Tumor-derived extracellular vesicles (EVs) are active contributors in metastasis and immunosuppression in tumor microenvironment. At least some of the EVs carry tumor surface molecules such as ...tumor-associated antigens (TAAs) and/or checkpoint inhibitors, and potentially could interact with T cells or CAR T cells. Upon contact with T cells, EVs could alter their phenotype and functions by triggering signaling through TCR or CAR reprogramming them to escape immune response. We hypothesize that EVs that possess TAA on the surface will probably interact with CAR T cells which can recognize and bind corresponding TAA. This interaction between EVs and CAR T cells may change the outcome of CAR T-based cancer immunotherapy since it should affect CAR T cells. Also, EVs could serve as adjuvants and antigenic components of antitumor vaccines. Herein, we isolated EVs from B cell precursor leukemia cell line (pre-B ALL) Nalm-6 and demonstrated that recognition and binding of CD19
EVs with CD19-CAR T cells strongly depends on the presence of CD19 antigen. CD19
EVs induce secretion of pro-inflammatory cytokines (IL-2 and IFN-y) and upregulated transcription of activation-related genes (IFNG, IFNGR1, FASLG, IL2) in CD19-CAR T cells. Tumor necrosis factor receptor superfamily (TNFRSF4 and TNFRSF9) and T-cell exhaustion markers (CTLA4, LAG3, TIM3 and PDCD1LG2) were also upregulated in CD19-CAR T cells after incubation with CD19
EVs. Long-term cultivation of CD19
or PD-L1
EVs with CD19-CAR T cells led to increased terminal differentiation and functional exhaustion according to elevated expression of PD-1, TIGIT, CD57. In summary, our results suggest that chronic exposure of CD19-CAR T cells to CD19
EVs mediates activation and systemic exhaustion in antigen-specific manner, and this negative effect is accompanied by the impaired cytotoxic activity in vitro.
Berberine is a compound with a wide spectrum of biological activity, synthesized in cell culture of
Thalictrum
minus
medicinal plant. The effect of an abiotic elicitor (Cu
2+
) on
Thalictrum
minus
...cell culture growth and biosynthesis of protoberberine alkaloids in it at different stages of the growth cycle was studied. The fast reaction (after 2 h) and the long reaction (at the end of the growth cycle) were evaluated. The greatest effect on the increase in protoberberine alkaloids was observed after exposure to 20 and 25 mg/L Cu
2+
on day 0 after 2 h, which was by 49 and 114% higher than the control, respectively, while maintaining growth at the control level. By the end of the growth cycle, the cell mass and the content of protoberberine alkaloids decreased by 67–70 and 27–53%, respectively (toxic effect). At 5 mg/L (Cu
2+
), the reaction was the opposite. After 2 h, growth stimulation was observed by 48% and a decrease in the content of protoberberine alkaloids by 48% relative to the control. By the end of the growth cycle, the excess of growth by 50% remained, and the content of protoberberine alkaloids increased by 60% relative to the control. If the impact of Cu
2+
was carried out in the middle of the growth cycle, at a concentration of 20 and 25 mg/L, both with a quick reaction (after 2 h) and by the end of the growth cycle, there was a decrease in growth by 65–71% and the content of protoberberine alkaloids by 52–70%. At 5 mg/L of copper ions, the excess of growth by 50–54% remained, and the content of alkaloids remained at the control level. Reaction at 10 mg/L of Cu
2+
ions was intermediate. The conducted studies have shown the promise of using low concentrations of copper ions for
Thalictrum
minus
cell culture. The content of protoberberine alkaloids increased against the background of cell culture growth stimulation at the end of the growth cycle.
The
Aids to Management
are a product of the Global Campaign against Headache, a worldwide programme of action conducted in official relations with the World Health Organization. Developed in ...partnership with the European Headache Federation, they update the first edition published 11 years ago.
The common headache disorders (migraine, tension-type headache and medication-overuse headache) are major causes of ill health. They should be managed in primary care, firstly because their management is generally not difficult, and secondly because they are so common. These
Aids to Management
, with the
European principles of management of headache disorders in primary care
as the core of their content, combine educational materials with practical management aids. They are supplemented by translation protocols, to ensure that translations are unchanged in meaning from the English-language originals.
The
Aids to Management
may be individually downloaded and, as is the case for all products of the Global Campaign against Headache, are available without restriction for non-commercial use.
The review analyzes modern criteria for early diagnosis of renal damage in hypertensive patients. Based on numerous studies, the role of impaired renal function markers and renal artery Doppler ...ultrasound in the diagnosis of hypertensive nephropathy is indicated. A search was made for the relationship between laboratory criteria for kidney damage and renal Doppler ultrasound characteristics in hypertensive patients. In addition, the importance of revealing intrarenal hemodynamic disorders in the early diagnosis of hypertensive nephropathy was established.
The article studies promising varieties of spring rape and makes an agrobiological assessment of them in conditions of summer sowing in Novgorod region on the example of the varieties Oredezh 1, ...Oredezh 2 and Oredezh 4. We indicate the varieties with the biggest yield of green mass and seeds, as well as having an advantage in a number of other economically valuable traits, relevant and significant for agricultural production. Features of rape in compositions with two varieties of vetch sown for green mass were studied for the first time. The most optimal composition for highest green mass yield and the best sowing season are established. The varieties of rape giving the biggest yield are identified.
