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The Journal of Clinical Investigation Jun 2024Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML),...
Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.
Topics: Humans; Leukemia, Myeloid, Acute; fms-Like Tyrosine Kinase 3; Drug Resistance, Neoplasm; Animals; Mice; Niacinamide; Cell Line, Tumor; Xenograft Model Antitumor Assays; Female; Antineoplastic Agents; Mutation; Mice, SCID; Mice, Inbred NOD
PubMed: 38950330
DOI: 10.1172/JCI169245 -
Journal of Cancer 2024Bone cancer among adolescents and children exhibits varying survival outcomes based on disease state. While localized bone cancer cases have a survival rate exceeding... (Review)
Review
Bone cancer among adolescents and children exhibits varying survival outcomes based on disease state. While localized bone cancer cases have a survival rate exceeding 70%, metastatic, refractory, and recurrent forms are associated with significantly poorer prognoses. Initially believed to be mere vehicles for cellular waste disposal, exosomes are now recognized as extracellular vesicles facilitating intercellular communication. These vesicles influence cellular behaviors by transporting various biomolecules, such as proteins, DNA, RNA, and lipids, among cells. The role of exosomes in regulating the progression of bone cancer is increasingly evident, impacting critical processes like tumorigenesis, proliferation, metastasis, angiogenesis, immune evasion, and drug resistance. Current research underscores the substantial potential of exosomes in promoting the progression and development of bone cancer. This review delves into the complex process of exosome biogenesis, the variety of cell-derived exosome sources, and their applications in drug delivery and therapeutics. It also examines ongoing clinical trials focused on exosome cargo levels and discusses the challenges and future directions in exosome research. Unlike costly and invasive traditional diagnostic methods, exosomal biomarkers offer a non-invasive, cost-effective, and readily accessible routine screening through simple fluid collection that aims to inspire researchers to investigate the potential of exosomes for cancer theragnostic. Through comprehensive exploration of these areas, the review seeks to enhance understanding and foster innovative solutions to cancer biology in the near future.
PubMed: 38947401
DOI: 10.7150/jca.95709 -
Frontiers in Immunology 2024CD39 plays an important role in the immunoregulation and inhibition of effector cells. It is expressed on immune cells, including Tregs, and on extracellular vesicles...
INTRODUCTION
CD39 plays an important role in the immunoregulation and inhibition of effector cells. It is expressed on immune cells, including Tregs, and on extracellular vesicles (EVs) budding from the plasma membrane. Platelet transfusion may induce alloimmunization against HLA-I antigens, leading to refractoriness to platelet transfusion with severe consequences for patients. Tregs may play a key role in determining whether alloimmunization occurs in patients with hematologic disorders. We hypothesized that CD39 EVs might play an immunoregulatory role, particularly in the context of platelet transfusions in patients with hematologic disorders. Such alloimmunization leads to the production of alloantibodies and is sensitive to the regulatory action of CD39.
METHODS
We characterized CD39 EVs in platelet concentrates by flow cytometry. The absolute numbers and cellular origins of CD39 EVs were evaluated. We also performed functional tests to evaluate interactions with immune cells and their functions.
RESULTS
We found that CD39 EVs from platelet concentrates had an inhibitory phenotype that could be transferred to the immune cells with which they interacted: CD4 and CD8 T lymphocytes (TLs), dendritic cells, monocytes, and B lymphocytes (BLs). Moreover, the concentration of CD39 EVs in platelet concentrates varied and was very high in 10% of concentrates. The number of these EVs present was determinant for EV-cell interactions. Finally, functional interactions were observed with BLs, CD4 TLs and CD39 EVs for immunoglobulin production and lymphoproliferation, with potential implications for the immunological management of patients.
Topics: Humans; Extracellular Vesicles; Blood Platelets; Tetraspanin 29; Cell Communication; Platelet Transfusion; Female; B-Lymphocytes; Male; Apyrase; T-Lymphocytes, Regulatory; Antigens, CD
PubMed: 38947317
DOI: 10.3389/fimmu.2024.1397967 -
Journal of Blood Medicine 2024Primary cranial neurolymphomatosis (PCNL) is a rare subtype of primary CNS lymphoma (PCNSL) in which infiltrative lymphomatous involvement is confined to cranial nerves....
