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Abstract Relapsed/refractory (R/R) primary and secondary central nervous system lymphomas (PCNSL, SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies. We retrospectively compared the safety and efficacy of CD19/22 CAR-T-cell therapy following ASCT (ASCT + CAR-T group), CD19/22 CAR-T-cell cocktail therapy (CAR-T group) and chemoimmunotherapy (CIT group) in treating R/R CNSL patients. Analysis of the differences in clinical characteristics among the three groups revealed that the median age in the CIT group was older than that in the ASCT + CAR-T group and CAR-T group, and the median number of prior lines of therapy in the CIT group was less than that in the other groups. Patients in the two CAR-T-therapy groups exhibited comparable incidences and severities of CRS and ICANS. Grade 4–5 CRS and ICANS were not observed in either CAR-T-cell therapy group. The incidence of Grade 3/4 hematological toxicity in the ASCT + CAR-T and CAR-T groups was greater than that in the CIT group. The ORR was 82.75% in the ASCT + CAR-T group, 60.00% in the CAR-T group and 58.83% in the CIT group. As of December 31, 2022, the median follow-up after therapy was 16.73 months (range, 0.67-42.00 months). The median durations of PFS and OS were not reached in the ASCT + CAR-T group. The median PFS in the CAR-T group was 4.72 months, and OS was not reached. In the CIT group, the median PFS and OS were 6.63 months and 16.77 months, respectively. The 2-year PFS rate of patients in the ASCT + CAR-T group (65.52%) was significantly greater than that of patients in the CAR-T group (30.00%, P = 0.0321) and CIT group (23.53%, P = 0.0043). Our results support the development of CAR-T-cell therapy for R/R CNSL. With the durability of remission and low toxicity, ASCT combined with CAR-T-cell therapy appears to be a more effective and safer treatment option for primary and secondary R/R CNS lymphoma.

Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, the pharmacological mechanism and target has not yet been fully elucidated. In this study, liver fibrosis was induced by CCl4 in wild-type mice and hepatocyte-specific extracellular matrix protein 1 (Ecm1)-deficient mice, which were separately treated with Sal B, ferrostatin-1, sorafenib or cilengitide. Erastin- or CCl4-induced hepatocyte ferroptosis models with or without Ecm1 gene knockdown were evaluated in vitro. Subsequently, the interaction between Ecm1 and xCT and the binding kinetics of Sal B and Ecm1 were determined. We found that Sal B significantly attenuated liver fibrosis in CCl4-induced mice. Ecm1 deletion in hepatocytes abolished the antifibrotic effect of Sal B. Mechanistically, Sal B protected against hepatocyte ferroptosis by upregulating Ecm1. Further research revealed that Ecm1 as a direct target for treating liver fibrosis with Sal B. Interestingly, Ecm1 interacted with xCT to regulate hepatocyte ferroptosis. Hepatocyte ferroptosis in vitro was significantly attenuated by Sal B treatment, which was abrogated after knockdown of Ecm1 in LO2 cells. Therefore, Sal B alleviates liver fibrosis in mice by targeting up-regulation of Ecm1 and inhibiting hepatocyte ferroptosis. The interaction between Ecm1 and xCT regulates hepatocyte ferroptosis.

Abstract Background MCD (MYD88L265P/CD79Bmut) diffuse large B‐cell lymphoma has a poor prognosis. There is no published clinical research conclusion regarding zanubrutinib or orelabrutinib for the initial treatment of MCD DLBCL. Aims This study aimed to analyse the efficacy and safety of Bruton's tyrosine kinase inhibitor (BTKi) (zanubrutinib or orelabrutinib) therapy for newly diagnosed DLBCL patients with MYD88mut and/or CD79Bmut. Materials and Methods Twenty‐three newly diagnosed DLBCL patients with MYD88mut and/or CD79Bmut from June 2020 to June 2022 received BTKi combined with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) or rituximab + lenalidomide (R2). A control group of 17 patients with MYD88mut and/or CD79Bmut DLBCL who received the standard R‐CHOP therapy was also assessed. We retrospectively analysed clinical characteristics, safety, overall response rate (ORR), complete response (CR) rate and progression‐free survival (PFS) of the two groups. Results The main clinical features were a high International Prognostic Index (IPI) score (≥3, 22/40, 55%) and a high rate of extranodal involvement (27/40,67.5%). Among the 23 DLBCL patients, 18 received BTKi + R‐CHOP, and five elderly DLBCL patients were treated with BTKi + R2. Compared with those in the control group (ORR 70.6%, CRR 52.9%, 1‐year PFS rate 41.2%), improved ORR, CRR and PFS results were observed in the BTKi + R‐CHOP group (100%, 94.4% and 88.9%, p = 0.019, 0.007, and 0.0001). In subgroup analyses based on genetic subtypes, cell origin, dual expression or IPI score, patients in the BTKi + R‐CHOP group had better PFS than patients in the control group. In the BTKi + R‐CHOP group, no significant difference was found in ORR, CRR and PFS based on subtype analysis, while BTKi‐type subgroups exhibited statistically significant differences in 1‐year PFS (p = 0.028). There were no significant differences in grade 3–4 haematological toxicity (p = 1) and grade 3–4 non‐haematological toxicity (p = 0.49) between the BTKi + R‐CHOP and R‐CHOP treatment groups. In the BTKi + R2 group, the ORR was 100%, the CRR was 80%, and the 1‐year PFS rate was 80%. The incidences of grade 3–4 haematologic toxicity and non‐haematological toxicity were both 40%. No bleeding or cardiovascular events of grade 3 or higher occurred in any patients. Discussion The efficacy of BTKi combined with R‐CHOP was similar to previous reports, which was significantly better than R‐CHOP alone. It is necessary to fully consider that 14 patients in the BTKi + R‐CHOP group received a BTKi as maintenance therapy when evaluating efficacy. Meanwhile, the addition of a BTKi may improve the prognosis of non‐GCB, DEL or high‐IPI‐score DLBCL patients with MYD88mut and/or CD79Bmut. In our study, five elderly DLBCL patients with MYD88mut and/or CD79Bmut were achieved better ORR, CRR, PFS than the historical data of R‐miniCHOP treatment and Ibrutinib + R2 treatment. However, the efficacy and benefit of BTKis for this type of DLBCL need to be further analysed using a larger sample size. Conclusion This study suggests that newly diagnosed DLBCL patients with MYD88mut and/or CD79Bmut may benefit from BTKis according to real‐world clinical data.

