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Cancer Chemotherapy and Pharmacology Jun 2024Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages...
Immunoregulatory cyclophilin a improves low-dose chemotherapy with a modulation of the immune tumor microenvironment in experimental models of melanoma B16 and lymphoma EL4 in vivo.
PURPOSE
Different regimens of low-dose chemotherapy (LDC) are currently being actively developed and introduced into clinical practice. Along with its obvious advantages compared to conventional chemotherapy (low toxicity, prevention of drug resistance), LDC could also stimulate anti-tumor immune responses in a patient by activating effectors of innate and adaptive immunity and diminishing tumor-associated immunosuppression. As non-myeloablative, LDC could be successfully combined with different anti-cancer immunotherapeutic strategies, including immunoregulatory cytokines. Secreted cyclophilin A (CypA) is of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Thus, rhCypA could be potentially proposed as a perspective component of combined therapy with LDC.
METHODS
In this work, we evaluated the anti-tumor effects of rhCypA combined with low doses of cyclophosphamide, doxorubicin, dacarbazine, and paclitaxel in the experimental mouse tumor models of melanoma B16 and lymphoma EL4 in vivo.
RESULTS
Synergic and potentiating effects of rhCypA combined with LDC were shown in these studies. Furthermore, as a monotherapeutic agent and a component of combined chemoimmunotherapy, rhCypA was shown to modulate the immune tumor microenvironment by enhancing tumor infiltration with macrophages, NK cells, and T cells. It was also found that rhCypA stimulated both systemic and local anti-tumor immune responses.
CONCLUSION
RhCypA could be potentially proposed as a perspective component of the combined cancer chemoimmunotherapy.
PubMed: 38913118
DOI: 10.1007/s00280-024-04691-3 -
Infection and Drug Resistance 2024Syphilis is a complex, systemic infectious disease caused by . Secondary syphilitic lesions typically manifest within 3 months following initial exposure to . The...
Syphilis is a complex, systemic infectious disease caused by . Secondary syphilitic lesions typically manifest within 3 months following initial exposure to . The predominant cutaneous manifestations of secondary syphilis are macula and papule. Certain individuals with syphilis may present with an atypical rash during the secondary stage owing to immunosuppression and other factors. Herein, we report a rare case of atypical recurrent secondary syphilis around the anus in a 65-year-old woman. Based on cerebrospinal fluid findings and skin biopsy results, the patient was ultimately diagnosed as neurosyphilis and recurrent secondary syphilis. Following intravenous antibiotic therapy, the patient's rash improved significantly. This case underscores the importance for physicians to remain vigilant regarding the possibility of syphilis when encountering cases exhibiting unusual clinical manifestations, as a definitive diagnosis necessitates a comprehensive evaluation.
PubMed: 38912217
DOI: 10.2147/IDR.S470153 -
Frontiers in Immunology 2024Immunocompromised patients are at particular risk of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection and previous findings suggest that the...
BACKGROUND
Immunocompromised patients are at particular risk of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection and previous findings suggest that the infection or vaccination induced immune response decreases over time. Our main goal was to investigate the SARS-CoV-2-specific immune response in rheumatoid arthritis patients and healthy controls over prolonged time.
METHODS
The SARS-CoV-2-specific humoral immune response was measured by Elecsys Anti-SARS-CoV-2 Spike (S) immunoassay, and antibodies against SARS-CoV-2 nucleocapsid protein (NCP) were also evaluated by Euroimmun enzyme-linked immunosorbent assay (ELISA) test. The SARS-CoV-2-specific T-cell response was detected by an IFN- γ release assay.
RESULTS
We prospectively enrolled 84 patients diagnosed with rheumatoid arthritis (RA) and 43 healthy controls in our longitudinal study. Our findings demonstrate that RA patients had significantly lower anti-S antibody response and reduced SARS-CoV-2-specific T-cell response compared to healthy controls (p<0.01 for healthy controls, p<0.001 for RA patients). Furthermore, our results present evidence of a notable increase in the SARS-CoV-2-specific humoral immune response during the follow-up period in both study groups (p<0.05 for healthy volunteers, p<0.0001 for RA patients, rank-sum test). Participants who were vaccinated against Coronavirus disease-19 (COVID-19) during the interim period had 2.72 (CI 95%: 1.25-5.95, p<0.05) times higher anti-S levels compared to those who were not vaccinated during this period. Additionally, individuals with a confirmed SARS-CoV-2 infection exhibited 2.1 times higher (CI 95%: 1.31-3.37, p<0.01) anti-S levels compared to those who were not infected during the interim period. It is worth noting that patients treated with targeted therapy had 52% (CI 95%: 0.25-0.94, p<0.05) lower anti-S levels compared to matched patients who did not receive targeted therapy. Concerning the SARS-CoV-2-specific T-cell response, our findings revealed that its level had not changed substantially in the study groups.
