Tislelizumab augment the efficacy of CD19/22 dual-targeted chimeric antigen receptor T cell in advanced stage relapsed or refractory B-cell non-Hodgkin lymphoma.

Dual-targeted chimeric antigen receptor T (CAR-T) cell is an important strategy to improve the efficacy of CD19 CAR-T cell against refractory or relapsed B cell non-Hodgkin lymphoma (R/R B-NHL). However, durable responses are not achieved in most patients, in part owing CAR-T cell exhaustion caused by PD-1/PD-L1 pathway. We conducted a prospective, single-arm study of dual-targeted CD19/22 CAR-T cell combined with anti-PD-1 antibody, tislelizumab, in R/R B-NHL (NCT04539444). Tislelizumab was administrated on +1 day after patients received infusion of CD19/22 CAR-T cell. Responses, survival and safety were evaluated. From 1 August 2020 to 30 March 2023, 16 patients were enrolled. The median follow-up time is 16.0 (range: 5.0-32.0 months) months. Overall response was achieved in 14 of 16 (87.5%) patients, and the complete response (CR) was achieved in 11 of 16 (68.8%) patients. The 1-year progression-free survival and overall survival rates were 68.8% and 81.3%, respectively. Of the 14 patients responded, 9 patients maintained their response until the end of follow-up. Among the 15 out of 16 (93.8%) patients who had extranodal involvement, 14 (93.3%) patients achieved overall response rate with 11 (73.3%) patients achieving CR. Eight (50%) patients experienced cytokine release syndrome. No neurologic adverse events were reported. Gene Ontology-Biological Process enrichment analysis showed that immune response-related signaling pathways were enriched in CR patients. Our results suggest that CD19/22 CAR-T cell combined with tislelizumab elicit a safe and durable response in R/R B-NHL and may improve the prognosis of those patients.

Bibliometric and literature review of the development of mineral fertilizers.

Mineral fertilizers are a new type of sustainable fertilizers, containing natural ores as the primary raw material with various nutrients and organic matters. This study combines two methods of bibliometric analysis to comprehensively review the progress of mineral fertilizers from 2000 to 2021. The results showed that the research on mineral fertilizers has increased in the past 21 years, especially after 2014. Developed countries studied mineral fertilizers more extensively than developing countries, but some developing countries, such as China and India, are also paying attention to this area in recent years. Chinese Academic of Sciences, Agriculture and Agri-Food Canada, and Chinese Academy of Agricultural Sciences were the main publishing institutions. Nutrient elements, changes in soil properties, and the effects on promoting crop growth were the main contents of the research. Still, such issues as bioremediation, soil environment improvement, and crop resistance are becoming hot spots. The field of mineral fertilizers showed a strong interdisciplinary nature and an increasingly comprehensive research perspective. The goal is that this synthesis will be used as a starting point for a broader study on responsible environmental management and research on improving fertilizer use efficiency.

Efficacy and safety of zanubrutinib plus R-CHOP in treatment of non-GCB DLBCL with extranodal involvement.

Introduction: Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) shows poor response rates in non-germinal center B cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL) patients with multiple extranodal involvement. This study aims to evaluate anti-tumor activity and safety of zanubrutinib with R-CHOP (ZR-CHOP) in treatment naïve non-GCB DLBCL with extranodal involvement. Methods: In this single-arm, phase 2, prospective, single-center study, patients with newly diagnosed non-GCB DLBCL with extranodal involvement enrolled between October 2020 to March 2022 received ZR-CHOP for 6 cycles followed by 2 cycles of maintenance treatment with rituximab and zanubrutinib. The primary endpoint included progression-free survival (PFS) in the intent-to-treat (ITT) population whereas the secondary endpoints included overall response rate (ORR), complete response (CR), and duration of response. Further, next-generation sequencing (NGS) was used for detection of different oncogenic mutations closely related to DLBCL pathogenesis. Results: From October 2020 to March 2022, 26 patients were enrolled, and 23 of them were evaluated for efficacy after receiving 3 cycles of ZR-CHOP treatment. 1-year PFS and OS were 80.8% and 88.5% respectively while expected PFS and OS for 2-years are 74.0% and 88.5% respectively with median follow-up of 16.7 months and ORR was 91.3% (CR: 82.61%; PR: 8.70%). Oncogenic mutations closely related to DLBCL pathogenesis were assessed in 20 patients using NGS. B-cell receptor and NF-κB pathway gene mutations were detected in 10 patients, which occurred in MYD88 (7/19), CD79B (4/19), CARD11 (5/19), and TNFAIP3 (2/19). Hematological adverse events (AEs) ≥ grade 3 included neutropenia (50%), thrombocytopenia (23.1%), and anemia (7.7%) whereas non-hematological AEs ≥ grade 3 included pulmonary infection (19.2%). Conclusion: ZR-CHOP is safe and effective for treating treatment naïve non-GCB DLBCL patients with extranodal involvement. Clinical Trial Registration: Clinicaltrials.gov, NCT04835870.

