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Research (Washington, D.C.) 2024Hyperthermia therapy is considered an effective anticancer strategy. However, high temperature can trigger an excessive inflammatory response, leading to tumor...
Hyperthermia therapy is considered an effective anticancer strategy. However, high temperature can trigger an excessive inflammatory response, leading to tumor self-protection, immunosuppression, metastasis, and recurrence. To address this issue, we reported a multifunctional photothermal nanoplatform to achieve mild hyperthermia photothermal therapy (mild PTT) based on cisplatin (DDP) and a ferrocene metal-organic framework (MOF-Fc) nanocomposite, which can specifically enhance ferroptosis-triggered oxidative stress levels and synchronously amplify mild hyperthermia PTT-mediated anticancer responses. Both in vitro and in vivo antineoplastic results verify the superiority of mild PTT with DDP/MOF-Fc@HA. The combination of DDP and MOF-Fc exhibits Fenton catalytic activity and glutathione depletion capacity, magnifying mild hyperthermia effects via the radical oxygen species (ROS)-adenosine triphosphate (ATP)-HSP silencing pathway, with important implications for clinical hyperthermia therapy.
PubMed: 38952997
DOI: 10.34133/research.0397 -
Zhongguo Xue Xi Chong Bing Fang Zhi Za... Jun 2024To investigate the involvement of the high mobility group box protein B1 (HMGB1)-Toll-like receptor 2 (TLR2)/TLR4-nuclear factor κB (NF-κB) pathway in the intestinal...
OBJECTIVE
To investigate the involvement of the high mobility group box protein B1 (HMGB1)-Toll-like receptor 2 (TLR2)/TLR4-nuclear factor κB (NF-κB) pathway in the intestinal mucosal injury induced by infection, and to examine the effect of oxymatrine (OMT) on in mice.
METHODS
Forty SPF 4-week-old BALB/c mice were randomly divided into four groups, including the control group, infection group, glycyrrhizin (GA) group and OMT group. Each mouse was orally administered with 1 × 10 oocysts one week in the infection, GA and OMT groups following dexamethasone-induced immunosuppression to model intestinal infections in mice. Upon successful modeling, mice in the GA group were intraperitoneally injected with GA at a daily dose of 25.9 mL/kg for successive two weeks, and animals in the OMT group were orally administered OMT at a daily dose of 50 mg/kg for successive two weeks, while mice in the control group were given normal food and water. All mice were sacrificed two weeks post-treatment, and proximal jejunal tissues were sampled. The pathological changes of mouse intestinal mucosal specimens were observed using hematoxylin-eosin (HE) staining, and the mouse intestinal villous height, intestinal crypt depth and the ratio of intestinal villous height to intestinal crypt depth were measured. The occludin and zonula occludens protein 1 (ZO1) expression was determined in mouse intestinal epithelial cells using immunohistochemistry, and the relative expression of , , , myeloid differentiation primary response gene 88 () and was quantified in mouse jejunal tissues using quantitative real-time PCR (qPCR) assay.
RESULTS
HE staining showed that the mouse intestinal villi were obviously atrophic, shortened, and detached, and the submucosal layer of the mouse intestine was edematous in the infection group as compared with the control group, while the mouse intestinal villi tended to be structurally intact and neatly arranged in the GA and OMT groups. There were significant differences among the four groups in terms of the mouse intestinal villous height ( = 6.207, = 0.000 5), intestinal crypt depth ( = 6.903, = 0.000 3) and the ratio of intestinal villous height to intestinal crypt depth ( = 37.190, < 0.000 1). The mouse intestinal villous height was lower in the infection group than in the control group [(321.9 ± 41.1) μm vs. (399.5 ± 30.9) μm; = 4.178, < 0.01] and the GA group [(321.9 ± 41.1) μm vs. (383.7 ± 42.7) μm; = 3.130, < 0.01], and the mouse intestinal crypt depth was greater in the infection group [(185.0 ± 35.9) μm] than in the control group [(128.4 ± 23.6) μm] ( = 3.877, < 0.01) and GA group [(143.3 ± 24.7) μm] ( = 2.710, < 0.05). The mouse intestinal villous height was greater in the OMT