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Drug Design, Development and Therapy 2024This study probed the mechanism of action of Xinfeng Capsule (XFC) in myocardial injury in rats with adjuvant arthritis (AA) via the growth arrest-specific transcript 5...
PURPOSE
This study probed the mechanism of action of Xinfeng Capsule (XFC) in myocardial injury in rats with adjuvant arthritis (AA) via the growth arrest-specific transcript 5 (GAS5)/microRNA-21 (miR-21)/Toll-like receptor 4 (TLR4) axis.
METHODS
Rats were injected with Freund's complete adjuvant to establish a rat model of AA. Then, some modeled rats were given normal saline or drugs only, and some modeled rats were injected with adeno-associated viruses or necrosulfonamide (NSA; a pyroptosis inhibitor) before drug administration. Toe swelling and arthritis index (AI) were calculated. Pathological and morphological changes in synovial and myocardial tissues were analyzed with hematoxylin-eosin staining, and pyroptotic vesicles and the ultrastructural changes of myocardial tissues were observed with transmission electron microscopy. The serum levels of interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor (TNF)-α were detected, and lactate dehydrogenase (LDH) release was measured in myocardial tissues, accompanied by the examination of GAS5, miR-21, TLR4, nuclear factor-kB (NF-κB) p65, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Caspase-1, and Gasdermin D (GSDMD) expression in myocardial tissues.
RESULTS
After AA modeling, rats presented with significantly increased toe swelling and AI scores, synovial and myocardial tissue damage, elevated pyroptotic vesicles, and markedly enhanced serum levels of IL-1β, IL-18, IL-6, and TNF-α, accompanied by significantly diminished GAS5 expression, substantially augmented miR-21, TLR4, NF-κB p65, NLRP3, Caspase-1, and GSDMD expression, greatly increased LDH release in myocardial tissues. XFC treatment significantly declined toe swelling, AI scores, synovial and myocardial tissue damage, and the serum levels of IL-1β, IL-18, IL-6, and TNF-α in AA rats. Additionally, XFC treatment markedly elevated GAS5 expression and substantially lowered LDH release and miR-21, TLR4, NF-κB p65, NLRP3, Caspase-1, and GSDMD expression in myocardial tissues of AA rats. Moreover, the above effects of XFC in AA rats were further promoted by GAS5 overexpression or NSA treatment.
CONCLUSION
XFC alleviated myocardial injury in AA rats by regulating the GAS5/miR-21/TLR4 axis and inhibiting pyroptosis and pro-inflammatory cytokine secretion.
Topics: Animals; Toll-Like Receptor 4; Pyroptosis; Rats; Arthritis, Experimental; MicroRNAs; Drugs, Chinese Herbal; Rats, Sprague-Dawley; Male; Phosphate-Binding Proteins; Freund's Adjuvant; Gasdermins
PubMed: 38915862
DOI: 10.2147/DDDT.S456783 -
Acute kidney injury after CAR-T cell therapy: exploring clinical patterns, management, and outcomes.Clinical Kidney Journal Jun 2024Acute kidney injury (AKI) has been reported after CAR-T cells, but available data are limited. We sought to describe the incidence of AKI in a cohort of patients...
BACKGROUND
Acute kidney injury (AKI) has been reported after CAR-T cells, but available data are limited. We sought to describe the incidence of AKI in a cohort of patients hospitalized in the intensive care unit (ICU) following CAR-T cell reinjection, identify the primary factors linked to the onset of AKI, and ascertain the key determinants associated with kidney outcomes and mortality.
METHODS
We retrospectively analyzed 119 patients hospitalized in ICU after CAR-T cell therapy between 2017 and 2023. Factors associated with AKI, mortality, and kidney sequelae were identified using multivariate analyses.
