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BMC Nephrology May 2024Multiple myeloma (MM) is a malignant disorder characterized by monoclonal differentiated plasma cells. While it is more commonly diagnosed in elderly individuals, it can...
BACKGROUND
Multiple myeloma (MM) is a malignant disorder characterized by monoclonal differentiated plasma cells. While it is more commonly diagnosed in elderly individuals, it can also affect younger populations, though with a lower incidence.
CASE PRESENTATION
Here, we present the case of a 32-year-old woman diagnosed with IgA lambda MM. She presented with fatigue, nausea, acute kidney injury (AKI) with a rapid increase in creatinine, and anemia. A kidney biopsy was done to rule out a rapidly progressive glomerular disease and a diagnosis was thus reached. A genetic workup revealed t(14;16) translocation and an extra copy of TP53. The patient received aggressive intravenous steroids and intravenous fluid resuscitation, resulting in an improvement in renal function. Treatment with daratumumab in combination with bortezomib, thalidomide, and dexamethasone was initiated and well tolerated. Despite the generally poor prognosis of IgA MM, our case emphasizes the importance of considering MM in young patients with unexplained kidney injury.
CONCLUSION
Early recognition and prompt intervention are essential in managing MM patients, especially in those with high-risk cytogenetic abnormalities. This case serves as a reminder for clinicians to maintain a high index of suspicion for MM, even in younger populations, when presented with unexplained kidney injury.
Topics: Humans; Female; Adult; Multiple Myeloma; Proteinuria; Translocation, Genetic; Acute Kidney Injury; Immunoglobulin A; Immunoglobulin lambda-Chains; Chromosomes, Human, Pair 14
PubMed: 38755555
DOI: 10.1186/s12882-024-03600-3 -
BMC Nephrology May 2024Global studies exploring the relationship between parity and chronic kidney disease (CKD) are scarce. Furthermore, no study has examined the relationship between parity...
BACKGROUND
Global studies exploring the relationship between parity and chronic kidney disease (CKD) are scarce. Furthermore, no study has examined the relationship between parity and CKD in Japan. Therefore, this study aimed to examine the relationship between parity and the prevalence of CKD in a Japanese population, considering the clinical history of hypertensive disorders of pregnancy (HDP) and current body mass index (BMI) based on menopausal status.
METHODS
This cross-sectional study included 26,945 Japanese multiparous women (5,006 premenopausal and 21,939 postmenopausal women) and 3,247 nulliparous women (1,599 premenopausal and 1,648 postmenopausal women). Participants were divided into two groups based on their menopausal status (premenopausal and postmenopausal women). The relationship between parity and the prevalence of CKD was evaluated using a multiple logistic regression model adjusted for several covariates, including a clinical history of HDP and current BMI.
RESULTS
The relationship between parity and the prevalence of CKD was not statistically significant in either premenopausal or postmenopausal multiparous women. A clinical history of HDP was significantly associated with an increased risk of CKD in premenopausal and postmenopausal multiparous women. However, the relationship between a clinical history of HDP and CKD in premenopausal women was weakened after adjusting for current BMI. Furthermore, the current BMI was significantly associated with an increased risk of CKD in both premenopausal and postmenopausal women.
CONCLUSIONS
Parity is not significantly associated with the prevalence of CKD in premenopausal and postmenopausal multiparous women. A clinical history of HDP is a risk factor for CKD in both premenopausal and postmenopausal women. Current BMI is also associated with an increased risk of CKD in premenopausal and postmenopausal women. Therefore, continuous surveillance and preventive measures against CKD should be provided to women with a clinical history of HDP. In addition, maintaining an appropriate body weight is beneficial in reducing the risk of CKD.
Topics: Humans; Female; Parity; Body Mass Index; Japan; Renal Insufficiency, Chronic; Prevalence; Cross-Sectional Studies; Adult; Hypertension, Pregnancy-Induced; Middle Aged; Pregnancy; Postmenopause; Premenopause; Risk Factors; Aged
PubMed: 38755546
DOI: 10.1186/s12882-024-03604-z -
Life Science Alliance Aug 2024Diabetes complications such as nephropathy, retinopathy, or cardiovascular disease arise from vascular dysfunction. In this context, it has been observed that past...
