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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 -
International Journal of Nanomedicine 2024It is well-established that osteoclast activity is significantly influenced by fluctuations in intracellular pH. Consequently, a pH-sensitive gated nano-drug delivery...
BACKGROUND
It is well-established that osteoclast activity is significantly influenced by fluctuations in intracellular pH. Consequently, a pH-sensitive gated nano-drug delivery system represents a promising therapeutic approach to mitigate osteoclast overactivity. Our prior research indicated that naringin, a natural flavonoid, effectively mitigates osteoclast activity. However, naringin showed low oral availability and short half-life, which hinders its clinical application. We developed a drug delivery system wherein chitosan, as gatekeepers, coats mesoporous silica nanoparticles loaded with naringin (CS@MSNs-Naringin). However, the inhibitory effects of CS@MSNs-Naringin on osteoclasts and the underlying mechanisms remain unclear, warranting further research.
METHODS
First, we synthesized CS@MSNs-Naringin and conducted a comprehensive characterization. We also measured drug release rates in a pH gradient solution and verified its biosafety. Subsequently, we investigated the impact of CS@MSNs-Naringin on osteoclasts induced by bone marrow-derived macrophages, focusing on differentiation and bone resorption activity while exploring potential mechanisms. Finally, we established a rat model of bilateral critical-sized calvarial bone defects, in which CS@MSNs-Naringin was dispersed in GelMA hydrogel to achieve in situ drug delivery. We observed the ability of CS@MSNs-Naringin to promote bone regeneration and inhibit osteoclast activity in vivo.
RESULTS
CS@MSNs-Naringin exhibited high uniformity and dispersity, low cytotoxicity (concentration≤120 μg/mL), and significant pH sensitivity. In vitro, compared to Naringin and MSNs-Naringin, CS@MSNs-Naringin more effectively inhibited the formation and bone resorption activity of osteoclasts. This effect was accompanied by decreased phosphorylation of key factors in the NF-κB and MAPK signaling pathways, increased apoptosis levels, and a subsequent reduction in the production of osteoclast-specific genes and proteins. In vivo, CS@MSNs-Naringin outperformed Naringin and MSNs-Naringin, promoting new bone formation while inhibiting osteoclast activity to a greater extent.
CONCLUSION
Our research suggested that CS@MSNs-Naringin exhibited the strikingly ability to anti-osteoclasts in vitro and in vivo, moreover promoted bone regeneration in the calvarial bone defect.
Topics: Flavanones; Animals; Osteoclasts; Bone Regeneration; Silicon Dioxide; Hydrogen-Ion Concentration; Nanoparticles; Rats; Mice; Rats, Sprague-Dawley; Chitosan; Male; Drug Liberation; Porosity; Drug Carriers; Bone Resorption; RAW 264.7 Cells; Drug Delivery Systems; Cell Differentiation
PubMed: 38946884
DOI: 10.2147/IJN.S456545 -
Physiological Reports Jul 2024The present study aimed to investigate the effect of catechin-loaded Chitosan-Alginate nanoparticles (NPs) on cognitive function in an aluminum chloride (AlCl)-induced...
Oral administration of encapsulated catechin in chitosan-alginate nanoparticles improves cognitive function and neurodegeneration in an aluminum chloride-induced rat model of Alzheimer's disease.
The present study aimed to investigate the effect of catechin-loaded Chitosan-Alginate nanoparticles (NPs) on cognitive function in an aluminum chloride (AlCl)-induced rat model of Alzheimer's disease (AD). The Catechin-loaded Chitosan-Alginate nanocarriers were synthesized through ionotropic gelation (IG) method. Physio-chemical characterization was conducted with the Zetasizer Nano system, the scanning electron microscope, and the Fourier transform infrared spectroscopy. The experiments were performed over 21 days on six groups of male Wistar rats. The control group, AlCl treated group, Catechin group, nanocarrier group, treatment group 1 (AlCl + Catechin), and treatment group 2 (AlCl + nanocarrier). A behavioral study was done by the Morris water maze (MWM) test. In addition, the level of oxidative indices and acetylcholine esterase (AChE) activity was determined by standard procedures at the end of the study. AlCl induced a significant increase in AChE activity, along with a significant decrease in the level of Catalase (CAT) and total antioxidant capacity (TAC) in the hippocampus. Moreover, the significant effect of AlCl was observed on the behavioral parameters of the MWM test. Both forms of Catechin markedly improved AChE activity, oxidative biomarkers, spatial memory, and learning. The present study indicated that the administration of Catechin-loaded Chitosan-Alginate NPs is a beneficial therapeutic option against behavioral and chemical alteration of AD in male Wistar rats.