BackgroundAnaplastic Large Cell Lymphoma (ALCL) is one of the most common subtypes of T-cell lymphoma. Among these, refractory and relapsed (r/r) ALK positive ALCL lacks effective therapies. The chimeric antigen receptor-modified T (CAR-T) cell therapy holds great promise as a therapeutic strategy for this disease. However, it is not known yet whether anti-CD5 CAR-T cells are sufficient for the definitive treatment of relapsed ALK+ ALCL, nor the role of accurate laboratory-based diagnoses during CAR-T treatment.Case presentationThe adolescent patient received autologous T cells containing sequences encoding VH domains specific to CD5. Following the infusion, there was an increase in both the copy number and proportion of CAR-T cells in peripheral blood. IL-6 and ferritin levels in the patient exhibited significant fluctuations, with increases of 13 and 70 folds respectively, compared to baseline after the treatment. Additionally, adverse effects were observed, including grade 4 rash, grade 1 headache, nausea, and neck-pain. Surprisingly, a relapsed disease phenotype was identified based on the results of PET/CT and histopathological analysis of the inguinal lymph node biopsy. After conducting a thorough diagnostic assessment, which included flow cytometry, next-generation sequencing (NGS), examination of immune-related gene rearrangements, and analysis of the immune repertoire of T-cell receptors (TCR), we conclusively determined that the hyperplastic T cells identified in the lymph node were the result of an expansion of CAR-T cells. Ultimately, the patient has attained complete remission (CR) and has sustained a disease-free survival state for 815 days as of the cutoff date on August 30, 2023.ConclusionTaken together, the results demonstrate that anti-CD5 CAR-T cells can induce a clinical response in r/r ALK+ ALCL patient. Furthermore, this case underscores the importance of utilizing advanced technologies with high sensitivity and accuracy for biological detection in clinical laboratory diagnosis and prognosis in CAR-T cell treatment.Trial registration numberNCT04767308.

Summary: Understanding of cellular evolution and molecular programs of chimeric antigen receptor-engineered (CAR)-T cells post-infusion is pivotal for developing better treatment strategies. Here, we construct a longitudinal high-precision single-cell transcriptomic landscape of 7,578 CAR-T cells from 26 patients with B cell acute lymphoblastic leukemia (B-ALL) post-infusion. We molecularly identify eight CAR-T cell subtypes, including three cytotoxic subtypes with distinct kinetics and three dual-identity subtypes with non-T cell characteristics. Remarkably, long-term remission is coincident with the dominance of cytotoxic subtypes, while leukemia progression is correlated with the emergence of subtypes with B cell transcriptional profiles, which have dysfunctional features and might predict relapse. We further validate in vitro that the generation of B-featured CAR-T cells is induced by excessive tumor antigen stimulation or suppressed TCR signaling, while it is relieved by exogenous IL-12. Moreover, we define transcriptional hallmarks of CAR-T cell subtypes and reveal their molecular changes along computationally inferred cellular evolution in vivo. Collectively, these results decipher functional diversification and dynamics of peripheral CAR-T cells post-infusion.

Background Venous thromboembolism (VTE) is a severe preventable complication among ophthalmic surgical patients. The knowledge, attitude, and practice (KAP) of nurses play a key role in effective VTE prevention. However, little is known about the KAP of ophthalmic nurses’ VTE prevention. This study aimed to examine the level of KAP toward VTE prevention among Chinese ophthalmic nurses and to investigate the influencing factors of their VTE practice. Methods A total of 610 ophthalmic nurses from 17 cities in Hunan and Zhejiang Provinces, China, participated in this study. Data was collected via the Sojump online platform from March to April 2021. A self-administered VTE questionnaire was developed to assess nurses’ KAP toward VTE prevention. Multiple linear regression analysis was used to analyze the influencing factors of ophthalmic nurses’ VTE prevention practice. Results The scores (correct rates) of ophthalmic nurses’ knowledge, attitude, and practice were 103.87 ± 20.50 (76.4%), 21.96 ± 2.72, and 48.96 ± 11.23 (81.6%), respectively. The three lowest-scored knowledge items were related to VTE complications, physical prevention, and risk assessment. The three lowest-scored attitude items were related to nurses’ training, VTE risk, and patient education. The three lowest-scored practice items were related to the assessment scale, VTE assessment, and patient education. Nurses’ knowledge, attitude, and practice were significantly correlated with each other. Multiple linear regression analysis showed that Hunan Province (B = 2.77, p = 0.006), general hospital (B = 2.97, p = 0.009), outpatient department (B = 3.93, p = 0.021), inpatient department (B = 2.50, p = 0.001), previous VTE prevention training (B = 3.46, p < 0.001), VTE prevention management in hospital (B = 4.93, p < 0.001), better knowledge (B = 0.04, p = 0.038), and positive attitude towards VTE prevention (B = 1.35, p < 0.001) were all significantly and positively associated with higher practice scores in VTE prevention. Conclusions Our study provided a comprehensive understanding of the ophthalmic nurses’ knowledge, attitude, and practice in VTE prevention, as well as identified specific items in each dimension for improvement. In addition, our study showed multiple factors were associated with ophthalmic nurses’ practice in VTE prevention, including environmental factors, training and management, knowledge and attitudes toward VTE prevention. Our findings provide important implications and guidance for future intervention programs to improve the ophthalmic nurses’ knowledge, attitude, and practice in VTE prevention.