Primary cranial neurolymphomatosis (PCNL) is a rare subtype of primary CNS lymphoma (PCNSL) in which infiltrative lymphomatous involvement is confined to cranial nerves. Here, we report a case of PCNL with successful genomic profiling. A 57-year-old male had a lengthy prediagnostic phase spanning approximately 30 months, characterized by multiple episodes of cranial neuropathies managed by steroids. At the time of diagnosis, the patient had right-sided cranial neuropathies involving cranial nerves (CN) V, VI, and VII. Pathological findings of the right cavernous lesion biopsy were consistent with large B-cell lymphoma-infiltrating nerve fibers. The clinical course was aggressive and refractory, characterized by relentless progression with the development of cervical spinal neurolymphomatosis, cerebrospinal fluid involvement, and ependymal and intraparenchymal cerebral involvement, despite multiple lines of therapy, including chemoimmunotherapy, Bruton's tyrosine kinase inhibitor, radiation, autologous stem cell transplant, chimeric antigen receptor T-cell therapy (CAR-T), and whole-brain radiation. The patient survived for 22 months from the time of the initial diagnosis and 52 months after the first episode of cranial neuropathy. Next-generation sequencing identified mutations (MYD88, CD79b, and PIM1) that are frequently observed in PCNSL. The unusual findings included a total of 22 mutations involving PIM1, indicating a highly active aberrant somatic hypermutation and two missense CXCR4 mutations. CXCR4 mutations have never been described in PCNSL and may have implications for disease biology and therapeutic interventions. We provide a literature review to further elucidate PCNL.
PubMed: 38947230
DOI: 10.2147/JBM.S459123 -
Annals of Coloproctology Jun 2024This study assessed the long-term outcomes and quality of life in patients who underwent sacral neuromodulation (SNM) due to low anterior resection syndrome (LARS).
PURPOSE
This study assessed the long-term outcomes and quality of life in patients who underwent sacral neuromodulation (SNM) due to low anterior resection syndrome (LARS).
METHODS
This single-center retrospective study, conducted from 2005 to 2021, included 30 patients (21 men; median age, 70 years) who had undergone total mesorectal excision with stoma closure and had no recurrence at inclusion. All patients were diagnosed with LARS refractory to conservative treatment. We evaluated clinical and quality-of-life outcomes after SNM through a stool diary, Wexner score, LARS score, the Fecal Incontinence Quality of Life (FIQL) questionnaire, and EuroQol-5D (EQ-5D) questionnaire.
RESULTS
Peripheral nerve stimulation was successful in all but one patient. Of the 29 patients who underwent percutaneous nerve evaluation, 17 (58.62%) responded well to SNM and received permanent implants. The median follow-up period was 48 months (range, 18-153 months). The number of days per week with fecal incontinence episodes decreased from a median of 7 (range, 2-7) to 0.38 (range, 0-1). The median number of bowel movements recorded in patient diaries fell from 5 (range, 4-12) to 2 (range, 1-6). The median Wexner score decreased from 18 (range, 13-20) to 6 (range, 0-16), while the LARS score declined from 38.5 (range, 37-42) to 19 (range, 4-28). The FIQL and EQ-5D questionnaires demonstrated enhanced quality of life.
CONCLUSION
SNM may benefit patients diagnosed with LARS following rectal cancer surgery when conservative options have failed, and the treatment outcomes may possess long-term sustainability.
PubMed: 38946094
DOI: 10.3393/ac.2023.00542.0077 -
Internal Medicine (Tokyo, Japan) 2024Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The...
Activated CD4 T Cell Proportion in the Peripheral Blood Correlates with the Duration of Cytokine Release Syndrome and Predicts Clinical Outcome after Chimeric Antigen Receptor T Cell Therapy.
Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The characteristic toxicities of CAR T cell therapy include cytokine release syndrome (CRS) and prolonged cytopenia. We investigated the factors associated with these complications after CAR T cell therapy by analyzing lymphocyte subsets following CAR T cell infusion. Methods We retrospectively analyzed peripheral blood samples on days 7, 14, and 28 after tisagenlecleucel (tisa-cel) infusion by flow cytometry at our institution between June 2020 and September 2022. Patients Thirty-five patients with R/R DLBCL who received tisa-cel therapy were included. Results A flow cytometry-based analysis of blood samples from these patients revealed that the proportion of CD4CD25CD127 T cells (hereafter referred to as "activated CD4 T cells" ) among the total CD4 T cells on day 7 after tisa-cel infusion correlated with the duration of CRS (r=0.79, p<0.01). In addition, a prognostic analysis of the overall survival (OS) using time-dependent receiver operating characteristic curves indicated a significantly more favorable OS and progression-free survival of patients with a proportion of activated CD4 T cells among the total CD4 T cells <0.73 (p=0.01, and p<0.01, respectively). Conclusion These results suggest that the proportion of activated CD4 T cells on day 7 after tisa-cel infusion correlates with the CRS duration and predicts clinical outcomes after CAR T cell therapy. Further studies with a larger number of patients are required to validate these observations.
Topics: Humans; Male; Female; Cytokine Release Syndrome; Immunotherapy, Adoptive; Middle Aged; Lymphoma, Large B-Cell, Diffuse; Aged; Retrospective Studies; CD4-Positive T-Lymphocytes; Adult; Treatment Outcome; Receptors, Chimeric Antigen; Prognosis; Receptors, Antigen, T-Cell
PubMed: 38945932
DOI: 10.2169/internalmedicine.2556-23 -
International Journal of Surgery Case... Jun 2024Idiopathic granulomatous mastitis (IGM) is a benign inflammatory breast disease, commonly presented with a sensitive breast lump and developing scars. Currently, there...
INTRODUCTION AND IMPORTANCE
Idiopathic granulomatous mastitis (IGM) is a benign inflammatory breast disease, commonly presented with a sensitive breast lump and developing scars. Currently, there is no definitive treatment for IGM but Antibiotics, steroids, immunosuppressive drugs or a surgical treatments are the usual options. This case series aimed to evaluate the effectiveness of cotrimoxazole in treatment of IGM as there is no clinical consensus on the best and most widely acknowledged therapeutic management for IGM.
CASE PRESENTATION
All IGM patients were treated by Cotrimoxazole (800 mg BD for one week), and they were assessed at a month, 3 months, and 6 months after that. The primary outcome was an improvement in presenting complaints and symptoms such as palpable mass, bulging, pain, erythema and hypersensitivity of breast skin, breast discharge and fluctuation. The secondary outcome was the refractory rate within 6 months. Number of 20 patients were included. At the baseline, participants exhibited various symptoms such as bulging, pain and erythema (100 %), breast discharge (80 %), and fluctuation (30 %). After the intervention, there was a significant decrease in the prevalence of symptoms over the study period. The prevalence of bulging and pain, erythema, discharge, and fluctuation symptoms were decreasedto 5 %, 0 %, and 0 %, respectively. The refractory rate of IGM within six months of cotrimoxazole treatment was estimated 30 %.
CLINICAL DISCUSSION
In this study, the treatment approach did not involve corticosteroids and invasive procedures and the recurrence rate of IGM within the six months was lower than in similar studies that employed steroids alone or any more invasive treatments. Additionally, our study showed a high healing rate with resolution of inflammation, pain, discharge, and fluctuation. These results suggest that cotrimoxazole may be a more favorable option than high-dose corticosteroids and a comparable alternative to low-dose corticosteroids regarding recurrence rates.
CONCLUSION
Cotrimoxazole may be an effective treatment option for idiopathic granulomatous mastitis. However, further research is needed on different treatment options.
PubMed: 38945013
DOI: 10.1016/j.ijscr.2024.109959 -
Nature Communications Jun 2024Children in malaria-endemic regions can experience repeated Plasmodium infections over short periods of time. Effects of re-infection on multiple co-existing CD4 T cell...
