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Journal of Hazardous Materials Aug 2024Plants are widely existing in the environments and have been considered as potential sentinel species of toxic chemicals' exposure. In this study, the deadly toxic...
Unambiguous identification of γ-aminobutyric acid adducts as novel plant biomarkers and their ultra-sensitive detection by UPLC-MS/MS for retrospective analyses of nitrogen mustards exposure.
Plants are widely existing in the environments and have been considered as potential sentinel species of toxic chemicals' exposure. In this study, the deadly toxic chemicals of three nitrogen mustards (NMs, including NH1, NH2 and NH3) were selected as the investigated targets. First, the reactivities of common endogenous plant components with NMs were examined in vitro. Then, the model plant Nicotiana benthamiana Domin was exposed to NMs. Three γ-aminobutyric acid-nitrogen mustard adducts (GABA-NMs) were identified in the living plant by high resolution mass spectrometry and comparison with the synthesized references. A sensitive detection method with the limits of quantification of 0.0500 ng mL was developed using ultrahigh performance liquid chromatography-triple quadrupole mass spectrometry. The GABA-NMs could be detected after 120 days of the exposure and even in the dead leaves without obvious decrease. Furthermore, 20 different plant species grown in diverse climate zones were exposed to HN1, and the adduct of GABA-HN1 was identified in all the leaves. The results showed the good universality and specificity of GABA-NMs as plant biomarkers for NMs exposure. This work provides a new approach for the pollution investigation of toxic chemicals through analysing biomarkers in plant materials.
Topics: gamma-Aminobutyric Acid; Tandem Mass Spectrometry; Biomarkers; Chromatography, High Pressure Liquid; Plant Leaves; Mechlorethamine; Nicotiana; Plants; Limit of Detection; Liquid Chromatography-Mass Spectrometry
PubMed: 38820753
DOI: 10.1016/j.jhazmat.2024.134620 -
Transplantation and Cellular Therapy Jun 2024
Topics: Humans; Cyclophosphamide; ABO Blood-Group System; Hematopoietic Stem Cell Transplantation; HLA Antigens; Graft Rejection; Male; Female; Middle Aged; Adult; Transplantation, Homologous
PubMed: 38816168
DOI: 10.1016/j.jtct.2024.05.004 -
Frontiers in Immunology 2024To explore the clinical characteristics and treatment outcomes of children with central nervous system (CNS) involvement in eosinophilic granulomatosis with polyangiitis... (Review)
Review
OBJECTIVE
To explore the clinical characteristics and treatment outcomes of children with central nervous system (CNS) involvement in eosinophilic granulomatosis with polyangiitis (EGPA).
METHODS
A child who presented with EGPA complicated by CNS involvement was admitted to our hospital in June 2023. The clinical features were analyzed retrospectively, and relevant literatures were reviewed to provide a comprehensive overview of this condition.
RESULTS
A ten-year-old girl, who had a history of recurrent cough and asthma accompanied by peripheral blood eosinophilia for eight months, was admitted to our hospital. On admission, spotted papules were visible on her hands and feet, bilateral pulmonary rales were audible. The laboratory examination revealed that the proportion of eosinophils (EOS) exceeded 10% of white blood cells, the anti-neutrophil cytoplasmic antibody (MPO-ANCA) was positive, the immunoglobulin G level was 15.80g/L, and the immunoglobulin E level was greater than 2500.00IU/mL. The imaging examination showed multiple patchy and nodular high-density shadows in both lungs as well as sinusitis. Pulmonary function tests indicated moderate ventilation and diffusion dysfunction. Bone marrow cytology demonstrated a significant increase in the proportion of eosinophils. Skin pathology confirmed leukocytoclastic vasculitis. During the hospitalization, the child had a convulsion. The magnetic resonance imaging (MRI) scan of the brain showed multiple abnormal signal shadows in the bilateral cerebral cortex and the electroencephalogram (EEG) showed epileptic waves. Following the administration of methylprednisolone pulse therapy in combination with cyclophosphamide treatment, her cough and asthma resolved, the skin rash disappeared without any further convulsions. We found that only a young EGPA patient with CNS involvement had been previously reported. The previously reported case began with long-term fever, weight loss, and purpuric rash. Both patients responded well to treatment with glucocorticoids and cyclophosphamide, experiencing significant improvement in their clinical symptoms and normalization of their peripheral blood eosinophils.
CONCLUSION
The diagnosis of EGPA in children can be challenging. When a child is affected by EGPA, it is essential to remain vigilant for signs of CNS involvement. The treatment with glucocorticoids and cyclophosphamide is effective in managing EGPA in children.