Neural stem cell (NSC) has gained considerable attention in traumatic brain injury (TBI) treatment because of their ability to replenish dysfunctional neurons and stimulate endogenous neurorestorative processes. However, their therapeutic effects are hindered by the low cell retention rate after transplantation into the dynamic brain. In this study, we found cerebrospinal fluid (CSF) flow after TBI is an important factor associated with cell loss following NSC transplantation. Recently, several studies have shown that hydrogels could serve as a beneficial carrier for stem cell transplantation, which provides a solution to prevent CSF flow-induced cell loss after TBI. For this purpose, we evaluated three different hydrogel scaffolds and found the gelatin methacrylate (GelMA)/sodium alginate (Alg) (GelMA/Alg) hydrogel scaffold showed the best capabilities for NSC adherence, growth, and differentiation. Additionally, we detected that pre-differentiated NSCs, which were loaded on the GelMA/Alg hydrogel and cultured for 7 days in neuronal differentiation medium (NSC [7d]), had the highest cell retention rate after CSF impact. Next, the neuroprotective effects of the NSC-loaded GelMA/Alg hydrogel scaffold were evaluated in a rat model of TBI. NSC [7d]-loaded GelMA/Alg markedly decreased microglial activation and neuronal death in the acute phase, reduced tissue loss, alleviated astrogliosis, promoted neurogenesis, and improved neurological recovery in the chronic phase. In summary, we demonstrated that the integration with the GelMA/Alg and modification of NSC differentiation could inhibit the influence of CSF flow on transplanted NSCs, leading to increased number of retained NSCs and improved neuroprotective effects, providing a promising alternative for TBI treatment.

IntroductionSeveral prognostic factors of chronic lymphocytic leukemia (CLL) have been identified, such as cytogenetic aberrations and recurrent gene mutations. B-cell receptor (BCR) signaling plays an important role in the tumorigenesis of CLL, and its clinical significance in predicting prognosis is also under study.MethodsTherefore, we assessed the already-known prognostic markers, immunoglobulin heavy chain (IGH) gene usage and the associations among these factors in 71 patients diagnosed with CLL in our center from October 2017 to March 2022. Sequencing of IGH gene rearrangements was performed using Sanger sequencing or IGH-based next-generation sequencing, and the results were further analyzed for distinct IGH/IGHD/IGHJ genes and the mutational status of the clonotypic IGHV (IGH variable) gene.ResultsIn summary, by analyzing the distribution of potential prognostic factors in CLL patients, we displayed a landscape of molecular profiles, confirmed the predictive value of recurrent genetic mutations and chromosome aberrations, and found that IGHJ3 was associated with favorable markers (mutated IGHV, trisomy 12), while IGHJ6 tended to correlate with unfavorable factors (unmutated IGHV, del17p).DiscussionThese results provided an indication for IGH gene sequencing in predicting the prognosis of CLL.

Background Our previous study showed that transmembrane tumor necrosis factor alpha (tmTNF-α) is overexpressed in primary breast cancers including triple-negative breast cancers (TNBCs). Chimeric antigen receptor engineered-T (CAR-T) cells have been successfully used mainly in B-cell malignancies.Methods We generated CAR-T cells targeting tmTNF-α but not secreted tumor necrosis factor alpha and assessed the antitumor effect of the CAR-T cells on tmTNF-α-expressing breast cancer cells in vitro and in vivo.Results Our tmTNF-α CAR-T cells showed potent cytotoxicity against tmTNF-α-expressing breast cancer cells but not tmTNF-α-negative tumor cells with increased secretion of interferon gamma (IFN-γ) and interleukin (IL)-2 in vitro. In tmTNF-α-overexpressing TNBC-bearing mice, the tmTNF-α CAR-T therapy induced evident tumor regression, prolonged survival and increased serum concentrations of IFN-γ and IL-2. However, we found thattmTNF-α induced programmed death-ligand 1 (PD-L1) expression through the p38 pathway via TNF receptor (TNFR) and through the NF-κB and AKT pathways via outside-to-inside (reverse) signaling, which might limit the efficacy of the CAR-T cell therapy. Blockage of the PD-L1/programmed death-1 (PD-1) pathway by PD-1 monoclonal antibody significantly enhanced the antitumor effect of the tmTNF-α CAR-T cell therapy in vitro and in vivo, and the combination was effective for antiprimary tumors and had a tendency to increase the antimetastasis effect of the CAR-T cell therapy.Conclusion Our findings suggest a potent antitumor efficacy of the tmTNF-α CAR-T cells that can be enhanced by anti-PD-L1/PD-1 because high PD-L1 expression in TNBC was induced by the tmTNF-α signaling, indicating a promising individual therapy for tmTNF-α-positive breast cancers including TNBC.

We study the dispersions of the guided modes in the continuous uniaxial crystal slab waveguide and engineer their degeneracies through dielectric anisotropy. By switching the uniaxial positivity and negativity, we can obtain distinctive nodal types, point and line, for the lowest degeneracy in frequency. The mirror symmetry protections, Mx and My, are pointed out, and the degeneracy properties are intuitively analyzed through comparing the approximate slopes of the guided modes. Our results reveal a link between the lowest nodal types and the positivity/negativity of the uniaxial crystal, and provide a new approach to regulate the topology of degeneracy in two-dimensional photonic bands.

Abstract Objective To evaluate the diagnostic performance of short state homeobox 2 (SHOX2) promoter methylation as biomarker for lung cancer identification through aggregating the open published data. Methods We did an electronic search in Pubmed, EMBASE, Ovid, Web of Science, Google Scholar, and the China National Knowledge Infrastructure (CNKI) to identify the publications related to SHOX2 promoter methylation and lung cancer. The diagnostic performance of sensitivity (SEN), specificity (SPE), odds ratio (DOR), and summary receiver operating characteristic (SROC) cure were aggregated by fixed or random effect model. Fagan's nomogram was used to investigate the post‐test diagnostic probability. Deek's funnel plot and line regression test was applied to evaluate the publication bias. Results In total, 18 clinical studies about SHOX2 promoter methylation and lung cancer were included in the meta‐analysis. The combined diagnostic SEN, SPE, DOR were 0.63 (95% CI = 0.54–0.70), 0.91 (95% CI = 0.87–0.94), and 16.84 (95% CI = 11.18–25.36) in random effect model respectively. The pooled area under the curve (AUC) of SROC was 0.88 (95% CI = 0.84–0.90). The post‐test probability of lung cancer was 88% and 29% when SHOX2 methylated and unmethylated in humoral components given a pre‐test probability of 50%. Deek's funnel plot and regression test indicated no publication bias (p = 0.62). Conclusion SHOX2 promoter methylation in humoral components may be a potential biomarker for lung cancer diagnosis with relative high diagnostic specificity.

