolomics and lipidomics plasma profile in a well-characterized cohort of COVID-19 patients ranging from asymptomatic to critical illness. Methods: This multicenter case-control study enrolled 273 adults with SARS-CoV-2 infection, confirmed by Polymerase chain reaction (PCR), who were recruited within the first 21 days of the infection during the first wave (March-May 2020) of COVID-19 pandemic. Participants were categorized into three groups of severity according to the inclusion criteria described in "Diagnosis and Treatment Protocol for COVID-19 Patients" and distributed as mild (n=77), severe (n=134) and critical (n=62). Serum profile of COVID-19 patients was characterized in the acute phase of the infection using a nontargeted multiomics approach. Univariate and multivariate analyses were performed to identify key molecules involved in critical COVID-19 and to evaluate their predictive power as biomarkers of COVID-19 severity. Results: COVID-19 critically ill patients presented a well-differentiated blood pattern for severe disease. The multiomic analysis identified specific alterations in pathways linked to complement and coagulation cascades, platelet activation, cell adhesion, acute inflammation, energy production (Krebs cycle and Warburg effect), amino acid catabolism and lipid transport as hallmarks of critical COVID-19. A new biomarker panel including the combination of selected proteins, metabolites and lipids predicted with high accuracy the most adverse COVID-19 outcomes (AUC: 0.994, 85.9% specificity and 100% sensitivity). Conclusion: The identification of predictive molecules related to critical COVID-19 outcomes provides a valuable tool for the rapid and efficient identification of clinical worsening in the early stage of SARS-CoV-2 infection. The association of a distinctive proteomic, metabolomic and lipidomic fingerprint with COVID-19 severity provides a better understanding of the immunopathogenesis and the host response to SARS-CoV-2 infection which could help in the identification of potential therapeutic targets.
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Introduction: Patients (pts) with primary refractory or relapsed high-grade lymphoma (HGL) including Burkitt lymphoma (BL) and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphoma, DHL) have a dismal prognosis with patients almost never achieving a meaningful remission to second line therapy. No standard second line therapeutic approach exists, particularly for BL. The characteristic hallmark of these diseases is a dysregulated MYC oncogene with both downstream effects on proliferation and a high metabolic fluxes which use tricarboxylic acid (TCA) cycle intermediates as biosynthetic precursors. CPI-613 (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis. In the initial phase I trial (n=26) one patient with multiply refractory BL had a partial remission sustained for over one year and then consolidated by surgical resection. She remains alive 7 years later. As of July 2021, 20 clinical studies for various cancers have been conducted (ongoing/completed) with devimistat with over 700 patients having received study drug. We initiated a phase II trial to further explore efficacy in HGL. Devimistat has FDA orphan status for BL and 4 other cancers. Methods: NCT03793140 is a multicenter study aiming to enroll 17 patients on each of two cohorts, BL and DHL, with a Simon's 2-stage design for each cohort, requiring one response among the first 9 treated patients to expand to 17. Patients must have had at least one prior line of therapy or are refusing standard of care and must be more than 3 months after a prior stem cell transplant. Active central nervous system (CNS) parenchymal disease is excluded, but prior leptomeningeal disease is allowed if the CSF is negative for more than 4 weeks at enrollment and maintenance intrathecal therapy is ongoing. Devimistat is given by central line over 2 hours daily x 5 days for two 14-day cycles and then as maintenance x5 days every 21 days. Pts were evaluable for response if they received at least 4 infusions over 5 days of the first cycle. Results: 9 pts were enrolled in the DHL/THL arm. Mediannumber of prior therapies were 3 (range, 1-6). No responses were seen, with only 1 patient achieving stable disease as best response, resulting in cohort closure. Thus far, 8 BL pts were enrolled. Median number of prior therapies was 3 (range, 2-4). Two patients were inevaluable for response. 1/6 patients had stable disease through cycle 7 and one had a complete response (CR). This CR patient (HIV+) with 4 prior therapies entered the study with only a biopsy proven thigh mass. He was not a transplant candidate for social reasons. He had a near complete metabolic remission after 4 cycles of devimistat and a CR after cycle 7. (Table and Figure) As of July 2021, he is in cycle 11, having had a 4-week treatment delay of cycle 5 due to CoVID 19 infection. ECOG improved from 3 to 0. Adverse events (AE): As of July30, 2021, no patient experienced a serious adverse event related to study drug. Four patients had grade 3 events at least possibly related: 2 neutropenia, 1 thrombocytopenia and 1 elevated bilirubin. 