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Project description:Total RNA-seq in patients with hematological malignancy
| PRJNA486089 | ENA
Project description:The objective of this study was to explore the following aspects of teicoplanin use in patients with hematological malignancy: early attainment of target trough concentrations with current high-dose teicoplanin regimens, variability in unbound teicoplanin fractions, factors associated with observed total and unbound trough concentrations, efficacy and toxicity, and renal function estimation. This was a single-center, prospective study. Samples for determination of trough concentrations were taken on days 3, 4, 7, and 10. Total and unbound teicoplanin concentrations were determined using validated high-performance liquid chromatography methods. Regression analyses were used to identify the factors associated with the trough concentration. Thirty teicoplanin-treated adults with hematological malignancy were recruited. Despite the use of dosages higher than the conventional dosages, the proportions of patients with a trough concentration of ≥20 mg/liter at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations at 48 h and 72 h (P < 0.05). For an average hematological malignancy patient (creatinine clearance = 70 ml/min), sequential loading doses of at least 12 mg/kg of body weight may be needed to achieve early adequate exposure. In the absence of measured creatinine clearance, estimates obtained using the Cockcroft-Gault (total body weight) equation could prove to be an acceptable surrogate. The unbound fractions of teicoplanin were highly variable (3.4 to 18.8%). Higher unbound fractions were observed in patients with low serum albumin concentrations. Teicoplanin was well tolerated. Teicoplanin loading doses higher than those in current use appear to be necessary. Increased dosing is needed in patients with increased renal function. The high variability in protein binding supports the contention for therapeutic drug monitoring of unbound teicoplanin concentrations. (This study has been registered with EudraCT under registration no. 2013-004535-72.).
| S-EPMC5444128 | biostudies-literature
Project description:Severe coronavirus disease 2019 (COVID-19) infection may lead to lung injury, multi-organ failure, and eventually death. Cytokine storm due to excess cytokine production has been associated with fatality in severe infections. However, the specific molecular signatures associated with the elevated immune response are yet to be elucidated. We performed a mass-spectrometry-based proteomic and metabolomic analysis of COVID-19 plasma samples collected at two time points. Using Orbitrap Fusion LC-MS/MS-based label-free proteomic analysis, we identified around 10 significant proteins, 32 significant peptides, and 5 metabolites that were dysregulated at the severe time points. Few of these proteins identified by quantitative proteomics were validated using the multiple reaction monitoring (MRM) assay. Integrated pathway analysis using distinct proteomic and metabolomic signatures revealed alterations in complement and coagulation cascade, platelet aggregation, myeloid leukocyte activation pathway, and arginine metabolism. Further, we highlight the role of leukocyte activation and arginine metabolism in COVID-19 pathogenesis and targeting these pathways for COVID-19 therapeutics.
2022-01-18 | MTBLS2469 | MetaboLights
Project description:We report the differential expression of miRNA in serum exosome of heat strok patints. Compared with those from healthy volunteers, exosomes from patients with HS showed substantial changes in the expression of 202 exosomal miRNAs (154 upregulated and 48 downregulated miRNAs). The most upregulated miRNAs included miR-511-3p, miR-122-5p, miR-155-3p, miR-1290, and let7-5p, whereas the most downregulated ones included miR-150-3p, 146a-5p, and 151a-3p. Gene ontology enrichment of the miRNAs of patients with HS compared with control subjects were associated mostly with inflammatory response, including T cell activation, B cell receptor signaling, dendritic cell chemotaxis and leukocyte migration, and platelet activation and blood coagulation. The identified miRNAs were primarily enriched to the signal transduction pathways namely, T cell receptor signaling, Ras signaling, chemokine signaling, platelet activation, and leukocyte transendothelial migration, all of which are associated with inflammation and hemostasis. Multiple targeted mRNAs associated with the inflammatory response, blood coagulation, and platelet activation were further verified in serum exosomes. Exosomes from patients with HS convey miRNAs and mRNAs associated with pathogenic pathways, including inflammatory response and coagulation cascade. Exosomes may represent a novel mechanism for intercellular communication during HS.