Remediation of soil polluted with Pb and Cd and alleviation of oxidative stress in Brassica rapa plant using nanoscale zerovalent iron supported with coconut-husk biochar.

Accumulation of toxic elements by plants from polluted soil can induce the excessive formation of reactive oxygen species (ROS), thereby causing retarded plants' physiological attributes. Several researchers have remediated soil using various forms of zerovalent iron; however, their residual impacts on oxidative stress indicators and health risks in leafy vegetables have not yet been investigated. In this research, nanoscale zerovalent iron supported with coconut-husk biochar (nZVI-CHB) was synthesized through carbothermal reduction process using Fe2O3 and coconut-husk. The stabilization effects of varying concentrations of nZVI-CHB and CHB (250 and 500 mg/kg) on cadmium (Cd) and lead (Pb) in soil were analyzed, and their effects on toxic metals induced oxidative stress, physiological properties, and antioxidant defence systems of the Brassica rapa plant were also checked. The results revealed that the immobilization of Pb and Cd in soil treated with CHB was low, leading to a higher accumulation of metals in plants grown. However, nZVI-CHB could significantly immobilize Pb (57.5-62.12%) and Cd (64.1-75.9%) in the soil, leading to their lower accumulation in plants below recommended safe limits and eventually reduced carcinogenic risk (CR) and hazard quotient (HQ) for both Pb and Cd in children and adults below the recommended tolerable range of <1 for HQ and 10-6 - 10-4 for CR. Also, a low dose of nZVI-CHB significantly mitigated toxic metal-induced oxidative stress in the vegetable plant by inhibiting the toxic metals uptake and increasing antioxidant enzyme activities. Thus, this study provided another insightful way of converting environmental wastes to sustainable adsorbents for soil remediation and proved that a low-dose of nZVI-CHB can effectively improve soil quality, plant physiological attributes and reduce the toxic metals exposure health risk below the tolerable range.

Cytopenia after chimeric antigen receptor T cell immunotherapy in relapsed or refractory lymphoma.

Background: Patients with relapsed or refractory (R/R) lymphomas have benefited from chimeric antigen receptor (CAR)-T-cell therapy. However, this treatment is linked to a high frequency of adverse events (AEs), such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematologic toxicity. There has been increasing interest in hematological toxicity in recent years, as it can result in additional complications, such as infection or hemorrhage, which remain intractable. Methods: We conducted a retrospective, single-institution study to evaluate the patterns and outcomes of cytopenia following CAR-T-cell infusion and potential associated factors. Results: Overall, 133 patients with R/R lymphoma who received CAR-T-cell therapy from June, 2017 to April, 2022 were included in this analysis. Severe neutropenia, anemia and thrombocytopenia occurred frequently (71, 30 and 41%, respectively) after CAR-T-cell infusion. A total of 98% of severe neutropenia and all severe thrombocytopenia cases occurred in the early phase. Early severe cytopenia was associated with CRS incidence and severity, as well as peak inflammatory factor (IL-6, C-reactive protein (CRP), and ferritin) levels. In multivariate analysis, prior hematopoietic stem cell transplantation (HSCT), baseline hemoglobin (HB), and lymphodepleting chemotherapy were independent adverse factors associated with early severe cytopenia. In addition, 18% and 35% of patients had late neutrophil- and platelet (PLT)-related toxicity, respectively. In multivariate analysis, lower baseline PLT count was an independent factor associated with late thrombocytopenia. More severe cytopenia was associated with higher infection rates and poorer survival. Conclusions: This research indicates that improved selection of patients and management of CRS may help to decrease the severity of cytopenias and associated AEs and improve survival following CAR-T-cell therapy. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT03196830, identifier NCT03196830.