Children in malaria-endemic regions can experience repeated Plasmodium infections over short periods of time. Effects of re-infection on multiple co-existing CD4 T cell subsets remain unresolved. Here, we examine antigen-experienced CD4 T cells during re-infection in mice, using scRNA-seq/TCR-seq and spatial transcriptomics. TCR transgenic T cells initiate rapid Th1/Tr1 recall responses prior to proliferating, while GC Tfh counterparts are refractory, with T/Tfh-like cells exhibiting modest non-proliferative responses. Th1-recall is a partial facsimile of primary Th1-responses, with no upregulated effector-associated genes being unique to recall. Polyclonal, TCR-diverse, CD4 T cells exhibit similar recall dynamics, with individual clones giving rise to multiple effectors including highly proliferative Th1/Tr1 cells, as well as GC Tfh and Tfh-like cells lacking proliferative capacity. Thus, we show substantial diversity in recall responses mounted by multiple co-existing CD4 T cell subsets in the spleen, and present graphical user interfaces for studying gene expression dynamics and clonal relationships during re-infection.
Topics: Animals; Malaria; CD4-Positive T-Lymphocytes; Mice; Reinfection; Th1 Cells; Mice, Inbred C57BL; Spleen; Receptors, Antigen, T-Cell; Mice, Transgenic; Female; Immunologic Memory
PubMed: 38944658
DOI: 10.1038/s41467-024-49879-6 -
Antiviral Research Jun 2024Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that establishes a lifelong infection in sensory neurons of infected individuals, accompanied with...
Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that establishes a lifelong infection in sensory neurons of infected individuals, accompanied with intermittent reactivation of latent virus causing (a)symptomatic virus shedding. Whereas acyclovir (ACV) is a safe and highly effective antiviral to treat HSV-1 infections, long-term usage can lead to emergence of ACV resistant (ACV) HSV-1 and subsequently ACV refractory disease. Here, we isolated an HSV-1 strain from a patient with reactivated herpetic eye disease that did not respond to ACV treatment. The isolate carried a novel non-synonymous F289S mutation in the viral UL23 gene encoding the thymidine kinase (TK) protein. Because ACV needs conversion by viral TK and subsequently cellular kinases to inhibit HSV-1 replication, the UL23 gene is commonly mutated in ACV HSV-1 strains. The potential role of the F289S mutation causing ACV was investigated using CRISPR/Cas9-mediated HSV-1 genome editing. Reverting the F289S mutation in the original clinical isolate to the wild-type sequence S289F resulted in an ACV-sensitive (ACV) phenotype, and introduction of the F289S substitution in an ACV HSV-1 reference strain led to an ACV phenotype. In summary, we identified a new HSV-1 TK mutation in the eye of a patient with ACV refractory herpetic eye disease, which was identified as the causative ACV mutation with the aid of CRISPR/Cas9-mediated genome engineering technology. Direct editing of clinical HSV-1 isolates by CRISPR/Cas9 is a powerful strategy to assess whether single residue substitutions are causative to a clinical ACV phenotype.
PubMed: 38944159
DOI: 10.1016/j.antiviral.2024.105950 -
Epilepsy & Behavior : E&B Jun 2024Status epilepticus (SE) is a medical and neurologic emergency that may lead to permanent brain damage, morbidity, or death. Animal models of SE are particularly...
Status epilepticus (SE) is a medical and neurologic emergency that may lead to permanent brain damage, morbidity, or death. Animal models of SE are particularly important to study the pathophysiology of SE and mechanisms of SE resistance to antiseizure medications with the aim to develop new, more effective treatments. In addition to rodents (rats or mice), larger mammalian species such as dogs, pigs, and nonhuman primates are used. This short review describes and discusses the value and limitations of the most frequently used mammalian models of SE. Issues that are discussed include (1) differences between chemical and electrical SE models; (2) the role of genetic background and environment on SE in rodents; (3) the use of rodent models (a) to study the pathophysiology of SE and mechanisms of SE resistance; (b) to study developmental aspects of SE; (c) to study the efficacy of new treatments, including drug combinations, for refractory SE; (d) to study the long-term consequences of SE and identify biomarkers; (e) to develop treatments that prevent or modify epilepsy; (e) to study the pharmacology of spontaneous seizures; (4) the limitations of animal models of induced SE; and (5) the advantages (and limitations) of naturally (spontaneously) occurring SE in epileptic dogs and nonhuman primates. Overall, mammalian models of SE have significantly increased our understanding of the pathophysiology and drug resistance of SE and identified potential targets for new, more effective treatments. This paper was presented at the 9th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in April 2024.
PubMed: 38944026
DOI: 10.1016/j.yebeh.2024.109923