Construction and efficacy testing of DNA vaccines containing HLA-A*02:01-restricted SARS-CoV-2 T-cell epitopes predicted by immunoinformatics.

Vaccines play essential roles in the fight against the COVID-19 pandemic. The development and assessment of COVID-19 vaccines have generally focused on the induction and boosting of neutralizing antibodies targeting the SARS-CoV-2 spike (S) protein. Due to rapid and continuous variation in the S protein, such vaccines need to be regularly updated to match newly emerged dominant variants. T-cell vaccines that target MHC I- or II-restricted epitopes in both structural and non-structural viral proteins have the potential to induce broadly cross-protective and long-lasting responses. In this work, the entire proteome encoded by SARS-CoV-2 (Wuhan-hu-1) is subjected to immunoinformatics-based prediction of HLA-A*02:01-restricted epitopes. The immunogenicity of the predicted epitopes is evaluated using peripheral blood mononuclear cells from convalescent Wuhan-hu-1-infected patients. Furthermore, predicted epitopes that are conserved across major SARS-CoV-2 lineages and variants are used to construct DNA vaccines expressing multi-epitope polypeptides. Most importantly, two DNA vaccine constructs induce epitope-specific CD8 + T-cell responses in a mouse model of HLA-A*02:01 restriction and protect immunized mice from challenge with Wuhan-hu-1 virus after hACE2 transduction. These data provide candidate T-cell epitopes useful for the development of T-cell vaccines against SARS-CoV-2 and demonstrate a strategy for quick T-cell vaccine candidate development applicable to other emerging pathogens.

Sequential CD7 CAR T-Cell Therapy and Allogeneic HSCT without GVHD Prophylaxis.

BACKGROUND: Patients with relapsed or refractory hematologic cancers have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy as a bridge to allogeneic hematopoietic stem-cell transplantation (HSCT) has the potential for long-term tumor elimination. However, pre-HSCT myeloablation and graft-versus-host disease (GVHD) prophylaxis agents have toxic effects and could eradicate residual CAR T cells and compromise antitumor effects. Whether the integration of CAR T-cell therapy and allogeneic HSCT can preserve CAR T-cell function and improve tumor control is unclear. METHODS: We tested a novel "all-in-one" strategy consisting of sequential CD7 CAR T-cell therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma. After CAR T-cell therapy led to complete remission with incomplete hematologic recovery, patients received haploidentical HSCT without pharmacologic myeloablation or GVHD prophylaxis drugs. Toxic effects and efficacy were closely monitored. RESULTS: After CAR T-cell therapy, all 10 patients had complete remission with incomplete hematologic recovery and grade 4 pancytopenia. After haploidentical HSCT, 1 patient died on day 13 of septic shock and encephalitis, 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T-cell therapy. Six patients remained in minimal residual disease-negative complete remission, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% confidence interval [CI], 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100). CONCLUSIONS: Our findings suggest that sequential CD7 CAR T-cell therapy and haploidentical HSCT is safe and effective, with remission and serious but reversible adverse events. This strategy offers a feasible approach for patients with CD7-positive tumors who are ineligible for conventional allogeneic HSCT. (Funded by the National Natural Science Foundation of China and the Key Project of Science and Technology Department of Zhejiang Province; ClinicalTrials.gov numbers, NCT04599556 and NCT04538599.).

Cytokine release syndrome was an independent risk factor associated with hypoalbuminemia for patients with relapsed/refractory hematological malignancies after CAR-T cell therapy.

