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Leukemia & Lymphoma Jul 2024This study investigates acute myeloid leukemia/lymphoblastic leukemia (AML/ALL) through a 14-year analysis (2009-2022) of 46 autopsied cases (age >12 years). B-ALL was...
This study investigates acute myeloid leukemia/lymphoblastic leukemia (AML/ALL) through a 14-year analysis (2009-2022) of 46 autopsied cases (age >12 years). B-ALL was the dominant subtype (34.8%). Liver and spleen were the common sites of active leukemia (63% cases). Symptoms like dyspnea and altered sensorium associated significantly with heart ( = .031) and brain leukostasis ( = .006). Measurable residual disease (MRD) negativity correlated with disease-free status outside the bone marrow, while MRD-positive cases displayed leukemic infiltrates. Infections were identified in 23 autopsied cases, notably linked to post-induction and post-transplant fatalities. Surprisingly, 18 of these 23 cases had unexpected infections mainly fungal (13 cases) with species as the most common. Diagnostic discrepancies were identified in 48% of cases. Malignant infiltration (46%) and infections (25%) were the leading causes of death. This research sheds light on leukemia in extra-medullary tissues, uncovers novel clinical-pathological associations, and highlights overlooked therapy side effects, offering insights for future case management.
PubMed: 38949830
DOI: 10.1080/10428194.2024.2372408 -
Journal of Neurovirology Jun 2024HIV-associated neurocognitive disorders (HAND) is hypothesized to be a result of myeloid cell-induced neuro-inflammation in the central nervous system that may be...
BACKGROUND
HIV-associated neurocognitive disorders (HAND) is hypothesized to be a result of myeloid cell-induced neuro-inflammation in the central nervous system that may be initiated in the periphery, but the contribution of peripheral T cells in HAND pathogenesis remains poorly understood.
METHODS
We assessed markers of T cell activation (HLA-DR + CD38+), immunosenescence (CD57 + CD28-), and immune-exhaustion (TIM-3, PD-1 and TIGIT) as well as monocyte subsets (classical, intermediate, and non-classical) by flow cytometry in peripheral blood derived from individuals with HIV on long-term stable anti-retroviral therapy (ART). Additionally, normalized neuropsychological (NP) composite test z-scores were obtained and regional brain volumes were assessed by magnetic resonance imaging (MRI). Relationships between proportions of immune phenotypes (of T-cells and monocytes), NP z-scores, and brain volumes were analyzed using Pearson correlations and multiple linear regression models.
RESULTS
Of N = 51 participants, 84.3% were male, 86.3% had undetectable HIV RNA < 50 copies/ml, median age was 52 [47, 57] years and median CD4 T cell count was 479 [376, 717] cells/uL. Higher CD4 T cells expressing PD-1 + and/or TIM-3 + were associated with lower executive function and working memory and higher CD8 T cells expressing PD-1 and/or TIM-3 were associated with reduced brain volumes in multiple regions (putamen, nucleus accumbens, cerebellar cortex, and subcortical gray matter). Furthermore, higher single or dual frequencies of PD-1 + and TIM-3 + expressing CD4 and CD8 T-cells correlated with higher CD16 + monocyte numbers.
CONCLUSIONS
This study reinforces evidence that T cells, particularly those with immune exhaustion phenotypes, are associated with neurocognitive impairment and brain atrophy in people living with HIV on ART. Relationships revealed between T-cell immune exhaustion and inflammatory in CD16 monocytes uncover interrelated cellular processes likely involved in the immunopathogenesis of HAND.
PubMed: 38949728
DOI: 10.1007/s13365-024-01223-w -
HemaSphere Jul 2024Twenty percent of children with T-cell lymphoblastic lymphoma (T-LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low-risk...