2021-06-14 | GSE174224 | GEO
Project description:BackgroundNeutrophil gelatinase-associated lipocalin (NGAL) is a urine biomarker related to acute renal injury. Whereas several studies have evaluated NGAL levels in hematological malignancy, using peripheral blood (PB). Recently, bone marrow (BM) NGAL level was reported to be higher than PB NGAL level in individuals with hematological malignancy, suggesting that BM NGAL would reflect BM microenvironment better than PB NGAL. We measured BM NGAL levels in patients with hematological malignancy, comparing those with NGAL levels in normal BM. We evaluated the association of BM NGAL with hematological parameters including neutrophil counts.MethodsBM samples were collected from 107 patients who underwent BM examination. Immunoassays were used to assess NGAL levels. Data on hematological parameters were collected from medical records. Intergroup comparisons were performed using the Kruskal-Wallis H test and Pearson chi-square test. Single and multiple regression analyses were performed to analyze the relationships.ResultsThe independent factors that affected the BM NGAL level were neutrophil counts and BM band neutrophil%, while neutrophil count was the main influencing factor. The acute myeloid leukemia (n = 18) and myelodysplastic syndrome (n = 25) groups showed statistically lower BM NGAL levels than patients with normal BM. The myeloproliferative neoplasm group (n = 34) showed higher BM NGAL levels than patients with normal BM, but this difference was not statistically significant. Neutrophil counts and BM band neutrophil% showed intergroup patterns similar to those of BM NGAL levels.ConclusionBM NGAL was related to neutrophil count and BM band neutrophil%, showing different levels according to hematological malignant disease entities.
| S-EPMC7307352 | biostudies-literature
Project description:We conducted population pharmacokinetic (PPK) analysis and Monte Carlo simulations to determine the appropriate prophylactic dose of fluconazole to prevent invasive candidiasis in patients with hematological malignancies. Patients receiving chemotherapy or hematopoietic stem cell transplantation at Yokohama City University Hospital between November 2018 and March 2020 were included. Additionally, patients receiving oral fluconazole for prophylaxis were recruited. We set the free area under the curve/minimum inhibitory concentration (MIC) = 50 as the target and determined the largest MIC (breakpoint MIC) that could achieve more than 90% probability of target attainment. The blood fluconazole concentration of 54 patients (119 points) was used for PPK analysis. The optimal model was the one-compartment model with first-order administration and first-order elimination incorporating creatinine clearance (CLcr) as a covariate of clearance and body weight as a covariate of distribution volume. We conducted Monte Carlo simulation with fluconazole at 200 mg/day or 400 mg/day dosing schedules and patient body weight and CLcr ranging from 40 to 70 kg and 40-140 mL/min, respectively. The breakpoint MICs on the first dosing day and at steady state were 0.5-1.0 μg/mL and 1.0-2.0 μg/mL for 200 mg/day and 1.0-2.0 μg/mL and 2.0-4.0 μg/mL for 400 mg/day, respectively. The recommended dose was 400-700 mg/day for the loading dose and 200-400 mg/day for the maintenance dose. Our findings suggest that the optimal prophylactic dose of fluconazole in hematological malignancy patients depends on CLcr and body weight, and a sufficient loading and maintenance dose may be needed to completely prevent invasive candidiasis.
| S-EPMC8618010 | biostudies-literature
Project description:BackgroundInvasive fungal disease (IFD) causes morbidity and mortality in patients with hematological malignancy. Recurrence of IFD after chemotherapy or hematopoietic stem cell transplantation (HSCT) is associated with poor prognosis. The present study aimed to investigate the efficacy of different strategies of secondary antifungal prophylaxis (SAP) for IFD and choose an appropriate SAP regimen.MethodsClinical data of patients with previous IFD who underwent chemotherapy or HSCT between Jan 2008 and Jun 2013 were retrospectively reviewed and followed up to 180 days post-chemotherapy or HSCT. The clinical characteristics and diagnosis were analyzed according to the diagnostic criteria for IFD. The efficacy of different strategies for SAP and risk factors influencing the failure of SAP were evaluated.ResultsOf the 164 patients enrolled, 121 patients received SAP regimen (73.78%), and IFD recurred in 40 patients: 16.5% (20/121) in SAP group and 46.5% (20/43) in non-SAP group. In SAP group, 58 received SAP agents which were proven effective for their previous IFD, while other 63 patients received other broad-spectrum antifungal agents. There was no significant difference in the recurrence rates between these two subgroups (13.8% (8/58) vs 19.0% (12/63), P = 0.437). The IFD recurrence rates were statistically significant between patients with allogeneic HSCT and chemotherapy or autologous HSCT (25% vs 8.2%, P = 0.013). Multivariate analysis indicated that allogeneic HSCT was the independent risk factor of IFD recurrence after SAP.ConclusionsSecondary antifungal prophylaxis is necessary to prevent IFD recurrence in patients with hematological malignancy, especially for patients in the setting of allogeneic HSCT.