BACKGROUND & AIMS: This study aims to assess the nutritional status of patients during the different phases of the Chimeric Antigen Receptor (CAR)-T cell therapy and to identify prominent risk factors of hypoalbuminemia in patients after CAR-T treatment. The clinical consequences of malnutrition in cancer patients have been highlighted by growing evidence from previous clinical studies. Given CAR-T cell therapy's treatment intensity and possible side effects, it is important to provide patients with sufficient medical attention and support for their nutritional well-being. METHODS: This study was conducted from May 2021 to December 2021 among patients undergoing CAR-T cell therapy at the Bone Marrow Transplantation Center in The First Affiliated Hospital of Zhejiang University School of Medicine. Logistic regression analysis was performed to investigate the risk factors associated with hypoalbuminemia. Participants were divided into the cytokine release syndrome (CRS) group (n = 60) and the non-CRS group (n = 11) to further analyze the relationship between hypoalbuminemia and CRS. RESULTS: CRS (OR = 13.618; 95% CI = 1.499-123.709; P = 0.013) and baseline albumin (ALB) (OR = 0.854; 95% CI = 0.754-0.967; P = 0.020) were identified as the independent clinical factors associated with post-CAR-T hypoalbuminemia. According to the nadir of serum albumin, hypoalbuminemia occurred most frequently in patients with severe CRS (78.57%). The nadir of serum albumin (r = - 0.587, P < 0.001) and serum albumin at discharge (r = - 0.315, P = 0.01) were negatively correlated for the duration of CRS. Furthermore, patients with hypoalbuminemia deserved longer hospitalization (P = 0.04). CONCLUSIONS: CRS was identified as a significant risk factor associated with post-CAR-T hypoalbuminemia. An obvious decline in serum albumin was observed as the grade and duration of CRS increase. However, further research is still needed to elucidate the mechanisms of CRS-associated hypoalbuminemia.

HLA Fully-Mismatched Sibling-Derived CD7 CAR-T Therapy Bridging to Haploidentical Hematopoietic Stem Cell Transplantation for Hepatosplenic γδ T-cell Lymphoma.

While chimeric antigen receptor (CAR)-T-cell therapy has demonstrated remarkable effectiveness in the treatment of B-cell lymphomas and leukemias, research on T-cell malignancies is still limited. Here, we reported a patient with hepatosplenic γδ T-cell lymphoma refractory to multiple lines of chemotherapy, who eventually achieved first complete remission with flow cytometry-confirmed minimal residual disease negativity after human leukocyte antigen (HLA) fully-mismatched sibling-derived CD7 CAR-T therapy. However, given the allogeneic nature, CAR-T cells dropped rapidly after a peak of 83.4% of circulating T-cells. Cytokine release syndrome, cytopenia, and infections occurred but were manageable after treatments. After the consolidative haploidentical hematopoietic stem cell transplantation (HSCT), the patient remained in remission at the end of the follow-up (13 months post-CAR-T infusion). This is the first case of relapsed/refractory hepatosplenic γδ T-cell lymphoma who achieved lasting CR after HLA fully-mismatched sibling-derived CD7 CAR-T therapy bridging to haploidentical HSCT.

A distinct cytokine network distinguishes chimeric antigen receptor T cell (CAR-T)-associated hemophagocytic lymphohistiocytosis-like toxicity (carHLH) from severe cytokine release syndrome following CAR-T therapy.

BACKGROUND AIMS: With the increasing application of chimeric antigen receptor (CAR)-T cell therapy in various malignancies, an extra toxicity profile has been revealed, including a severe complication resembling hemophagocytic lymphohistiocytosis (HLH), which is usually disguised by severe cytokine release syndrome (CRS). METHODS: In a clinical trial in whom 99 patients received B-cell maturation antigen CAR-T cells, we identified 20 (20.20%) cases of CAR-T cell-associated HLH (carHLH), most of whom possessed a background of severe CRS (grade ≥3). The overlapping features of carHLH and severe CRS attracted us to further explore the differences between them. RESULTS: We showed that carHLH can be distinguished by extreme elevation of interferon-γ, granzyme B, interleukin-1RA and interleukin-10, which can be informative in developing prevention and management strategies of this toxicity. Moreover, we developed a predictive model of carHLH with a mean area under the curve of 0.81 ± 0.07, incorporating serum lactate dehydrogenase at day 6 post-CRS and serum fibrinogen at day 3 post-CRS. CONCLUSIONS: The incidence of carHLH in CAR-T recipients might be relatively higher than we previously thought. relatively higher than we previously. A cytokine network distinguished from CRS is responsible for carHLH. And corresponding cytokine-directed therapies, especially targeting IL-10, are worth trying.

