BACKGROUND: Several studies have demonstrated the occurrence of secondary tumors as a rare but significant complication of chimeric antigen receptor T (CAR-T) cell therapy, underscoring the need for a detailed investigation. Given the limited variety of secondary tumor types reported to date, a comprehensive characterization of the various secondary tumors arising after CAR-T therapy is essential to understand the associated risks and to define the role of the immune microenvironment in malignant transformation. This study aims to characterize the immune microenvironment of a newly identified secondary tumor post-CAR-T therapy, to clarify its pathogenesis and potential therapeutic targets. METHODS: In this study, the bone marrow (BM) samples were collected by aspiration from the primary and secondary tumors before and after CD19 CAR-T treatment. The CD45 + BM cells were enriched with human CD45 microbeads. The CD45 + cells were then sent for 10× genomics single-cell RNA sequencing (scRNA-seq) to identify cell populations. The Cell Ranger pipeline and CellChat were used for detailed analysis. RESULTS: In this study, a rare type of secondary chronic myelomonocytic leukemia (CMML) were reported in a patient with diffuse large B-cell lymphoma (DLBCL) who had previously received CD19 CAR-T therapy. The scRNA-seq analysis revealed increased inflammatory cytokines, chemokines, and an immunosuppressive state of monocytes/macrophages, which may impair cytotoxic activity in both T and natural killer (NK) cells in secondary CMML before treatment. In contrast, their cytotoxicity was restored in secondary CMML after treatment. CONCLUSIONS This finding delineates a previously unrecognized type of secondary tumor, CMML, after CAR-T therapy and provide a framework for defining the immune microenvironment of secondary tumor occurrence after CAR-T therapy. In addition, the results provide a rationale for targeting macrophages to improve treatment strategies for CMML treatment.
Humans ; Lymphoma, Large B-Cell, Diffuse/therapy* ; Tumor Microenvironment/genetics* ; Antigens, CD19/metabolism* ; Leukemia, Myelomonocytic, Chronic/genetics* ; Immunotherapy, Adoptive/adverse effects* ; Male ; Single-Cell Analysis/methods* ; Female ; Sequence Analysis, RNA/methods* ; Receptors, Chimeric Antigen ; Middle Aged

Objective To establish the ultra-high performance liquid chromatography(UPLC)chromatographic fingerprint of Notopterygii Rhizoma et Radix;To determine the contents of ferulic acid,nodakenin,ammijin,notopterol,isoimperatorin and volatile oil of Notopterygii Rhizoma et Radix from different producing areas;To provide reference for quality evaluation of Notopterygii Rhizoma et Radix.Methods Waters BEH C18 chromatographic column(2.1 mm×150 mm,1.7 μm)was used,with mobile phase acetonitrile-0.02%formic acid aqueous solution gradient elution,flow rate 0.25 mL/min,column temperature 25℃,detection wavelength 330 nm,injection volume 2 μL.UPLC fingerprints of 25 batches of Notopterygii Rhizoma et Radix were established,and the similarity analysis and chemometrics analysis were carried out.The contents of ferulic acid,nodakenin,ammijin,notopterol and isoimperatorin were determined simultaneously,and the contents of volatile oil was determined by steam distillation method.Results Totally 23 common fingerprint peaks were calibrated,11 known components were identified.According to the results of the cluster analysis and principal component analysis,25 batches of Notopterygii Rhizoma et Radix samples were divided into 3 categories,and the 6 potential differential components were screened out by orthogonal partial least squares-discriminant analysis(OPLS-DA).The results showed that the contents of notopterol and volatile oil from Sichuan Province were higher than those from Gansu Province and Qinghai Province.Conclusion The method established in the study is accurate and reliable,which can provide scientific basis and reference for the quality evaluation and control of Notopterygii Rhizoma et Radix.

Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment (TME). Some bacteria exhibit spontaneous chemotaxis toward the anaerobic and immune-suppressive TME, which makes them ideal natural vehicles for cancer gene therapy. Here, we conjugated ZIF-8 metal-organic frameworks encapsulating eukaryotic murine interleukin 2 (Il2) expression plasmid onto the surface of VNP20009, an attenuated Salmonella typhimurium strain with well-documented anti-cancer activity, and constructed a TME-targeted Il2 delivery system named Il2/ZIF-8@Salmonella. Both in vitro and in vivo experiments demonstrated that Il2/ZIF-8@Salmonella maintained the tumor-targeting feature of bacteria, and could be effectively phagocytosed by intratumoral macrophages, thus leading to the expression and secretion of IL2 in TME. The detailed analysis of tumor immune microenvironment (TIME) showed that one dose of combinatorial Il2/ZIF-8@Salmonella achieved synergistic actions on a potent remodeling of TIME, marked by the activation of cytotoxic T cells and M1-polarization of macrophages in TME, thus leading to significant anti-tumor effects in melanoma, orthotopic hepatocellular carcinoma, and pulmonary metastasis models. More importantly, Il2/ZIF-8@Salmonella exhibited high safety to major organs and hematopoietic systems. Taken together, we report a novel plasmid/ZIF-8@Salmonella system that simultaneously achieves effective TME-targeted delivery of therapeutic gene, as well as synergistic re-activation of TIME.