Topics: Animals; Catechin; Aluminum Chloride; Chitosan; Alginates; Male; Rats, Wistar; Alzheimer Disease; Rats; Nanoparticles; Administration, Oral; Cognition; Acetylcholinesterase; Maze Learning; Hippocampus; Disease Models, Animal; Antioxidants; Oxidative Stress; Drug Carriers
PubMed: 38946616
DOI: 10.14814/phy2.16095 -
Physiological Reports Jul 2024Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle...
Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin-1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC-conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1-specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.
Topics: Animals; Cachexia; Sirtuin 1; Muscle Fibers, Skeletal; Mice; Oxidative Stress; Mice, Inbred C57BL; Carcinoma, Lewis Lung; Male; Heterocyclic Compounds, 4 or More Rings; Mitochondria, Muscle; Cell Line; Niacin; Mitochondria; Reactive Oxygen Species
PubMed: 38946587
DOI: 10.14814/phy2.16103 -
Journal of Oleo Science 2024Eleven kinds of Camellia oleifera seed oils (CSOs) were evaluated in terms of chemical constituents, antioxidant activities, acid value (AV) as well as peroxide value... (Comparative Study)
Comparative Study
Eleven kinds of Camellia oleifera seed oils (CSOs) were evaluated in terms of chemical constituents, antioxidant activities, acid value (AV) as well as peroxide value (POV). These CSOs contained abundant β-sitosterol, squalene, α-tocopherol and phenolics, in which the squalene was the distinct constituent with the content between 45.8±0.8 and 184.1±5.5 mg/kg. The β-sitosterol ranging from 143.7±4.8 to 1704.6±72.0 mg/kg contributed a considerable content to total accompaniments. Palmitic acid, stearic acid, oleic acid, linoleic acid and linolenic acid were present in these CSOs, in which the dominant fatty acid was oleic acid with the content between 59.66±0.72 and 82.89±2.16 g/100 g. The AV ranged from 0.1±0.0 to 1.3±0.0 mg KOH/g, and the POV was between 0.1±0.0 and 1.0±0.0 g/100 g. These CSOs showed antioxidant activity based on DPPH and ABTS radical scavenging assay. Both α-tocopherol and β-sitosterol contents showed a positive correlation with DPPH and ABTS values, respectively, while the α-tocopherol content showed a negative correlation with AV. These results suggested that CSO can be categorized into high oleic acid vegetable oil with abundant active constituents, of which the quality presented variation among different origins. These accompaniments may contribute to the delay of its quality deterioration.
Topics: Camellia; Antioxidants; Plant Oils; Sitosterols; Seeds; Squalene; China; alpha-Tocopherol; Oleic Acid; Chemical Phenomena; Fatty Acids; Palmitic Acid; Phenols; Linoleic Acid; Peroxides
PubMed: 38945923
DOI: 10.5650/jos.ess23228 -
Journal of Nutritional Science and... 2024Niacin is a cofactor in many biological reactions related to energy metabolism, redox reactions, DNA repair and longevity. Although it has been considered that...
Niacin is a cofactor in many biological reactions related to energy metabolism, redox reactions, DNA repair and longevity. Although it has been considered that increasing energy expenditure increases NAD consumption, little study has directly demonstrated the effect of exercise on niacin nutritional status. We have recently established the niacin insufficient model mice using kynurenine 3-monooxygenase knock out (KMO) mice with niacin-limited diet, which lack the de novo NAD synthesis pathway from tryptophan. To evaluate the effects of chronic endurance exercise on niacin nutritional status, 4 wk old KMO mice were fed 4 or 30 mg/kg nicotinic acid containing diets, and forced to swim in a running water pool every other day for 35 d. The swim-exercised mice fed 4 mg/kg nicotinic acid diet showed lower body weight gain and niacin nutritional markers such as liver and blood NAD, and urine nicotinamide metabolites than the sedentary mice. These animals did not show any difference in the NAD synthesis, NAD salvage and nicotinamide catabolic pathways. Chronic endurance exercise failed to affect any indices in the mice fed the 30 mg/kg nicotinic acid diet. When the diet was exchanged the 4 mg/kg for 30 mg/kg nicotinic acid diet to the mice showed chronic endurance exercise-induced growth retardation, their body weight rapidly increased. These results show that chronic endurance exercise impairs niacin nutritional status in the niacin insufficient mice, and enough niacin intake can prevent this impairment. Our findings also suggest that chronic endurance exercise increases niacin requirement by increase of NAD consumption.
