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

Allergic rhinitis (AR), a globally prevalent immune-mediated inflammatory condition, is still an incurable disease. In the present study, we have validated the impact of the Kelch-like ECH associated protein 1 (Keap1)-related oxidative stress and inflammatory response in clinical AR patient peripheral blood and nasal swab samples, emphasizing the biological relevance of Keap1 and AR. Targeting Keap1 -nuclear factor erythroid 2-related factor 2 (Nrf2) related anti-oxidative stress may be effective for AR intervention. Drawing inspiration from the Keap1 homodimerization and the E3 ligase characteristics, we herein present a design of novel bivalent molecules for chemical knockdown of Keap1. For the first time, we characterized ternary complexes of Keap1 dimer and one molecule of bivalent compounds. The best bivalent molecule 8 encompasses robust capacity to degrade Keap1 as a homoPROTAC^KEAP1. It efficaciously suppresses inflammatory cytokines in extensively different cells, including human nasal epithelial cells. Moreover, in an AR mouse model, we confirmed that the chemical degradation induced by homoPROTAC^KEAP1 led to therapeutic benefits in managing AR symptoms, oxidative stress and inflammation. In summary, our findings underscore the efficacy of targeting the Keap1 system through the homoPROTAC-ing technology as an innovative and promising treatment strategy for the incurable allergic disorders.

Objective To investigate the association between four single nucleotide polymorphisms(SNP)(rs9340 in MAPK1,rs14804 in NRAS,rs712 and rs7973450 in KRAS)in the 3'UTR of ERK1/2 signaling pathway-related genes and non-small cell lung cancer(NSCLC).Methods A total of 478 NSCLC patients and 480 healthy controls were enrolled in this study.Four SNPs were genotyped by using TaqMan assays.The association between the four SNPs and NSCLC was analyzed.Results The distribution frequency difference of the allele of rs9340 was statistically significant between the control group and the non-small cell squamous cell carcinoma(SCC)group(P = 0.009),suggesting that the G allele of rs9340 may be a protective factor for non-small cell lung squamous cell carcinoma(OR = 0.67,95%CI:0.50～0.91).In addition,in the<50 years age group,the distribution frequency difference of the allele of rs9340 was statistically significant between the control group and the NSCLC group(P = 5.07×10-4),indicating that the G allele of rs9340 may be a protective factor for NSCLC(OR = 0.46,95%CI:0.29～0.72).Conclusion The SNP rs9340 in MAPK1 may be associated with the risk of NSCLC.

Atractylodis rhizoma is a perennial herb of the Asteraceae family,which mainly divided into A.chinensis(DC)Koidz and Atractyiodes lancea(Thunb)DC,with the effects of strengthening the spleen,drying dampness,brightening the eyes,etc.Atractylodis rhizoma is mainly used in the clinical treatment of spleen deficiency and dampness,night blindness,eye fatigue and other symptoms.According to the clinical effect,and modern pharmacological researches have confirmed,the Chinese herbal medicine Atractylodis rhizoma contains a variety of active ingredients,such as volatile oils,alkynes,glycosides,etc.In recent years,pharmacological studies on Atractylodis rhizoma have found that atractylodin in polyalkynes has good activity in anti-inflammation,treatment of bacterial resistance,and inhibition of cholangiocarcinoma cell migration,and its high biological activity may be related to the conjugated enyne structure.Therefore,this article summarizes the studies on chemical components and pharmacological effects of polyalkynes in Atractylodis rhizoma that have been published in recent years,and comprehensively expounds the research progress of polyalkynes in Atractylodis rhizoma,so as to provide reference for scientific researchers and promote the in-depth development and utilization of the medicinal value of Atractylodis rhizoma.