Reduced-Dose Full-Body CT in Lymphoma Follow-up: A Pilot Study.

BACKGROUND: How to reduce the radiation dose received from full-body CT scans during the follow-up of lymphoma patients is a concern. OBJECTIVE: The aim of the study was to investigate the image quality and radiation dose of reduced-dose full-body computerized tomography (CT) in lymphoma patients during the follow-up. METHODS: 121 patients were included and divided into conventional CT group (group 1, 120-kVp, n = 61) or reduced-dose CT group (group 2, 100-kVp combined dual-energy CT (DECT), n = 60). 140-kVp polychromatic images and 70-keV monochromatic images were reconstructed from DECT. The abdominal virtual non-enhanced (VNE) images were reconstructed from monochromatic images. Two radiologists rated the overall image quality with a five-point scale and graded the depiction of lesions using a four-point scale. The objective image quality was evaluated using image noise, signal-to-noise ratio, and contrast-to-noise ratio. The radiation dose and image quality were compared between the groups. RESULTS: The comparable subjective image quality was observed between 70-keV and 120-kVp images in the neck, while 120-kVp images showed better objective image quality. 70-keV images showed better objective image quality in the chest. While the subjective image quality of abdominal VNE images was inferior to that of true non-enhanced images, the improved objective image quality was observed in VNE images. In the abdominal arterial phase, similar subjective image quality was observed between the groups. Abdominal 70-keV images in the arterial phase showed improved objective image quality. Similar image quality was obtained in the abdominal venous phase between the groups. The effective radiation dose in group 2 showed a significant reduction. CONCLUSION: The application of reduced-dose full-body CT can significantly reduce the radiation dose for lymphoma patients during the follow-up while maintaining or improving the image quality.

Anti-PD-1 Therapy Enhances the Efficacy of CD30-Directed Chimeric Antigen Receptor T Cell Therapy in Patients With Relapsed/Refractory CD30+ Lymphoma.

Anti-CD30 CAR-T is a potent candidate therapy for relapsed/refractory (r/r) CD30+ lymphomas with therapy limitations, and the efficacy needed to be further improved. Herein a multi-center phase II clinical trial (NCT03196830) of anti-CD30 CAR-T treatment combined with PD-1 inhibitor in r/r CD30+ lymphoma was conducted. After a lymphocyte-depleting chemotherapy with fludarabine and cyclophosphamide, 4 patients in cohort 1 and 3 patients in cohort 2 received 106/kg and 107/kg CAR-T cells, respectively, and 5 patients in cohort 3 received 107/kg CAR-T cells combined with anti-PD-1 antibody. The safety and the efficacy of CAR-T cell therapy were analyzed. Cytokine release syndrome (CRS) was observed in 4 of 12 patients, and only 1 patient (patient 9) experienced grade 3 CRS and was treated with glucocorticoid and tocilizumab. No CAR-T-related encephalopathy syndrome was observed. Only two patients in cohorts 2 and 3 experienced obviously high plasma levels of IL-6 and ferritin after CD30 CAR-T cell infusion. The overall response rate (ORR) was 91.7% (11/12), with 6 patients achieving complete remission (CR) (50%). In cohorts 1 and 2, 6 patients got a response (85.7%), with 2 patients achieving CR (28.6%). In cohort 3, 100% ORR and 80% CR were obtained in 5 patients without ≥3 grade CRS. With a median follow-up of 21.5 months (range: 3-50 months), the progression-free survival and the overall survival rates were 45 and 70%, respectively. Of the 11 patients who got a response after CAR-T therapy, 7 patients (63.6%) maintained their response until the end of follow-up. Three patients died last because of disease progression. Taken together, the combination of anti-PD-1 antibody showed an enhancement effect on CD30 CAR-T therapy in r/r CD30+ lymphoma patients with minimal toxicities.