Diabetes complications such as nephropathy, retinopathy, or cardiovascular disease arise from vascular dysfunction. In this context, it has been observed that past hyperglycemic events can induce long-lasting alterations, a phenomenon termed "metabolic memory." In this study, we evaluated the genome-wide gene expression and chromatin accessibility alterations caused by transient high-glucose exposure in human endothelial cells (ECs) in vitro. We found that cells exposed to high glucose exhibited substantial gene expression changes in pathways known to be impaired in diabetes, many of which persist after glucose normalization. Chromatin accessibility analysis also revealed that transient hyperglycemia induces persistent alterations, mainly in non-promoter regions identified as enhancers with neighboring genes showing lasting alterations. Notably, activation of the NRF2 pathway through NRF2 overexpression or supplementation with the plant-derived compound sulforaphane, effectively reverses the glucose-induced transcriptional and chromatin accessibility memories in ECs. These findings underscore the enduring impact of transient hyperglycemia on ECs' transcriptomic and chromatin accessibility profiles, emphasizing the potential utility of pharmacological NRF2 pathway activation in mitigating and reversing the high-glucose-induced transcriptional and epigenetic alterations.
Topics: NF-E2-Related Factor 2; Humans; Glucose; Epigenesis, Genetic; Signal Transduction; Hyperglycemia; Chromatin; Endothelial Cells; Transcription, Genetic; Gene Expression Regulation; Isothiocyanates; Human Umbilical Vein Endothelial Cells; Sulfoxides
PubMed: 38755006
DOI: 10.26508/lsa.202302382 -
International Journal of Hyperthermia :... 2024Radiomics may aid in predicting prognosis in patients with colorectal liver metastases (CLM). Consistent data is available on CT, yet limited data is available on MRI....
PURPOSE
Radiomics may aid in predicting prognosis in patients with colorectal liver metastases (CLM). Consistent data is available on CT, yet limited data is available on MRI. This study assesses the capability of MRI-derived radiomic features (RFs) to predict local tumor progression-free survival (LTPFS) in patients with CLMs treated with microwave ablation (MWA).
METHODS
All CLM patients with pre-operative Gadoxetic acid-MRI treated with MWA in a single institution between September 2015 and February 2022 were evaluated. Pre-procedural information was retrieved retrospectively. Two observers manually segmented CLMs on T2 and T1-Hepatobiliary phase (T1-HBP) scans. After inter-observer variability testing, 148/182 RFs showed robustness on T1-HBP, and 141/182 on T2 (ICC > 0.7).Cox multivariate analysis was run to establish clinical (CLIN-mod), radiomic (RAD-T1, RAD-T2), and combined (COMB-T1, COMB-T2) models for LTPFS prediction.
RESULTS
Seventy-six CLMs (43 patients) were assessed. Median follow-up was 14 months. LTP occurred in 19 lesions (25%).CLIN-mod was composed of minimal ablation margins (MAMs), intra-segment progression and primary tumor grade and exhibited moderately high discriminatory power in predicting LTPFS (AUC = 0.89, = 0.0001). Both RAD-T1 and RAD-T2 were able to predict LTPFS: (RAD-T1: AUC = 0.83, = 0.0003; RAD-T2: AUC = 0.79, = 0.001). Combined models yielded the strongest performance (COMB-T1: AUC = 0.98, = 0.0001; COMB-T2: AUC = 0.95, = 0.0003). Both combined models included MAMs and tumor regression grade; COMB-T1 also featured 10 percentile of signal intensity, while tumor flatness was present in COMB-T2.
CONCLUSION
MRI-based radiomic evaluation of CLMs is feasible and potentially useful for LTP prediction. Combined models outperformed clinical or radiomic models alone for LTPFS prediction.
Topics: Humans; Colorectal Neoplasms; Liver Neoplasms; Magnetic Resonance Imaging; Male; Female; Middle Aged; Aged; Microwaves; Retrospective Studies; Disease Progression; Adult; Radiomics
PubMed: 38754994
DOI: 10.1080/02656736.2024.2349059 -
Journal For Immunotherapy of Cancer May 2024Cancer neoantigens arise from protein-altering somatic mutations in tumor and rank among the most promising next-generation immuno-oncology agents when used in...
BACKGROUND
Cancer neoantigens arise from protein-altering somatic mutations in tumor and rank among the most promising next-generation immuno-oncology agents when used in combination with immune checkpoint inhibitors. We previously developed a computational framework, REAL-neo, for identification, quality control, and prioritization of both class-I and class-II human leucocyte antigen (HLA)-presented neoantigens resulting from somatic single-nucleotide mutations, small insertions and deletions, and gene fusions. In this study, we developed a new module, SPLICE-neo, to identify neoantigens from aberrant RNA transcripts from two distinct sources: (1) DNA mutations within splice sites and (2) de novo RNA aberrant splicings.