CONCLUSION
Our present data revealed that the level of SARS-CoV-2-specific humoral immune response is actually higher, and the SARS-CoV-2-specific T-cell response remained at the same level over time in both study groups. This heightened humoral response, the nearly permanent SARS-CoV-2-specific T-cell response and the coexistence of different SARS-CoV-2 variants within the population, might be contributing to the decline in severe COVID-19 cases.
Topics: Humans; Arthritis, Rheumatoid; SARS-CoV-2; Male; Female; Middle Aged; COVID-19; Antibodies, Viral; Immunity, Humoral; Aged; Spike Glycoprotein, Coronavirus; Adult; T-Lymphocytes; Coronavirus Nucleocapsid Proteins; Prospective Studies; Phosphoproteins; Case-Control Studies; Longitudinal Studies
PubMed: 38911866
DOI: 10.3389/fimmu.2024.1397052 -
Transplantation Direct Jul 2024The mammalian target of rapamycin inhibitor (mTORi) therapy after kidney transplantation is solely monitored pharmacokinetically, not necessarily reflecting...
BACKGROUND
The mammalian target of rapamycin inhibitor (mTORi) therapy after kidney transplantation is solely monitored pharmacokinetically, not necessarily reflecting PI3K-Akt-mTOR pathway blockade efficacy leading to potential under-or overimmunosuppression.
METHODS
In this cross-sectional study, phosphoflow cytometry was used to determine the efficacy of mTOR inhibition in peripheral T- and B-lymphocyte subsets by assessing p70S6 kinase (p70S6K) phosphorylation in renal transplant recipients upon treatment with a combination of either mTORi and calcineurin inhibitors (n = 18), or mTORi with mycophenolic acid (n = 9). Nine dialysis patients with end-stage renal disease and 17 healthy age-matched volunteers served as controls.
RESULTS
mTORi treatment reduced p70S6K phosphorylation in CD4, CD8 T, and CD19 B cells compared with healthy controls (HCs). Subpopulation analysis of CD4 T cells and CD19 B cells revealed a significant reduction of p70S6K phosphorylation in CD4CD45RACD25 Th cells ( < 0.05), CD24CD38 transitional B cells ( < 0.001), CD24CD38 memory B cells ( < 0.001), and CD24CD38-naive B cells ( < 0.05) upon mTORi treatment, whereas CD4CD45RACD25CD127 regulatory T cells and CD24CD38 plasmablasts were not affected. Compared with mTORi + mycophenolic acid therapy, mTORi + calcineurin inhibitor treatment exhibited an even stronger inhibition of p70S6K phosphorylation in CD4CD45RACD25 Th cells and CD8 T cells. However, trough levels of mTORi did not correlate with p70S6K phosphorylation.
CONCLUSIONS
mTORi selectively inhibited p70S6K phosphorylation in select lymphocyte subtypes. Assessing p70S6K phosphorylation by phosphoflow cytometry may serve as an approach to understand cell subset specific effects of mTORi providing detailed pharmacodynamic information for individualizing immunosuppression.
PubMed: 38911271
DOI: 10.1097/TXD.0000000000001666 -
Cureus May 2024Background Erythema nodosum leprosum (ENL) is an immune complex-mediated reaction that clinically presents as tender erythematous evanescent nodules, mostly associated...
Background Erythema nodosum leprosum (ENL) is an immune complex-mediated reaction that clinically presents as tender erythematous evanescent nodules, mostly associated with systemic symptoms. Oral prednisolone is the drug of choice, with doses ranging from 0.5 to 1 mg/kg. Some cases may develop new lesions and systemic symptoms despite 1 mg/kg prednisolone, and in ideal practice, physicians escalate the prednisolone dose for immediate arrest of inflammation to prevent complications. However, a high dose of prednisolone has more side effects in the long term and causes more immunosuppression. Methods In cases of ENL, those not responding to a conventional once-daily regimen were given a split dose of oral prednisolone instead of increasing the dose. They were followed up for response, and serum cortisol was measured to see for hypothalamic-pituitary-adrenal (HPA) axis suppression. Results Eight cases of ENL (three nodular, three necrotic, one pustular, and one nodulcerative) had a dramatic response to split-dose therapy without any relapse and HPA axis suppression. Conclusion A split-dosing regimen can be a good treatment option in ENL with better control, less steroid dependency, and a lower relapse rate.