Safety and efficacy of CRISPR-based non-viral PD1 locus specifically integrated anti-CD19 CAR-T cells in patients with relapsed or refractory Non-Hodgkin's lymphoma: a first-in-human phase I study.

Background: Thus far, all approved chimeric antigen receptor (CAR)-T products are manufactured using modified viruses, which increases the risk of tumorigenesis, costs and production time. We aimed to evaluate the safety and efficacy of a kind of virus-free CAR-T cells (PD1-19bbz), in which an anti-CD19 CAR sequence is specifically integrated at the PD1 locus using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, in adults with relapsed/refractory (r/r) B cell non-Hodgkin's lymphoma (B-NHL). Methods: This single-arm phase I dose-escalation clinical trial evaluated PD1-19bbz in adult patients with r/r B-NHL from May 3rd 2020 to August 10th 2021. The patients were recruited and treated at the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Patients underwent leukapheresis and lymphodepleting chemotherapy before PD1-19bbz infusion. After the dose-escalation phase including three cohorts: 2 × 106/kg, 4 × 106/kg, 6 × 106/kg with three patients at each dose level, the optimal biological dose was determined to be 2 × 106/kg, which was then applied to an extended cohort of nine patients. The primary endpoint was the incidence of dose-limiting toxicities (DLT). The secondary endpoint was the response and survival. This trial was registered at www.clinicaltrials.gov as #NCT04213469. Findings: Twenty-one patients received PD1-19bbz infusion. Among all treated patients, 19 (90%) patients were diagnosed with stage III or IV disease. Meanwhile, 19 (90%) were stratified as intermediate risk or worse. Of note, four participants had >50% programmed death ligand-1 (PD-L1) expression in pre-treatment tumour sample, including two with extremely high levels (∼80%). There was no DLT identified. Fourteen patients had low-grade (1-2) cytokine release syndrome and two patients received tocilizumab. Four patients experienced immune effector cell-associated neurotoxicity syndrome of grade 1-2. The most common adverse events were hematologic toxicities, including anaemia (n = 6), lymphocyte count decreased (n = 19), neutrophil count decreased (n = 17), white blood cell count decreased (n = 10), and platelet count decreased (n = 2). All patients had objective response and 18 patients reached complete response. At a median follow-up of 19.2 months, nine patients remained in remission, and the estimated median progression-free survival duration was 19.5 months (95% confidence interval: 9.9-infinity), with the median overall survival not reached. Interpretation: In this first-in-human study of non-viral specifically integrated CAR-T products, PD1-19bbz exhibited promising efficacy with a manageable toxicity profile. A phase I/II trial of PD1-19bbz in a larger patient cohort is underway. Funding: National Key R&D Program of China, National Natural Science Foundation of China, Key Project of Science and Technology Department of Zhejiang Province, Shanghai Zhangjiang National Independent Innovation Demonstration Area, Key Projects of Special Development Funds.

Incidence, clinical characteristics and prognosis of tumor lysis syndrome following B-cell maturation antigen-targeted chimeric antigen receptor-T cell therapy in relapsed/refractory multiple myeloma.