group [(375.3 ± 22.9) μm] than in the infection group ( = 3.888, < 0.01), and there was no significant difference in mouse intestinal villous height between the OMT group and the control group ( = 1.989, > 0.05). The mouse intestinal crypt depth was significantly lower in the OMT group [(121.5 ± 27.3) μm] than in the infection group ( = 4.133, < 0.01), and there was no significant difference in mouse intestinal crypt depth between the OMT group and the control group ( = 0.575, > 0.05). The ratio of the mouse intestinal villous height to intestinal crypt depth was significantly lower in the infection group (1.8 ± 0.2) than in the control group (3.1 ± 0.3) ( = 10.540, < 0.01) and the GA group (2.7 ± 0.3) ( = 7.370, < 0.01), and the ratio of the mouse intestinal villous height to intestinal crypt depth was significantly higher in the OMT group (3.1 ± 0.2) than in the infection group ( = 15.020, < 0.01); however, there was no significant difference in the ratio of the mouse intestinal villous height to intestinal crypt depth between the OMT group and the control group ( = 0.404, > 0.05). Immunohistochemical staining showed significant differences among the four groups in terms of occludin ( = 28.031, < 0.000 1) and ZO1 expression ( = 14.122, < 0.000 1) in mouse intestinal epithelial cells. The proportion of positive occluding expression was significantly lower in mouse intestinal epithelial cells in the infection group than in the control group [(14.3 ± 4.5)% vs. (28.3 ± 0.5)%; = 3.810, < 0.01], and the proportions of positive occluding expression were significantly higher in mouse intestinal epithelial cells in the GA group [(30.3 ± 1.3)%] and OMT group [(25.8 ± 1.5)%] than in the infection group ( = 7.620 and 5.391, both values < 0.01); however, there was no significant differences in the proportion of positive occluding expression in mouse intestinal epithelial cells between the GA or OMT groups and the control group ( = 1.791 and 2.033, both values > 0.05). The proportion of positive ZO1 expression was significantly lower in mouse intestinal epithelial cells in the infection group than in the control group [(14.4 ± 1.8)% vs. (24.2 ± 2.8)%; = 4.485, < 0.01], and the proportions of positive ZO1 expression were significantly higher in mouse intestinal epithelial cells in the GA group [(24.1 ± 2.3)%] ( = 5.159, < 0.01) and OMT group than in the infection group [(22.5 ± 1.9)%] ( = 4.441, < 0.05); however, there were no significant differences in the proportion of positive ZO1 expression in mouse intestinal epithelial cells between the GA or OMT groups and the control group ( = 0.037 and 0.742, both values > 0.05). qPCR assay showed significant differences among the four groups in terms of ( = 21.980, < 0.000 1), ( = 20.630, < 0.000 1), ( = 17.000, = 0.000 6), ( = 8.907, = 0.000 5) and expression in mouse jejunal tissues ( = 8.889, = 0.000 7). The relative expression of [(5.97 ± 1.07) vs. (1.05 ± 0.07); = 6.482, < 0.05] 、 [(5.92 ± 1.29) vs. (1.10 ± 0.14); = 5.272, < 0.05] 、 [(5.96 ± 1.50) vs. (1.02 ± 0.03); = 4.644, < 0.05] 、 [(3.00 ± 1.26) vs. (1.02 ± 0.05); = 2.734, < 0.05] and [(2.33 ± 0.72) vs. (1.04 ± 0.06); = 2.665, < 0.05] was all significantly higher in mouse jejunal tissues in the infection group than in the control group. A significant reduction was detected in the relative expression of (0.63 ± 0.01), (0.42 ± 0.10), (0.35 ± 0.07), (0.70 ± 0.11) and (0.75 ± 0.01) in mouse jejunal tissues in the GA group relative to the control group ( = 8.629, 5.830, 11.500, 4.729 and 6.898, all values < 0.05), and the relative expression of , , , and significantly reduced in mouse jejunal tissues in the GA group as compared to the infection group ( = 7.052, 6.035, 4.084, 3.165 and 3.274, all values < 0.05). In addition, the relative expression of (1.14 ± 0.60), (1.00 ± 0.24), (1.14 ± 0.07), (0.96 ± 0.25) and N (1.12 ± 0.17) was significantly lower in mouse jejunal tissues in the OMT group than in the infection group ( = 7.059, 5.320, 3.510, 3.466 and 3.273, all values < 0.05); however, there were no significant differences between the OMT and control groups in terms of relative expression of , , , or in mouse jejunal tissues ( = 0.239, 0.518, 1.887, 0.427 and 0.641, all values > 0.05).