Topics: Animals; Niacin; Nutritional Status; Physical Conditioning, Animal; Male; Mice; Mice, Knockout; Physical Endurance; Liver; NAD; Swimming; Weight Gain; Diet; Body Weight; Mice, Inbred C57BL; Niacinamide
PubMed: 38945883
DOI: 10.3177/jnsv.70.185 -
Journal of Medical Case Reports Jun 2024Choriocarcinoma is a highly malignant pregnancy-related trophoblastic neoplasm, characterized by early metastasis to the lungs. Therefore, patients may manifest...
BACKGROUND
Choriocarcinoma is a highly malignant pregnancy-related trophoblastic neoplasm, characterized by early metastasis to the lungs. Therefore, patients may manifest nongynecological symptoms owing to distant metastases. The incidence of choriocarcinoma after a term pregnancy is really rare (1/160,000 pregnancies).
CASE PRESENTATION
We report a case of a 20-year-old Iranian woman, gravida 2 para 1 live 1 abortion 1, who was referred to our gynecology department with sudden onset dyspnea and pain in the left hemithorax the day after her labor. The index pregnancy was without any complications. After the initial workup, the elevation of β-human chorionic gonadotropin (HCG) levels (> 1,000,000) along with the identification of clinical (vaginal lesions) and radiological evidence of distant metastases (bilateral pulmonary nodes) directed us toward pulmonary metastatic choriocarcinoma diagnosis. After the oncology consult, the etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy regimen was started for the patient. She responded well to the treatment and is currently continuing her chemotherapy process.
CONCLUSION
The prognosis of choriocarcinoma is very good if the treatment is started on time. We suggest that clinicians should consider gestational trophoblastic neoplasia in their differential diagnosis of the post-natal period complications, especially after a term and nonmolar pregnancy.
Topics: Humans; Female; Pregnancy; Lung Neoplasms; Choriocarcinoma; Uterine Neoplasms; Young Adult; Antineoplastic Combined Chemotherapy Protocols; Methotrexate; Vincristine; Dactinomycin; Etoposide; Chorionic Gonadotropin, beta Subunit, Human; Cyclophosphamide; Dyspnea; Pregnancy Complications, Neoplastic
PubMed: 38944668
DOI: 10.1186/s13256-024-04615-y -
Cancer Genomics & Proteomics 2024It has been recently demonstrated that a methionine-restricted diet increases the response to immune checkpoint inhibitors (ICIs) via an increase in PD-L1 in a syngeneic...
BACKGROUND/AIM
It has been recently demonstrated that a methionine-restricted diet increases the response to immune checkpoint inhibitors (ICIs) via an increase in PD-L1 in a syngeneic mouse colorectal-cancer model. Our laboratory has developed recombinant methioninase (rMETase) to restrict methionine. The aim of the present study was to determine if rMETase can increase PD-L1 expression in a human colorectal cancer cell line in vitro.
MATERIALS AND METHODS
We evaluated the half-maximal inhibitory concentration (IC) value of rMETase on HCT-116 human colorectal cancer cells. HCT-116 cells were treated with rMETase at the IC Western immunoblotting was used to compare PD-L1 expression in HCT-116 cells treated with and without rMETase.
RESULTS
The IC value of rMETase on HCT-116 was 0.79 U/ml. Methionine restriction using rMETase increased PD-L1 expression compared to the untreated control (p<0.05).
CONCLUSION
Methionine restriction with rMETase up-regulates PD-L1 expression in human colorectal cancer cells and the combination of rMETase and ICIs may have the potential to improve immunotherapy in human colorectal cancer.
Topics: Humans; Carbon-Sulfur Lyases; Methionine; B7-H1 Antigen; Colorectal Neoplasms; Recombinant Proteins; HCT116 Cells
PubMed: 38944421
DOI: 10.21873/cgp.20457 -
The American Journal of Case Reports Jun 2024BACKGROUND SARS-CoV-2 infection can persist in immunocompromised patients with hematological malignancies, despite antiviral treatment. This report is of a 67-year-old...