1 patient had a dose reduction for grade 2 alanine aminotransferase increase. Conclusions: Although our results are preliminary, the complete remission in this patient is promising in a disease where no viable treatment options exist in the relapsed, refractory BL. Enrollment to the BL cohort is ongoing. [Formula presented] Disclosures: Nikolaenko: Pfizer: Research Funding;Rafael Pharmaceuticals: Research Funding. Pardee: Celgene/BMS: Consultancy, Speakers Bureau;Amgen: Consultancy, Speakers Bureau;Pharmacyclics: Consultancy, Speakers Bureau;Janssen: Consultancy, Speakers Bureau;AbbVie: Membership on an entity's Board of Directors or advisor committees;CBM Biopharma: Membership on an entity's Board of Directors or advisory committees;Karyopharm: Research Funding;Rafael Pharmaceuticals: Research Funding. Abramson: Genentech: Consultancy;Kymera: Consultancy;Karyopharm: Consultancy;AbbVie: Consultancy;Seagen Inc.: Research Funding;Allogene Therapeutics: Consultancy;Astra-Zeneca: Consultancy;Incyte Corporation: Consultancy;BeiGene: Consultancy;Bluebird Bio: Consultancy;Genmab: Consultancy;EMD Serono: Consultancy;Bristol-Myers Squibb Company: Consultancy, Research Funding;C4 Therapeutics: Consultancy;Morphosys: Consultancy;Kite Pharma: Consultancy;Novartis: Consultancy. Horwitz: Vividion Therapeutics: Consultancy;Shoreline Biosciences, Inc.: Consultancy;Tubulis: Consultancy;Verastem: Research Funding;ONO Pharmaceuticals: Consultancy;Myeloid Therapeutics: Consultancy;SecuraBio: Consultancy, Research Funding;Trillium Therapeutics: Consultancy, Research Funding;Seattle Genetics: Consultancy, Research Funding;Millennium /Takeda: Consultancy, Research Funding;Kura Oncology: Consultancy;Janssen: Consultancy;Kyowa Hakko Kirin: Consultancy, Research Funding;Forty Seven, Inc.: Research Funding;Daiichi Sankyo: Research Funding;C4 Therapeutics: Consultancy;Celgene: Research Funding;Aileron: Research Funding;Affimed: Research Funding;Acrotech Biopharma: Consultancy;ADC Therapeutics: Consultancy, Research Funding. Matasar: GlaxoSmithKline: Honoraria, Research Funding;Teva: Consultancy;Janssen: Honoraria, Research Funding;Bayer: Consultancy, Honoraria, Research Funding;Genentech, Inc.: Consultancy, Honoraria, Research Funding;Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company;F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding;IGM Biosciences: Research Funding;Merck: Consultancy;Juno Therapeutics: Consultancy;TG Therapeutics: Consultancy, Honoraria;Seattle Genetics: Consultancy, Honoraria, Research Funding;Memorial Sloan Kettering Cancer Center: Current Employment;Pharmacyclics: Honoraria, Research Funding;Daiichi Sankyo: Consultancy;ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding;Takeda: Consultancy, Honoraria;Rocket Medical: Consultancy, Research Funding. Noy: Rafael Parhma: Research Funding;Morphosys: Consultancy;Targeted Oncology: Consultancy;Medscape: Consultancy;Pharmacyclics: Consultancy, Research Funding;Janssen: Consultancy, Honoraria;Epizyme: Consultancy. OffLabel Disclosure: CPI-613 (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis
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Background and Aim: The metabolomic profile is a valuable tool in biomedicine. In the framework of the COMETA project, metabolomic analyses are used to identify specific biochemical alterations of the CoViD-19 disease, of its severity and evolution over time. Materials and Methods: Four different groups of subjects are enrolled in the study: 1) CoViD-19 positive patients at different stages of the disease;2) CoViD-19 recovered patients;3) patients with CoViD-19-like symptoms but with negative nasopharyngeal swab;4) control subjects. Metabolomic analyses are conducted on blood plasma samples using proton nuclear magnetic resonance (1H NMR) spectroscopy. The 1H NMR spectra contain information on the number and relative concentration of the most abundant metabolites in each sample (>1 μM) and represent the metabolic fingerprint of each patient. Results: 1H NMR spectra on a first set of approximately 400 plasma samples have been acquired allowing us to measure 25 metabolites among those involved in the main biochemical pathways (glucose metabolism, glycolysis and Krebs cycle, ketone bodies, amino acids) as well as 114 parameters related to plasmatic lipoproteins. Conclusions: Based on previous studies by some of us and considering the high number of patients be enrolled in COMETA, we expect an excellent discrimination and characterization of the pathology in its various clinical manifestations. Long-term effects of the disease will be evaluated via a follow-up at 3-6 months from disease onset.