RESULTS
Of the 119 patients, 41 patients fulfilled diagnostic criteria of AKI (34%). By multivariate analysis, grade ≥3 cytokine release syndrome (CRS) [OR = 1.20 CI95% (1.01-1.43)] and elevated lactate dehydrogenase (LDH) levels at admission [OR = 1.44 CI95% (1.04-1.99)] were significantly associated with the occurrence of AKI during ICU stay. AKI KDIGO ≥2 was an independent risk factor for hospital mortality [OR = 1.50 (1.22-1.85), < 0.001]. Nine out of 12 (75%) and 6/9 (67%) patients who had experienced AKI and survived had chronic kidney disease (CKD) at 6 months and 1 year, respectively. We did not identify any specific factor associated with kidney recovery.
CONCLUSION
AKI may occur in ICU patients receiving CAR-T cell therapy, especially those who experience CRS and exhibit elevated LDH levels. Early recognition of AKI is of utmost importance as it substantially compromises survival in these patients. Future studies should aim to elucidate the underlying pathophysiological mechanisms of AKI in this context and pinpoint predictive factors for long-term risks of CKD.
PubMed: 38915438
DOI: 10.1093/ckj/sfae123 -
Heliyon Jun 2024To explore the relationship and difference between ventricular and lumbar cerebrospinal fluid(CSF), this study presents equations transforming their measures. By...
Exploring the correlation and difference between cerebrospinal fluid in the lateral ventricle and lumbar subarachnoid based on infants with intraventricular hemorrhage treated by the ommaya reservoir.
OBJECTIVE
To explore the relationship and difference between ventricular and lumbar cerebrospinal fluid(CSF), this study presents equations transforming their measures. By assessing the viability of substituting lumbar puncture, we aim to minimize the associated medical risks and trauma faced by infants with intraventricular hemorrhage(IVH) from anesthesia and lumbar puncture.
METHODS
We retrospectively analyzed CSF data from 27 infants diagnosed with IVH treated by Ommaya reservoir and lumbar puncture at our center, comprising 35 paired samples. Paired-sample and regression analyses were employed to determine test correlations, differences, and to derive transformation equations for the measurements.
RESULTS
Comparative analyses between the CSF from the lateral ventricle and the lumbar vertebrae revealed significant differences in the levels of chloride, glucose, protein, erythrocytes, total cells, and Pandy's test. Specifically:1. Levels of chloride, glucose, protein, and Pandy's test were higher in the lumbar vertebrae.2. Conversely, erythrocyte and total cell counts were higher in the lateral ventricle.There were no significant differences observed for lumbar lactate dehydrogenase(LDH), leukocytes, occult blood, clot, clarity, and color. Nevertheless, significant correlations were identified between various measures, including LDH, glucose, chloride, protein, erythrocyte, leukocyte, total cell count, Pandy's test, occult blood, clot, transparency, and color. Interestingly, the correlation strength and equation fit for each component are inversely proportional to its molecular weight.Notably, well-fitting regression equations were found for LDH, glucose, chloride, protein, leukocytes, erythrocytes, and total cells.
CONCLUSION
In infants with IVH and unobstructed CSF channels, a robust correlation was noted between ventricular CSF sourced via the Ommaya reservoir and lumbar CSF. This correlation tended to be inversely related to molecular weight, with smaller molecular weights showing lesser disparities. Ventricular CSF data could anticipate lumbar CSF trends, and using regression equations with Ommaya-obtained CSF, one can derive approximate values for lumbar CSF.
PubMed: 38912498
DOI: 10.1016/j.heliyon.2024.e32252 -
Clinical Medicine Insights. Oncology 2024There have been no reports about the application of random survival forest (RSF) model to predict disease progression of HIV-associated B-cell lymphoma.
BACKGROUND
There have been no reports about the application of random survival forest (RSF) model to predict disease progression of HIV-associated B-cell lymphoma.
METHODS
A total of 44 patients with HIV-associated B-cell lymphoma who were referred to Nanjing Second Hospital from 2012 to 2019 were included. The RSF model was used to find predictors of survival, and the results of the RSF model were compared with those of the Cox model. The data were analyzed using R software (version 4.1.1).
