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

Background and purpose:Accurate preoperative differentiation between vagal nerve cervical schwannomas(SCCS)and sympathetic chain cervical schwannomas(SCCS)in the neck is crucial because of their different postoperative complication.This study aimed to construct and validate a Diagnosis Score and vascular displacement nomogram for the preoperative differentiation of VNCS from SCCS in the neck.Methods:This cross-sectional study retrospectively analyzed patients with pathologically confirmed VNCS and SCCS at Fudan University Shanghai Cancer Center from January 2017 to April 2022.This study was approved by the medical ethics committee of Fudan University Shanghai Cancer Center(approval number:1612167-18).Inclusion criteria:① histopathological diagnosis of VNCS or SCCS through biopsy or surgical resection;② patients with complete clinic data;③availability of preoperative contrast-enhanced computed tomography(CT)or magnetic resonance imaging(MRI)examinations.Patients were excluded for:① contrast agent contraindications;② poor image quality;③ severe artifacts;④ non-standard scanning protocols.The cohort was randomly divided into training and validation sets in a 7∶3 ratio.Two radiologists(one resident and one attending physician)independently evaluated tumor characteristics(location,size and vascular displacement patterns)on preoperative imaging.Independent predictors were selected using LASSO regression analysis to construct a diagnostic scoring system and nomogram,with model performance evaluated by the receiver operating characteristic(ROC)curve.Results:A total of 110 patients were enrolled,with 77 cases allocated to the training set and 33 cases to the validation set.The age range was 24-78 years,and the mean age was(51.22±12.36)years.There were no statistically significant differences in baseline characteristics including age,gender,tumor location and size between the two patient groups(P＞0.05).ICA/ECA splaying was significantly associated with SCCS(P＜0.001),while the ICA/IJV splaying was significantly associated with VNCS(P＜0.001).Lateral and posterior ICA displacement were significantly associated with SCCS(P＜0.001),and medial and anterior ICA displacement were significantly associated with VNCS(P＜0.001).Five features including tumor size,ICA displacement direction,IJV displacement direction,ICA/ECA splaying and ICA/IJV splaying were used to establish the Diagnosis Score and nomogram.The nomogram combined imaging features showed favorable preference value for differentiating VNCS from SCCS,with area under curve(AUC)values of 0.953(95%CI:0.912-0.994)and 0.939(95%CI:0.885-0.993)for the training and validation cohorts,respectively.Conclusion:The Diagnosis Score and vascular displacement nomogram showed favorable predictive efficacy for differentiating VNCS from SCCS in the neck,and might be useful for clinical decision-making.

Objective To study the related molecular mechanism of andrographolide(AGP)in inhibi-ting the proliferation of human colon cancer LoVo cells and promoting their apoptosis.Methods The LoVo cells were set up as the control group and experimental group.The cells were treated with different concentra-tions of AGP(0,20,40,80 μmol/L).The cell viability was detected by CCK-8,the cellular cycle and apoptosis were detected by flow cytometery,and Western blot was used to detect protein level of PCNA,Bad and Bcl-2,and the effect of AGP of BMP9 overexpression or silencing AGP on PCNA,Bad and Bcl-2 protein levels;West-ern blot was used to analyze the effect of AGP on PTEN,Akt1/2/3 and p-Akt1/2/3 levels.Results AGP could inhibit the proliferation of LoVo cells,promoted their apoptosis and increased the BMP9 expression lev-el.The BMP9 overexpression could enhance the effect of AGP for inhibiting the proliferation and promoting the apoptosis,silencing BMP9 could weaken the above effects of AGP(P＜0.05).AGP decreased the expres-sion level of p-Akt1/2/3 in the LoVo cells and increased the PTEN expression level(P＜0.05).BMP9 over-expression enhanced AGP and decreased the p-Akt 1/2/3 expression level in the LoVo cells,and silencing BMP9 could weaken the above effects of AGP(P＜0.05).Conclusion AGP could inhibit the proliferation of human colon cancer LoVo cells,its mechanism may be related with up-regulating BMP9 expression,thus in-crease PTEN protein level and inhibit P13K/Akt signal.