BACKGROUND SARS-CoV-2 infection can persist in immunocompromised patients with hematological malignancies, despite antiviral treatment. This report is of a 67-year-old man with chronic lymphocytic leukemia (CLL), secondary hypogammaglobulinemia, and thrombocytopenia on maintenance therapy with ibrutinib, with persistent SARS-CoV-2 infection unresponsive to antiviral treatment, including remdesivir, nirmatrelvir/ritonavir (Paxlovid), and tixagevimab/cilgavimab (Evusheld). CASE REPORT The patient was admitted to our hospital 3 times. During his first hospitalization, he was treated with 5-day course of remdesivir and intravenous steroids; however, antigen and molecular nasopharyngeal swabs were persistently positive, and he was discharged home. Due to respiratory worsening, he was rehospitalized, and despite being treated initially with tixagevimab/cilgavimab, and subsequently with a remdesivir course of 5 days, SARS-CoV-2 tests remained persistently positive. During his third hospital stay, our patient was subjected to combined therapy with remdesivir and nirmatrelvir/ritonavir for 5 days, obtaining a significant reduction of viral load at both antigen and molecular testing. As an ultimate attempt to achieve a negative status before discharge, a 10-day course of combined remdesivir and nirmatrelvir/ritonavir was administered, with a temporary reduction of viral load, followed by a sudden increase immediately after the discontinuation of Paxlovid. Due to worsening hematological disease and bacterial over-infections, the patient gradually worsened until death. CONCLUSIONS This is an emblematic case of correlation between persistent SARS-CoV-2 infection and immunosuppression status in hematological hosts. In these patients, the viral load remains high, favoring the evolution of the virus, and the immunodeficiency makes it difficult to identify the appropriate therapeutic approach.
Topics: Humans; Male; Aged; Leukemia, Lymphocytic, Chronic, B-Cell; Adenine; COVID-19; Piperidines; Antiviral Agents; COVID-19 Drug Treatment; SARS-CoV-2; Adenosine Monophosphate; Alanine; Immunocompromised Host; Maintenance Chemotherapy
PubMed: 38943241
DOI: 10.12659/AJCR.941165 -
Nutrition Journal Jun 2024Choline is a nutrient necessary for the proper functioning of the body with a multidimensional impact on human health. However, comprehensive studies evaluating the... (Review)
Review
BACKGROUND
Choline is a nutrient necessary for the proper functioning of the body with a multidimensional impact on human health. However, comprehensive studies evaluating the dietary intake of choline are limited. The aim of this narrative review is to analyze current trends in choline intake in European and non-European populations. The secondary aim was to discuss possible future choline trends.
METHODS
The search strategy involved a systematic approach to identifying relevant literature that met specific inclusion criteria. Observational studies and randomized clinical trials were searched for in PubMed and Scopus databases from January 2016 to April 2024. This review includes the characteristics of study groups, sample sizes, methods used to assess choline intake and time period, databases used to determine intake, choline intakes, and the main sources of choline in the diet. The review considered all population groups for which information on choline intake was collected.
RESULTS
In most studies performed in Europe after 2015 choline intake did not exceed 80% of the AI standard value. The mean choline intake for adults in different European countries were 310 mg/day, while the highest value was reported for Polish men at 519 mg/day. In non-European countries, mean choline intakes were 293 mg/day and above. The main reported sources of choline in the diet are products of animal origin, mainly eggs and meat. The available data describing the potential intake of these products in the EU in the future predict an increase in egg intake by another 8% compared to 2008-2019 and a decrease in meat intake by about 2 kg per capita from 2018 to 2030.
CONCLUSIONS
In the last decade, choline intake among adults has been insufficient, both in Europe and outside it. In each population group, including pregnant women, choline intake has been lower than recommended. Future choline intake may depend on trends in meat and egg consumption, but also on the rapidly growing market of plant-based products. However, the possible changes in the intake of the main sources of choline may lead to either no change or a slight increase in overall choline intake.
Topics: Humans; Choline; Europe; Diet; Female; Male; Adult
PubMed: 38943150
DOI: 10.1186/s12937-024-00970-0