CONCLUSIONS
infection causes intestinal inflammatory responses and destruction of intestinal mucosal barrier through up-regulating of the HMGB1-TLR2/TLR4-NF-κB pathway. OMT may suppress the intestinal inflammation and repair the intestinal mucosal barrier through inhibiting the activity of the HMGB1-TLR2/TLR4-NF-κB pathway.
Topics: Animals; Cryptosporidiosis; Quinolizines; Mice, Inbred BALB C; Cryptosporidium parvum; Toll-Like Receptor 4; Mice; Toll-Like Receptor 2; NF-kappa B; Alkaloids; HMGB1 Protein; Signal Transduction; Male; Intestinal Mucosa; Matrines
PubMed: 38952315
DOI: 10.16250/j.32.1374.2024019 -
Journal of Medical Case Reports Jul 2024Pulmonary aspergillosis is a prevalent opportunistic fungal infection that can lead to mortality in pediatric patients with underlying immunosuppression. Appropriate and...
BACKGROUND
Pulmonary aspergillosis is a prevalent opportunistic fungal infection that can lead to mortality in pediatric patients with underlying immunosuppression. Appropriate and timely treatment of pulmonary aspergillosis can play a crucial role in reducing mortality among children admitted with suspected infections.
CASE PRESENTATION
The present study reports three cases of inappropriate treatment of pulmonary aspergillosis caused by Aspergillus flavus in two Iranian pediatric patients under investigation and one Afghan patient. Unfortunately, two of them died. The cases involved patients aged 9, 1.5, and 3 years. They had been diagnosed with pulmonary disorders, presenting nonspecific clinical signs and radiographic images suggestive of pneumonia. The identification of A. flavus was confirmed through DNA sequencing of the calmodulin (CaM) region.
CONCLUSION
A. flavus was the most prevalent cause of pulmonary aspergillosis in pediatric patients. Early diagnosis and accurate antifungal treatment of pulmonary aspergillosis could be crucial in reducing the mortality rate and also have significant potential for preventing other complications among children. Moreover, antifungal prophylaxis seems to be essential for enhancing survival in these patients.
Topics: Humans; Aspergillus flavus; Antifungal Agents; Child; Male; Child, Preschool; Pulmonary Aspergillosis; Infant; Female; Fatal Outcome; Iran
PubMed: 38951939
DOI: 10.1186/s13256-024-04599-9 -
Cureus May 2024Histoplasma capsulatum is a dimorphic fungus that grows in nature as a mold or in culture but converts to a small yeast during cellular invasion. While most...
Histoplasma capsulatum is a dimorphic fungus that grows in nature as a mold or in culture but converts to a small yeast during cellular invasion. While most histoplasmosis infections are primarily asymptomatic or mildly symptomatic, disseminated histoplasmosis is a relentlessly progressive granulomatous disease that can mimic other granulomatous diseases, such as tuberculosis, sarcoidosis or coccidioidomycosis, more so in the proper context of immunosuppression. The current global migrant crisis, particularly the United States migrant crisis conversation is mostly socio-political; however, it also has a public health implication as exemplified by the case of a 35-year-old male who migrated from Haiti via Chile and Mexico to the United States. He presented with a four-day history of fever, generalized body aches, and cough. This case underscores the importance of entertaining a myriad of differentials and avoiding the tendency for anchoring, especially when initial therapy yields little clinical response.
PubMed: 38947682
DOI: 10.7759/cureus.61434 -
Frontiers in Immunology 2024Lymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC... (Comparative Study)
Comparative Study
INTRODUCTION
Lymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC regimen, including dose and frequency.
METHODS
We retrospectively reviewed consecutive patients at a single institution that received LDC prior to treatment with the CD19 directed CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel. Patients treated at our center received fludarabine 30 mg/m and cyclophosphamide 500 mg/m for 3 consecutive days prior to May 2019. After this timepoint patients routinely received fludarabine 40 mg/m and cyclophosphamide 500 mg/m for 2 consecutive days. Clinical data from each cohort were obtained from the electronic medical record and compared for differences in CAR T-cell efficacy and toxicity.
