[Clinical analysis of the correlation between the expression of soluble B cell maturation antigen and the efficacy of chimeric antigen receptor T cell targeting B cell maturation antigen in patients with multiple myeloma].

Objective: The effect of bone marrow soluble B cell maturation antigen (sBCMA) expression on the efficacy and side effects of chimeric antigen receptor (CAR) -modified T-cell-targeting B cell maturation antigen (BCMA) in patients with multiple myeloma (MM) . Methods: This study involved 29 patients with relapsed or refractory MM (RRMM) who received humanized anti-BCMA CAR-T cell clinical trials from January 2018 to December 2021. The expression of sBCMA in bone marrow before and after anti-BCMA CAR-T cell treatment was detected by flow cytometry and compared. Results: ①Two months after BCMA CAR-T cell treatment, 20 patients (68.97%) achieved an overall response (OR), whereas nine patients had stable disease (SD) or miner emission (MR). ②The expression of sBCMA in the bone marrow of 20 patients with OR was higher before treatment than after [26 926 (18 215, 32 488) ng/L vs 9 968 (6 634, 11 459) ng/L; P<0.001]; no significant difference was observed in patients with MR and SD [41 187 (33 816, 47 046) ng/L vs. 33 954 (31 569, 36 256) ng/L; P=0.145]; sBCMA expression in patients with OR before CAR-T cell treatment was lower than in patients with MR and SD (P=0.005). ③No significant linear correlation was found between the peak value of CAR-T cells and sBCMA expression in the bone marrow of all 29 patients with RRMM (R(2)=0.035, P=0.330). ④No significant difference in sBCMA expression was found between grades 0-1 CRS group (13 patients) and grades 2-4 CRS group [16 patients; 32 045 (18 742, 40 801) ng/L vs 29 102 (24 679, 38 776) ng/L, P=0.879], nor between grade 0 ICANS group (22 patients) and grade 1-3 ICANS group [seven patients; 30 073 (19 375, 40 065) ng/L vs 33 816 (22 933, 43 459) ng/L, P=0.763]. Conclusion: sBCMA expression in the bone marrow is related to the efficacy of BCMA CAR-T cell therapy in patients with RRMM, but is not significantly correlated with the severity of adverse events. It may serve as a predictive biomarker for the efficacy of BCMA CAR-T cell therapy in these patients.

[Efficacy and safety of CD19 chimeric antigen receptor T cells for the treatment of 22 patients with B-cell lymphoma].

Objective: To investigate the efficacy and safety of CD19 chimeric antigen receptor T (CAR-T) lymphocytes for the treatment of B cell lymphoma. Methods: A total of 22 patients with B-cell lymphoma from February 1, 2017 to July 1, 2018 were reviewed to evaluate the efficacy and adverse reactions of CD19 CAR-T. Results: Of 22 patients with B-cell lymphoma received CD19 CAR-T cells, the median dose of CAR-T cells was 7.2 (2.0-12.0) ×106/kg. Nine of 12 cases of relapse refractory patients were overall response. Complete remission (CR) occurred in 2 of 12 patients, partial remission (PR) in 7 of 12 patients. The overall response in minor residual disease positive (MRD) group was 8 of 10 patients. CD19 CAR-T cells proliferated in vivo and were detectable in the blood of patients. The peak timepoints of CAR-T cells proliferated in the relapsed refractory and MRD positive groups were 12 (5-19) and 4.5 (1-12) days after treatment respectively, and among peripheral blood cells, CAR-T cells accounted for 10.10% (3.55%-24.74%) and 4.02% (2.23%-28.60%) of T lymphocytes respectively. The MRD positive patients achieved sustained remissions during a median follow-up of 8 months (rang 3-18 months) . None of all the patients relapsed during a median follow-up time of 10 months (3-18 months) . However, 7 PR responders of the relapsed refractory patients maintained a good condition for 1.5-6.0 months. One patient bridged to hematopoietic stem cell transplantation, another one sustained remission for 12 months. Cytokine-release syndrome (CRS) occurred in 14 patients with grade 1-2 CRS in MRD positive group and grade 3 CRS in relapsed refractory group. Conclusions: CAR-T cell therapy not only played a role in the rescue treatment of relapsed and refractory patients, but also produced a surprising effect in the consolidation and maintenance of B-cell lymphoma. CD19 CAR-T cells might be more effective in the treatment of MRD positive B-cell lymphoma patients than in the refractory or relapsed cases. High response rate was observed with fewer adverse reactions.