Abstract Background The aim of this study was to quantitatively analysis the diagnostic performance of adenomatous polyposis coli (APC) gene promoter methylation in serum or sputum/bronchoalveolar lavage fluid (BLAF) as a biomarker for lung cancer identification through pooling of open published data. Methods The relevant electronic MEDLINE, EMBASE, Ovid, web of science and CNKI databases were systematically searched to identify the studies related to APC gene promoter methylation for lung cancer diagnosis. Data of true positive (tp), false positive (fp), false negative (fn) and true negative (tn) were extracted from the publications included in the study. The pooled diagnostic sensitivity, specificity and area under summary receiver operating characteristic (SROC) curve (AUC‐SROC) of APC gene promoter methylation were calculated. Publication bias was evaluated by Begg's funnel plot and Egger's line regression test. Results Fourteen studies associated with APC gene promoter methylation and lung cancer were identified in the databases and finally included in the meta‐analysis. The data was pooled using a random effect model due to significant statistical heterogeneity across the 14 studies (p

Backgroud and aims: Ductular reaction (DR) is a common pathological change and thought to have a key role in the pathogenesis and progression of liver fibrosis. Our previous study reported Gypenosides (GPs) ameliorated liver fibrosis, however, the anti-fibrotic mechanisms of GPs are still unclear.Methods: Liver fibrosis was induced in rats by carbon tetrachloride combining with 2-acerylaminofluorene (CCl4/2-AAF), and Mdr2 knockout (Mdr2−/−) mice to evaluate the anti-fibrotic role of GPs. In vitro, WB-F344 cells, a hepatic progenitor cells (HPCs) line, with or without Gli1 overexpressing lentiviral vectors, were induced by sodium butyrate (SB) to validate the mechanism of GPs and NPLC0393, the main ingredient of GPs.Results: Both in CCl4/2-AAF-treated rats and Mdr2−/− mice, GPs obviously reduced the deposition of collagen and hydroxyproline content, inhibited the activation of hepatic stellate cells and inflammatory cell infiltration. Notably, GPs reduced the expressions of Epcam, CK19, CK7, Dhh, Smo, Ptch2, Gli1 and Gli2. Furthermore, CK19+ cells co-expressed Gli1, while the number of CK19+/Gli1+ cells was decreased by GPs. In vitro, GPs and NPLC0393 inhibited the differentiation of WB-F344 cells toward a biliary phenotype. Mechanistically, GPs and NPLC0393 protected against DR by inhibiting hedgehog signaling, which was supported by the results that DR, triggered directly by Gli1 overexpressing lentiviral vector was blocked by administration with GPs or NPLC0393.Conclusion: GPs attenuated DR and liver fibrosis by inhibiting hedgehog signaling, which provided more evidences and a novel mechanism of anti-fibrotic effect of GPs.

With the success of chimeric antigen receptor-modified (CAR) T-cell therapy for relapsed/refractory (r/r) B-cell malignancies, severe complications after CAR T-cell infusion have emerged as nonnegligible prognosis-related factors. However, the prognosis of patients with CAR T-cell-related hyperferritinaemia (HFA) is unclear. We report the efficacy and safety of CAR T-cell therapy in 16 r/r B-cell malignancy patients with CAR T-cell-related HFA. The rates of serum ferritin levels above 10,000 ng/ml during CAR T-cell therapy were 6.2% and 14.3% in B-cell non-Hodgkin’s lymphoma (B-NHL) and acute B lymphocyte leukemia (B-ALL), respectively. These patients were characterized by an extremely high tumor burden and a high rate of extranodal involvement. In lymphoma, the complete remission (CR) rate was 37.5% (3/8), which was lower than that in the control group with the lowest value of ferritin (CR was 87.5% (7/8), P=0.0406), and it could also be seen that the OS of the control group (1-year OS rate 100%) had a better trend than HFA group (1-year OS rate 50%). In the B-ALL patients, the OS of the control group (1-year OS rate 100%) was higher than HFA group (1-year OS rate 45%, P=0.0189), although there was no significant difference in CR rate. High-grade CRS (≥3) occurred in 56.25% of the patients, and the mortality rate was 56.25%, which was significantly higher than control group (12.5% and 12.5%, P=0.009). The peak serum ferritin level in the patients who died of CRS was significantly higher than others (P=0.0168). Regardless of whether the CAR T-related MAS diagnostic criteria were met, there was no significant difference in ORR and OS in HFA group, however patients with MAS showed a higher rate of high-grade CRS. Interestingly, in our study, glucocorticoid intervention in HFA group showed little impact on expansion of CAR-T cells, whether compared with control group or compared within HFA group by dividing patients into high and low dosage subgroups based on the median dose of glucocorticoid. High mortality was observed in patients with CAR T-cell-related HFA. Early glucocorticoid intervention might be worth trying to improve the safety of CAR T therapy in these patients.

Accumulating evidence has demonstrated that the immune cells have an emerging role in controlling anti-tumor immune responses and tumor progression. The comprehensive role of mast cell in glioma has not been illustrated yet. In this study, 1,991 diffuse glioma samples were collected from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). xCell algorithm was employed to define the mast cell-related genes. Based on mast cell-related genes, gliomas were divided into two clusters with distinct clinical and immunological characteristics. The survival probability of cluster 1 was significantly lower than that of cluster 2 in the TCGA dataset, three CGGA datasets, and the Xiangya cohort. Meanwhile, the hypoxic and metabolic pathways were active in cluster 1, which were beneficial to the proliferation of tumor cells. A potent prognostic model based on mast cell was constructed. Via machine learning, DRG2 was screened out as a characteristic gene, which was demonstrated to predict treatment response and predict survival outcome in the Xiangya cohort. In conclusion, mast cells could be used as a potential effective prognostic factor for gliomas.

Ferroptosis, an iron-dependent non-apoptotic cell death characterized by lipid peroxidation, is a cell death pathway discovered in recent years. Ferroptosis plays an important role in tumors, ischemia-reperfusion injury, neurological diseases, blood diseases, etc. Recent studies have shown the importance of ferroptosis in chronic liver disease. This article summarizes the pathological mechanisms of ferroptosis involved in System Xc−, iron metabolism, lipid metabolism, and some GPX4-independent pathways, and the latest research on ferroptosis in chronic liver diseases such as alcoholic liver disease, non-alcoholic fatty liver disease, liver fibrosis, hepatocellular carcinoma. In addition, the current bottleneck issues that restrict the research on ferroptosis are proposed to provide ideas and strategies for exploring new therapeutic targets for chronic liver diseases.