Background and purpose:Accurate preoperative differentiation between vagal nerve cervical schwannomas(SCCS)and sympathetic chain cervical schwannomas(SCCS)in the neck is crucial because of their different postoperative complication.This study aimed to construct and validate a Diagnosis Score and vascular displacement nomogram for the preoperative differentiation of VNCS from SCCS in the neck.Methods:This cross-sectional study retrospectively analyzed patients with pathologically confirmed VNCS and SCCS at Fudan University Shanghai Cancer Center from January 2017 to April 2022.This study was approved by the medical ethics committee of Fudan University Shanghai Cancer Center(approval number:1612167-18).Inclusion criteria:① histopathological diagnosis of VNCS or SCCS through biopsy or surgical resection;② patients with complete clinic data;③availability of preoperative contrast-enhanced computed tomography(CT)or magnetic resonance imaging(MRI)examinations.Patients were excluded for:① contrast agent contraindications;② poor image quality;③ severe artifacts;④ non-standard scanning protocols.The cohort was randomly divided into training and validation sets in a 7∶3 ratio.Two radiologists(one resident and one attending physician)independently evaluated tumor characteristics(location,size and vascular displacement patterns)on preoperative imaging.Independent predictors were selected using LASSO regression analysis to construct a diagnostic scoring system and nomogram,with model performance evaluated by the receiver operating characteristic(ROC)curve.Results:A total of 110 patients were enrolled,with 77 cases allocated to the training set and 33 cases to the validation set.The age range was 24-78 years,and the mean age was(51.22±12.36)years.There were no statistically significant differences in baseline characteristics including age,gender,tumor location and size between the two patient groups(P＞0.05).ICA/ECA splaying was significantly associated with SCCS(P＜0.001),while the ICA/IJV splaying was significantly associated with VNCS(P＜0.001).Lateral and posterior ICA displacement were significantly associated with SCCS(P＜0.001),and medial and anterior ICA displacement were significantly associated with VNCS(P＜0.001).Five features including tumor size,ICA displacement direction,IJV displacement direction,ICA/ECA splaying and ICA/IJV splaying were used to establish the Diagnosis Score and nomogram.The nomogram combined imaging features showed favorable preference value for differentiating VNCS from SCCS,with area under curve(AUC)values of 0.953(95%CI:0.912-0.994)and 0.939(95%CI:0.885-0.993)for the training and validation cohorts,respectively.Conclusion:The Diagnosis Score and vascular displacement nomogram showed favorable predictive efficacy for differentiating VNCS from SCCS in the neck,and might be useful for clinical decision-making.

Gene therapy, harnessing the power of CRISPR-Cas9 and/or DNAzyme systems, stands as a pivotal approach in cancer therapy, enabling the meticulous manipulation of genes pivotal to tumorigenesis and immunity. However, the pursuit of precise gene therapy encounters formidable hurdles. Herein, a near-infrared upconversion theranostic nanomachine is devised and tailors for CRISPR-Cas9/DNAzyme systems mediate precise gene therapy. An ingenious logic DNAzyme system consists of Chain 1 (C1)/Chain 2 (C2) and endogenous lncRNA is designed. We employ manganese modified upconversion nanoparticles for carrying ultraviolet-responsive C1-PC linker-C2 (C₂P) chain and Cas9 ribonucleoprotein (RNP), with outermost coats with hyaluronic acid. Upon reaching tumor microenvironment (TME), the released Mn²⁺ ions orchestrate a trifecta: facilitating endosomal escape, activating cGAS-STING signaling, and enabling T1-magnetic resonance imaging. Under near-infrared irradiation, Cas9 RNP/C₂P complex dissociates, releasing Cas9 RNP into the nucleus to perform gene editing of Ptpn2, while C1/C2 chains self-assemble with endogenous lncRNA to form a functional DNAzyme system, targeting PD-L1 mRNA for gene silencing. This strategy remodels the TME by activating cGAS-STING signaling and dual immune checkpoints blockade, thus realizing tumor elimination. Our theranostic nanomachine armed with the CRISPR-Cas9/DNAzyme logic systems, represents a resourceful and promising strategy for advancing cancer systemic immunotherapy and precise gene therapy.