A multi-level drill guide template improves the accuracy of pedicle screw placement in lumbar spine.

OBJECTIVE: Free-hand technique is widely used in pedicle screw placement for lumbar spine and generally safe; however, screw malposition still occurs. To develop a novel multi-level drill guide template for pedicle screw placement in lumbar spine and evaluate its accuracy. MATERIALS AND METHODS: Twelve lumbar cadaveric specimens were randomly allocated into guide template group (n=6) and free-hand group (n=6). Computed tomography (CT) scans were obtained for reconstruction of three-dimensional (3D) model of each lumbar vertebra, and further an individual guide template was designed. Then the templates and their corresponding vertebra were developed by rapid prototyping (RP) technology. With the guide of the templates, screws were inserted via mini-open Wiltse approach. The positions of the screws were assessed based on postoperative CT images. RESULTS: In total, 120 pedicle screws inserted (guide template group: n=60 vs. free-hand group: n=60). For all 30 vertebras in the guide template group, all pre-designed personalized drill guide templates can be fitted into the facet joints of each vertebra well. Furthermore, our results revealed a significant improvement for the guide template group in the accuracy rate (p=0.026). CONCLUSIONS: Armed with advantages of minimal invasion, enhanced accuracy and safety, the novel technique of multi-level drill guide template can be properly applied in pedicle screw placement for lumbar spine and promises to be a potential option in clinical application.

Association between H19 polymorphisms and osteosarcoma risk.

OBJECTIVE: The long non-coding RNA (lncRNA) H19, a maternally expressed imprinted gene, has involvement in cancer susceptibility and disease progression. However, the association between H19 polymorphisms and osteosarcoma susceptibility has remained elusive. We designed this case-control study to explore the association between H19 polymorphism and osteosarcoma risk. PATIENTS AND METHODS: In this study, we genotyped 4 tagger SNPs of the H19 gene in a case-control study including 193 osteosarcoma cases and 393 cancer-free controls. RESULTS: For the main effect analysis, rs217727 (G>A) was associated with osteosarcoma risk (GA/GG: adjusted OR = 1.51, 95% CI: 1.06-2.17, p = 0.024; AA/GG: adjusted OR = 1.89, 95% CI: 1.23-2.91, p = 0.004; additive model: adjusted OR = 1.35, 95% CI: 1.01-1.80, p = 0.043). CONCLUSIONS: This finding indicates that rs217727 polymorphism may play a role in genetic susceptibility to the risk of osteosarcoma, which may improve our understanding of the potential contribution of H19 SNPs to cancer pathogenesis.

Immortalized Parkinson's disease lymphocytes have enhanced mitochondrial respiratory activity.

In combination with studies of post-mortem Parkinson's disease (PD) brains, pharmacological and genetic models of PD have suggested that two fundamental interacting cellular processes are impaired - proteostasis and mitochondrial respiration. We have re-examined the role of mitochondrial dysfunction in lymphoblasts isolated from individuals with idiopathic PD and an age-matched control group. As previously reported for various PD cell types, the production of reactive oxygen species (ROS) by PD lymphoblasts was significantly elevated. However, this was not due to an impairment of mitochondrial respiration, as is often assumed. Instead, basal mitochondrial respiration and ATP synthesis are dramatically elevated in PD lymphoblasts. The mitochondrial mass, genome copy number and membrane potential were unaltered, but the expression of indicative respiratory complex proteins was also elevated. This explains the increased oxygen consumption rates by each of the respiratory complexes in experimentally uncoupled mitochondria of iPD cells. However, it was not attributable to increased activity of the stress- and energy-sensing protein kinase AMPK, a regulator of mitochondrial biogenesis and activity. The respiratory differences between iPD and control cells were sufficiently dramatic as to provide a potentially sensitive and reliable biomarker of the disease state, unaffected by disease duration (time since diagnosis) or clinical severity. Lymphoblasts from control and PD individuals thus occupy two distinct, quasi-stable steady states; a 'normal' and a 'hyperactive' state characterized by two different metabolic rates. The apparent stability of the 'hyperactive' state in patient-derived lymphoblasts in the face of patient ageing, ongoing disease and mounting disease severity suggests an early, permanent switch to an alternative metabolic steady state. With its associated, elevated ROS production, the 'hyperactive' state might not cause pathology to cells that are rapidly turned over, but brain cells might accumulate long-term damage leading ultimately to neurodegeneration and the loss of mitochondrial function observed post-mortem. Whether the 'hyperactive' state in lymphoblasts is a biomarker specifically of PD or more generally of neurodegenerative disease remains to be determined.

