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

Abstract OBJECTIVE To analyze and summarize the research history, development status, trends and hotspots of Codonopsis Radix by bibliometrics. METHODS Search and screen the related literatures of Codonopsis Radix from the CNKI database and the Web of Science core collection database from Januar 1, 1992 to June 30, 2022. VOSviewer and CiteSpace softwares were used for visual analysis of the number of publications, authors, institutions, countries, funding funds, published journals, literature citation frequency, keywords, clustering and emergent word, and a visual graph was drew. RESULTS A total of 594 effective literature, 484 in Chinese and 110 in English were included. GAO Jianping and ZOU Yuanfeng were the scholars with the largest amount of Chinese and English literature. China was the country with the most published researches on Codonopsis Radix. The School of Pharmaceutical Science of Shanxi Medical University and the Chinese Academy of Sciences were the institutions with the largest number of Chinese and English literature publications respectively. The National Science Foundation of China was the largest fund to support the research of Codonopsis Radix. The journal that received the most Chinese and English literature were Journal of Chinese Medicinal Materials and International Journal of Biological Macromolecules respectively. The most frequently cited Chinese literature was a summary of the chemical constituents and pharmacological effects of Codonopsis Radix. The most frequently cited English literature was a study on the structure identification and pharmacological effects of Codonopsis Radix polysaccharides. The map of key words, clustering and emergent words in Chinese literature showed that the main research directions of Codonopsis Radix were compatibility formula, resource planting, pharmacological action and quality control. The map of key words, clustering and emergent words in English literature indicated that the study of Codonopsis Radix always focused on the material basis and mechanism of its active ingredients. CONCLUSION The annual publications on of Codonopsis Radix show an increasing trend, and the main research institutions are distributed in many universities and research institutes in China. Both Chinese and English literature have their own research directions, and the pharmacological effects of active ingredients are the common trend hotspots.

Cyperi Rhizoma is a common Chinese medicine in clinical practice， which has a long history of processing. In order to sort out the process of its processing， starting with the angle of processing excipients， the historical evolution and developmental venation of Cyperi Rhizoma processing were analyzed and summarized by consulting relevant literature of ancient medical records and modern codes. After combing the ancient and modern literature， it was found that there were many processing methods of Cyperi Rhizoma， the processing methods without auxiliary materials included frying， boiling， steaming and so on， and the adding auxiliary materials included vinegar， ginger， salt， multiple excipients， etc. However， with the evolution of history， some characteristic excipients have gradually disappeared， while vinegar-processed products are mainly used in modern times. Meanwhile， processing methods of Cyperi Rhizoma are well documented in various processing standards， the phenomenon of multiple methods adopted in one place and different methods in different places exists， which lacks unified quality standards and leads to uneven quality of Cyperi Rhizoma decoction pieces， which may even affect the safety and effectiveness of its clinical medication. Based on this， the problems existing in the processing research of Cyperi Rhizoma were analyzed in this paper， and made an outlook on the inheritance of the ancient processing methods and the quality standard improvement of the decoction pieces， in order to provide important literature evidence and theoretical support for the study of processing process and mechanism of Cyperi Rhizoma.

ObjectiveTo investigate the relative content changes of differential metabolites and reducing sugars during the processing process of Rehmanniae Radix Praeparata （RRP） processed with Amomi Fructus （AF） and Citri Reticulatae Pericarpium （CRP）， and to lay the foundation for revealing the processing principle of this characteristic variety. MethodThe samples of the 0-54 h processing process of RRP processed with AF and CRP were taken as the research object， and their secondary metabolites were detected by ultra performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF-MS）. The 0.1% formic acid aqueous solution （A）-acetonitrile （B） was used as the mobile phase for gradient elution （0-1 min， 1%-3%B； 1-10 min， 3%-9%B； 10-15 min， 9%-12%B； 15-22 min， 12%-18%B； 22-31 min， 18%-24%B； 31-35 min， 24%-100%B； 35-36 min， 100%-5%B； 36-40 min， 5%-1%B； 40-45 min， 1%B）， column temperature was 40 ℃， injection volume was 3 μL， flow rate was 0.3 mL·min^-1. Electrospray ionization （ESI） was used to scan and collect MS data in the negative ion mode， the scanning range was m/z 50-1 250. Data analysis was carried out using PeakView 1.2 software， and the chemical composition of RRP processed with AF and CRP was identified by combining the literature information and chemical composition databases. The MS data were normalized by MarkerView 1.2， and then the multivariate statistical analysis was applied to screen the differential metabolites， and the changes of the relative contents of the differential metabolites with different processing times was analyzed， finally， correlation analysis was performed between the differential metabolites， the change of the reducing sugar content was combined to determine the most suitable processing time of RRP processed with AF and CRP. ResultA total of 121 compounds were identified from RRP processed with AF and CRP at different processing times， and 12 differential metabolites were screened out by multivariate statistical analysis， including catalpol， hesperidin， isoacteoside， acteoside， narirutin， echinacoside， isomartynoside， decaffeoylacteoside， 6-O-E-feruloylajugol， dihydroxy-7-O-neohesperidin， jionoside D， and rehmapicroside. With the prolongation of processing time， the relative contents of these 12 differential metabolites and reducing sugars changed slightly at 52-54 h. ConclusionUPLC-Q-TOF-MS can comprehensively and accurately identify the chemical constituents of RRP processed with AF and CRP at different processing times， and the suitable processing time of 52-54 h is determined according to the content changes of different metabolites and reducing sugars， which provides a basis for revealing the scientific connotation of the processing principle of this variety.