Background aims: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). However, CAR-T-related tumor lysis syndrome (TLS) has been observed. We aimed to elucidate the incidence, clinical and laboratory characteristics, and prognosis of CAR-T cell-related TLS. Methods: Patients (n=105) with r/r MM treated with BCMA-targeted CAR-T cell therapy were included. Patient characteristics, laboratory parameters, and clinical outcomes were assessed. Results: Eighteen (17.1%) patients developed TLS after BCMA-targeted CAR-T cell therapy. The median time till TLS onset was 8 days. Patients with TLS had steep rise in uric acid (UA), creatinine, and lactate dehydrogenase (LDH) within 6 days following CAR-T cell infusion and presented earlier and persistent escalation of cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-γ [IFN-γ], and ferritin levels). All 18 patients had cytokine release syndrome (CRS), of which 13 (72.2%) developed grade 3-4 CRS. Three of 18 patients (16.7%) developed immune effector cell-associated neurotoxicity syndrome (ICANS): two patients with grade 1 ICANS and one with grade 2 ICANS. TLS development had a negative effect on the objective response rate (77.8% in the TLS group vs. 95.4% in the non-TLS group, p<0.01). During the median follow-up of 15.1 months, the median PFS was poorer of patients with TLS (median: 3.4 months in the TLS group vs. 14.7 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.5 [95% confidence interval [CI] 1.5-8.5]). Also, TLS development exhibited significant effects on OS (median: 5.0 months in the TLS group vs. 39.8 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.7 [95% CI 1.3-10.3]). TLS was associated with a higher tumor burden, elevated baseline creatinine and UA levels, severe CRS, pronounced CAR-T cell expansion, and corticosteroid use. Conclusion: TLS is a frequently observed CAR-T therapy complication and negatively influences clinical response and prognosis. Close monitoring for TLS should be implemented during CAR-T cell therapy, especially for those at high TLS risk.

HBV reactivation in patients with chronic or resolved HBV infection following BCMA-targeted CAR-T cell therapy.

B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). Concern of the safety and efficacy of CAR-T cell therapy in patients with chronic or resolved HBV infection is raised. In this study, we retrospectively reviewed 99 patients with r/r MM treated with BCMA-targeted CAR-T cell therapy, of which 7 (7.1%) patients had chronic HBV infection, 43 (43.4%) with resolved HBV infection, and the remaining 49 (49.49%) HBV-uninfected. Patients' characteristics before CAR-T cell administration were comparable in different status of HBV infection. Patients' liver function, cytokine levels, CAR-T cell expansion and cytokine release syndrome (CRS) grade after CAR-T cell therapy did not differ in different HBV serologic status. Furthermore, chronic HBV infection or resolved HBV infection did not affect clinical response, progress-free survival (PFS), or overall survival (OS). Four (4.04%) patients experienced HBV reactivation, 3 (6.98%) with resolved HBV infection, and 1 (14.29%) chronic HBV infection. Of 4 patients with HBV reactivation, 2 cases (50%) of severe hepatitis were noted and reported. Drops of serum IgG and elevation of alanine aminotransferase (ALT), alanine aminotransferase (AST), total bilirubin (TB) were observed in all four patients around the date of HBV reactivation.

Identification of three small nucleolar RNAs (snoRNAs) as potential prognostic markers in diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a non-Hodgkin lymphoma with high mortality rates. Small nucleolar RNAs (snoRNAs) are tumor-specific biological markers, but there are few studies on the role of snoRNAs in DLBCL. MATERIALS AND METHODS: Survival-related snoRNAs were selected to construct a specific snoRNA-based signature via computational analyses (Cox regression and independent prognostic analyses) to predict the prognosis of DLBCL patients. To assist in clinical applications, a nomogram was built by combining the risk model and other independent prognostic factors. Pathway analysis, gene ontology analysis, transcription factor enrichment, protein-protein interactions, and single nucleotide variant analysis were used to explore the potential biological mechanisms of co-expressed genes. RESULTS: Twelve prognosis-correlated snoRNAs were selected from the DLBCL patient cohort of microarray profiles, and a three-snoRNA signature consisting of SNORD1A, SNORA60, and SNORA66 was constructed. DLBCL patients could be divided into high-risk and low-risk cohorts using the risk model, and the high-risk group and activated B cell-like (ABC) type DLBCL were linked with disappointing survival. In addition, SNORD1A co-expressed genes were inseparably linked to the biological functions of the ribosome and mitochondria. Potential transcriptional regulatory networks have also been identified. MYC and RPL10A were the most mutated SNORD1A co-expressed genes in DLBCL. CONCLUSION: Put together, our findings explored the potential biological effects of snoRNAs in DLBCL, and provided a new predictor for DLBCL prediction.