Acute and chronic steroid-refractory graft-versus-host disease (srGVHD) is a life-threatening complication of allogeneic stem cell transplantation. There are a number of reports on case series ...describing efficacy of ruxolitinib in both acute and chronic srGVHD. We conducted a prospective study (NCT02997280) in 75 patients with srGVHD (32 acute, 43 chronic, 41 adults, and 34 children). Patients with chronic GVHD had severe disease in 83% of cases, and acute GVHD patients had grade III-IV disease in 66% of cases. The overall response rate (ORR) was 75% (95% CI 57-89%) in acute GVHD and 81% (95% CI 67-92%) in chronic. Overall survival was 59% (95% CI 49-74%) in acute group and 85% (95% CI 70-93%). The major risk factors for lower survival were grade III-IV gastrointestinal involvement (29% vs 93%, p = 0.0001) in acute form and high disease risk score in chronic (65% vs 90%, p = 0.038). Toxicity was predominantly hematologic with 79% and 44% of grade III-IV neutropenia in acute and chronic groups, respectively. There was no difference between adults and children in terms of ORR (p = 0.31, p = 0.35), survival (p = 0.44, p = 0.12) and toxicity (p > 0.93). The study demonstrated that ruxolitinib is an effective option in acute and chronic srGVHD and can be used both in adults and children.
One of the key problems of glioblastoma treatment is the low effectiveness of chemotherapeutic drugs. Incorporation of doxorubicin into PLGA nanoparticles allows increasing the antitumor effect of ...the cytostatics against experimental rat glioblastoma 101.8. Animal survival, tumor volume, and oncogene expression in tumor cells were compared after early (days 2, 5, and 8 after tumor implantation) and late (days 8, 11, and 14) start of the therapy. At late start, a significant increase in the expression of oncogenes
Gdnf
,
Pdgfra
, and
Melk
and genes determining the development of multidrug resistance
Abcb1b
and
Mgmt
was revealed. At early start of therapy, only the expression of oncogenes
Gdnf
,
Pdgfra
, and
Melk
was enhanced. Early start of treatment prolonged the survival time and increased tumor growth inhibition by 141.4 and 95.7%, respectively, in comparison with the untreated group; these differences were not observed in the group with late start of therapy. The results indicate that the time of initiation of therapy is a critical parameter affecting the antitumor efficacy of DOX-PLGA.
The results of an analytical review of various antennas used in medicine are presented. Issues of modern microwave radiothermometry related to the development of new antennas are discussed, as well ...as possible ways to solve them. The tasks of further research aimed at creating new designs for conformal antennas and antenna arrays providing a significant expansion of the functionality and improvements in the characteristics of medical radiothermographs are formulated. The study was supported by the Russian Science Foundation (Grant No. 22-19-00113),
https://rscf.ru/project/22-19-00113/
.
An approach was developed for the synthesis of polyfunctionalized pyrimidines based on analogs of 1,2,4-triketones. Acetal-substituted β-diketones are involved in the condensation with amidines in ...the presence of an excess of (EtO)
3
B/Et
3
N in acetonitrile. The conditions of the acid hydrolysis of acetal-containing pyrimidines were found to depend on the nature of substituents in diazine. The use of 1,2,4-triketone in the condensation with amidine allows the synthesis of acetylpyrimidine in one step.
Objective:
to prove the therapeutic equivalence and similar safety profile of “Sibazon, rectal solution” (international nonproprietary name: diazepam) and “Sibazon, solution for intravenous and ...intramuscular administration” in children with primary generalized and bilateral tonic, clonic and tonic-clonic seizures.
Material and methods.
An open-label, randomized clinical trial on efficacy and safety was conducted in 20 patients suffering from epilepsy with generalized seizures aged 1 to 17 years. Clinical blood and urine tests, biochemical blood analysis were used for diagnostics (glucose, total protein, albumin, total bilirubin, cholesterol, aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, alkaline phosphatase, creatinine, urea, creatinine clearance), as well as data on electrocardiographic (ECG) and electroencephalographic (EEG) studies. The patients were divided into two groups: in Group 1 (n=8), a rectal solution was used, in Group 2 (n=12) – a solution for intravenous and intramuscular administration.
Results.
The number of cases in which seizures were completed within 10 minutes after using the drug without resuming within subsequent 60 minutes, in Group 1 was 7 (87.5%), and in Group 2 – 9 (75.0%) (Fisher exact test (FET): p=0.617). Repeated primary generalized or bilateral tonic/clonic/tonic-clonic seizures within 24 hours after drug administration, in Group 1 were absent in 5 (62.5%) patients, in Group 2 – in 6 (50%) (FET: p=0.670); within 48 hours after drug administration – in 5 (62.5%) and 7 (58.3%) children, respectively (FET: p=1.00). Physical examination revealed no pathology in all patients at the final visit. While comparing ECG and EEG data at the final visit, no inter-group differences were found by the number of children with deviations from the norm. The results of laboratory studies confirmed that using the studied drugs had no negative effect on the main indicators of clinical and biochemical blood tests as well as clinical urine analysis.
Conclusion.
The effectiveness of the rectal form of Sibazon in relieving pediatric generalized epileptic seizures is comparable to that of Sibazon for intramuscular administration. The drug rectal form, due to easy-to-use administration, is preferable for outpatient practice. “Sibazon, rectal solution” is safe and has good tolerability.
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