Topics: Humans; Female; Child; Churg-Strauss Syndrome; Treatment Outcome; Granulomatosis with Polyangiitis; Cyclophosphamide; Antibodies, Antineutrophil Cytoplasmic
PubMed: 38812515
DOI: 10.3389/fimmu.2024.1406424 -
BMJ Open May 2024People with mustard gas lung disease experience cough, sputum, breathlessness and exercise limitation. We hypothesised that pulmonary rehabilitation (PR) would be... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
People with mustard gas lung disease experience cough, sputum, breathlessness and exercise limitation. We hypothesised that pulmonary rehabilitation (PR) would be beneficial in this condition.
DESIGN
An assessor-blind, two-armed, parallel-design randomised controlled clinical trial.
SETTING
Secondary care clinics in Iran.
PARTICIPANTS
60 men with breathlessness due to respiratory disease caused by documented mustard gas exposure, mean (SD) age 52.7 (4.36) years, MRC dyspnoea score 3.5 (0.7), St. George's Respiratory Questionnaire (SGRQ) 72.3 (15.2).
INTERVENTIONS
Participants were allocated either to a 6-week course of thrice-weekly PR (n=31) or to usual care (n=29), with 6-week data for 28 and 26, respectively.
OUTCOME MEASURES
Primary endpoint was change in cycle endurance time at 70% baseline exercise capacity at 6 weeks. Secondary endpoints included 6 min walk distance, quadriceps strength and bulk, body composition and health status. For logistical reasons, blood tests that had been originally planned were not performed and 12-month follow-up was available for only a small proportion.
RESULTS
At 6 weeks, cycle endurance time increased from 377 (140) s to 787 (343) s with PR vs 495 (171) s to 479 (159) s for usual care, effect size +383 (231) s (p<0.001). PR also improved 6 min walk distance+103.2 m (63.6-142.9) (p<0.001), MRC dyspnoea score -0.36 (-0.65 to -0.07) (p=0.016) and quality of life; SGRQ -8.43 (-13.38 to -3.48) p<0.001, as well as quadriceps strength+9.28 Nm (1.89 to 16.66) p=0.015.
CONCLUSION
These data suggest that PR can improve exercise capacity and quality of life in people with breathlessness due to mustard gas lung disease and support the wider provision of this form of care.
TRIAL REGISTRATION NUMBER
IRCT2016051127848N1.
Topics: Humans; Male; Iran; Mustard Gas; Middle Aged; Exercise Tolerance; Quality of Life; Dyspnea; Lung Diseases; Adult; Outpatients; Treatment Outcome; Chemical Warfare Agents
PubMed: 38806414
DOI: 10.1136/bmjopen-2023-083085 -
Molecular Immunology Jul 2024This study determines the role and mechanism of APS in cyclophosphamide-induced myelosuppression in mice and bone mesenchymal stem cells (BMSCs) cell model.
BACKGROUND
This study determines the role and mechanism of APS in cyclophosphamide-induced myelosuppression in mice and bone mesenchymal stem cells (BMSCs) cell model.
METHODS
Cy-induced myelosuppression mice and BMSCs cell model were established. Fifty C57BL/6 mice (weighing 20 ± 2 g) were randomly divided into five groups. Femur and tibia samples, bone marrow samples, and blood samples were collected 3 days after the last injection of Cy. Histopathology changes and cell apoptosis were detected. Cell viability, apoptosis, cycle distribution, reactive oxygen species activity, osteogenesis ability, and protein levels were detected. γ-H2AX and senescence-associated β-galactosidase activity expression was detected by immunofluorescence. Cy-induced senescence and Wnt/β-catenin related protein levels were detected using western blotting.
RESULTS
The results showed that APS effectively induced Cy-induced histological injury and cell apoptosis rate. After treated with APS, ROS and ALP levels were significantly increased. In BMSCs, cell viability, apoptosis, and cell cycle distribution were also influenced by APS treatment. Compared with the control group, cell viability was significantly increased, the cell apoptosis rate was decreased while the number of cells remained in the G0-G1 phase was increased. Meanwhile, ROS levels were significantly increased in APS group. Cell senescence and Wnt/β-catenin related protein (γ-H2AX, SA-β-gal, p21, p16, p-β-catenin/ β-catenin, c-Myc, and AXIN2) levels were also altered both in vivo and in vitro. Interestingly, the effects of APS were reversed by BML-284.