Objective To systematically review the present status of oral Chinese patent medicines(CPMs)for treating functional dyspepsia(FD),explore the formation rules of CPMs,and reveal the potential problems by referring to the methods and procedures of Scoping review.Methods First,we screened all CPMs from the domestic-related drug catalogs which are generally accepted and own the force of law,then we sorted the CPMs based on the drug instructions while carrying out Chinese and English database document retrieval to review the clinical studies.Descriptive analysis of the basic feature and clinical research evidence of CPMs was performed combined with visual charts.Results This study included 42 CPMs for treating FD.Among the formulas of CPMs,Tangerine peel,Radices saussureae,Poria cocos,Glycyrrhiza,Atractylodes macrocephala,and Six Divine Qu appeared frequently.In addition,96 studies involving 21 CPMs were included,among which Zhizhu Kuanzhong Capsule,Liuwei Anxiao capsule,and Dalitong granules had more clinical literature.By analyzing the included 96 clinical studies,we found that the combination of Chinese and Western medicine was the main intervention,and the effective rate,clinical symptom score,and adverse reactions were the main outcomes that were concerned.In addition,8 studies had off-label use of diseases,involving the Wuling capsule to treat the FD whether the disease was accompanied by depression and anxiety symptoms or not,and Zhizhu Kuanzhong Capsule to treat the FD with anxiety and depression.Although the Wuling capsule and Zhizhu Kuanzhong capsule were off-label used in clinical practice,there was no beyond the scope of the guideline.Conclusion The qi-regulating drug,spleen-strengthening drug and digestant drugs are the usual Chinese medicines used for treating adult FD.In recent years,research on CPMs for treating adult FD has increased rapidly.But there is insufficient reflection of CPMs treatment characteristics,ambiguous differences from the primary and secondary outcomes,multiple composite outcomes,and not explicit information on FD or its symptoms in drug package insert,which needs to be improved in the future.

The chemical complexity of traditional Chinese medicines (TCMs) makes the active and functional annotation of natural compounds challenging. Herein, we developed the TCMs-Compounds Functional Annotation platform (TCMs-CFA) for large-scale predicting active compounds with potential mechanisms from TCM complex system, without isolating and activity testing every single compound one by one. The platform was established based on the integration of TCMs knowledge base, chemome profiling, and high-content imaging. It mainly included: (1) selection of herbal drugs of target based on TCMs knowledge base; (2) chemome profiling of TCMs extract library by LC‒MS; (3) cytological profiling of TCMs extract library by high-content cell-based imaging; (4) active compounds discovery by combining each mass signal and multi-parametric cell phenotypes; (5) construction of functional annotation map for predicting the potential mechanisms of lead compounds. In this stud TCMs with myocardial protection were applied as a case study, and validated for the feasibility and utility of the platform. Seven frequently used herbal drugs (Ginseng, etc.) were screened from 100,000 TCMs formulas for myocardial protection and subsequently prepared as a library of 700 extracts. By using TCMs-CFA platform, 81 lead compounds, including 10 novel bioactive ones, were quickly identified by correlating 8089 mass signals with 170,100 cytological parameters from an extract library. The TCMs-CFA platform described a new evidence-led tool for the rapid discovery process by data mining strategies, which is valuable for novel lead compounds from TCMs. All computations are done through Python and are publicly available on GitHub.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