By reviewing the relevant literature of ancient herbal works and modern codices， this paper sorted out the historical evolution and developmental venation of processing of Notoginseng Radix et Rhizoma. On this basis， the modern research of processed products of Notoginseng Radix et Rhizoma was used as the breakthrough point to analyze the literature in terms of processing technology， chemical composition changes and changes in pharmacological effects before and after processing. According to the research status of processing of Notoginseng Radix et Rhizoma， some existing problems were analyzed in this paper， such as not many ancient processing methods used in modern time， lack of standardized research on processing technology. And saponins， polysaccharides， amino acids， flavonoids and other chemical components in Notoginseng Radix et Rhizoma may change to different degrees before and after processing， which was the main reason for the difference of efficacy before and after processing. However， the current research on the pharmacological effects of Notoginseng Radix et Rhizoma mainly focuses on raw products， resulting in a lack of in-depth research on the transformation mechanism of Notoginseng Radix et Rhizoma in processing difference， and the scientific connotation of "Shengxiao Shubu" has not been clearly elaborated， which is not conducive to the standardized clinical use of drugs. Therefore， it is necessary to further analyze the material basis of Notoginseng Radix et Rhizoma and its processed products， and to explore the change rule of chemical components before and after processing and its correlation with pharmacodynamic activity， so as to clarify the processing mechanism for providing scientific basis for its standardized processing， quality control and clinical rational use.

【Objective】 To analyze the HIV-, HCV- and HBV- NAT yield rate in different areas of Henan province, so as to provide the basis for disease prevention and control as well as the establishment of a unified quality control standard for nucleic acid testing(NAT) in the Henan province. 【Methods】 The number and prevalence of NAT yielding samples with isolated infectious virus, namely HIV, HCV and HBV, in 18 blood stations in Henan province from 2017~2019, as well as the trends were analyzed. The NAT quality of each laboratory and each testing system was analyzed according to the ratio of reactive individual donation(ID) results to reactive minipools(MP). 【Results】 The HBV, HCV and HIV ID-NAT yield numbers in 3 501 251 blood donations were HBV 2 606(74/100 000), HCV 21 (0.63/100 000), and HIV 34(1.00/100 000). The HBV ID-NAT yield rate showed an upward trend in the whole province from 2017 to 2019, while the prevalence of HIV and HCV ID-NAT yield didn′t differ significantly during three years. 5 kinds of NAT detection systems were applied in 18 blood centers. among which Ⅰ, Ⅱ, Ⅳ and Ⅴ were triplex detection systems. 2661 ID-reactive samples were implicated in 5 595 MP-reactive samples, with a resolution rate of 47.56%. The resolution rate of triplex NAT system Ⅰ, Ⅱ, Ⅳ and Ⅳ was 39.63%~47.95%, 40.43%~54.36%, 51.61% and 70.00%~45.45%, respectively. An upward trend in triplex NAT resolution rate was observed in 8 laboratories, i. e.B, D, E, F, I, K, L and Q, and an descending trend in A and C. The NAT system Ⅲ, a ID-NAT system, was used only by laboratory C, presenting a NAT-yield rate of 0.19% (282/145 474) and resolution rate of 46.45% (131/282). 【Conclusion】 The majority of NAT-yield of one infectious virus in Henan province is HBV, presenting annual increasing trend. The quality management of NAT laboratories should be strengthened as the divergence was seen in the performance of different NAT laboratories.

Objective To study the effect of deep inspiration breath-hold(DIBH)technique on the heart dose in whole breast irradiation(WBI)for left breast cancer after breast-conserving surgery, and to investigate the anatomical factors for heart dose. Methods Fifteen patients with left breast cancer who received WBI after breast-conserving surgery and met breathing control requirements were prospectively enrolled as subjects. Simulated CT scans were performed during free breathing(FB)and DIBH. The WBI plans were optimized based on DIBH images.The position,volume,and radiation doses to the heart and lung were compared between the status of FB and DIBH. Correlation of heart dose with various anatomical factors was analyzed in FB status. Between-group comparison of categorical data was made by nonparametric Wilcoxon rank test.A two-variable correlation analysis was made by the Pearson method.Results There was no significant difference in heart volume between the status of FB and DIBH(P=0.773).The volume of both lungs was significantly larger in DIBH status than in FB status(P=0.001). The mean and maximum doses and V5-V40for the heart,left anterior descending coronary artery,left ventricle,right ventricle,and left lung were significantly lower in DIBH status than in FB status(all P<0.05). The greater DIBH increased the lung volume,the greater the mean heart dose decreased. In FB status,the left breast volume,heart-to-lung volume ratio,distance between the inferior margins of breast and heart,and maximum heart margin distance showed a linear correlation with heart dose. Particularly, the heart-to-lung volume ratio and maximum heart margin distance were independently correlated with heart dose. Conclusions DIBH technique in WBI for left breast cancer after breast-conserving surgery significantly reduces heart and lung doses compared with FB. Changes in lung volume are the basis for improving the relative anatomical location of the heart. The heart-to-lung volume ratio and maximum heart margin distance may provide a reference for DIBH technique.