Automated, effective and efficient sleep‐stage monitoring and structure analysis is an essential enabling procedure for healthcare automation. Sleep diagnosis by polysomnography is a golden standard but expensive procedure involving huge effort from patients. There remain challenges for smart devices to precisely identify sleep stage and minimize intrusive effect on sleep progression. Herein, a novel noncontact sleep structure prediction system (NSSPS) using a single radar sensor is presented to analyze sleep structure without any tethered unit. The NSSPS is realized through training a convolutional recurrent neural network and neural conditional random fields using reflected radio frequency (RF) waves acquired by radar antennas. By capturing implicit temporal information in RF signals and transitions of sleep progression, high accuracy of sleep‐stage prediction is achieved and characteristics of sleep structure are extracted. The performance of the NSSPS is validated by transfer learning between radar signals with different frequency bands and crossvalidation among different subjects. Moreover, the NSSPS is demonstrated to estimate overnight parameters that are critical for sleep diagnosis. Benefiting from its low cost, convenient setup, and accurate prediction capability of sleep‐stage identification, the NSSPS can be widely deployed in “smart” homes and exploited to conduct daily sleep structure analysis.

Patients with Burkitt lymphoma who are refractory to initial therapy or who relapse after undergoing intensive chemotherapy and autologous stem cell transplantation (ASCT) usually have a poor prognosis. While there has been considerable progress in the use of chimeric antigen receptor-modified (CAR) T cell immunotherapy for the treatment of relapsed and refractory (r/r) malignancies, explicit data on adult patients with r/r Burkitt lymphoma are limited. We conducted two single-arm clinical trials to evaluate the clinical efficacy and toxicity of CD19/CD22 CAR T cell immunotherapy both alone (trial A) and in combination with ASCT (trial B) in adult patients with r/r Burkitt lymphoma. In total, 28 adult patients with r/r Burkitt lymphoma were enrolled [trial A (n = 15) and trial B (n = 13)]. The median doses of CD22 and CD19 CAR T cell infusions were 4.1 × 106/kg and 4.0 × 106/kg, respectively. Subsequently, after CAR T cell infusion, overall and complete responses were observed in 19 (67.9%) and 16 (57.1%) patients, respectively. The cumulative incidence rates of grade 2–4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were 39.3% (11/28) and 10.7% (3/28), respectively. After a median follow-up duration of 12.5 months, 16 patients (5 in trial A and 11 in trial B) survived. Both the estimated 1-year progression-free and overall survival rates were 55.6%. Our preliminary results indicated that salvage therapy with CD19/CD22 CAR T cell infusion alone and that in combination with ASCT are effective in treating some adult patients with r/r Burkitt lymphoma.

Abstract Nodal chain (NC) semi-metals have the degeneracy of interlacing rings in their band structure in momentum space. With the projection of degenerate rings towards crystal boundaries, there is a special type of surface dispersion appearing at surface Brillouin zone and termed drumhead surface state (DSS). Previously, experimental investigations on photonic NC and DSS have been done on metallic photonic crystals at microwave frequencies. However, far-field detection of DSS and its coupling to radiative modes in free space have not been studied. In the work, we analyze the photonic DSS in a metallic lattice by angle-resolved far-field reflection measurement and numerical simulation at terahertz (THz) frequencies, and reveal its flatness and boundness in band structure, even in the radiation continuum. Particularly, the DSS band can be tuned being from negatively dispersive via flat to positively dispersive by a single surface parameter, and the DSS at Γ point in surface Brillouin zone is in fact a symmetry-protected bound state in the continuum. Our results might have some potential applications towards THz photonics.

BackgroundAberrant endoplasmic reticulum stress (ERS) plays an important role in multiple cardiovascular diseases. However, their implication in intracranial aneurysms (IAs) remains unclear. We designed this study to explore the general expression pattern and potential functions of ERS in IAs.MethodsFive Gene Expression Omnibus (GEO) microarray datasets were used as the training cohorts, and 3 GEO RNA sequencing (RNA-seq) datasets were used as the validating cohorts. Differentially expressed genes (DEGs), functional enrichment, Lasso regression, logistic regression, ROC analysis, immune cell profiling, vascular smooth muscle cell (VSMC) phenotyping, weighted gene coexpression network analysis (WGCNA), and protein-protein interaction (PPI) analysis were applied to investigate the role of ERS in IA. Finally, we predicted the upstream transcription factor (TF)/miRNA and potential drugs targeting ERS.ResultsSignificant DEGs were majorly associated with ERS, autophagy, and metabolism. Eight-gene ERS signature and IRE1 pathway were identified during the IA formation. WGCNA showed that ERS was highly associated with a VSMC synthesis phenotype. Next, ERS-VSMC-metabolism-autophagy PPI and ERS-TF-miRNA networks were constructed. Finally, we predicted 9 potential drugs targeting ERS in IAs.ConclusionERS is involved in IA formation. Upstream and downstream regulatory networks for ERS were identified in IAs. Novel potential drugs targeting ERS were also proposed, which may delay IA formation and progress.

Abstract Background The rapid spread of coronavirus disease 2019 (COVID-19) was declared as an emerging public health threat by the World Health Organization. As various measures have been taken successfully to combat the epidemic caused by SARS-CoV-2, a growing number of fully recovered patients have been discharged from hospitals. However, some of them have relapsed. Little is known about the causes that triggered the relapse. Case presentation We report a case of a 40 years old man who suffered from recurrent pulmonary infection with progression of lesions on chest computed tomography (CT), elevated levels of ferritin and IL2R, reduced lymphocyte count and positive oropharyngeal swab test for SARS-CoV-2 again after 5 days discharge from hospital. The anti-SARS-CoV-2 antibody level of this patient was very low at the time of relapse, suggesting a weak humoral immune response to the virus. Total exon sequencing revealed mutations in TRNT1 gene, which may be responsible for B cell immunodeficiency. Therefore, uncleared SARS-CoV-2 at his first discharge was likely to lead to his recurrence. However, viral superinfection and non-infectious organizing pneumonia could not be completely excluded. Conclusion COVID-19 relapse may occur in a part of discharged patients with low titers of anti-SARS-CoV-2 antibodies. These patients should be maintained in isolation for longer time even after discharge. A more sensitive method to detect SARS-CoV-2 needs to be established and serological testing for specific antibodies may be used as a reference to determine the duration of isolation.