RESULTS
One-, 2-, and 3-year survival rates were 74.5%, 57.7%, and 48.6%, respectively, and the median survival was 59.0 months. The first 3 most important predictors of survival included lactate dehydrogenase (LDH), absolute monocyte count (AMC), and white blood cells (WBCs) count. The median survival of high-risk patients was only 4.0 months. Areas under the curve (AUCs) of the RSF model remained at more than 0.90 at 1, 2, and 3 years. The RSF model displayed a lower prediction error rate (21.9%) than the Cox model (25.4%).
CONCLUSIONS
Lactate dehydrogenase, AMC, and WBCs count are the most important prognostic predictors for patients with HIV-associated B-cell lymphoma. Much larger prospective and/or multicentre studies are required to validtae this RSF model.
PubMed: 38911454
DOI: 10.1177/11795549241260572 -
PLoS Biology Jun 2024Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily...
Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment.
Topics: Humans; Breast Neoplasms; Female; Cell Proliferation; Animals; Cell Line, Tumor; Histones; Mice; Gene Expression Regulation, Neoplastic; Up-Regulation; Neoplasm Metastasis; Potassium Channels, Tandem Pore Domain; Lactate Dehydrogenase 5; Mice, Nude; Neoplasm Invasiveness; Glycolysis; L-Lactate Dehydrogenase; Mice, Inbred BALB C; Prognosis; Cell Movement
PubMed: 38905316
DOI: 10.1371/journal.pbio.3002666 -
Cureus May 2024Thiamine is an essential water-soluble vitamin that must be obtained through diet. This vitamin is crucial for various biochemical reactions and is vital for aerobic...
Thiamine is an essential water-soluble vitamin that must be obtained through diet. This vitamin is crucial for various biochemical reactions and is vital for aerobic metabolism. When individuals are deficient in thiamine, which can be due to hypermetabolism (such as in inflammation, ischemia, or malnutrition, among other reasons), anaerobic metabolism may be utilized to maintain energy needs. Such chemical processes produce lactic acid. Excess lactic acid can cause various clinical signs and symptoms, though lactate dehydrogenase (LDH) can typically break down this compound. The following case presents a very unusual instance where a 51-year-old Caucasian woman presented with the chief complaint of ongoing and severe abdominal pain. After an extensive work-up ruling out numerous diagnoses and an eight-day hospital stay, it was believed that she may be suffering from hyperlactatemia secondary to thiamine deficiency, as she improved significantly after administration of this vitamin. It was thought that this was likely due to her previous systemic lupus erythematosus (SLE) diagnosis, vasculitis, chronic inflammation, and a hypermetabolic state, in addition to concurrent LDH malfunction.
PubMed: 38903294
DOI: 10.7759/cureus.60760 -
BioRxiv : the Preprint Server For... Apr 2024D-2-Hydroxyglutarate and L-2-Hydroxyglutarate (D-2HG/L-2HG) are typically metabolites of non-specific enzymatic reactions that are kept in check by the housekeeping...