ObjectiveTo carry out the clinical comprehensive evaluation of Biantong capsules and Biantong tablets in the treatment of constipation guided by the clinical value of drugs， and to provide a scientific basis for the rational pricing， rational use， and cataloging of Biantong capsules/tablets. MethodThe available evidence and survey data were used for the clinical comprehensive evaluation of Biantong capsules/tablets and three control drugs in the treatment of constipation in terms of the six dimensions including effectiveness， safety， economics， innovation， suitability， and accessibility. ResultIn terms of effectiveness， Biantong capsules/tablets can improve the response rate， with clear pharmacological mechanism. In terms of safety， the absence of toxic reaction， the mild adverse reactions， and the favorable prognosis indicate high safety. In terms of economics， the average daily cost of Biantong capsules/tablets is the lowest among the tested drugs， which indicates a cost-effectiveness advantage. In terms of innovation， Biantong capsules/tablets have been authorized patents in China and listed as members in the third category of new drugs of traditional Chinese medicine/ninth new drugs of traditional Chinese medicine. In terms of suitability， Biantong capsules/tablets are convenient to store and take and have good suitability in terms of drug technical characteristics and drug usage. In terms of accessibility， Biantong capsules/tablets have a wide coverage in hospitals， sufficient capacity， low patient burden， extensive drug catalogue coverage， and no major environmental risk for long-term application. The comprehensive values of the tested drugs follow a descending order of control drug B （84.27 score）， Biantong capsules/tablets （82.47 score）， control drug A （70.47 score）， and control drug C （59.46 score）. The recommendations of the expert panel are Class A （18/18）， which can be directly converted into decision-making. ConclusionBiantong capsules/tablets demonstrate a high clinical comprehensive value in the treatment of constipation， providing a reference for the rational pricing， rational use， and cataloging of drugs.

Objective:To investigate the effect of different timing of urinary catheter removal on postoperative recovery of elderly patients undergoing transurethral resection of prostate (TURP) .Methods:A total of 159 elderly patients undergoing TURP from Beijing Friendship Hospital Affiliated to Capital Medical University from March 2021 to June 2022 were selected as research objects by convenience sampling method, and were divided into the urinary catheter removal within 48 h after surgery group ( n=47), urinary catheter removal within 48 to 72 h after surgery group, urinary catheter removal>72 h after surgery group. The degree of dysuria after catheter removal, incidence of urinary tract infection, secondary catheter insertion rate and postoperative hospital stay were compared among the three groups. Results:The proportion of patients with moderate or above dysuria of the urinary catheter removal within 48 to 72 h after surgery group was lower than those of the urinary catheter removal within 48 h after surgery group and the urinary catheter removal>72 h after surgery group, and the differences were statistically significant ( P<0.05). The incidence of urinary tract infection of the urinary catheter removal within 48 h after surgery group and the urinary catheter removal within 48 to 72 h after surgery group were lower than that of the urinary catheter removal>72 h after surgery group, and the differences were statistically significant ( P<0.05). The rate of secondary catheterization of the urinary catheter removal within 48 to 72 h after surgery group and the urinary catheter removal>72 h after surgery group were lower than that of the urinary catheter removal within 48 h after surgery group, and the differences were statistically significant ( P<0.05). The postoperative hospital stay of the curinary catheter removal within 48 to 72 h after surgery group was shorter than those of the urinary catheter removal within 48 h after surgery group and the urinary catheter removal>72 h after surgery group, and the differences were statistically significant ( P<0.05) . Conclusions:Removing urinary catheter within 48 to 72 h after surgery can effectively reduce the degree of urination difficulty in elderly patients undergoing TURP, the incidence of urinary tract infection and the rate of secondary catheterization, and shorten the postoperative hospital stay.