ObjectiveTo investigate whether enhanced recovery after surgery (ERAS) can promote rehabilitation of patients after neurosurgical craniotomy.MethodsThe clinical data of 100 patients with brain tumor undergoing craniotomy in the Department of Neurosurgery, Xiangya Hospital, Central South University, from January 2018 to August 2020 were collected, including 50 patients in the ERAS group and 50 patients in the control group. t-Test, Wilcoxon’s rank sum test, and chi-square analysis were used to compare the clinical characteristics, prognosis, and hospitalization time between the two groups.ResultsThere was no significant difference in gender, age, and other general clinical data between the two groups (p > 0.05). The days of antiemetic drugs applied in the ERAS group were less than those in the control group (1.00 vs. 2.00 days, p = 0.003), and the proportion of patients requiring analgesics was lower than that of the control group (30% vs. 52%, OR = 0.41, 95% CI 0.18–0.93, p = 0.031). The time of urinary catheter removal and that of patients starting ambulation in the ERAS group were shorter than those in the control group (16.00 vs. 24.00 h, and 1.00 vs. 2.00 days, p < 0.001, respectively); and the hospital length of stay (LOS) in the ERAS group was shorter than that in the control group (Total LOS, 13.00 vs. 15.50 days; Postoperative LOS, 7.00 vs. 10.00 days, p < 0.001). By analyzing the prognosis of patients in the ERAS group and control group, we found that there was no significant difference in postoperative complications and Karnofsky Performance Status (KPS) score 1 month after operation between the two groups.ConclusionThe application of ERAS in craniotomy can accelerate the postoperative recovery of patients without increasing the perioperative risk, which is worthy of wide application. However, whether the ERAS measures can reduce the postoperative complications and improve the prognosis of patients still needs more large-scale case validation and multicenter collaborative study.

Pyroptosis is a recently identified type of lytic programmed cell death, in which pores form in the plasma membrane, and cells swell, rupture, and then release their contents, including inflammatory cytokines. Molecular studies indicated that pyroptosis may occur via a gasdermin D (GSDMD) and caspase-1 (Casp1) -dependent classical pathway, a GSDMD and Casp11/4/5-dependent non-classical pathway, or a gasdermin E (GSDME) and Casp3-dependent pathway. Studies of animal models and humans indicated that pyroptosis can exacerbate several complications of diabetes, including diabetic nephropathy (DN), a serious microvascular complication of diabetes. Many studies investigated the mechanism mediating the renoprotective effect of GSDMD regulation in the kidneys of patients and animal models with diabetes. As a newly discovered regulatory mechanism, GSDME and Casp3-dependent pyroptotic pathway in the progression of DN has also attracted people’s attention. Z-DEVD-FMK, an inhibitor of Casp3, ameliorates albuminuria, improves renal function, and reduces tubulointerstitial fibrosis in diabetic mice, and these effects are associated with the inhibition of GSDME. Studies of HK-2 cells indicated that the molecular and histological features of secondary necrosis were present following glucose stimulation due to GSDME cleavage, such as cell swelling, and release of cellular contents. Therefore, therapies targeting Casp3/GSDME-dependent pyroptosis have potential for treatment of DN. A novel nephroprotective strategy that employs GSDME-derived peptides which are directed against Casp3-induced cell death may be a key breakthrough. This mini-review describes the discovery and history of research in this pyroptosis pathway and reviews the function of proteins in the gasdermin family, with a focus on the role of GSDME-mediated pyroptosis in DN. Many studies have investigated the impact of GSDME-mediated pyroptosis in kidney diseases, and these studies used multiple interventions, in vitro models, and in vivo models. We expect that further research on the function of GDSME in DN may provide valuable insights that may help to improve treatments for this disease.

Soluble tumor necrosis factor-α (sTNF-α) plays an important role in colitis-associated cancer (CAC); however, little is known about transmembrane TNF-α (tmTNF-α). Here, we observed an increase in sTNF-α mainly in colitis tissues from an azoxymethane/dextran sodium sulfate (DSS)-induced CAC mouse model whereas tmTNF-α levels were chiefly increased on epithelial cells at the tumor stage. The ratio of intracolonic tmTNF-α/sTNF-α was negatively correlated with the levels of pro-inflammatory mediators (IL-1β, IL-6, and NO) and M1 macrophages but positively correlated with the infiltration of myeloid-derived suppressor cells, regulatory T cells, and the level of the anti-inflammatory cytokine IL-10, suggesting an anti-inflammatory effect of tmTNF-α. This effect of tmTNF-α was confirmed again by the induction of resistance to LPS in colonic epithelial cell lines NCM460 and HCoEpiC through the addition of exogenous tmTNF-α or transfection of the tmTNF-α leading sequence that lacks the extracellular segment but retains the intracellular domain of tmTNF-α. A tmTNF-α antibody was used to block tmTNF-α shedding after the first or second round of inflammation induction by DSS drinking to shift the time window of tmTNF-α expression ahead to the inflammation stage. Antibody treatment significantly alleviated inflammation and suppressed subsequent adenoma formation, accompanied by increased apoptosis. An antitumor effect was also observed when the antibody was administered at the malignant phase of CAC. Our results reveal tmTNF-α as a novel molecular marker for malignant transformation in CAC and provide a new insight into blocking the pathological process by targeting tmTNF-α processing.