D-2-Hydroxyglutarate and L-2-Hydroxyglutarate (D-2HG/L-2HG) are typically metabolites of non-specific enzymatic reactions that are kept in check by the housekeeping enzymes, D-2HG /L-2HG dehydrogenase (D-2HGDH/L-2HGDH). In certain disease states, such as D-2HG or L-2HG aciduria and cancers, accumulation of these biomarkers interferes with oxoglutarate-dependent enzymes that regulate bioenergetic metabolism, histone methylation, post-translational modification, protein expression and others. D-2HG has a complex role in tumorigenesis that drives metabolomics investigations. Meanwhile, L-2HG is produced by non-specific action of malate dehydrogenase and lactate dehydrogenase under acidic or hypoxic environments. Characterization of divergent effects of D-2HG/L-2HG on the activity of specific enzymes in diseased metabolism depends on their accurate quantification via mass spectrometry. Despite advancements in high-resolution quadrupole time-of-flight mass spectrometry (HR-QTOF-MS), challenges are typically encountered when attempting to resolve of isobaric and isomeric metabolites such as D-2HG/L-2HG for quantitative analysis. Herein, available D-2HG/L-2HG derivatization and liquid chromatography (LC) MS quantification methods were examined. The outcome led to the development of a robust, high-throughput HR-QTOF-LC/MS approach that permits concomitant quantification of the D-2HG and L-2HG enantiomers with the benefit to quantify the dysregulation of other intermediates within interconnecting pathways. Calibration curve was obtained over the linear range of 0.8-104 nmol/mL with r ≥ 0.995 for each enantiomer. The LC/MS-based assay had an overall precision with intra-day CV % ≤ 8.0 and inter-day CV % ≤ 6.3 across the quality control level for commercial standard and pooled biological samples; relative error % ≤ 2.7 for accuracy; and resolution, R = 1.6 between 2HG enantiomers (m/z 147.030), D-2HG and L-2HG (at retention time of 5.82 min and 4.75 min, respectively) following chiral derivatization with diacetyl-L-tartaric anhydride (DATAN). Our methodology was applied to disease relevant samples to illustrate the implications of proper enantioselective quantification of both D-2HG and L-2HG. The stability of the method allows scaling to large cohorts of clinical samples in the future.
PubMed: 38903117
DOI: 10.1101/2024.04.26.591335 -
Clinical Nutrition ESPEN Aug 2024Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a revolutionary treatment for patients with refractory or relapsed B-cell malignancies. However, a...
BACKGROUND & AIMS
Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a revolutionary treatment for patients with refractory or relapsed B-cell malignancies. However, a significant proportion of patients experience negative outcomes, including severe inflammatory toxicities and relapse. Cachexia and malnutrition are known secondary syndromes in many cancer patients, attributed to the effects of active malignancy, systemic inflammation, and cumulative treatment burden; however, further research is required to accurately characterise these issues in CAR T-cell patients. The aims of this service evaluation were to explore the changes in nutritional status (malnutrition and cachexia) in CAR T-cell therapy patients and the potential impact on patient outcomes including survival. Additionally, we describe the utilisation of dietetic resources in this specific patient population in a London tertiary referral centre.
METHODS
Adult haematology patients receiving licensed CD19-targeting CAR T-cell therapy at University College London Hospital between 01/04/19 and 01/09/21 were included. Data were collected from the time of treatment consent, and throughout admission to day of discharge: body weight (BW), C-reactive protein, albumin, lactate dehydrogenase, nutrition-risk screening scores (hospital-specific) and dietetic input. Clinical outcomes such as 12-month all-cause mortality, intensive care unit (ICU) admission, high-grade toxicities, and length of hospital stay (LoS) were also recorded. Cachexia and malnutrition were defined using the modified Glasgow Prognostic Score (mGPS) and Global Leadership Initiative on Malnutrition (GLIM) consensus, respectively.
RESULTS
114 patients (55.6 ± 15.1 years; 57% males) with B-cell non-Hodgkin's lymphoma (n = 109) and B-cell acute lymphoblastic leukaemia (n = 5), receiving axicabtagene ciloleucel (n = 89) and tisagenlecleucel (n = 25) were included. Median LoS for treatment was 34 (27-38) days. Prior to treatment, 31.5% of patients developed malnutrition, with pre-cachexia/refractory cachexia (mGPS) identified in 43.6% of patients. This altered nutritional status pre-treatment was significantly associated with adverse patient outcomes post-infusion; mGPS was independently associated with inferior overall survival (HR = 3.158, CI = 1.36-7.323, p = 0.007), with malnutrition and mGPS associated with increased LoS (p = 0.037), sepsis (p = 0.022) and ICU admission (p = 0.039). During admission, patients experienced significant BW loss (-5.6% (-8.8 to -2.4); p=<0.001), with 68.4% developing malnutrition. Malnutrition screening during admission identified 57% patients at-risk, with 66.6% of patients referred to dietetics; however, there was a lack of malnutrition screening and dietetic referrals prior to treatment.