PubMed: 38910715
DOI: 10.7759/cureus.60888 -
Biochemical and Biophysical Research... Jun 2024Dendritic cells (DCs) mediated T-cell responses is critical to anti-tumor immunity. This study explores immunometabolic attributes of DC, emphasizing on mitochondrial... (Review)
Review
Immunometabolic characteristics of Dendritic Cells and its significant modulation by mitochondria-associated signaling in the tumor microenvironment influence cancer progression.
Dendritic cells (DCs) mediated T-cell responses is critical to anti-tumor immunity. This study explores immunometabolic attributes of DC, emphasizing on mitochondrial association, in Tumor Microenvironment (TME) that regulate cancer progression. Conventional DC subtypes cross-present tumor-associated antigens to activate lymphocytes. However, plasmacytoid DCs participate in both pro- and anti-tumor signaling where mitochondrial reactive oxygen species (mtROS) play crucial role. CTLA-4, CD-47 and other surface-receptors of DC negatively regulates T-cell. Increased glycolysis-mediated mitochondrial citrate buildup and translocation to cytosol with augmented NADPH, enhances mitochondrial fatty acid synthesis fueling DCs. Different DC subtypes and stages, exhibit variable mitochondrial content, membrane potential, structural dynamics and bioenergetic metabolism regulated by various cytokine stimulation, e.g., GM-CSF, IL-4, etc. CD8α cDC1s augmented oxidative phosphorylation (OXPHOS) which diminishes at advance effector stages. Glutaminolysis in mitochondria supplement energy in DCs but production of kynurenine and other oncometabolites leads to immunosuppression. Mitochondria-associated DAMPs cause activation of cGAS-STING pathway and inflammasome oligomerization stimulating DC and T cells. In this study, through a comprehensive survey and critical analysis of the latest literature, the potential of DC metabolism for more effective tumor therapy is highlighted. This underscores the need for future research to explore specific therapeutic targets and potential drug candidates.
PubMed: 38909531
DOI: 10.1016/j.bbrc.2024.150268 -
Journal For Immunotherapy of Cancer Jun 2024The dynamic interplay between tyrosine kinase inhibitors (TKIs) and the tumor immune microenvironment (TME) plays a crucial role in the therapeutic trajectory of...
BACKGROUND
The dynamic interplay between tyrosine kinase inhibitors (TKIs) and the tumor immune microenvironment (TME) plays a crucial role in the therapeutic trajectory of non-small cell lung cancer (NSCLC). Understanding the functional dynamics and resistance mechanisms of TKIs is essential for advancing the treatment of NSCLC.
METHODS
This study assessed the effects of short-term and long-term TKI treatments on the TME in NSCLC, particularly targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations. We analyzed changes in immune cell composition, cytokine profiles, and key proteins involved in immune evasion, such as laminin subunit γ-2 (LAMC2). We also explored the use of aspirin as an adjunct therapy to modulate the TME and counteract TKI resistance.
RESULTS
Short-term TKI treatment enhanced T cell-mediated tumor clearance, reduced immunosuppressive M2 macrophage infiltration, and downregulated LAMC2 expression. Conversely, long-term TKI treatment fostered an immunosuppressive TME, contributing to drug resistance and promoting immune escape. Differential responses were observed among various oncogenic mutations, with ALK-targeted therapies eliciting a stronger antitumor immune response compared with EGFR-targeted therapies. Notably, we found that aspirin has potential in overcoming TKI resistance by modulating the TME and enhancing T cell-mediated tumor clearance.
CONCLUSIONS
These findings offer new insights into the dynamics of TKI-induced changes in the TME, improving our understanding of NSCLC challenges. The study underscores the critical role of the TME in TKI resistance and suggests that adjunct therapies, like aspirin, may provide new strategies to enhance TKI efficacy and overcome resistance.
Topics: Tumor Microenvironment; Humans; Protein Kinase Inhibitors; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Animals; Mice; Drug Resistance, Neoplasm; Female; ErbB Receptors; Cell Line, Tumor; Mutation
PubMed: 38908857
DOI: 10.1136/jitc-2024-009165 -
Medicina 2024Pneumatosis intestinalis and pneumoperitoneum are not pathological entities in themselves, they are radiological signs that result from some underlying condition. In...