J-shaped association between dietary copper intake and all-cause mortality: a prospective cohort study in Chinese adults.

The association between dietary Cu intake and mortality risk remains uncertain. We aimed to investigate the relationship of dietary Cu intake with all-cause mortality among Chinese adults. A total of 17 310 participants from the China Health and Nutrition Survey, a national ongoing open cohort of Chinese participants, were included in the analysis. Dietary intake was measured by three consecutive 24-h dietary recalls in combination with a weighing inventory over the same 3 d. The average intakes of the 3-d dietary macronutrients and micronutrients were calculated. The study outcome was all-cause mortality. During a median follow-up of 9·0 years, 1324 (7·6 %) participants died. After adjusting for sex, age, BMI, ever alcohol drinking, ever smoking, education levels, occupations, urban or rural residents, systolic blood pressure, diastolic blood pressure and the intakes of fat, protein and carbohydrate, the association between dietary Cu intake and all-cause mortality followed a J-shape (Pfor nonlinearity = 0·047). When dietary Cu intake was assessed as quartiles, compared with those in the first quartile (<1·60 mg/d), the adjusted hazard ratios for all-cause mortality were 0·87 (95 % CI (0·71, 1·07)), 0·98 (95 % CI (0·79, 1·21)) and 1·49 (95 % CI (1·19, 1·86)), respectively, in participants in the second (1·60-<1·83 mg/d), third (1·83-<2·09 mg/d) and fourth (≥2·09 mg/d) quartiles. A series of subgroup analyses and sensitivity analyses showed similar results. Overall, our findings emphasised the importance of maintaining optimal dietary Cu intake levels for prevention of premature death.

Risk factors of tumor lysis syndrome in relapsed/refractory multiple myeloma patients undergoing BCMA CAR-T cell therapy.

OBJECTIVE: To investigate the risk factors of tumor lysis syndrome (TLS) in relapsed/refractory multiple myeloma (MM) patients undergoing B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy. METHOD: The clinical data of 99 relapsed/refractory MM patients receiving BCMA CAR-T cell therapy in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were collected in this study. Univariate analysis and multivariate logistic regression were performed to evaluate the risk factors of TLS following BCMA CAR-T cell therapy. RESULTS: Among the 99 patients, TLS occurred in 17 cases (17.2%) with an onset time of (8.9±3.0) d after BCMA CAR-T cell therapy. All TLS patients developed TLS-related clinical manifestations, including 17 cases with renal dysfunction, 8 cases with arrhythmia. All TLS patients developed cytokine release syndrome (CRS) with an onset of 1.0 (1.0, 6.5) d after CAR-T cell therapy, and 13 cases developed grade 3-4 CRS. The levels of serum uric acid, serum creatinine and the ratio of cases with grade 3-4 CRS were significantly higher in TLS patients than in non-TLS patients (all P<0.05). Multivariate logistic regression revealed that serum creatinine ( OR=1.015, P<0.01) and severe CRS ( OR=9.371, P<0.01) were independent risk factors of TLS. CONCLUSIONS: Relapsed/refractory MM patients undergoing BCMA CAR-T therapy shows high incidence of TLS, which are related to elevated levels of serum creatinine and severe CRS. TLS can be prevented clinically by reducing serum creatinine and controlling CRS severity.

Clinical features of hemophagocytic syndrome following BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma.