Anti-seizure medications (ASMs) are the main therapy for epilepsy.There are many kinds of ASMs with complex mechanism of action, so it is difficult for pharmacists to examine prescriptions.This paper put forward some suggestions on the indications, dosage forms/routes of administration, appropriateness of usage and dosage, combined medication and drug interaction, long-term prescription review, individual differences in pathophysiology of children, and drug selection when complicated with common epilepsy, for the reference of doctors and pharmacists.

Objective:To evaluate the long-term safety, tolerability and efficacy of Lacosamide add-on therapy in Chinese children with partial-onset seizures.Methods:SP848 was a global multicenter single-arm study involving 60 Chinese children with partial-onset seizures with the age of 4-17 years who were managed by Lacosamide add-on therapy at seven hospitals across China from April 2018 to May 2019.After treatment with at least two kinds of anti-seizure medications simultaneously or sequentially, partial seizures were still poorly controlled and Lacosamide oral solution (syrup) or tablets were added.The minimum initial oral dose was 2 mg/(kg·d), and the maximum allowable dose was 12 mg/(kg·d)or 600 mg/d during the study period.The dose was adjusted according to the tolerance and seizure control level of partial-onset seizures children.Seizure frequency and the median percentage change in partial-onset seizures per 28 days from baseline to the final visit were recorded, including 50% responder rate and 75% responder rate.Results:A total of 60 Chinese children with the mean age of 9.18 (4.00-15.40) years were included in this interim analysis, involving 39 males and 21 females.The mean course of epilepsy was 5.04 (0.50-15.20) years.A total of 43 patients (71.7%) still have been treated.One patient (1.7%) has completed the 6-12 months of follow-up, and 14 patients (23.3%) have completed the follow-up for less than 6 months.The median change in the frequency of partial seizures every 28 days from baseline to the last visit was -2.91, with its median percentage as -25.46%, and the proportions of ≥50%, while ≥75% responder rate were 40.0% and 28.3%, respectively.A total of 52 patients (86.7%) had 265 treatment emergent adverse events (TEAE), 11 patients (18.3%) had 19 serious TEAE, 37 patients (61.7%) had 127 drug-related TEAE, and 11 patients (18.3%) had 16 TEAE leading to the discontinuation of the trial.The most common TEAE were upper respiratory tract infections (20 cases, 33.3%), followed by drowsiness (16 cases, 26.7%), dizziness (15 cases, 25.0%) and vomiting (13 cases, 21.7%). There were no abnormal changes in the electrocardiographic findings during the treatment.Conclusions:For Chinese patients with partial seizures who are older than the age of 4 years and poorly controlled by other drugs, Lacosamide is effective and well tolerated as an add-on therapy drug.The safety characteristics are consistent with those reported in children and adults.No new safety concerns are identified.

Since the implementation of the Measures for the Management of Radiation Workers’ Occupational Health in November 2007, it has played an extremely important role in protecting the occupational health of radiation workers. There are more than 700 000 radiation workers in about 100 000 workplaces with potential radiation exposure, as well as a large number of miners exposed to high levels of radon. As the radiation health monitoring project suggests, measures of occupational health management such as personal dose monitoring and occupational health examination of radiation workers have been widely implemented and achieved good results in the protection of radiation workers. However, the risks of chromosomal aberration and specific turbidity of the eye lens of radiation workers have increased in high-risk positions such as interventional radiology, nuclear medicine, and industrial flaw detection. The control of high radon exposure in miners needs to be strengthened. It is necessary to adapt to the new situation in view of new challenges and actively promote the revision of the Measures for the Management of Radiation Workers’ Occupational Health, so as to further improve the occupational health management of radiation workers in China.