Objective To explore the effects of MOTOmed intelligent training combined with standing balance training on the recovery of lower limb motor function and balance in stroke patients with hemiplegia.Methods A total of 124 patients with post-stroke hemiplegia who received rehabilitation care in the Sixth People's Hospital of Nantong from May 2022 to May 2024 were selected as research objects.They were assigned to observation group(62 cases)or control group(62 cases)using a random number table.The control group received MOTOmed intelligent training,and the observation group received MOTOmed intelligent training combined with standing balance training.After 2 months of rehabilitation,the lower limb motor function(Fugl-Meyer assessment lower extremity subscale[FMA-LE]score,time up and go test[TUGT],balance function,postural stability[length and area of center of gravity movement,average trajectory error,completion time],quality of life(stroke specific quality of life[SS-QOL]),and self-care ability(Barthel index[BI])were compared between the two groups.Results After interventions,the FMA-LE scores of the observation group and control group were 19.41±5.72 and 16.08±4.41,respectively;the TUGT result was(40.06±12.35)s and(45.13±10.97)s;the station balance scores were 2.83±0.71 and 2.57±0.63;the walking function balance scores were 2.91±0.43 and 2.75±0.41;the lengths of center of gravity movement were(246.05±45.63)mm and(279.61±42.01)mm;the area of center of gravity movement was(92.75±22.16)mm2 and(102.36±27.84)mm2;the average trajectory error was(21.14±5.06)%and(25.78±5.42)%;the completion time of the tests was(79.24±5.06)s and(82.87±6.73)s;the SS-QOL scores were 138.91±32.05 and 125.65±34.83;BI was 51.24±7.91 and 46.05±6.63.There were significant differences in these indexes between the two groups(all P<0.05).Conclusion MOTOmed intelligent training combined with standing balance training can promote the recovery of lower limb motor function,improve lower limb motor balance,and enhance the quality of life of stroke patients with hemiplegia.

BACKGROUND:Unilateral chronic ankle instability has adverse effects on the affected limb,and evidence has shown that the nonaffected side may be similarly involved,but direct evidence is currently lacking.OBJECTIVE:To investigate the effects of unilateral chronic ankle instability on bilateral postural stability,proprioception,plantar tactile sensation,and muscle strength.METHODS:A total of 122 participants were recruited in this study,including 67 individuals with unilateral chronic ankle instability and 55 individuals without chronic ankle instability.Postural stability,proprioception,plantar tactile sensation and muscle strength were tested bilaterally in individuals with unilateral chronic ankle instability,as well as in those without chronic ankle instability.One-way analysis of variance or Kruskal-Wallis test was used for intergroup comparisons.RESULTS AND CONCLUSION:(1)Compared with individuals without chronic ankle instability,individuals with chronic ankle instability had longer time to stability in the anterior-posterior direction bilaterally(P=0.001-0.012),and longer time to stability in the medial-lateral direction on the affected side(P=0.012-0.025);had higher proprioception thresholds of plantarflexion,dorsiflexion,inversion,and eversion of the bilateral ankles(P=0.000-0.035);showed lower tactile sensation sensitivities of the bilateral great toe,first metatarsal head,fifth metatarsal head,arch,and heel(P=0.000-0.008);and had weaker muscle strength for inversion and eversion of the bilateral ankles(P=0.000-0.019).(2)Individuals with unilateral chronic ankle instability have bilateral deficits in postural stability,proprioception,plantar tactile sensation,and muscle strength.Therefore,the rehabilitation needs of both limbs should be fully considered when treating chronic ankle instability.

BACKGROUND:Unilateral chronic ankle instability has adverse effects on the affected limb,and evidence has shown that the nonaffected side may be similarly involved,but direct evidence is currently lacking.OBJECTIVE:To investigate the effects of unilateral chronic ankle instability on bilateral postural stability,proprioception,plantar tactile sensation,and muscle strength.METHODS:A total of 122 participants were recruited in this study,including 67 individuals with unilateral chronic ankle instability and 55 individuals without chronic ankle instability.Postural stability,proprioception,plantar tactile sensation and muscle strength were tested bilaterally in individuals with unilateral chronic ankle instability,as well as in those without chronic ankle instability.One-way analysis of variance or Kruskal-Wallis test was used for intergroup comparisons.RESULTS AND CONCLUSION:(1)Compared with individuals without chronic ankle instability,individuals with chronic ankle instability had longer time to stability in the anterior-posterior direction bilaterally(P=0.001-0.012),and longer time to stability in the medial-lateral direction on the affected side(P=0.012-0.025);had higher proprioception thresholds of plantarflexion,dorsiflexion,inversion,and eversion of the bilateral ankles(P=0.000-0.035);showed lower tactile sensation sensitivities of the bilateral great toe,first metatarsal head,fifth metatarsal head,arch,and heel(P=0.000-0.008);and had weaker muscle strength for inversion and eversion of the bilateral ankles(P=0.000-0.019).(2)Individuals with unilateral chronic ankle instability have bilateral deficits in postural stability,proprioception,plantar tactile sensation,and muscle strength.Therefore,the rehabilitation needs of both limbs should be fully considered when treating chronic ankle instability.