A female carrier of spinal and bulbar muscular atrophy diagnosed with DNAJB6-related distal myopathy.

Mutations in the DNAJB6 gene cause limb girdle muscular dystrophy D1 (LGMD D1) and distal myopathy with rimmed vacuoles. With the discovery of new mutations, the phenotypic spectrum of DNAJB6-related myopathy has been extended, making the diagnosis more complicated. In this study, we describe a female carrier of spinal and bulbar muscular atrophy (SBMA) diagnosed with DNAJB6-related distal myopathy. The c.292_294delGAT (p. Asp98del) mutation in the DNAJB6 gene and a 49 CAG repeat expansion in the androgen receptor (AR) gene were identified. According to the clinical manifestations of distal-dominant lower limb involvement, a myogenic pattern in the electrophysiological study, and rimmed vacuoles on muscle pathology, the patient was ultimately diagnosed with DNAJB6-related distal myopathy. A functional study in a zebrafish model indicated that the c.292_294delGAT (p. Asp98del) mutation contributed to muscle structure defects. This study offers useful insights for the differential diagnosis of a condition in which patients carry pathogenic variants in different genes.

Clinical and Electrophysiological Features of Chronic Motor Axonal Neuropathy.

PURPOSE: To determine the clinical and electrophysiological characteristics of chronic motor axonal neuropathy (CMAN) and identify the associated similarities and differences between CMAN, acute motor axonal neuropathy (AMAN), and motor neuropathy secondary to amyotrophic lateral sclerosis. METHODS: The study described clinical and electrophysiological features of five patients with CMAN and compared with 20 AMAN patients, 42 amyotrophic lateral sclerosis patients and 41 healthy controls. To compare the distribution of different nerve involvement in the same limb, split ratio was introduced. Split ratio of upper limb = amplitude of compound muscle action potential abductor pollicis brevis (APB)/amplitude of compound muscle action potential abductor digiti minimi, and split ratio of lower limb = amplitude of compound muscle action potential extensor digitorum brevis/amplitude of compound muscle action potential abductor hallucis. RESULTS: Chronic motor axonal neuropathy patients manifested lower motor neuron syndrome with positive IgG anti-monosialoganglioside antibodies and good outcome. The CMAN patients shared similar clinical manifestation with AMAN patients except for disease course and higher Medical Research Council scores. Compared with healthy controls, the split ratio of lower limb was higher in both CMAN and AMAN, despite comparable split ratio of upper limb. There was significant difference between CMAN group and amyotrophic lateral sclerosis group in nerve involvement presented as split hand and split leg signs in amyotrophic lateral sclerosis and reverse split leg sign in CMAN. CONCLUSIONS: Chronic motor axonal neuropathy associated with monosialoganglioside might be a "mild" AMAN with chronic onset by similar clinical and electrophysiological features. There was a unique pattern of nerve involvement presenting as reverse split leg sign in both CMAN and AMAN.

A Prospective Investigation of Bispecific CD19/22 CAR T Cell Therapy in Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma.