METHODS
First, SPLICE-neo was used to profile all DNA splice-site mutations in 11,892 tumors from The Cancer Genome Atlas (TCGA) and identified 11 profiles of splicing donor or acceptor site gains or losses. Transcript isoforms resulting from the top seven most frequent profiles were computed using novel logic models. Second, SPLICE-neo identified de novo RNA splicing events using RNA sequencing reads mapped to novel exon junctions from either single, double, or multiple exon-skipping events. The aberrant transcripts from both sources were then ranked based on isoform expression levels and z-scores assuming that individual aberrant splicing events are rare. Finally, top-ranked novel isoforms were translated into protein, and the resulting neoepitopes were evaluated for neoantigen potential using REAL-neo. The top splicing neoantigen candidates binding to HLA-A*02:01 were validated using in vitro T2 binding assays.
RESULTS
We identified abundant splicing neoantigens in four representative TCGA cancers: BRCA, LUAD, LUSC, and LIHC. In addition to their substantial contribution to neoantigen load, several splicing neoantigens were potent tumor antigens with stronger bindings to HLA compared with the positive control of antigens from influenza virus.
CONCLUSIONS
SPLICE-neo is the first tool to comprehensively identify and prioritize splicing neoantigens from both DNA splice-site mutations and de novo RNA aberrant splicings. There are two major advances of SPLICE-neo. First, we developed novel logic models that assemble and prioritize full-length aberrant transcripts from DNA splice-site mutations. Second, SPLICE-neo can identify exon-skipping events involving more than two exons, which account for a quarter to one-third of all skipping events.
Topics: Humans; Antigens, Neoplasm; Neoplasms; RNA Splicing
PubMed: 38754917
DOI: 10.1136/jitc-2024-008988 -
Journal For Immunotherapy of Cancer May 2024Chimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and...
BACKGROUND
Chimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and refractory B-cell malignancies. If CAR-T cell therapy for non-hematological malignancies is to achieve the same stage of clinical development, then iterative early-phase clinical testing can add value to the clinical development process for evaluating CAR-T cell products containing different CAR designs and manufactured under differing conditions.
METHODS
We conducted a phase 1 trial of third-generation GD2-specific CAR-T cell therapy, which has previously been tested in neuroblastoma patients. In this study, the GD2-CAR-T therapy was evaluated for the first time in metastatic melanoma patients in combination with BRAF/MEK inhibitor therapy, and as a monotherapy in patients with colorectal cancer and a patient with fibromyxoid sarcoma. Feasibility and safety were determined and persistence studies, multiplex cytokine arrays on sera and detailed immune phenotyping of the original CAR-T products, the circulating CAR-T cells, and, in select patients, the tumor-infiltrating CAR-T cells were performed.
RESULTS
We demonstrate the feasibility of manufacturing CAR-T products at point of care for patients with solid cancer and show that a single intravenous infusion was well tolerated with no dose-limiting toxicities or severe adverse events. In addition, we note significant improvements in CAR-T cell immune phenotype, and expansion when a modified manufacturing procedure was adopted for the latter 6 patients recruited to this 12-patient trial. We also show evidence of CAR-T cell-mediated immune activity and in some patients expanded subsets of circulating myeloid cells after CAR-T cell therapy.
CONCLUSIONS
This is the first report of third-generation GD2-targeting CAR-T cells in patients with metastatic melanoma and other solid cancers such as colorectal cancer, showing feasibility, safety and immune activity, but limited clinical effect.
TRIAL REGISTRATION NUMBER
ACTRN12613000198729.
Topics: Humans; Melanoma; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Male; Female; Middle Aged; Gangliosides; Adult; Aged; T-Lymphocytes; Treatment Outcome
PubMed: 38754916
DOI: 10.1136/jitc-2023-008659 -
Journal For Immunotherapy of Cancer May 2024Allogeneic hematopoietic stem cell transplantation (HSCT) remains the standard of care for chemotherapy-refractory leukemia patients, but cure rates are still dismal. To...