CONCLUSION
Our results indicate that APS protected Cy-induced myelosuppression through the Wnt/β-catenin pathway and APS is a potential therapeutic drug for Cy-induced myelosuppression.
Topics: Animals; Cyclophosphamide; Mesenchymal Stem Cells; Mice, Inbred C57BL; Apoptosis; Mice; Polysaccharides; Astragalus Plant; Reactive Oxygen Species; Cell Survival; Bone Marrow Cells; Wnt Signaling Pathway; Male; beta Catenin; Cellular Senescence; Bone Marrow; Osteogenesis; Cell Cycle
PubMed: 38805892
DOI: 10.1016/j.molimm.2024.05.008 -
Journal of Toxicology and Environmental... Aug 2024The present study aimed to determine the genoprotective activity and safety of leave and stem extracts against cyclophosphamide (CP)-induced genotoxicity utilizing...
The present study aimed to determine the genoprotective activity and safety of leave and stem extracts against cyclophosphamide (CP)-induced genotoxicity utilizing Swiss albino mice. Animals were divided into 14 groups for subacute treatment with either or extracts daily for 28 days. The extract doses selected were 100, 200 or 400 mg/kg b.w administered orally alone or combined with CP (50 mg/kg b.w. intraperitoneally daily for 5 days). Analyses performed included the comet assay, micronucleus test (MN) in bone marrow cells and sperm head abnormality assay (SHA). and extracts induced no significant genotoxic effects on somatic and germ cells. In contrast, for all cells examined and extracts inhibited DNA damage initiated by CP. Taken together data demonstrated that both plant extracts did not exhibit marked genotoxic effects but displayed potential chemoprotective properties against CP-induced genotoxicity in Swiss mice.
Topics: Animals; Tinospora; Mice; Cyclophosphamide; Moringa oleifera; Plant Extracts; Male; Plant Leaves; Micronucleus Tests; DNA Damage; Comet Assay; Plant Stems; Bone Marrow; Bone Marrow Cells; Mutagens; Antimutagenic Agents
PubMed: 38804873
DOI: 10.1080/15287394.2024.2356861 -
International Immunopharmacology Jun 2024IIrbesartan (IRB), an angiotensin II type 1 receptor (AT1R) antagonist, has been widely employed in the medical field for its effectiveness in managing hypertension....
IIrbesartan (IRB), an angiotensin II type 1 receptor (AT1R) antagonist, has been widely employed in the medical field for its effectiveness in managing hypertension. However, there have been no documented investigations regarding the immunostimulatory properties of IRB. To address this gap, this study has been performed to assess the neuroprotective impact of IRB as an immunostimulatory agent in mitigating acute neurotoxicity induced by cyclophosphamide (CYP) in rats. mRNA levels of nuclear factor erythroid 2 (Nrf-2), interleukin (IL)-18, IL-1β, and MMP-1 have been assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, the levels of malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) has been evaluated to assess the oxidative stress. Additionally, macrophage inflammatory protein 2 (MIP2) has been evaluated using enzyme-linked immunosorbent assay (ELISA). Western blotting has been used to investigate the protein expression of nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) and caspase-1 (CASP-1), along with an assessment of histopathological changes. Administration of IRB protected against oxidative stress by augmenting the levels of GSH and SOD as well as reducing MDA level. Also, administration of IRB led to a diminishment in the brain levels of MIP2 and MMP1. Furthermore, it led to a suppression of IL-1β and IL-18 levels, which are correlated with a reduction in the abundance of NLRP3 and subsequently CASP-1. This study provides new insights into the immunomodulatory effects of IRB in the context of CYP-induced acute neurotoxicity. Specifically, IRB exerts its effects by reducing oxidative stress, neuroinflammation, inhibiting chemokine recruitment, and mitigating neuronal degeneration through the modulation of immune markers. Therefore, it can be inferred that the use of IRB as an immunomodulator has the potential to effectively mitigate immune disorders associated with inflammation.
Topics: Animals; Cyclophosphamide; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Irbesartan; Male; Rats; Oxidative Stress; Neurotoxicity Syndromes; Neuroprotective Agents; Signal Transduction; Immunomodulation; Rats, Wistar
PubMed: 38801809
DOI: 10.1016/j.intimp.2024.112336 -
Zhonghua Fu Chan Ke Za Zhi May 2024To investigate the effect of rare ginsenosides (RGS) on reproductive injury induced by cyclophosphamide (CP) in female rats. Twenty-four female rats were divided into...