Twenty percent of children with T-cell lymphoblastic lymphoma (T-LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low-risk subgroup in pediatric T-LBL, yet these high-risk patients who need intensified or alternative treatment options remain undetected. Therefore, there is an urgent need to recognize these high-risk T-LBL patients through identification of molecular characteristics and biomarkers. By using RNA sequencing which was performed in 29/49 T-LBL patients who were diagnosed in the Princess Maxima Center for Pediatric Oncology between 2018 and 2023, we discovered a previously unknown high-risk biological subgroup of children with T-LBL. This subgroup is characterized by gene fusions, found in 21% of our T-LBL cohort (6/29). All patients presented with a large mediastinal mass, pleural/pericardial effusions, and absence of blasts in the bone marrow, blood, and central nervous system. Blood CCL17 (C-C Motif Chemokine Ligand 17, TARC) levels were measured at diagnosis in 26/29 patients, and all six patients with gene fusions patients exclusively expressed highly elevated blood CCL17 levels, defining a novel and previously not known clinically relevant biomarker for T-cell lymphoblastic lymphoma. Four out of these six patients relapsed during therapy, a fifth developed a therapy-related acute myeloid leukemia during maintenance therapy. These data indicate that T-LBL patients with a fusion have a high risk of relapse which can be easily identified using a blood CCL17 screening at diagnosis. Further molecular characterization through gene fusion analysis offers these patients the opportunity for treatment intensification or new treatment strategies.
PubMed: 38948925
DOI: 10.1002/hem3.117 -
BioRxiv : the Preprint Server For... Jun 2024Solid carcinomas are often highly heterogenous cancers, arising from multiple epithelial cells of origin. Yet, how the cell of origin influences the response of the...
Solid carcinomas are often highly heterogenous cancers, arising from multiple epithelial cells of origin. Yet, how the cell of origin influences the response of the tumor microenvironment is poorly understood. Lung adenocarcinoma (LUAD) arises in the distal alveolar epithelium which is populated primarily by alveolar epithelial type I (AT1) and type II (AT2) cells. It has been previously reported that AT1 cells can give rise to a histologically-defined LUAD that is distinct in pathology and transcriptomic identity from that arising from AT2 cells . To determine how cells of origin influence the tumor immune microenvironment (TIME) landscape, we comprehensively characterized transcriptomic, molecular, and cellular states within the TIME of AT1 and AT2-derived LUAD using KRAS oncogenic driver mouse models. Myeloid cells within the AT1-derived LUAD TIME were increased, specifically, immunoreactive monocytes and tumor associated macrophages (TAMs). In contrast, the AT2 LUAD TIME was enriched for Arginase-1 myeloid derived suppressor cells (MDSC) and TAMs expressing profiles suggestive of immunosuppressive function. Validation of immune infiltration was performed using flow cytometry, and intercellular interaction analysis between the cells of origin and major myeloid cell populations indicated that cell-type specific markers SFTPD in AT2 cells and CAV1 in AT1 cells mediated unique interactions with myeloid cells of the differential immunosuppressive states within each cell of origin mouse model. Taken together, AT1-derived LUAD presents with an anti-tumor, immunoreactive TIME, while the TIME of AT2-derived LUAD has hallmarks of immunosuppression. This study suggests that LUAD cell of origin influences the composition and suppression status of the TIME landscape and may hold critical implications for patient response to immunotherapy.