BACKGROUND
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the standard of care for chemotherapy-refractory leukemia patients, but cure rates are still dismal. To prevent leukemia relapse following HSCT, we aim to improve the early graft-versus-leukemia effect mediated by natural killer (NK) cells. Our approach is based on the adoptive transfer of Therapeutic Inducers of Natural Killer cell Killing (ThINKK). ThINKK are expanded and differentiated from HSC, and exhibit blood plasmacytoid dendritic cell (pDC) features. We previously demonstrated that ThINKK stimulate NK cells and control acute lymphoblastic leukemia (ALL) development in a preclinical mouse model of HSCT for ALL. Here, we assessed the cellular identity of ThINKK and investigated their potential to activate allogeneic T cells. We finally evaluated the effect of immunosuppressive drugs on ThINKK-NK cell interaction.
METHODS
ThINKK cellular identity was explored using single-cell RNA sequencing and flow cytometry. Their T-cell activating potential was investigated by coculture of allogeneic T cells and antigen-presenting cells in the presence or the absence of ThINKK. A preclinical human-to-mouse xenograft model was used to evaluate the impact of ThINKK injections on graft-versus-host disease (GvHD). Finally, the effect of immunosuppressive drugs on ThINKK-induced NK cell cytotoxicity against ALL cells was tested.
RESULTS
The large majority of ThINKK shared the key characteristics of canonical blood pDC, including potent type-I interferon (IFN) production following Toll-like receptor stimulation. A minor subset expressed some, although not all, markers of other dendritic cell populations. Importantly, while ThINKK were not killed by allogeneic T or NK cells, they did not increase T cell proliferation induced by antigen-presenting cells nor worsened GvHD in vivo. Finally, tacrolimus, sirolimus or mycophenolate did not decrease ThINKK-induced NK cell activation and cytotoxicity.
CONCLUSION
Our results indicate that ThINKK are type I IFN producing cells with low T cell activation capacity. Therefore, ThINKK adoptive immunotherapy is not expected to increase the risk of GvHD after allogeneic HSCT. Furthermore, our data predict that the use of tacrolimus, sirolimus or mycophenolate as anti-GvHD prophylaxis regimen will not decrease ThINKK therapeutic efficacy. Collectively, these preclinical data support the testing of ThINKK immunotherapy in a phase I clinical trial.
Topics: Killer Cells, Natural; Humans; Hematopoietic Stem Cell Transplantation; Animals; Mice; Transplantation, Homologous; Dendritic Cells; Female; Graft vs Host Disease
PubMed: 38754915
DOI: 10.1136/jitc-2023-008435 -
BMJ Open Respiratory Research May 2024Targeted low-dose CT lung cancer screening reduces lung cancer mortality. England's Targeted Lung Health Check programme uses risk prediction tools to determine...
INTRODUCTION
Targeted low-dose CT lung cancer screening reduces lung cancer mortality. England's Targeted Lung Health Check programme uses risk prediction tools to determine eligibility for biennial screening among people with a smoking history aged 55-74. Some participants initially ineligible for lung cancer screening will later become eligible with increasing age and ongoing tobacco exposure. It is, therefore, important to understand how many people could qualify for reinvitation, and after how long, to inform implementation of services.
METHODS
We prospectively predicted future risk (using Prostate, Lung, Colorectal and Ovarian trial's risk model (PLCO) and Liverpool Lung Project version 2 (LLP) risk models) and time-to-eligibility of 5345 participants to estimate how many would become eligible through the course of a Lung Health Check screening programme for 55-74 years.
RESULTS
Approximately a quarter eventually become eligible, with those with the lowest baseline risks unlikely to ever become eligible. Time-to-eligibility is shorter for participants with higher baseline risk, increasing age and ongoing smoking status. At a PLCO threshold ≥1.51%, 68% of those who continue to smoke become eligible compared with 18% of those who have quit.
DISCUSSION
Predicting which participants may become eligible, and when, during a screening programme can help inform reinvitation strategies and service planning. Those with risk scores closer to the eligibility threshold, particularly people who continue to smoke, will reach eligibility in subsequent rounds while those at the lowest risk may be discharged from the programme from the outset.
Topics: Humans; Lung Neoplasms; Middle Aged; Male; Aged; Early Detection of Cancer; Female; Tomography, X-Ray Computed; Prospective Studies; England; Smoking; Risk Assessment; Eligibility Determination; Mass Screening; Risk Factors
PubMed: 38754907
DOI: 10.1136/bmjresp-2023-002193 -
BMJ Open Respiratory Research May 2024Many interstitial lung diseases (ILDs) have clear causal relationships with environmental and occupational exposures. Exposure identification can assist with diagnosis,... (Review)
Review
BACKGROUND
Many interstitial lung diseases (ILDs) have clear causal relationships with environmental and occupational exposures. Exposure identification can assist with diagnosis, understanding disease pathogenesis, prognostication and prevention of disease progression and occurrence in others at risk. Despite the importance of exposure identification in ILD, there is no standardised assessment approach. Many questionnaires are in clinical and research use, yet their utility, applicability, relevance and performance characteristics are unknown.