Advanced liver fibrosis can lead to cirrhosis, resulting in an accelerated risk of hepatocellular carcinoma and liver failure. Fuzheng Huayu formula (FZHY) is a traditional Chinese medicine formula treated liver fibrosis in China approved by a Chinese State Food and Drug Administration (NO: Z20050546), composed of Salvia Miltiorrhiza bge., Prunus davidiana (Carr.) Franch., cultured Cordyceps sinensis (BerK.) Sacc. Mycelia, Schisandra chinensis (Turcz.) Baill., Pinus massoniana Lamb., and Gynostemma pentaphyllum (Thunb.) Makino. However, the main active substances and mechanism of FZHY are unclear. The aim of this study is to identify a novel anti-fibrotic compound, which consists of the main active ingredients of FZHY, and investigate its mechanism of pharmacological action. The main active ingredients of FZHY were investigated by quantitative analysis of FZHY extracts and FZHY-treated plasma and liver in rats. The anti-fibrotic composition of the main active ingredients was studied through uniform design in vivo, and its mechanism was evaluated in carbon tetrachloride (CCl4)- and bile duct ligation (BDL)-induced liver fibrosis models in rats and mice, and transforming growth factor beta 1-induced LX-2 cell activation model in vitro. A novel Chinese medicine, namely JY5 formula, consisting of salvianolic acid B, schisantherin A, and amygdalin, the main active ingredients of FZHY, significantly alleviated hepatic hydroxyproline content and collagen deposition in CCl4-and BDL-induced fibrotic liver in rats and mice. In addition, JY5 inhibited the activation of hepatic stellate cells (HSCs) by inactivating Notch signaling in vitro and in vivo. In this study, we found a novel JY5 formula, which exerted anti-hepatic fibrotic effects by inhibiting the Notch signaling pathway, consequently suppressing HSCs activation. These results provide an adequate scientific basis for clinical research and application of the JY5 formula, which may be a potential novel therapeutic candidate for liver fibrosis.

Abstract Background Chimeric antigen receptor-modified (CAR) T-cell immunotherapy is a novel promising therapy for treatment of B-cell malignancy. Cytokine release syndrome (CRS) and infection are the most common adverse events during CAR T-cell therapy. Similar clinical presentation of concurrent CRS and infection makes it difficult to differentially diagnose and timely treat the condition. Methods We analyzed the features of infection events during the first 30 days after CAR T-cell infusion (CTI) in 109 patients from three clinical trials (ChiCTR-OPN-16008526, ChiCTR-OPC-16009113, ChiCTR-OPN-16009847). Based on the dynamic changes of interleukin (IL)-6 and ferritin, we proposed the “double peaks of IL-6” pattern as a feature of life-threatening infection during the first 30 days after CTI. Meanwhile, we screened candidate biomarkers from 70-biomarker panel to establish a prediction model for life-threatening infection. Results In this study, 19 patients (17.4%) experienced a total of 19 infection events during the first 30 days after CAR T-cell infusion. Eleven patients (10.1%) had grade 4–5 infection, which were all bacterial infection and predominantly sepsis (N = 9). “Double peaks of IL-6” appeared in 9 out of 11 patients with life-threatening infection. The prediction model of three-cytokines (IL-8, IL-1β and interferon-γ) could predict life-threatening infection with high sensitivity (training: 100.0%; validation: 100.0%) and specificity (training: 97.6%; validation: 82.8%). On base of the aforementioned methods, we proposed a workflow for quick identification of life-threatening infection during CAR T-cell therapy. Conclusions In this study, we worked out two diagnostic methods for life-threatening infection during CAR T-cell therapy by analyzing inflammatory signatures, which contributed to reducing risks of infection-induced death.

Summary: Pincer complexes are a remarkably versatile family benefited from their stability, diversity, and tunability. Many of them contain aromatic organic rings at the periphery, and aromaticity plays an important role in their stability and properties, whereas their metallacyclic cores are not aromatic. Herein, we report rhodapentalenes, which can be viewed as pincer complexes in which the metallacyclic cores exhibit considerable aromatic character. Rhodapentalenes show good thermal stability, although the rhodium-carbon bonds in such compounds are fragile. Experimental and computational studies suggest that the stabilization of rigid CCC pincer architectures together with an intrinsic aromaticity is vital for these metallacyclic rhodium species. Dearomatization-aromatization reactions, corresponding to metal-ligand cooperation of classical aromatic pincer complexes, were observed in this system. These findings suggest a new concept for pincer chemistry, the internal aromaticity involving metal d-orbitals, which would be useful for exploiting the nature of construction motif and inspire further applications. : Chemistry; Inorganic Chemistry; Organometallic Chemistry Subject Areas: Chemistry, Inorganic Chemistry, Organometallic Chemistry

Coordination complexes based on polydentate ligands that contain both nitrogen and carbon ligating atoms are ubiquitous, but design of those with planar cores remains challenging. Here the authors show that complexes with planar CCCN, CCCCN and NCCCN cores can be accessed by modification of the coordinating atoms in CCCC core complexes.

Abstract Background The aggressive form of Mantle cell non-hodgkin B cell lymphoma (MCL) has a dismal prognosis. Dual targeting BTK and BCL2 with ibrutinib and venetoclax has improved outcomes in MCL patients who were predicted not to respond to conventional therapy, but it is unlikely to be curative. Chimeric antigen receptor-modified T (CAR T) cells exhibit very effective function in elimination of relapsed/refractory B-cell lymphoid malignancies, we investigated their use in a patient with relapsed MCL. Case presentation Here, we report a case of a refractory MCL in a patient who had relapsed after conventional chemotherapy and autologous CAR T cell therapy. The patient received multiple molecularly targeted therapies, including targeting BTK and BCL2, and haplo-identical CAR T (haplo-CAR T) cells from her daughter without previous allo-hematopoietic stem cell transplantation. Haplo-CAR T cells could effectively proliferate in vivo and had a clinically significant antitumor activity without serious side effects. The patient achieved a partial remission, with minimal residual disease. Conclusions This case suggests that haplo-CAR T cell therapy can be effective in controlling lymphoma that failed to respond to autologous CAR T cell therapy and overcome limitation of autologous CAR T cells, thus may be one possible regimen before the era of off-the-shelf “universal” CAR T cell therapy. Trial registration ChiCTR-OPN-16008526. http://www.chictr.org.cn/showproj.aspx?proj=13798; ChiCTR1800019385. http://www.chictr.org.cn/showproj.aspx?proj=32805; ChiCTR1800019449. http://www.chictr.org.cn/showproj.aspx?proj=32778.

