Search

Few studies have described chimeric antigen receptor–modified T cell (CAR-T) therapy for central nervous system (CNS) B-cell acute lymphocytic leukemia (B-ALL) patients due to life-threatening CAR-T-related encephalopathy (CRES) safety issues. In this study, CAR-Ts targeting CD19 with short hairpin RNA (shRNA)-IL-6 gene silencing technology (ssCART-19s) were prepared. We conducted a phase 1 clinical trial (ClinicalTrials.gov number, NCT03064269). Three patients with relapsed CNS B-ALL were enrolled, conditioned with the fludarabine and cyclophosphamide for lymphocyte depletion and infused with ssCART-19s for three consecutive days. Clinical symptoms and laboratory examinations were monitored. After ssCART-19 treatment, three patients' symptoms resolved almost entirely. Brain leukemic infiltration reduced significantly based on magnetic resonance imaging (MRI), and there were no leukemic blasts in cerebrospinal fluid (CSF), which was confirmed by cytological and molecular examinations. Additionally, increases in the levels of cytokines and immune cells were observed in the CSF of all patients. Only grade 1 cytokine release syndrome (CRS) manifesting as fever was noted in patients. In conclusion, CAR-Ts with shRNA-IL-6 gene knockdown migrated into the CNS, eradicated leukemic cells and elevated cytokines in CSF with mild, acceptable side effects.

Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC). Overabundance of Porphyromonas gingivalis is associated with shorter survival of ESCC patients. We investigated the molecular mechanisms driving aggressive progression of ESCC by P. gingivalis. Intracellular invasion of P. gingivalis potentiated proliferation, migration, invasion, and metastasis abilities of ESCC cells via transforming growth factor-β (TGFβ)-dependent Drosophila mothers against decapentaplegic homologs (Smads)/Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) activation. Smads/YAP/TAZ/TEA domain transcription factor1 (TEAD1) complex formation was essential to initiate downstream target gene expression, inducing an epithelial-mesenchymal transition (EMT) and stemness features. Furthermore, P. gingivalis augmented secretion and bioactivity of TGFβ through glycoprotein A repetitions predominant (GARP) up-regulation. Accordingly, disruption of either the GARP/TGFβ axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P. gingivalis. P. gingivalis signature genes based on its activated effector molecules can efficiently distinguish ESCC patients into low- and high-risk groups. Targeting P. gingivalis or its activated effectors may provide novel insights into clinical management of ESCC.

Protein interactions play an essential role in studying living systems and life phenomena. A considerable amount of literature has been published on analyzing and predicting protein interactions, such as support vector machine method, homology-based method and similarity-based method, each has its pros and cons. Most existing methods for predicting protein interactions require prior domain knowledge, making it difficult to effectively extract protein features. Single method is dissatisfactory in predicting protein interactions, declaring the need for a comprehensive method that combines the advantages of various methods. On this basis, a deep ensemble learning method called EnAmDNN (Ensemble Deep Neural Networks with Attention Mechanism) is proposed to predict protein interactions which is an appropriate candidate for comprehensive learning, combining multiple models, and considering the advantages of various methods. Particularly, it encode protein sequences by the local descriptor, auto covariance, conjoint triad, pseudo amino acid composition and combine the vector representation of each protein in the protein interaction network. Then it takes advantage of the multi-layer convolutional neural networks to automatically extract protein features and construct an attention mechanism to analyze deep-seated relationships between proteins. We set up four different structures of deep learning models. In the ensemble learning model, second layer data sets are generated with five-fold cross validation from basic learners, then predict the protein interaction network by combining 16 models. Results on five independent PPI data sets demonstrate that EnAmDNN achieves superior prediction performance than other comparing methods.