Import-associated translational inhibition: novel in vivo evidence for cotranslational protein import into Dictyostelium discoideum mitochondria.

To investigate protein import into the mitochondria of Dictyostelium discoideum, green fluorescent protein (GFP) was fused as a reporter protein either to variable lengths of the N-terminal region of chaperonin 60 (the first 23, 40, 80, 97, and 150 amino acids) or to the mitochondrial targeting sequence of DNA topoisomerase II. The fusion proteins were expressed in AX2 cells under the actin-15 promoter. Fluorescence images of GFP transformants confirmed that Dictyostelium chaperonin 60 is a mitochondrial protein. The level of the mitochondrially targeted GFP fusion proteins was unexpectedly much lower than the nontargeted (cytoplasmic) forms. The distinction between targeted and nontargeted protein activities was investigated at both the transcriptional and translational levels in vivo. We found that targeting GFP to the mitochondria results in reduced levels of the fusion protein even though transcription of the fusion gene and the stability of the protein are unaffected. [(35)S]methionine labeling and GFP immunoprecipitation confirmed that mitochondrially targeted GFP is translated at much slower rates than nontargeted GFP. The results indicate a novel phenomenon, import-associated translational inhibition, whereby protein import into the mitochondria limits the rate of translation. The simplest explanation for this is that import of the GFP fusion proteins occurs cotranslationally, i.e., protein synthesis and import into mitochondria are coupled events. Consistent with cotranslational import, Northern analysis showed that the GFP mRNA is associated with isolated mitochondria. This association occurred regardless of whether the GFP was fused to a mitochondrial leader peptide. However, the presence of an import-competent leader peptide stabilized the mRNA-mitochondria association, rendering it more resistant to extensive EDTA washing. In contrast with GFP, the mRNA of another test protein, aequorin, did not associate with the mitochondria, and its translation was unaffected by import of the encoded polypeptide into the mitochondria.

One-stage pedicled omentum majus transplantation into thoracic cavity for treatment of chronic persistent empyema with or without bronchopleural fistula.

OBJECTIVE: Assessment of the present results of surgical treatment for chronic persistent empyema with or without bronchopleural fistula (BPF) using one-stage pedicled omentum majus transplantation into the thoracic cavity. METHODS: From November 1979 to December 1996, 50 patients with chronic persistent empyema were treated by pedicled omentum majus transplanted into the thoracic cavity. There were 35 men and 15 women, and the age range was 15-58 years. Empyema had been present for 0.5-18 years. Twenty-six of 35 cases with chronic tuberculous empyema and six of 15 cases with chronic bacterial empyema suffered from concomitant BPF (n = 32). In the latter, the most common organisms were Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli. RESULTS: There were no perioperative deaths. Two cases had a significant air leak on the first postoperative day. One of them underwent rethoractomy 30 h after the initial operation to stop the fistula using intrathoracic omentum. Thoracic dead space disappeared in most of the operated cases and a sterilized dry cavity remained in some cases. CONCLUSIONS: One-stage pedicled omentum majus transposition is a safe and easy procedure for chronic persistent empyema and BPF, it breaks down residual or recurrent inflammatory foci mechanically and closes the BPF effectively with minimal deformity of the chest wall.