BACKGROUND: The use of T cells expressing chimeric antigen receptor (CAR T) engineered to target CD19 constitutes breakthrough treatment for relapsed or refractory B cell non-Hodgkin lymphoma (R/R B-NHL). Despite improved outcomes, high relapse rate remains a challenge to overcome. Here, we report the clinical results and the pharmacokinetics of bispecific CD19/22 CAR T in patients with R/R B-NHL. METHODS: We performed a prospective, single-arm study of bispecific CD19/22 CAR T cells in R/R B-NHL. We analyzed the safety and efficacy and investigated the kinetic profiles of the CAR T cells. CAR transgene levels were measured using quantitative polymerase chain reaction, and correlation analyses of pharmacodynamic markers and product characteristics, disease conditions, clinical efficacy and adverse events were performed. RESULTS: From August 2017 to September 2020, a total of 32 patients with CD19/22 CAR T administration were analyzed. The overall response rate was 79.3%, and the complete response rate was 34.5%. The progression-free survival (PFS) and overall survival (OS) rates at 12 months were 40.0% and 63.3%, respectively. Among patients who had a CR at 3 months, the PFS and OS rates at 12 months were 66.7% and 100%, respectively. Severe cytokine release syndrome (sCRS) (grade 3 and higher) occurred in nine patients (28.1%). Grade 3 or higher neurologic events occurred in four patients (12.5%). One patient died from irreversible severe CRS-associated acute kidney injury. Long-term CAR T cells persistence correlated with clinical efficacy (133 days vs 22 days, P = 0.004). Patients treated with more than three prior therapies and presenting extranodal organ involvement had lower maximal concentration (Cmax) values than other patients. Responders had higher Cmax and area under the curve values than non-responders. Tumour burden and Cmax were potentially associated with the severity of CRS. CONCLUSIONS: This study demonstrates the safety and potential clinical efficacy of bispecific CD19/22 CAR T cells in patients with R/R B-NHL and highlights the importance of measuring kinetic parameters in PB to predict efficacy and safety in clinical applications of CAR T cell therapy. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/ct2/show/NCT03196830, identifier NCT03196830.

Idebenone Protects against Atherosclerosis in Apolipoprotein E-Deficient Mice Via Activation of the SIRT3-SOD2-mtROS Pathway.

PURPOSE: Atherosclerosis, a chronic disease of the arteries, results from pathological processes including the accumulation and aggregation of oxidized low-density lipoprotein (oxLDL) in the vessel walls, development of neointima, formation of a fibrous cap, and migration of immune cells to damaged vascular endothelium. Recent studies have shown that mitochondrial dysfunction is closely associated with the development and progression of atherosclerosis. Idebenone, a short-chain benzoquinone similar in structure to coenzyme Q10, can effectively clear oxygen free radicals as an electron carrier and antioxidant. In the present study, we aim to investigate weather idebenone protects against atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. METHODS: apoE-/- mice receiving a high-fat diet (HFD) were treated with idebenone for 16 weeks. A total of 60 mice were randomized into the following four groups: (1) HFD, (2) HFD and low-dose idebenone (100 mg/kg/d), (3) HFD and medium-dose idebenone (200 mg/kg/d), and (4) HFD and high-dose (400 mg/kg/d). Proteomic analysis was performed between the HFD and idebenone-high-dose group. Plaque analysis was carried out by histological and immunohistochemical staining. Western blot, TUNEL staining, and MitoSOX assays were performed in human umbilical vein endothelial cells (HUVECs) to investigate the SIRT3-SOD2-mtROS pathway. RESULTS: Histological and morphological analysis demonstrated that idebenone significantly reduced plaque burden and plaque size. Idebenone treatment effectively stabilized the atherosclerotic plaques. In mice treated with idebenone, 351 up-regulated and 379 down-regulated proteins were found to be significantly altered in proteomic analysis. In particular, the expression of SIRT3, SOD2, and NLRP3 was significantly regulated in the idebenone treatment groups compared with the HFD group both in vivo and in vitro. We further confirmed that idebenone protected against endothelial cell damage and inhibited the production of mitochondrial reactive oxygen species (mtROS) in cholesterol-treated HUVECs. CONCLUSIONS: We demonstrated that idebenone acted as a mitochondrial protective agent by inhibiting the activation of NLPR3 via the SIRT3-SOD2-mtROS pathway. Idebenone may be a promising therapy for patients with atherosclerosis by improving mitochondrial dysfunction and inhibiting oxidative stress.

Distal myopathy due to TCAP variants in four unrelated Chinese patients.