RESULTS
From June 2018 to August 2023, LDC was given to 92 patients prior to CD19 directed CAR T-cell therapy for relapsed non-Hodgkin's lymphoma. Twenty-eight patients received a 3-day regimen, and 64 patients received a 2-day regimen. In the total cohort, 75% of patients received axicabtagene ciloleucel and 25% received tisagenlecleucel. The overall response rates in both the 2-day regimen group and the 3-day regimen group were similar (69% vs 75%, p= 0.21) as were the complete response rates (50% vs 54%, p=0.82). There were no significant differences between the 2-day and 3-day regimens for grade 2-4 cytokine release syndrome (55% vs 50%, p=0.82), grade 2-4 immune effector cell associated-neurotoxicity syndrome (42% vs 29%, p=0.25), or time to resolution of neutropenia or thrombocytopenia. The rate of prolonged platelet recovery lasting greater than 60 days was higher with the 3-day regimen (9% vs 27%, p=0.026).
DISCUSSION
As the number of patients eligible for CAR T-cell therapy continues to increase, optimizing each component of therapy is necessary. We show that a 2-day regimen of LDC with fludarabine and cyclophosphamide is feasible without significant impact on CAR T-cell efficacy or toxicity. Prospective studies are necessary to further determine the most effective LDC regimen.
Topics: Humans; Immunotherapy, Adoptive; Male; Middle Aged; Female; Antigens, CD19; Vidarabine; Retrospective Studies; Lymphoma, Non-Hodgkin; Aged; Cyclophosphamide; Adult; Lymphocyte Depletion; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Receptors, Antigen, T-Cell
PubMed: 38947326
DOI: 10.3389/fimmu.2024.1403145 -
Frontiers in Immunology 2024Neuromyelitis optica spectrum disorder (NMOSD) is a clinical syndrome characterized by attacks of acute optic neuritis and transverse myelitis. We report a case with... (Review)
Review
Neuromyelitis optica spectrum disorder (NMOSD) is a clinical syndrome characterized by attacks of acute optic neuritis and transverse myelitis. We report a case with paraneoplastic NMOSD that improved after immunosuppressive therapy, surgical resection, and chemotherapy. A 48-year-old woman initially presented with gradual binocular visual loss over the course of one week. The patient was evaluated using magnetic resonance imaging (MRI), computed tomography (CT), visual evoked potential (VEP), pathological biopsy, immunohistochemistry, and autoimmune antibody testing. The brain MRI findings were normal. The VEP revealed prolonged P100 latencies in the right eye and an absence of significant waves in the left eye. Positive serum AQP4-IgG antibodies were found. The patient was diagnosed as NMOSD. Then the patient responded well to treatment with methylprednisolone. An ovarian tumor was found in the patient using abdominal MRI and CT. The tumor was surgically resected, and a pathological biopsy revealed that it was ovarian dysgerminoma. The patient received four rounds of chemotherapy after surgery. One month after the final chemotherapy treatment, a positron emission tomography (PET) scan revealed no tumor. The vision of the patient gradually recovered and serum AQP4 was negative. Furthermore, we summarized the characteristics of patients diagnosed with paraneoplastic NMOSD associated with ovarian neoplasms in previous studies. This is a characteristic case of overlapping NMOSD and ovarian dysgerminoma, demonstrating the importance of tumor therapy in cases of paraneoplastic NMOSD.
Topics: Humans; Female; Ovarian Neoplasms; Middle Aged; Neuromyelitis Optica; Aquaporin 4; Dysgerminoma; Autoantibodies; Magnetic Resonance Imaging
PubMed: 38947316
DOI: 10.3389/fimmu.2024.1424243 -
Haematologica Jul 2024
Topics: Humans; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Transplantation, Homologous; Immunosuppressive Agents; Immunosuppression Therapy; Graft vs Host Disease; Male
PubMed: 38946648
DOI: 10.3324/haematol.2024.285749 -
Cellular Signalling Jun 2024Adenosine 5'-triphosphate (ATP) is a vital element in energy information. It plays a critical role in transmitting signals inside the body, which is necessary for...
Adenosine 5'-triphosphate (ATP) is a vital element in energy information. It plays a critical role in transmitting signals inside the body, which is necessary for controlling the life activities of all cells, including tumor cells [1]. Its significance extends from intracellular signaling pathways to tumor regression. Purinergic signaling, a form of extracellular paracrine signaling, relies on purine nucleotides. Extracellular ectonucleotidases convert these purine nucleotides to their respective di and mono-phosphate nucleoside forms, contributing significantly to immune biology, cancer biology, and inflammation studies. ATP functions as a mighty damage-linked molecular pattern when released outside the cell, accumulating in inflammatory areas. In the tumor microenvironment (TME), purinergic receptors such as ATP-gated ion channels PX1-5 and G protein-coupled receptors (GPCR) (PY) interact with ATP and other nucleotides, influencing diverse immune cell activities. CD39 and CD73-mediated extracellular ATP degradation contributes to immunosuppression by diminishing ATP-dependent activation and generating adenosine (ADO), potentially hindering antitumor immunity and promoting tumor development. Unraveling the complexities of extracellular ATP (e-ATP) and ADO effects on the TME poses challenges in identifying optimal treatment targets, yet ongoing investigations aim to devise strategies combating e-ATP/ADO-induced immunosuppression, ultimately enhancing anti-tumor immunity. This review explores e-ATP metabolism, its purinergic signaling, and therapeutic strategies targeting associated receptors and enzymes.