PubMed: 38948812
DOI: 10.1101/2024.06.19.599651 -
Journal of Family Medicine and Primary... May 2024Cancer chemotherapy remains an area of concern, as many of the therapies are uncomfortable involving side effects and unpleasant experiences. These factors could further... (Review)
Review
Cancer chemotherapy remains an area of concern, as many of the therapies are uncomfortable involving side effects and unpleasant experiences. These factors could further reduce patient's quality of life, and even endanger their life. Many therapeutic strategies have been tried to reduce the unpleasant side effects and increase the treatment effectiveness; however, none have shown to have promising effects. One of the main hindrances to cancer therapy is the escape strategies by tumor cells to the immune attack. Promoting inflammation in the tumor microenvironment is the cornerstone and key therapeutic target in cancer chemotherapy. High-salt diet (HSD) intake, though it has deleterious effects on human health by promoting chronic inflammation, is found to be advantageous in the tumor microenvironment. Studies identified HSD favors an increased abundance of species in the tumor environment due to gut barrier alteration, which, in turn, promotes inflammation and favors improved response to cancer chemotherapy. A review of the literature was carried out to find out the effects of an HSD on health and diseases, with special mention of its effect on cancer chemotherapy. Studies emphasized HSD would block the myeloid-derived suppressor cells which will enhance the tumor immunity. Exploration of the precise mechanism of simple HSD regime/ingestion of specific bacterial species as probiotics will be effective and essential to formulate the game-changing cancer chemotherapy. With the modern era of healthcare moving toward precision medicine where the physician can choose the treatment option suitable for the individual, HSD regime/ingestion of specific bacterial species can be considered.
PubMed: 38948582
DOI: 10.4103/jfmpc.jfmpc_1574_23 -
Journal of Pharmacopuncture Jun 2024This study investigates the therapeutic potential of (IN) in treating a Inflammatory Bowel Disease (IBD). The objective is to comprehensively examine the effects and... (Review)
Review
This study investigates the therapeutic potential of (IN) in treating a Inflammatory Bowel Disease (IBD). The objective is to comprehensively examine the effects and pharmacological mechanisms of IN on IBD, assessing its potential as an novel treatment for IBD. Analysis of 11 selected papers is conducted to understand the effects of IN, focusing on compounds like indirubin, isatin, indigo, and tryptanthrin. This study evaluates their impact on Disease Activity Index (DAI) score, colon length, mucosal damage, and macrophage infiltration in Dextran Sulfate Sodium (DSS)-induced colitis mice. Additionally, It investigate into the anti-inflammatory mechanisms, including Aryl hydrocarbon Receptor (AhR) pathway activation, Nuclear Factor kappa B (NF-κB)/nod-like receptor family pyrin domain containing 3 (NLRP3)/Interleukin 1 beta (IL-1β) inhibition, and modulation of Toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MYD88)/NF-κB and Mitogen Activated Protein Kinase (MAPK) pathways. Immunomodulatory effects on T helper 17 (Th17)/regulatory T cell (Treg cell) balance and Glycogen synthase kinase-3 beta (GSK3-β) expression are also explored. Furthermore, the study addresses the role of IN in restoring intestinal microbiota diversity, reducing pathogenic bacteria, and increasing beneficial bacteria. The findings reveal that IN, particularly indirubin and indigo, demonstrates significant improvements in DAI score, colon length, mucosal damage, and macrophage infiltration in DSS-induced colitis mice. The anti-inflammatory effects are attributed to the activation of the AhR pathway, inhibition of inflammatory pathways, and modulation of immune responses. These results exhibit the potential of IN in IBD treatment. Notably, the restoration of intestinal microbiota diversity and balance further supports its efficacy. IN emerges as a promising and effective treatment for IBD, demonstrating anti-inflammatory effects and positive outcomes in preclinical studies. However, potential side effects necessitate further investigation for safe therapeutic development. The study underscores the need for future research to explore a broader range of active ingredients in IN to enhance therapeutic efficacy and safety.
PubMed: 38948310
DOI: 10.3831/KPI.2024.27.2.59 -
ArXiv Jun 2024Single-cell datasets often lack individual cell labels, making it challenging to identify cells associated with disease. To address this, we introduce Mixture Modeling...