OBJECTIVE: To analyze the clinical features of hemophagocytic syndrome (HLH) following B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy in patients with relapsed/refractory multiple myeloma. METHODS: Ninety-nine patients with relapsed/refractory multiple myeloma (including 3 cases of plasma cell leukemia) undergoing BCMA CAR-T cell therapy (monocentric phaseⅠclinical trial, ChiCTR1800017404) in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were enrolled in the study. The baseline features, laboratory findings, treatment, and clinical response of these patients were analyzed. RESULTS: CAR-T cell associated HLH (carHLH) occurred in 20 patients (20.20%), and the median onset time was 7(0-19) d after cytokine release syndrome (CRS). Patients with carHLH were maily male patients, and manifested as high percentage of abnormal plasma cells, higher incidence of severe CRS (grade 3-4), and robust expansion of CAR-T cells in the peripheral blood (all P<0.05). The levels of interleukin (IL)-6, IL-10 and interferon (IFN)-γ, the peak value of international normalized ratio and D-dimer were elevated, and the valley value of fibrinogen was decreased in patients with carHLH (all P<0.01). All carHLH patients resolved with proper intervention (including 7 cases with tocilizumab, 5 with steroids, 6 with both). The objective response rate in carHLH patients was slightly higher than that in non-carHLH patients [100.0% (17/17) vs. 94.87% (74/78), P>0.05]. CONCLUSIONS: The incidence of carHLH is relatively high in BCMA CAR-T cell treated patients, which is closely related to pretreatment tumor cell percentage in bone marrow, expansion of CAR-T cells and the secretion of cytokines. Medication based on tocilizumab and steroids can achieve considerable therapeutic effects in patient with carHLH.

Genetically modified CD7-targeting allogeneic CAR-T cell therapy with enhanced efficacy for relapsed/refractory CD7-positive hematological malignancies: a phase I clinical study.

Chimeric antigen receptor (CAR)-T cell therapy against T cell malignancies faces major challenges including fratricide between CAR-T cells and product contamination from the blasts. Allogeneic CAR-T cells, generated from healthy donor T cells, can provide ready-to-use, blast-free therapeutic products, but their application could be complicated by graft-versus-host disease (GvHD) and host rejection. Here we developed healthy donor-derived, CD7-targeting CAR-T cells (RD13-01) with genetic modifications to resist fratricide, GvHD and allogeneic rejection, as well as to potentiate antitumor function. A phase I clinical trial (NCT04538599) was conducted with twelve patients recruited (eleven with T cell leukemia/lymphoma, and one with CD7-expressing acute myeloid leukemia). All patients achieved pre-set end points and eleven proceeded to efficacy evaluation. No dose-limiting toxicity, GvHD, immune effector cell-associated neurotoxicity or severe cytokine release syndrome (grade ≥ 3) were observed. 28 days post infusion, 81.8% of patients (9/11) showed objective responses and the complete response rate was 63.6% (7/11, including the patient with AML). 3 of the responding patients were bridged to allogeneic hematopoietic stem cell transplantation. With a median follow-up of 10.5 months, 4 patients remained in complete remission. Cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) reactivation was observed in several patients, and one died from EBV-associated diffuse large B-cell lymphoma (DLBCL). Expansion of CD7-negative normal T cells was detected post infusion. In summary, we present the first report of a Phase I clinical trial using healthy donor-derived CD7-targeting allogeneic CAR-T cells to treat CD7+ hematological malignancies. Our results demonstrated the encouraging safety and efficacy profiles of the RD13-01 allogeneic CAR-T cells for CD7+ tumors.

Bioinformatics analysis identified apolipoprotein E as a hub gene regulating neuroinflammation in macrophages and microglia following spinal cord injury.

Macrophages and microglia play important roles in chronic neuroinflammation following spinal cord injury (SCI). Although macrophages and microglia have similar functions, their phagocytic and homeostatic abilities differ. It is difficult to distinguish between these two populations in vivo, but single-cell analysis can improve our understanding of their identity and heterogeneity. We conducted bioinformatics analysis of the single-cell RNA sequencing dataset GSE159638, identifying apolipoprotein E (APOE) as a hub gene in both macrophages and microglia in the subacute and chronic phases of SCI. We then validated these transcriptomic changes in a mouse model of cervical spinal cord hemi-contusion and observed myelin uptake, lipid droplets, and lysosome accumulation in macrophages and microglia following SCI. Finally, we observed that knocking out APOE aggravated neurological dysfunction, increased neuroinflammation, and exacerbated the loss of white matter. Targeting APOE and the related cholesterol efflux represents a promising strategy for reducing neuroinflammation and promoting recovery following SCI.