Objective:To retrieve, evaluate and integrate the best evidence of blood glucose management in hemodialysis patients with end-stage diabetic kidney disease, so as to provide a basis for clinical evidence-based nursing practice.Methods:BMJ Best Clinical Practice, Cochrane, OVID, Scopus, UpToDate, CNKI, Wanfang Database, Medical Pulse database, and other guideline networks and professional association websites and databases were searched for blood glucose management in hemodialysis patients with end-stage diabetic kidney disease. The search time limit was from the establishment of the database to May 10, 2023.Results:A total of 14 articles were included, including 1 clinical decision, 5 guidelines, 6 systematic reviews, 1 randomized controlled trial, and 1 expert consensus. The best evidences for blood glucose management in hemodialysis patients were summarized, including 8 aspects of pre-dialysis assessment, pre-dialysis blood glucose management, blood glucose management during dialysis, blood glucose management during dialysis interval, diet and nutrition, exercise management, lifestyle intervention and health education, with 25 pieces of evidence.Conclusions:This study summarizes the best evidence of blood glucose management in hemodialysis patients with end-stage diabetic kidney disease, and provides evidence-based basis for clinical practice for medical staff.

BACKGROUND:Careful regulation of bone immune response during repair of bone scaffold is important for bone regeneration. OBJECTIVE:To review the influence of bone immune response on bone repair and the design of bone tissue engineering scaffold with regulating bone immune function and its application in bone repair. METHODS:Relevant articles published from 1973 to 2023 were retrieved from Science Direct,PubMed,Web of Science,and CNKI databases.English search terms were"osteoimmunology,macrophages,bone repair materials,bone scaffold,bone defects,bone regeneration".Chinese search terms were"bone immunity,macrophages,bone repair material,bone stent,bone defect,bone regeneration".Totally 80 articles of the latest research progress in this field were summarized and analyzed. RESULTS AND CONCLUSION:(1)A detailed review was conducted on the important time points in the origin and development process of bone immunity,and it was explained that macrophages,as important members of the bone immune regulatory system,can be divided into two phenotypes:M1(pro-inflammatory)and M2(anti-inflammatory),and play a key role in different stages of bone regeneration.During the inflammatory phase,M1 type macrophages can activate osteoclasts,initiate tissue repair processes,and participate in the reconstruction of bone microvascular networks.On the other hand,during the bone tissue regeneration process in the later stages of inflammation,sustained high expression of M1 type macrophages can hinder the formation of new bones.During the repair phase,M2 macrophages can secrete osteogenic cytokines,stimulate osteogenic differentiation and mineralization of bone marrow mesenchymal stem cells,and promote bone formation.On the other hand,long-term activation of M2 macrophages can increase the secretion of fibrogenic molecules,leading to excessive formation of scar tissue and delaying the healing process.Therefore,regulating macrophages to undergo phenotype transformation at appropriate stages and constructing an immune microenvironment beneficial for osteogenesis has great significance for bone regeneration.(2)In the process of designing bone scaffolds with bone immune regulation characteristics,the physical and chemical properties such as scaffold roughness,pore structure,stiffness,hydrophilicity,surface charge,and surface functional groups can be changed to affect non-specific protein and cell adhesion,thereby affecting the interaction between bone scaffolds and the immune system.By designing surface functional coatings of bioactive substances such as hydroxyapatite,bioactive glass,metal ions,extracellular matrix,drugs,cytokines,and exosomes,the immune microenvironment can be actively regulated by releasing bioactive substances after implantation into the body,affecting macrophage polarization and crosstalk between macrophages and bone cells,and promoting more M2 polarization of macrophages,so as to build a bone immune microenvironment that is conducive to bone regeneration.(3)Based on the research and development of bone tissue engineering scaffolds,in addition to focusing on the direct regulatory factors of stem cell osteogenic differentiation,this article also proposes that attention should be paid to the management of the immune microenvironment of stem cell differentiation.By regulating the appropriate bone immune microenvironment,more stem cell osteogenic differentiation can be induced;the osteogenic efficiency of the scaffold can be enhanced,and the concept of"bone immune regulatory characteristics"can be condensed;deeply elucidated the multi-directional regulatory role of the bone immune microenvironment and introduced the existing strategies for changing the physicochemical properties and surface functional coating of scaffolds to endow them with bone immune regulatory potential,providing new ideas for guiding the development of a new generation of bone tissue engineering scaffolds with bone immune regulatory characteristics.However,the bone immune microenvironment is a dynamic equilibrium state,and most of the existing regulatory strategies do not consider the dynamic matching of regulation.Therefore,the research and development of intelligent bone immune regulatory scaffolds with efficient and targeted regulation of the immune microenvironment will be a key focus of attention for scholars in future.