Single-cell datasets often lack individual cell labels, making it challenging to identify cells associated with disease. To address this, we introduce Mixture Modeling for Multiple Instance Learning (MMIL), an expectation maximization method that enables the training and calibration of cell-level classifiers using patient-level labels. Our approach can be used to train e.g. lasso logistic regression models, gradient boosted trees, and neural networks. When applied to clinically-annotated, primary patient samples in Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL), our method accurately identifies cancer cells, generalizes across tissues and treatment timepoints, and selects biologically relevant features. In addition, MMIL is capable of incorporating cell labels into model training when they are known, providing a powerful framework for leveraging both labeled and unlabeled data simultaneously. Mixture Modeling for MIL offers a novel approach for cell classification, with significant potential to advance disease understanding and management, especially in scenarios with unknown gold-standard labels and high dimensionality.
PubMed: 38947923
DOI: No ID Found -
Nature Cardiovascular Research Oct 2023Among the diverse populations of myeloid cells that reside within the healthy and diseased heart, C-C chemokine receptor 2 (CCR2) is specifically expressed on...
Among the diverse populations of myeloid cells that reside within the healthy and diseased heart, C-C chemokine receptor 2 (CCR2) is specifically expressed on inflammatory populations of monocytes and macrophages that contribute to the development and progression of heart failure. Here, we evaluated a peptide-based imaging probe (Cu-DOTA-ECL1i) that specifically recognizes CCR2 monocytes and macrophages for human cardiac imaging. Compared to healthy controls, Cu-DOTA-ECL1i heart uptake was increased in subjects following acute myocardial infarction, predominately localized within the infarct area, and was associated with impaired myocardial wall motion. These findings establish the feasibility of molecular imaging of CCR2 expression to visualize inflammatory monocytes and macrophages in the injured human heart.
PubMed: 38947883
DOI: No ID Found -
Genes & Diseases Sep 2024The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia (CML), greatly prolonged the... (Review)
Review
The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia (CML), greatly prolonged the life of CML patients, and improved their prognosis. However, TKI resistance is still a major problem with CML patients, reducing the efficacy of treatment and their quality of life. TKI resistance is mainly divided into BCR-ABL-dependent and BCR-ABL-independent resistance. Now, the main clinical strategy addressing TKI resistance is to switch to newly developed TKIs. However, data have shown that these new drugs may cause serious adverse reactions and intolerance and cannot address all resistance mutations. Therefore, finding new therapeutic targets to overcome TKI resistance is crucial and the ubiquitin-proteasome system (UPS) has emerged as a focus. The UPS mediates the degradation of most proteins in organisms and controls a wide range of physiological processes. In recent years, the study of UPS in hematological malignant tumors has resulted in effective treatments, such as bortezomib in the treatment of multiple myeloma and mantle cell lymphoma. In CML, the components of UPS cooperate or antagonize the efficacy of TKI by directly or indirectly affecting the ubiquitination of BCR-ABL, interfering with CML-related signaling pathways, and negatively or positively affecting leukemia stem cells. Some of these molecules may help overcome TKI resistance and treat CML. In this review, the mechanism of TKI resistance is briefly described, the components of UPS are introduced, existing studies on UPS participating in TKI resistance are listed, and UPS as the therapeutic target and strategies are discussed.
PubMed: 38947742
DOI: 10.1016/j.gendis.2023.101150 -
Cureus May 2024Cytoreduction in leukostasis can be achieved using leukapheresis. We report a case of chronic myeloid leukemia (CML) identified by a persistent erection, which was...
Cytoreduction in leukostasis can be achieved using leukapheresis. We report a case of chronic myeloid leukemia (CML) identified by a persistent erection, which was successfully treated using the Spectra Optia®︎ apheresis system. A 29-year-old male presented with an erection for 12 hours without identified triggers and no improvement despite penile corpus cavernosum puncture. His white blood cell count was 458,930/μL. A diagnosis of CML-induced persistent erection with secondary hyperleukocytosis was established. Following an emergency bilateral penile corpus cavernosum incision (distal shunting), he received hydroxyurea and febuxostat. Persistent erection resolved after leukapheresis for two consecutive days. Rapid leukocyte count reduction can effectively address leukostasis in CML without major complications.
PubMed: 38947668
DOI: 10.7759/cureus.61351