OBJECTIVES
This scoping review aimed to summarise the available evidence relating to ILD exposure assessment questionnaires, identify research gaps and inform the content for a future single evidence-based ILD questionnaire.
METHODS
A scoping review based on Arksey and O'Malley's methodological framework was conducted.
ELIGIBILITY CRITERIA
Any questionnaire that elicited exposures specific to ILD was included. A modified COSMIN Risk of Bias Framework was used to assess quality.
SOURCES OF EVIDENCE
Relevant articles were identified from MEDLINE and EMBASE up to 23 July 2023.
RESULTS
22 exposure questionnaires were identified, including 15 generally pertaining to ILD, along with several disease-specific questionnaires for hypersensitivity pneumonitis (n=4), chronic beryllium disease, sarcoidosis and silicosis (1 questionnaire each). For most questionnaires, quality was low, whereby the methods used to determine exposure inclusion and questionnaire validation were not reported or not performed. Collectively the questionnaires covered 158 unique exposures and at-risk occupations, most commonly birds, mould/water damage, wood dust, asbestos, farming, automotive mechanic and miners. Only five questionnaires also provided free-text fields, and 13 queried qualifiers such as temporality or respiratory protection.
CONCLUSIONS
Designing a robust ILD-specific questionnaire should include an evidence-based and relevance-based approach to exposure derivation, with clinicians and patients involved in its development and tested to ensure relevance and feasibility.
Topics: Humans; Lung Diseases, Interstitial; Surveys and Questionnaires; Occupational Exposure; Environmental Exposure
PubMed: 38754906
DOI: 10.1136/bmjresp-2023-002155 -
Lupus Science & Medicine May 2024Trauma history is associated with SLE onset and worse patient-reported outcomes; perceived stress is associated with greater SLE disease activity. Stress perceptions...
OBJECTIVE
Trauma history is associated with SLE onset and worse patient-reported outcomes; perceived stress is associated with greater SLE disease activity. Stress perceptions vary in response to life events and may be influenced by psychosocial factors. In an SLE cohort, we examined whether stressful events associated with perceived stress, whether psychosocial factors affected perceived stress, and whether these relationships varied by prior trauma exposure.
METHODS
This is a cross-sectional analysis of data from the California Lupus Epidemiology Study, an adult SLE cohort. Multivariable linear regression analyses controlling for age, gender, educational attainment, income, SLE damage, comorbid conditions, glucocorticoids ≥7.5 mg/day and depression examined associations of recent stressful events (Life Events Inventory) and positive (resilience, self-efficacy, emotional support) and negative (social isolation) psychosocial factors with perceived stress. Analyses were stratified by lifetime trauma history (Brief Trauma Questionnaire (BTQ)) and by adverse childhood experiences (ACEs) in a subset.
RESULTS
Among 242 individuals with SLE, a greater number of recent stressful events was associated with greater perceived stress (beta (95% CI)=0.20 (0.07 to 0.33), p=0.003). Positive psychosocial factor score representing resilience, self-efficacy and emotional support was associated with lower perceived stress when accounting for number of stressful events (-0.67 (-0.94 to -0.40), p<0.0001); social isolation was associated with higher stress (0.20 (0.14 to 0.25), p<0.0001). In analyses stratified by BTQ trauma and ACEs, associations of psychosocial factors and perceived stress were similar between groups. However, the number of recent stressful events was significantly associated with perceived stress only for people with BTQ trauma (0.17 (0.05 to 0.29), p=0.0077) and ACEs (0.37 (0.15 to 0.58), p=0.0011).
CONCLUSION
Enhancing positive and lessening negative psychosocial factors may mitigate deleterious perceived stress, which may improve outcomes in SLE, even among individuals with a history of prior trauma who may be more vulnerable to recent stressful events.
Topics: Humans; Female; Lupus Erythematosus, Systemic; Male; Adult; Stress, Psychological; Cross-Sectional Studies; Middle Aged; Self Efficacy; Social Support; Resilience, Psychological; California; Life Change Events; Adverse Childhood Experiences; Surveys and Questionnaires; Social Isolation; Depression
PubMed: 38754905
DOI: 10.1136/lupus-2023-001060