Distal myopathies are a group of clinically and genetically heterogeneous hereditary muscle disorders characterized by progressive muscular weakness starting in the distal parts of the limbs. The most common subtype of distal myopathy is GNE myopathy, a rare muscle disease with autosomal recessive inheritance. Limb-girdle muscular dystrophy 2G (LGMD2G) is a rare autosomal recessive subtype of LGMDs caused by TCAP variant. Patients with LGMD2G can present with distal myopathy and rimmed vacuoles on muscle pathology. Thus far, the most reported TCAP mutations related to LGMD2G were recessive frameshift or nonsense variants. Here, we described four Chinese patients from unrelated families with LGMD2G due to TCAP mutations. The clinical symptoms of our patients were similar to those previously reported in LGMD2G patients. Three different pathogenic TCAP variants were identified in these patients, including two frameshift variants and one intronic variant. Autophagolysosomes have been observed in one patient by electron microscopy. Our research expands the genetic spectrum of TCAP mutations in China, indicating c.165-166insG is likely the common pathogenic variant. We also provide evidences that autophagy may be involved in the pathophysiology of LGMD2G.

[Vertical Spatial Distribution of Denitrification Intensity in the Vadose Zone of Typical Sections of Chaobai River Alluvial Fan].

In this study, the Chaobai River alluvial fan area, Beijing City, was chosen as the study area, and two typical profiles (S6 and S8) were selected to determine the denitrification intensity value of the vadose zone at different sampling depths (0-10 m). The vertical spatial distribution of denitrification in the vadose zone was analyzed, and the influencing factors of the vertical distribution of denitrification strength in the aeration zone were identified. The results showed that the NO3--N concentrations in the denitrification process of soil samples in different vadose zones experienced three main stages:rising, falling, and rising. The vadose zone denitrification intensities in S6 and S8 ranged from 0.0026 to 0.0185 mg·(kg·d)-1 and 0.0017 to 0.0233 mg·(kg·d)-1, respectively. That the overall denitrification intensity was low. The denitrification intensity of the vertical space showed an "S"-type trend. The main controlling factors for denitrification intensity in S6 and S8 vadose zones included clay, nitrate, and nitrite and showed significant correlations with the diversity of microorganisms, such as the ACE and Shannon indices, and the nitrate reductase (nirK) gene of denitrifying bacteria at a certain depth range.

[Pathological factors associated with staging of metastatic lymph node ratio and metastatic lymph node number in advanced gastric carcinoma].

OBJECTIVE: To explore the association of pathologic factors with the staging of metastatic lymph node ratio (rN) and metastatic lymph node number (pN), and to provide evidence for reasonable tumor staging in advanced gastric carcinoma (AGC). METHODS: The clinicopathological data of 555 patients, who received radical resection for primary tumor of AGC between November 2003 and December 2011 in The First Affiliated Hospital of Xinjiang Medical University, were reviewed retrospectively. The clinicopathological factors influencing rN and pN were analyzed. RESULTS: Univariate analysis showed that differentiation degree, vascular invasion, tumor diameter, gross type and invasion depth were significantly associated with rN or pN (all P<0.05). Histological type was significantly associated with rN (P<0.05), but not with pN. Logistic regression analysis revealed that vascular invasion, tumor diameter≥4 cm and invasion depth were independent risk factors for lymph node distant metastasis in AGC (all P<0.05). ROC curves showed that rN was consistent with pN in evaluating the diagnostic value of lymph node distant metastasis for tumor staging in AGC (P>0.05). CONCLUSIONS: Vascular invasion tumor diameter≥4 cm and invasion depth are independent risk factors for lymph node metastasis in AGC based on either metastatic lymph node ratio (rN) or metastatic lymph node number (pN). The rN staging is consistent with the pN staging in evaluating the diagnostic value of metastatic lymph node for tumor staging in AGC.

Anterior gradient 2: a new target to treat colorectal cancer.

Colorectal cancer is one of the leading causes of cancer-associated morbidity and mortality across the world. Every year many patients died from the advanced colorectal cancer. We had tried our best to stop the progress by the chemotherapy and radiotherapy, but the process has not stopped. And we just can use the target drug to extend the survival time of the patient who is in advanced stage. It is said that the circulating tumor cells, distributed in the peripheral blood, is the initial material leading to metastases formation. And Anterior gradient 2 is a biomarker of these cells. It shows an enormous role in the process of cancer's occurrence, development and metastasis. It may be a useful target for us to prevent colorectal cancer from progress. And it may be a new way to treat the colorectal cancer.