PubMed: 38945420
DOI: 10.1016/j.cellsig.2024.111281 -
Cancer Letters Jun 2024The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This...
The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This creates a hostile immune landscape that impedes effective immune responses. The interleukin-1 (IL-1) receptor antagonist (IL1RN), a key anti-inflammatory molecule, plays a significant role in suppressing IL-1-related immune and inflammatory responses. Our research investigates the oncogenic role of IL1RN in PCa, particularly its interactions with muscarinic acetylcholine receptor 4 (CHRM4), and its involvement in driving immunosuppressive pathways and M2-like macrophage polarization within the PCa TME. We demonstrate that following androgen deprivation therapy (ADT), the IL1RN-CHRM4 interaction in PCa activates the MAPK/AKT signaling pathway. This activation upregulates the transcription factors E2F1 and MYCN, stimulating IL1RN production and creating a positive feedback loop that increases CHRM4 abundance in both PCa cells and M2-like macrophages. This ADT-driven IL1RN/CHRM4 axis significantly enhances immune checkpoint markers associated with neuroendocrine differentiation and treatment-resistant outcomes. Higher serum IL1RN levels are associated with increased disease aggressiveness and M2-like macrophage markers in advanced PCa patients. Additionally, elevated IL1RN levels correlate with better clinical outcomes following immunotherapy. Clinical correlations between IL1RN and CHRM4 expression in advanced PCa patients and neuroendocrine PCa organoid models highlight their potential as therapeutic targets. Our data suggest that targeting the IL1RN/CHRM4 signaling could be a promising strategy for managing PCa progression and enhancing treatment responses.
PubMed: 38945201
DOI: 10.1016/j.canlet.2024.217090 -
Journal of Extracellular Vesicles Jul 2024Haematopoiesis dysregulation with the presence of immature myeloid and erythroid immunosuppressive cells are key characteristics of the immune escape phase of tumour...
Haematopoiesis dysregulation with the presence of immature myeloid and erythroid immunosuppressive cells are key characteristics of the immune escape phase of tumour development. Here, the role of in vitro generated B16F10 tumour cell-derived extracellular vesicles (tEVs) as indirect cellular communicators, participating in tumour-induced dysregulation of haematopoiesis, was explored. The isolated tEVs displayed features of small EVs with a size range of 100-200 nm, expressed the common EV markers CD63, CD9, and Alix, and had a spherical shape with a lipid bilayer membrane. Proteomic profiling revealed significant levels of angiogenic factors, particularly vascular endothelial growth factor (VEGF), osteopontin, and tissue factor, associated with the tEVs. Systemic administration of these tEVs in syngeneic mice induced splenomegaly and disrupted haematopoiesis, leading to extramedullary haematopoiesis, expansion of splenic immature erythroid progenitors, reduced bone marrow cellularity, medullary expansion of granulocytic myeloid suppressor cells, and the development of anaemia. These effects closely mirrored those observed in tumour-bearing mice and were not seen after heat inactivating the tEVs. In vitro studies demonstrated that tEVs independently induced the expansion of bone marrow granulocytic myeloid suppressor cells and B cells while reducing the frequency of cells in the erythropoietic lineage. These effects of tEVs were significantly abrogated by the blockade of VEGF or heat inactivation. Our findings underscore the important role of tEVs in dysregulating haematopoiesis during the immune escape phase of cancer immunoediting, suggesting their potential as targets for addressing immune evasion and reinstating normal hematopoietic processes.
Topics: Animals; Extracellular Vesicles; Mice; Hematopoiesis; Melanoma, Experimental; Mice, Inbred C57BL; Vascular Endothelial Growth Factor A; Cell Line, Tumor
PubMed: 38944672
DOI: 10.1002/jev2.12471