Transportation physical activity and new-onset hypertension: A nationwide cohort study in China.

The association between transportation physical activity (PA) and the risk of hypertension remains uncertain. We aimed to evaluated the prospective relation of transportation PA and new-onset hypertension among Chinese adults. A total of 9350 adults who were free of hypertension at baseline were enrolled from the China Health and Nutrition Survey (CHNS). Data on transportation PA were obtained by using self-reported questionnaires, and calculated as metabolic equivalent task (MET)-minutes/week. MET-minutes/week may account for both intensity and time spent on activities. The study outcome was new-onset hypertension, defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or diagnosed by physician or under antihypertensive treatment during the follow-up. During a median of 8.0 years (82,410 person-years) of follow-up, a total of 2949 participants developed hypertension. Overall, there was a U-shaped association between transportation PA and new-onset hypertension (P values for nonlinearity <0.001). Accordingly, compared with those with moderate transportation PA (213-<394 MET-minutes/week, the second quartile), significantly higher risks of new-onset hypertension were observed not only in participants with transportation PA < 213 MET-minutes/week (the first quartile) (HR, 1.29; 95%CI: 1.15-1.44), but in those with transportation PA ≥ 394 MET-minutes/ week (the 3-4 quartiles) (HR, 1.15; 95%CI: 1.04-1.27). Similar U-shaped correlations were found for various types of transportation PA (walking, bicycling, and motorized PA) and new-onset hypertension. In summary, moderate transportation PA is associated with a lower risk of new-onset hypertension among Chinese adults.

CAR-T cells for cancer immunotherapy-the barriers ahead and the paths through.

This review discusses the major concerns and changes emerged during the rapidly extended clinical application of chimeric antigen receptor (CAR) T therapy based on our experience and understanding. In the past decades, the CAR-T cells have been questioned, sequentially, about their capability of inducing initial remission, their safety profile, their ability to sustain long-term persistence and response, and their potential to be industrialized. Significant advances, novel targeting strategies, innovative molecular structure, fine tuning of both CAR-T and host immune system, combination with other therapies, streamlined manufacturing, and etc., have been made to overcome these challenges. Although not perfectly resolved, rational pathways have been proposed to pass through the barriers. Here, we present the recent achievements on these pathways, and look into the possible future directions.

Cytomegalovirus Retinitis and Retinal Detachment following Chimeric Antigen Receptor T Cell Therapy for Relapsed/Refractory Multiple Myeloma.

Cytomegalovirus (CMV) retinitis is a rare end-organ disease of CMV infection and is a marker of severe immunosuppression, especially in human immunodeficiency virus (HIV)-positive patients. In multiple myeloma (MM) patients, CMV retinitis has been reported in the post-transplant setting, with an incidence lower than 0.2%, and in patients receiving lenalidomide. Here, we describe the first case of CMV retinitis in myeloma patients following B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (BCMA CAR-T) cell therapy. In addition to CMV, the patient developed multiple infections including a mouth ulcer, pneumonia, and fungal enteritis. While the complete remission (CR) status of MM was maintained, he regained a visual acuity of 20/1000 after appropriate ophthalmologic treatment. This single case illustrates the potential of BCMA CAR-T therapy to induce profound humoral immunosuppression, and demonstrates an imperative need for an established standard of monitoring and prophylaxis of post-CAR-T infections.

Cervical Alignment of Patients with Basilar Invagination: A Radiological Study.