Pneumatosis intestinalis and pneumoperitoneum are not pathological entities in themselves, they are radiological signs that result from some underlying condition. In general, these are associated with serious intra-abdominal processes that result in emergency surgeries with bowel resections. Below, we present the case of an 80-year-old woman, diagnosed with stage IV breast cancer under treatment with fulvestrant and ribociclib, who was admitted to our center due to abdominal pain and vomiting. She was diagnosed with intestinal pneumatosis and pneumoperitoneum, so she underwent exploratory laparotomy for suspected intestinal ischemia. There was no evidence of intestinal necrosis or perforation, so resection was not performed. She progressed satisfactorily during hospitalization and in the tomographic control one month after discharge there was complete resolution of the condition. Although this condition has been described in relation to episodes of increased intra-abdominal pressure, such as emesis, it has also been described in patients with neoplasms, mainly of the digestive tract, either due to local damage or toxicity associated with chemotherapy. We found no reports in the literature of pneumatosis intestinalis linked to this antineoplastic medication in humans. Probably in our case the etiology was multifactorial. It is possible that ribociclib played a role, either through an indirect mechanism associated with vomiting and immunosuppression or directly on the enterocyte due to its non-specific cellular mechanism of action.
Topics: Humans; Female; Aged, 80 and over; Pneumatosis Cystoides Intestinalis; Pneumoperitoneum; Breast Neoplasms
PubMed: 38907977
DOI: No ID Found -
Frontiers of Medicine Jun 2024RNA modification is an essential component of the epitranscriptome, regulating RNA metabolism and cellular functions. Several types of RNA modifications have been... (Review)
Review
RNA modification is an essential component of the epitranscriptome, regulating RNA metabolism and cellular functions. Several types of RNA modifications have been identified to date; they include N-methyladenosine (mA), N-methyladenosine (mA), 5-methylcytosine (mC), N-methylguanosine (mG), N,2'-O-dimethyladenosine (mA), N-acetylcytidine (acC), etc. RNA modifications, mediated by regulators including writers, erasers, and readers, are associated with carcinogenesis, tumor microenvironment, metabolic reprogramming, immunosuppression, immunotherapy, chemotherapy, etc. A novel perspective indicates that regulatory subunits and post-translational modifications (PTMs) are involved in the regulation of writer, eraser, and reader functions in mediating RNA modifications, tumorigenesis, and anticancer therapy. In this review, we summarize the advances made in the knowledge of different RNA modifications (especially mA) and focus on RNA modification regulators with functions modulated by a series of factors in cancer, including regulatory subunits (proteins, noncoding RNA or peptides encoded by long noncoding RNA) and PTMs (acetylation, SUMOylation, lactylation, phosphorylation, etc.). We also delineate the relationship between RNA modification regulator functions and carcinogenesis or cancer progression. Additionally, inhibitors that target RNA modification regulators for anticancer therapy and their synergistic effect combined with immunotherapy or chemotherapy are discussed.
PubMed: 38907157
DOI: 10.1007/s11684-024-1064-8 -
Digestive Diseases and Sciences Jun 2024Healthy populations have high rates of sustained vaccine-induced seroprotection to hepatitis B virus, but previous studies in immunosuppressed patients with inflammatory...
High Rates of Seroprotection to Hepatitis B After a Hepatitis B Challenge Dose in Previously Vaccinated Patients with Inflammatory Bowel Disease on Immunosuppressive Therapy.
BACKGROUND
Healthy populations have high rates of sustained vaccine-induced seroprotection to hepatitis B virus, but previous studies in immunosuppressed patients with inflammatory bowel disease (IBD) have shown suboptimal seroprotection rates. A challenge dose of hepatitis B vaccine (HepB) is recommended in previously vaccinated individuals who are seronegative to elicit an anamnestic response and determine if they are seroprotected. The aim of our study was to determine sustained seroprotection rates to hepatitis B vaccine (HepB) in patients with IBD.
METHODS
This was a single-center prospective study of patients with IBD previously vaccinated with a three dose HepB series. Patients had a hepatitis B surface antibody (anti-HBs) drawn; if it was below 10 mIU/mL, they received a challenge dose of the HepB vaccine to assess for anamnestic response and sustained seroprotection. The primary outcome was to determine the rate of sustained seroprotection (anti-HBs ≥ 10).
RESULTS
A total of 168 patients met inclusion criteria, mean age 35.7 years ± 13.6 standard deviation (SD). Initially 120 (71.4%) had anti-HBs ≥ 10 mIU/mL, with median anti-HBs of 37 mIU/mL (interquartile range 0-234); 48 (28.6%) needed a challenge dose, of which 34 responded with anti-HBs ≥ 10 mIU/mL. In total, 154 (91.7%) demonstrated sustained seroprotection to HepB. Those not seroprotected were more likely to have been vaccinated on immunosuppressive therapy or after their diagnosis of IBD.
CONCLUSIONS
Most vaccinated patients with IBD maintain sustained seroprotection to HepB despite prolonged exposure to immunosuppression. This contradicts prior studies and shows that immunosuppression does not lead to loss of seroprotection.
PubMed: 38907090
DOI: 10.1007/s10620-024-08527-1