Objective:To prepare specific anti- Fusarium yolk immunoglobulin (IgY) and investigate its tolerance to temperature and pH and verify its antifungal effect against Fusarium. Methods:Eighteen 22-week-old Leghorn laying hens were selected and randomized into negative control group and experimental group according to the random number table method, with 9 hens in each group.The 2×10 7 colony forming units (CFU)/ml suspension of inactivated hyphae of Fusarium and Freund complete adjuvant was mixed in a 1∶1 ratio and emulsified.The hens in the experimental group were injected with 1 ml of the mixture to immunize and received 1 ml of Freund incomplete adjuvant as booster injection at two weeks after the initial injection.The egg yolk was collected from the 5th to 16th week after immunization.Specific anti- Fusarium IgY protein was prepared by salting out method using ammonium sulfate.The obtained protein solution was put into a freeze dryer and made into freeze-dried powder stored at 4 ℃.The hens in the negative control group were injected with 0.9% sodium chloride to prepare the non-specific antibody as the negative control.Bradford method was used to determine the concentration of specific egg IgY protein and the indirect enzyme-linked immunosorbent assay (ELISA) was employed to measure its titer.The 1×10 5 CFU/ml and 1×10 3 CFU/ml Fusarium suspension were cultured with different concentrations of IgY and phosphate buffered saline (PBS) for 4 days, and the absorbance value at 600 nm was measured.The co-incubated PBS/negative IgY with Fusarium solution was set as blank control/negative control accordingly.The concentration-killing curve of anti- Fusarium IgY against Fusarium was obtained.The specific IgY solution was diluted to 0.02 mg/ml with PBS pH 7.4, and the diluted specific IgY solution was placed into the water bath for 30 minutes at 30, 40, 50, 60, 70, 80, 90 ℃, respectively, and was cooled down to room temperature.The specific IgY solution was diluted to 0.02 mg/ml with PBS pH 1, pH 2, pH 3, pH 4, pH 5, pH 6, pH 7, pH 8, pH 9, pH 10, pH 11, pH 12, respectively, and the diluted specific IgY solution was placed at 4 ℃ for one hour.The activity of diluted specific IgY solution by different methods was measured by indirect ELISA, and the tolerance of IgY to various temperatures and pH was evaluated.Twelve 8-week-old SPF female C57BL/6 mice were selected and randomized into the PBS control group and specific IgY treatment group according to the random table method, with 6 mice in each group.The right eyes of the 12 mice were infected with Fusarium to establish mice model of fungal keratitis.One day after modeling, 200 mg/ml of anti- Fusarium IgY was dropped to the right eyes of mice in the specific IgY treatment group, and PBS was dropped to the right eyes of mice in the PBS control group.The corneas of mice in the two groups were observed under the slit lamp microscope at 1, 3 and 5 days following modeling, and the corneal ulcer was scored according to the grading scale for inflammation score.The use and care of experimental animals followed the Association for Research in Vision and Ophthalmology statement.This study protocol was approved by an Ethics Committee of The Affiliated Hospital of Qingdao University (No.QYFYWZLL26168). Results:The IgY protein concentration from the 5th to 16th week after immunization was 1.57, 2.89, 24.98, 25.09, 23.89, 25.78, 21.57, 21.37, 18.98, 15.78, 14.67, 12.67 mg/ml, respectively.The titer of IgY was increased from the 5th week, and it reached the highest titer 1∶10 000 at the 7th week, which could be maintained until the 12th week after immunization before it dropped gradually.The concentration-killing curve showed that compared with the blank control group and negative control group, Fusarium grew slowly in the specific IgY treatment group.The specific IgY with a titer greater than 1∶10 000 had thermal stability below 60 ℃.The activity of specific IgY was highest at pH 4 to 6, which could be maintained above 70% at pH 3 to 9 and was further reduced with the decrease or increase of pH.At 1, 3 and 5 days after Fusarium infection, the inflammation scores were 3.50±0.55, 7.33±0.82, 4.00±0.63 in the PBS control group, and 3.33±0.82, 4.17±0.75, 2.50±0.55 in the specific IgY treatment group.There was a statistically significant overall difference in inflammation scores at various time points between the two groups ( Fgroup=247.35, P<0.05; Ftime=23.19, P<0.05). At 3 and 5 days after Fusarium infection, there was a smaller ulcer area and decreased inflammation scores in the specific IgY treatment group compared with the PBS control group, and the differences were statistically significant (all at P<0.05). Conclusions:The high titer specific IgY can be successfully prepared by salting out method using ammonium sulfate, which is with high stability, tolerance to temperature and pH.Moreover, it can alleviate the severity of corneal ulcers and reduce inflammation scores in the mouse model of fungal keratitis.