Objective:To understand the non-uranium miners′ awareness of radon and health risks in China and analyze the relevant influencing factors, in order to provide research basis for radiological protection institutions and employers to carry out radon health education.Methods:Male miners in 32 typical non-uranium mines from 11 provinces were selected by using cluster random sampling method from June 2020 to December 2021. The awareness of radon and health risks was investigated, and the influencing factors were analyzed by binary logistic regression model.Results:A total of 1 184 non-uranium miners were investigated, and the radon awareness rate of them was 19.17%. 36.56% of the non-uranium miners heard about radon knew the radon health risks accurately, and 18.06% could identify the measures to reduce radon concentration correctly. Univariate analysis showed that the radon awareness rate of non-uranium miners varied with different education levels, labor relations, post categories, and regions ( χ2=55.92, 21.89, 64.31, 11.26, P<0.05 ). The result of logistic regression analysis showed that a bachelor degree or above, regular employee, administrative personnel and technical personnel were influencing factors of the radon awareness level ( χ2=12.81, 6.58, 5.66, 21.44, P<0.05 ). There was no statistically significant difference of radon awareness rate in different ages, working years, regions, and smoke groups ( P>0.05 ). Conclusions:The awareness level of radon and health risks of non-uranium miners was relatively low in China. Radiological protection institutions and employers should strengthen education and training of radon related knowledge in non-uranium miners through mass media, on-duty training, contract notification and workplace publicity board notification, so as to improve their personal protection consciousness.

Objective:To study the healthcare level (HCL) in China and its influencing factors.Methods:By using the data reported in the China statistical yearbook published by the National Bureau of Statistics and in other public literature, HCL was calculated in terms of the number of population and physicians in the whole country and various provinces. Multiple regression was used to analyze the relationship between HCL and regional population, area, number of administrative divisions and gross domestic product (GDP). Pearson correlation analysis was applied to analyze the relationship between healthcare level and medical radiation frequency. Results:Since 2015, Chinese HCL value was lower than 1 000, but there were two provinces with HCL value greater than 1 000 in 2019. Population and GDP were the influencing factors for the HCL, with correlation coefficients of 0.416 and -0.583, respectively. There was a correlation between HCL and medical exposure frequency of Chinese population( r= -0.620, P=0.028). Conclusions:Chinese HCL value was 542 in 2020, but there has been great differences between various provinces. HCL as an indicator of medical exposure assessment needs further research in China.

Objective:To investigate and analyze the eye lens dose to interventional radiology workers in China from 2019 to 2021.Methods:The monitoring data on eye lens dose to interventional radiology workers from 31 province-level units during 2019-2021 were collected through the National Radiological Health Information Platform. The eye lens dose evaluation indicator was Hp(3), with each monitoring period of no more than 3 months. Kusall-Wallis H test was used for the comparison of multiple groups and pairwise. Results:A total of 6 643 interventional radiology workers were investigated from 2019 to 2021. The average annual eye lens dose was 1.03 mSv, with the median of 0.17 mSv and the maximum of 94.88 mSv. The annual eye lens dose to 59 workers exceeded 20 mSv. It was also found that the annual eye lens dose to the doctors in 2019 and 2020 was slightly higher than that to nurses (rank mean difference=118.29, 129.71, P<0.01), and the lens dose to interventional radiology workers who performed cardiac interventions in 2019 was higher than that to workers who performed peripheral vascular interventions (rank mean difference=46.52, P<0.05). Conclusions:The lens dose to interventional radiology workers is lower than the limits given in Chinese national standard currently in effect, but exceed the latest internationally recommended limit for a few ones. In order to protect the occupational health of interventional radiology workers, the monitoring of lens dose should be strengthened.

Objective:To investigate 131I activity in thyroid of workers at the place of radioiodine therapy and its main influencing factors. Methods:In terms of the types of hospitals, six hospitals that performed radioiodine therapy procedure were selected by quota sampling in the provinces of Shandong and Shanxi. 131I activity in thyroids of 76 workers at the place of radioiodine therapy was measured directly, and their internal doses were estimated. Results:131I activity in thyroids was found to be above the detection limit for 29 subjects (38.16%) in five hospitals. The maximum value of 131I activity was 2 468.45 Bq for a doctor who was responsible for manual distribution of radioisotopes. In general 131I activities in thyroid of workers at the place of radioiodine therapy of six hospitals were not significantly different ( P>0.05). But the measurement result in the hospitals where radioiodine was distributed manually were significantly higher than that in the hospitals where radioiodine was distributed automatically ( Z=1.75, P<0.01). Thyroid measurement result of 12 workers in two hospitals where radioiodine was distributed manually were all above the detection limit, with medians of 324.59 Bq and 331.98 Bq, respectively. The medians of 131I activities in thyroid of 12 staff in the remaining 4 hospitals were all below the detection limit. The detection frequencies of 131I above dose limit were 32.61%, 25.00%, 10.00% and 0. The measurement result for the doctors who participated in distributing 131I and the relevent cleaners were significantly higher than for the doctors who did not participate in distributing 131I at the same hospital ( Z=2.44, 2.12, P<0.05). Conclusions:There was a significant difference in the internal exposure level among workers at the different places of radioiodine therapy. Using automatic loading device could reduce the internal exposure level of the workers at the place of radioiodine therapy. It is necessary to strengthen the radiological protection for workers at the control area of the place of radioiodine therapy.