Abstract Background Relapsed/refractory (R/R) multiple myeloma (MM) patients and primary plasma cell leukemia (PCL) have an unfavorable prognosis and no effective treatment. This study was designed to assess the safety and preliminary efficacy of a novel anti‐B‐cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell in R/R MM and PCL. Methods Between February 22, 2017, and June 25, 2018, 28 R/R and two R/R primary PCL patients received a median dose of 11.2 × 106 CAR+ cells/kg. The subjects were refractory to a proteasome inhibitor and/or an immunomodulatory agent. Fludarabine and cyclophosphamide were given as lymphodepletion chemotherapy. Results Results for these 30 consecutive patients who received an anti‐BCMA CAR T cell infusion are reported. The patients had received a median of four prior lines of therapy. A total of 44 different types of adverse events were recorded, and hematologic toxic effects were the most common events of any grade during treatment. Hematologic toxic effects were also the most common events of grade 3 or higher. A total of 29 patients (96.7%) had cytokine release syndrome, which was of grade 1 or 2 in 24 patients (80%) and grade 3 in five patients (16.7%). Neurologic toxic effects only occurred in one patient (3.3%) and were of grade 1. The objective response rate was 90%, and the complete response rate was 43.3%. With a median follow‐up of 12.6 months, the median progression‐free survival (PFS) and overall survival were 5.2 months and 14.0 months. One of the two primary PCL achieved a complete response with a PFS of 307 days. The other patients achieved a very good partial response with a PFS of 117 days. Conclusions Anti‐BCMA CAR T cell treatment is safe and highly active in R/R multiple myeloma.

Advanced central nervous system (CNS) lymphoma is an exclusion criterion for most chimeric antigen receptor (CAR) T-cell studies due to the associated levels of neurotoxicity. In this study, we described five patients with chemorefractory B-cell CNS lymphoma who received CAR19 and CAR22 T-cell “Cocktail” therapy and follow-up for 6–16 months. All patients experienced cytokine release syndrome (CRS). Two patients experienced CAR T-cell-related encephalopathy syndrome (CRES), which was controllable. The best response was observed in two patients, who successfully achieved complete remissions (CR), and the other three patients achieved partial remissions (PR). Four patients had progressive disease (PD) after remission. In addition, one CR patient and one PD patient accepted CAR T-cell infusion following hematopoietic stem cell transplantation therapy in the 3rd month and were in ongoing remission for 14 and 6 months of follow-up, respectively. The targeted antigens in two patients were still positive, and CAR T-cells were reboosted in the cerebrospinal fluid (CSF) after PD, but a small number of CD3-positive T-cells were observed to infiltrate into the tumor. Our study indicates the efficacy of CAR T-cell therapy for CNS lymphoma with an acceptable safety profile; however, the remission did not last long, perhaps due to the tumor immunosuppressive microenvironment (TME) of the CNS. CAR T-cell therapy should be combined with other treatments to help improve the TME of cerebral lymphoma.

Metal-carbon σ bonds mark the basis of organometallic chemistry, but the formation of multiple such bonds between single organic and metal entities remains a challenge. Here, the authors report a one-pot aromaticity-driven method to construct osmium-based multidentate complexes containing three metal-carbon σ bonds from multiyn chains.

Red blood cell (RBC) alloimmunization represents a significant immunological challenge for some patients. While a variety of immune constituents likely contribute to the initiation and orchestration of alloantibodies to RBC antigens, identification of key immune factors that initiate alloantibody formation may aid in the development of a therapeutic modality to minimize or prevent this process. To define the immune factors that may be important in driving alloimmunization to an RBC antigen, we determined the specific immune compartment and distinct cells that may initially engage transfused RBCs and facilitate subsequent alloimmunization. Our findings demonstrate that the splenic compartment is essential for formation of anti-KEL antibodies following KEL RBC transfusion. Within the spleen, transfused KEL RBCs are found within the marginal sinus, where they appear to specifically co-localize with marginal zone (MZ) B cells. Consistent with this, removal of MZ B cells completely prevented alloantibody formation following KEL RBC transfusion. While MZ B cells can mediate a variety of key downstream immune pathways, depletion of follicular B cells or CD4 T cells failed to similarly impact the anti-KEL antibody response, suggesting that MZ B cells may play a key role in the development of anti-KEL IgM and IgG following KEL RBC transfusion. These findings highlight a key contributor to KEL RBC-induced antibody formation, wherein MZ B cells facilitate antibody formation following RBC transfusion.

BackgroundT cell immunoglobulin mucin-3 (Tim-3) has been identified as a negative regulator of anti-tumor immunity. Recent studies highlight the important role of Tim-3 in the CD8(+) T cell exhaustion that takes place in both human and animal cancer models. However, the nature of Tim-3 expression in the tumor cell and the mechanism by which it inhibits anti-tumor immunity are unclear. This present study aims to determine Tim-3 is expressed in cervical cancer cells and to evaluate the role of Tim-3 in cervical cancer progression.MethodologyA total of 85 cervical tissue specimens including 43 human cervical cancer, 22 cervical intraepithelial neoplasia (CIN) and 20 chronic cervicitis were involved. Tim-3 expression in tumor cells was detected and was found to correlate with clinicopathological parameters. Meanwhile, expression of Tim-3 was assessed by RT-PCR, Western Blot and confocal microscopy in cervical cancer cell lines, HeLa and SiHa. The migration and invasion potential of Hela cells was evaluated after inhibiting Tim-3 expression by ADV-antisense Tim-3.ConclusionsWe found that Tim-3 was expressed at a higher level in the clinical cervical cancer cells compared to the CIN and chronic cervicitis controls. We supported this finding by confirming the presence of Tim-3 mRNA and protein in the cervical cell lines. Tim-3 expression in tumor cells correlated with clinicopathological parameters. Patients with high expression of Tim-3 had a significant metastatic potential, advanced cancer grades and shorter overall survival than those with lower expression. Multivariate analysis showed that Tim-3 expression was an independent factor for predicting the prognosis of cervical cancer. Significantly, down-regulating the expression of Tim-3 protein inhibited migration and invasion of Hela cells. Our study suggests that the expression of Tim-3 in tumor cells may be an independent prognostic factor for patients with cervical cancer. Moreover, Tim-3 expression may promote metastatic potential in cervical cancers.

SIL-TAL1 rearrangement is common in T-cell acute lymphoblastic leukemia (T-ALL), however its prognostic implication remains controversial. To investigate the clinical characteristics and outcome of this subtype in Chinese population, we systemically reviewed 62 patients with newly diagnosed T-ALL, including 15 patients with SIL-TAL1 rearrangement. We found that SIL-TAL1(+) T-ALL was characterized by higher white blood cell count (P = 0.029) at diagnosis, predominant cortical T-ALL immunophenotype (P = 0.028) of the leukemic blasts, and a higher prevalence of tumor lysis syndrome (TLS, P