OBJECTIVE: To investigate the cervical alignment and the relative range of motion (ROM) in patients with basilar invagination (BI). METHODS: A total of 40 BI cases (38.1 years old ± 17.9 years old, 19 male and 21 female) and 80 asymptomatic individuals (33.8 years old ± 10.8 years old, 40 male and 40 female) were included. The Skull-C2 /Skull-BV, Skull-C7 , C2 -C7 /BV-C7 wall angles, C0 -C2 /C0 -BV, C0 -C7 , C1 -C7 , and C2 -C7 /BV-C7 angles were measured in dynamic X-ray images (including neutral, extension, and flexion positions). Correlation between the upper and lower cervical curvatures were analyzed. The total, extension, and flexion ROMs of these angles were calculated, respectively. RESULTS: The BI patients had a smaller C0 -C2 /C0 -BV angle (18.2° ± 16.4° vs 30.9° ± 9.3°), but larger C2 -C7 /BV-C7 (32.2° ± 16.1° vs 19.4° ± 10.6°) and C2 -C7 /BV-C7 wall angles (37.8° ± 17.2° vs 23.6° ± 10.2°) than the control group in neutral position. The upper and lower curvatures correlated negatively in neutral (r = -0.371), extension (r = -0.429), and flexion (r = -0.648) positions among BI patients, as well as in extension position (r = -0.317) among control group. The BI patients presented smaller total ROMs in Skull-C2 /Skull-BV (12.3° ± 16.6° vs 19.7° ± 10.9°), C0 -C2 /C0 -BV (8.1° ± 11.1° vs 17.6° ± 10.5°), and C0 -C7 angles (57.8° ± 14.2° vs 78.3° ± 17.9°), but a larger total ROM in C2 -C7 /BV-C7 wall angle (52.8° ± 13.9° vs 27.0° ± 16.1°) than the control group. The BI patients also presented smaller extension ROMs in Skull-C2 /Skull-BV (6.9° ± 9.4° vs 12.5° ± 9.3°), Skull-C7 (24.5° ± 10.9° vs 30.7° ± 12.5°), and C0 -C2 /C0 -BV angles (4.4° ± 7.8° vs 9.9° ± 8.6°) than the control group. Moreover, the BI patients showed smaller absolute values of flexion ROMs in Skull-C2 /Skull-BV (-5.2° ± 9.4° vs -7.3° ± 8.0°), C0 -C2 /C0 -BV (-3.2° ± 8.8° vs -7.7° ± 8.7°), and C0 -C7 angles (-33.2° ± 13.0° vs -52.8° ± 19.2°), but a larger absolute value of flexion ROM in C2 -C7 /BV-C7 wall angle (-33.9° ± 14.8° vs -8.2° ± 15.1°). CONCLUSION: The cervical spine was stiffer in BI patients than the asymptomatic individuals, especially in the upper cervical curvature. The negative correlation between upper and lower cervical curvatures was more obvious in BI patients.

BCMA CAR-T Therapy Is Safe and Effective for Refractory/Relapsed Multiple Myeloma With Central Nervous System Involvement.

Central nervous system (CNS) involvement is a rare complication of multiple myeloma (MM) that portends an extremely poor prognosis. Although chimeric antigen receptor (CAR)-T cell therapy is considered a promising strategy for patients with MM, the role of CAR-T cell therapy in MM involving the CNS has not been fully elucidated. In this study, we retrospectively analyzed 4 cases of B-cell maturation antigen CAR-T cell therapy for patients with relapsed/refractory MM involving the CNS. Patients received a range of 2-7 lines of prior therapy, including 1 autologous hematopoietic stem cell transplant. The most common adverse event was cytokine release syndrome, which was observed in all 4 patients, including 2 with grade 1 and 2 with grade 2. No patient was complicated with immune effector cell-associated neurotoxicity syndrome. Within the follow-up (median: 257 d, range: 116-392 d), 3 of 4 patients reached complete remission (CR), and 1 patient reached partial response. At the data cutoff, 1 patient continued to remain in CR at day 220, and the patient with partial response died at day 116. The other 2 patients relapsed at 317 and 111 days with CR durations of 287 and 81 days, respectively. Our results show promising effectiveness and acceptable safety of CAR-T cell therapy for heavily pretreated patients with CNS MM.