To investigate the effect of rare ginsenosides (RGS) on reproductive injury induced by cyclophosphamide (CP) in female rats. Twenty-four female rats were divided into four groups [normal control (NC), RGS, CP, and CP+RGS group] with 6 rats in each group. CP group (the model group) and CP+RGS group (the treatment group) were intraperitoneally injected with CP 30 mg/kg for 5 days for modeling, and CP+RGS group was given RGS intragastric intervention. General growth status of rats in each group was observed, the organ index was calculated, and the pathological changes of ovary, uterus, liver and kidney were observed by hematoxylin-eosin staining. Serum levels of estradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH), pro-inflammatory factors interleukin (IL) 6, IL-1β, tumor necrosis factor-α were detected. The urine samples were collected after RGS treatment for metabonomics analysis. Metabolomic profiling based on ultra performance liquid chromatography (UPLC) coupled with mass spectrometry (MS) was used to analyze and determine the urine metabolites of rats in each group. Compared with NC group, the ovary index of CP group [(0.054±0.015) %] was significantly decreased (<0.05), the uterus index [(0.293±0.036) %] and estradiol level [(62.9±6.4) pmol/L] were significantly decreased (all <0.01), serum levels of FSH, LH, IL-6 and IL-1β [(20.4±1.0) U/L, (29.0±3.0) U/L, (185.4±28.6) ng/L, (72.9±2.0) ng/L, respectively] were significantly increased (all <0.01). Compared with CP group, the ovary index in CP+RGS group [(0.075±0.010) %] was significantly increased (<0.05), serum estradiol level [(122.1±16.2) pmol/L] was significantly increased (<0.01), serum FSH, IL-1β and IL-6 levels [(16.7±1.0) U/L, (111.8±17.4) ng/L, (60.1±2.2) ng/L, respectively] were significantly decreased (all <0.01). Metabonomics analysis results showed that, a total of 352 metabolites were detected in urine, of which 12 were found to be potential markers associated with reproductive injury according to the screening standard. After treatment with RGS, differential metabolites were improved in the direction of NC group. Pathway enrichment suggests that the therapeutic effect of RGS was related to multiple metabolic pathways, including purine metabolism and taurine and hypotaurine metabolism. RGS might reduce inflammation and thus ameliorate the damage caused by CP to the reproductive system of female rats by affecting purine metabolism and other pathways.
Topics: Animals; Female; Rats; Cyclophosphamide; Metabolomics; Ginsenosides; Follicle Stimulating Hormone; Estradiol; Ovary; Uterus; Rats, Sprague-Dawley; Luteinizing Hormone; Chromatography, High Pressure Liquid; Interleukin-6; Disease Models, Animal; Interleukin-1beta; Tumor Necrosis Factor-alpha; Liver; Mass Spectrometry; Kidney
PubMed: 38797569
DOI: 10.3760/cma.j.cn112141-20240116-00038 -
European Journal of Radiology Jul 2024To investigate the value of quantitative contrast-enhanced ultrasonography (CEUS) in assessing and predicting early therapy response of non-Hodgkin's lymphoma (NHL).
OBJECTIVE
To investigate the value of quantitative contrast-enhanced ultrasonography (CEUS) in assessing and predicting early therapy response of non-Hodgkin's lymphoma (NHL).
METHODS
Fifty-six cases of NHL were studied using CEUS before and after three cycles of R-CHOP / CHOP. Quantitative parameters such as arrival time (ATM), time to peak (TTP), △T = TTP-ATM, area under the gamma curve (Area), curve gradient (Grad), wash-out time (WT), base intensity (BI), peak intensity (PI) and ΔI = PI-BI were compared between the lymphoma and normal lymph nodes before and at mid-treatment, respectively. Changes in quantitative CEUS parameters were also compared between complete response (CR) and incomplete response(non-CR) groups. Besides, the correlation analysis was performed between pretreatment PI and changes in quantitative parameters.
RESULTS
After three cycles of R-CHOP/CHOP, S/L (P < 0.001), PI (P = 0.002), ΔI (P < 0.001), Grad (P < 0.001), and Area (P < 0.001) of NHL were significantly decreased. The CR group and non-CR group only differed in ATM before treatment. In contrast, there was no statistical difference in any of the parameters between the two groups at mid-treatment. Finally, a significant correlation was observed between pre-treatment PI and PI% (r = 0.736, P < 0.001).