Objective To analyze the correlation between treatment time and radiotherapy plan of deep inspiration breath-hold (DIBH) technique for the whole breast irradiation (WBI) in the left breast cancer after breast-conserving surgery,verify the inter-fractional reproducibility of radiotherapy,observe the heart location and dosimetric changes and calculate the effect of DIBH upon the WBI setup error after the surgery.Methods We prospectively enrolled 15 patients with left breast cancer undergoing WBI after breast-conserving surgery,who met the requirement of D1BH.Treatment time was recorded,its correlation with the number of field and monitor unit was analyzed.Inter-fractional setup errors and PTV delineation were calculated using cone beam CT (CBCT).The accuracy of the position and dose of the heart during radiotherapy was verified by the imaging fusion of CBCT and CT images.The variables among groups were analyzed by non-parametric Firedman test.Results The average treatment time of DIBH radiotherapy was 4.6 minutes.The treatment time was correlated with the maximal and total number of sub-fields and total monitor units.During DIBH treatment,the mean cardiac displacement volume was 19.1 cm3(3.8％).The mean cardiac dose difference between CBCT and planning CT was 5.1 cGy,and there was no significant difference in the heart V5-V30.The mean inter-fractional system setup error (∑) and random setup error (σ) in the left-right (x),superior-inferior (y) and anterior-posterior (z) direction were ∑x 1.9 mm,∑y 2.1 mm,∑z 2.0 mm,σx 1.3 mm,σy 1.3 mm,σz 1.4 mm,respectively.The corresponding minimal margins for setup error were 5.7 mm,6.2 mm and 6.0 mm,respectively.Conclusion DIBH for WBI after breast-conserving surgery does not significantly prolong the treatment time.Treatment time is related to treatment plan.DIBH yields high inter-fractional reproducibility and protects the heart.

Objective: To compare the clinical efficacy and safety between tocilizumab (TCZ) combined with methotrexate (MTX) and TCZ used alone in the patients with active rheumatoid arthritis (RA) by meta-analysis to provide reference for the treatment adjustment for the patients with poor response to MTX.Methods: Literature searches were conducted in sinoMed, VIP, PubMed, Cochrane Library and OVID, and then identified according to the inclusion and exclusion criteria.Meta-analysis was conducted using Rev Man 5.3.5 software.Results: Totally 7 randomized controlled trials (RCTs) were included in the analysis.A total number of patients were 1534 cases.The meta-analysis showed that in the treatment of RA, TCZ combined with MTX had significantly higher odds of DAS28≤2.6 remission and CDAI≤2.8 remission when compared with TCZ alone , and the incidence of adverse events (AE), serious adverse events (SAE) and serious inection had no statistical differences.Conclusion: The efficacy of TCZ combined with MTX is higher than that of TCZ alone in RA patients, and the safety is similar.The conclusion still needs further confirmation by RCTs with large samples and high quality.

Objective To evaluate the range of motion of gastroesophageal junction (GEJ) adenocarcinoma during preoperative radiotherapy.Methods Fourteen consecutive patients who received preoperative chemoradiotherapy for GEJ adenocarcinoma were included in this study.Fiducial markers were placed on the upper and lower edges of and around the primary tumor under a gastroscope.Eight patients underwent four-dimensional computed tomography to obtain 98 intrafractional images containing 8 fiducial markers at the GEJ.Twelve patients underwent cone-beam computed tomography at the 1 st to 5th,7th,12th,17th,and 22nd courses of radiotherapy to obtain 90 interfractional images.The paired t test was used for difference analysis.Results The intrafractional tumor displacements in left-right (LR),ventro-dorsal (VD),and cranio-caudal (CC) directions were 0.92±0.95 mm,2.27±2.73 mm,and 9.95±5.48 mm,respectively;the motion in CC direction was larger than that in LR or VD direction (P=0.000 or P=0.000);the motion in VD direction was larger than that in LR direction (P=0.000).The interfractional tumor displacements in LR,VD,and CC were 6.56±4.19 mm,5.69±3.29 mm,and 6.49±4.37 mm,respectively;the motion in LR or CC direction was larger than that in VD direction (P=0.031 or P=0.044);there was no significant difference between the motions in LR and CC directions (P=0.956).In order to ensure 95% of prescribed dose to at least 90% of the tumor volume,the margins from GEJ lesion in LR,VD,and CC directions were 19.4 mm,14.6 mm,and 27.2 mm,respectively,which could cover both intrafractional and interfractional tumor displacements during preoperative radiotherapy.Conclusions GEJ tumor has a wide range of movement in preoperative intra-and inter-fractional radiotherapy.This should be considered for precise radiotherapy,and a new method should be selected to limit tumor movement.