CONCLUSION
Pre-treatment malnutrition and cachexia was significantly associated with adverse CAR T patient outcomes, including mGPS cachexia status independently associated with inferior overall survival. Further research in this novel space is essential to confirm the extent and impact of nutritional issues, to assist with implementing dietetic pathways, and to identify potential interventions with a view to optimising outcomes.
Topics: Humans; Cachexia; Male; Female; Middle Aged; Malnutrition; Aged; Immunotherapy, Adoptive; Treatment Outcome; Adult; Nutritional Status; London
PubMed: 38901943
DOI: 10.1016/j.clnesp.2024.05.020 -
Acta Tropica Jun 2024Soluble factors in the secretome of Acanthamoeba castellanii play crucial roles in the pathogenesis of Acanthamoeba keratitis (AK). Investigating the pathological...
Soluble factors in the secretome of Acanthamoeba castellanii play crucial roles in the pathogenesis of Acanthamoeba keratitis (AK). Investigating the pathological effects of A. castellanii-derived conditioned medium (ACCM) on ocular cells can provide insights into the damage inflicted during AK. This study examined ACCM-induced cytotoxicity in primary human corneal stromal cells (CSCs) and a human SV40 immortalized corneal epithelial cell line (ihCECs) at varying ACCM concentrations (25 %, 50 %, 75 %, and 100 %). MTT, AlamarBlue, Sulforhodamine B, lactate dehydrogenase, and Caspase-3/7 activation assays were used to assess the impact of ACCM on the cell viability, proliferation and apoptosis. Additionally, fluorescent staining was used to reveal actin cytoskeleton changes. ACCM exposure significantly decreased cell viability, increased apoptosis, and disrupted the actin cytoskeleton, particularly at higher concentrations and longer exposures. Proteases were found to mediate these cytopathogenic effects, highlighting the need for characterization of A. castellanii proteases as key virulence factors in AK pathogenesis.
PubMed: 38901524
DOI: 10.1016/j.actatropica.2024.107288 -
World Journal of Clinical Cases Jun 2024Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma. Approximately half of patients with AITL may concurrently present with...
BACKGROUND
Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma. Approximately half of patients with AITL may concurrently present with hypergammaglobulinemia. Increased numbers of plasma cells in the bone marrow are commonly observed at diagnosis. These tumors mimic plasma cell myelomas, hindering a conundrum of clinical diagnoses and potentially delaying appropriate treatment.
CASE SUMMARY
A 78-year-old woman experienced poor appetite, weight loss of 5 kg, fatigue 2 months before presentation, and shortness of breath 2 d before presentation, but no fever or night sweats. Physical examination revealed splenomegaly and many palpable masses over the bilateral axillary regions, approximately > 2 cm in size, with rubbery consistency and no tenderness. Blood tests revealed anemia and thrombocytopenia, lactate dehydrogenase level of 153 U/L, total protein level of 10.9 g/dL, albumin to globulin ratio of 0.2, and immunoglobulin G level more than the upper limit of 3000 mg/dL. The free kappa and lambda light chain concentrations were 451 and 614 mg/L, respectively. A pathological examination confirmed the diagnosis of AITL. The initial treatment was the cyclophosphamide, epirubicin, vincristine, and prednisolone regimen. Following this treatment, pleural effusion was controlled, and the patient was discharged in a stable condition and followed up in our outpatient department.
CONCLUSION
This report highlights the importance of differentiating reactive plasmacytosis from plasma cell myeloma in patients with hypergammaglobulinemia. A precise diagnosis of AITL requires a comprehensive evaluation, involving clinical, immunophenotypic, and histological findings conducted by a multidisciplinary team to ensure appropriate treatment.
PubMed: 38898855
DOI: 10.12998/wjcc.v12.i17.3226