| S-EPMC4274009 | biostudies-literature
Project description:Oral colonization and infection by Candida species are common in cancer patients receiving chemoradiotherapy, which has significantly increased in recent years. This study aimed to evaluate the frequency, distribution, and antifungal susceptibility profiles of Candida species isolates in patients with hematological malignancy and solid tumors. This study was conducted on a total of 45 cancer patients undergoing treatment with concurrent chemoradiotherapy within 2019-2020. The identification of Candida species was accomplished based on conventional examination and molecular assays. The minimum inhibitory concentrations were determined based on the guidelines of Clinical and Laboratory Standards Institute. The highest prevalence rates of oral candidiasis were observed in patients with chronic lymphoid leukemia (24.4%) and lymphoma (20%). The majority of the patients had oral candidiasis caused by non-albicans Candida species (64.4%). The results of the multiplex PCR for the identification of Candida glabrata, Candida nivariensis, Candida bracarensis, and species-specific Candida parapsilosis complex showed that all isolate amplification products at 397 bp and 171 bp were related to C. glabrata and C. parapsilosis, respectively. There was a significant difference in the Candida species distribution between the hematological malignancies and solid tumors patients. The results of MIC showed that clotrimazole, voriconazole, and caspofungin were the most effective antifungal drugs against oral non-Candida albicans isolates. An understanding of the epidemiology of oral candidiasis among hematological malignancies and solid tumors patients is currently imperative to guide optimal empirical treatment strategies for affected patients.
| S-EPMC9943986 | biostudies-literature
Project description:Transcriptomic profiling was performed on six cell lines derived from infants with KMT2A-rearranged ALL following treatment with two hypomethylating drugs (azacitidine and decitabine) administered at low doses for 72 hours in vitro. We identified changes in gene expression following treatment with hypomethylating agents, with decitabine exerting a greater effect than azacitidine.
2022-12-31 | GSE212591 | GEO
Project description:BACKGROUND:Mucormycosis is an invasive fungal infection, with an increasing incidence especially in patients with hematological malignancies. Its prognosis is poor because of its high invasive power and its intrinsic low susceptibility to antifungal agents. We aimed to describe the epidemiology of mucormycosis in intensive care units (ICU) and evaluate the outcomes. We performed a retrospective multi-center study in 16 French ICUs between 2008 and 2017. We compared the patients who survived in ICU and the patients who did not to identify factors associated with ICU survival. Then, we focused on the subgroup of patients with hematological malignancies. RESULTS:Mucormycosis was diagnosed in 74 patients during the study period. Among them, 60 patients (81%) were immunocompromised: 41 had hematological malignancies, 9 were solid organ transplant recipients, 31 received long-term steroids, 11 had diabetes, 24 had malnutrition. Only 21 patients survived to ICU stay (28.4%) with a median survival of 22 days (Q1-Q3?=?9-106) and a survival rate at day 28 and day 90, respectively, of 35.1% and 26.4%. Survivors were significantly younger (p?=?0.001), with less frequently hematological malignancies (p?=?0.02), and less malnutrition (p?=?0.05). Median survival in patients with hematological malignancies (n?=?41) was 15 days (Q1-Q3?=?5-23.5 days). In this subgroup, curative surgery was a major factor associated with survival in multivariate analysis (odds ratio?=?0.71, [0.45-0.97], p?<?0.001). CONCLUSION:Overall prognosis of mucormycosis in ICU remains poor, especially in patients with hematological malignancies. In this subgroup of patients, a therapeutic strategy including curative surgery was the main factor associated with survival.
| S-EPMC7280386 | biostudies-literature