CONCLUSIONS
CEUS is promising for the assessment of response of NHL to R-CHOP/CHOP. Intra-lesion perfusion changes take precedence over morphological changes suggesting treatment efficacy. Pre-treatment ATM values may help to suggest efficacy outcomes and pre-treatment PI values may be a valid predictor of lymphoma perfusion response.
Topics: Humans; Male; Female; Lymphoma, Non-Hodgkin; Middle Aged; Contrast Media; Prospective Studies; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Ultrasonography; Case-Control Studies; Adult; Cyclophosphamide; Aged; Vincristine; Doxorubicin; Prednisone; Rituximab; Image Enhancement; Sulfur Hexafluoride; Reproducibility of Results; Phospholipids; Sensitivity and Specificity; Young Adult
PubMed: 38796885
DOI: 10.1016/j.ejrad.2024.111525 -
The Lancet. Haematology Jun 2024Follicular helper T-cell lymphomas (TFHL) harbour frequent alterations in genes that regulate DNA methylation. Preliminary reports suggest that treatment with... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Oral azacitidine compared with standard therapy in patients with relapsed or refractory follicular helper T-cell lymphoma (ORACLE): an open-label randomised, phase 3 study.
BACKGROUND
Follicular helper T-cell lymphomas (TFHL) harbour frequent alterations in genes that regulate DNA methylation. Preliminary reports suggest that treatment with 5-azacitidine has clinical activity in patients with relapsed or refractory TFHL. We aimed to compare the oral form of azacitidine with investigator's choice standard therapy (ICT; ie, gemcitabine, bendamustine, or romidepsin) in patients with relapsed or refractory TFHL.
METHODS
Patients older than 18 years with relapsed or refractory TFHL (angioimmunoblastic T-cell lymphoma, follicular lymphoma, or nodal T-cell lymphoma with phenotype, ie, positive with two or more markers among CD10, BCL6, CXCL13, PD1, or ICOS) based on the 2017 WHO classification of haematological neoplasms, with an Eastern Cooperative Oncology Group performance status score of 0-3, were recruited in university hospitals from five European countries and from Japan. Patients were randomly assigned 1:1 to treatment with either azacitidine given at a dose of 300 mg once a day (200 mg in Japanese patients) for 14 days in a 28-day cycle or gemcitabine, bendamustine, or romidepsin according to the investigator's choice. Random assignment was stratified by the number of previous lines of therapy and by the presence of previous or concomitant myeloid malignancy. The primary endpoint was investigator-assessed progression-free survival, presented in the intention-to-treat population. This Article is the final analysis of this trial, registered at ClinicalTrials.gov (Europe NCT03593018 and Japan NCT03703375).
FINDINGS
86 patients (median age 69 years [IQR 62-76], 50 patients were male, 36 were female) were enrolled between Nov 9, 2018, to Feb 22, 2021; 42 in the azacitidine group and 44 in the ICT group. With a median follow-up of 27·4 months (IQR 20·2-32·9), the median progression-free survival was 5·6 months (95% CI 2·7 -8·1) in the azacitidine group versus 2·8 months (1·9-4·8) in the ICT group (hazard ratio of 0·63 (95% CI 0·38-1·07); 1-sided p=0·042). Grade 3-4 adverse events were reported in 32 (76%) of 42 patients in the azacitidine group versus 42 (98%) of 43 patients in the ICT group. The most adverse grade 3 or worse adverse events were haematological (28 [67%] of 42 patients vs 40 [93%] of 43 patients), infection (8 [19%] and 14 [33%]), and gastrointestinal (5 [12%] vs 1 [2%] for azacitidine and ICT, respectively). There were two treatment-related deaths in the azacitidine group (one endocarditis and one candidiasis) and three in the ICT group (one heart failure, one COVID-19, and one cause unknown).
INTERPRETATION
Although the pre-specified primary outcome of the trial was not met, the favourable safety profile suggests that azacitidine could add to the treatment options in these difficult to treat diseases especially in combination with other drugs. Trials with combination are in preparation in a platform trial.
FUNDING
Bristol-Myers Squibb.
TRANSLATION
For the French translation of the abstract see Supplementary Materials section.
Topics: Humans; Male; Female; Aged; Middle Aged; Azacitidine; Administration, Oral; Bendamustine Hydrochloride; Gemcitabine; Lymphoma, Follicular; Deoxycytidine; Depsipeptides; Antineoplastic Combined Chemotherapy Protocols; Antimetabolites, Antineoplastic; Aged, 80 and over
PubMed: 38796193
DOI: 10.1016/S2352-3026(24)00102-9