Objective: Anti-GABA-B (gamma aminobutyric acid-B) receptor encephalitis is an autoimmune disease mediated by GABA-B-related antibodies. To fully understand the disease, we collected clinical data from patients with GABA-B receptor encephalitis and conducted an analysis to draw conclusions.Methods: All patients with GABA-B receptor encephalitis from the Neurology Department of Beijing Tiantan Hospital, affiliated with Capital Medical University, from August 2015 to September 2019 were accepted as study subjects. The clinical data of the patients were analyzed retrospectively and included the general demographic characteristics, clinical manifestations, and auxiliary examinations, including laboratory results, electroencephalograms (EEGs), brain magnetic resonance imaging (MRI), and positron emission tomography (PET-CT) results, as well as treatments.Results: From August 2015 to September 2019, 14 cases of anti-GABA-B receptor encephalitis were diagnosed. Among these patients, middle-aged and elderly men were the main demographic, with an average age of 52 years; moreover, the onset of the disease was relatively sudden, and the time from onset to diagnosis was ~1 month. The main clinical symptoms were frequent epileptic seizures, cognitive dysfunction, and mental behavioral disorders. In seven (50%) patients, the leukocyte in cerebrospinal fluid (CSF) were increased. Five (36%) patients had elevated cerebrospinal fluid protein. In most patients, the oligoclonal bands (83%) of CSF were positive, and 24 h IgG levels (92%) were increased. Anti-Hu or anti-Yo antibodies were positive in two (14%) patients. Tumor markers in 10 (71%) patients indicated that neuron-specific enolase, gastrin-releasing precursor, non-small cell lung cancer-related antigen, or carcinoembryonic antigen levels were increased. EEG results often indicated slow waves, sharp waves, or spike waves in temporal areas. Brain MRI always showed high T2 signals in the medial temporal lobe, hippocampus, and amygdala and swelling in the medial temporal lobe and hippocampus. PET-CT scans almost showed abnormal metabolism in the hippocampus and temporal lobe. Three (21%) patients who underwent systemic PET-CT showed hypermetabolism in pulmonary parenchymal nodules and enlargement of mediastinal lymph nodes. All patients underwent high-dose hormone therapy or immunoglobulin immunotherapy. After treatment, the symptoms of epilepsy, cognitive disorders, and mental behavioral disorders improved to varying degrees. However, one patient died of lung cancer.Conclusion: Anti-GABA-B receptor encephalitis mainly occurred in middle-aged and elderly men, and the disease onset was relatively sudden. Before disease onset, some patients experienced fever and non-specific respiratory symptoms, which mainly manifested as frequent epileptic seizures, cognitive dysfunction, and abnormal mental behavior. MRI and PET-CT revealed abnormal signals and local metabolism, respectively, in the temporal lobe. Moreover, the disease has a close relationship with lung cancer, which requires long-term follow-up observation.

Sudden cardiac death (SCD), which can deprive a person of life within minutes, is a destructive heart abnormality. Thus, providing early warning information for patients at risk of SCD, especially those outside hospitals, is essential. In this study, we investigated the performances of ensemble empirical mode decomposition (EEMD)-based entropy features on SCD identification. EEMD-based entropy features were obtained by using the following technology: (1) EEMD was performed on HRV beats to decompose them into intrinsic mode functions (IMFs), (2) five entropy parameters, namely Rényi entropy (RenEn), fuzzy entropy (FuEn), dispersion Entropy (DisEn), improved multiscale permutation entropy (IMPE), and Renyi distribution entropy(RdisEn), were computed from the first four IMFs obtained, which were named EEMD-based entropy features. Additionally, an automated scheme combining EEMD-based entropy and classical linear (time and frequency domains) features was proposed with the intention of detecting SCD early by analyzing 14 min (at seven successive intervals of 2 min) heart rate variability (HRV) in signals from a normal population and subjects at risk of SCD. Firstly, EEMD-based entropy and classical linear measurements were extracted from HRV beats, and then the integrated measurements were ranked by various methodologies, i.e., t-test, entropy, receiver-operating characteristics (ROC), Wilcoxon, and Bhattacharyya. Finally, these ranked features were fed into a k-Nearest Neighbor algorithm for classification. Compared with several state-of-the-art methods, the proposed scheme firstly predicted subjects at risk of SCD up to 14 min earlier with an accuracy of 96.1%, a sensitivity of 97.5%, and a specificity of 94.4% 14 min before SCD onset. The simulation results exhibited that EEMD-based entropy estimators showed significant difference between SCD patients and normal individuals and outperformed the classical linear estimators in SCD detection, the EEMD-based FuEn and IMPE indexes were particularly useful assessments for identification of patients at risk of SCD and can be used as novel indices to reveal the disorders of rhythm variations of the autonomic nervous system when affected by SCD.

To clarify the different regional brain electroencephalogram (EEG) activities and biochemical responses in seizure and epilepsy models, we assessed the EEG and c-Fos immunolabeling characteristics in a lithium-pilocarpine-induced status epilepticus (SE) model and pentylenetetrazol (PTZ)-induced seizure model. The regional brain activities were evaluated by EEG and c-Fos immunolabeling. ZnT3 immunostaining was performed to observe hippocampal mossy fiber sprouting (MFS) within 7 days after the induction of SE in the lithium-pilocarpine model. The EEG recordings showed distinctive features of activation in different brain areas. With the aggravation of the behavioral manifestations of the seizures, the frequency and amplitude of the discharges on EEG gradually increased. SE was eventually induced and sustained. The labeling of c-Fos was enhanced in the cortex and hippocampal CA1, CA3, and dentate gyrus (DG); however, compared to the PTZ-induced seizure model, c-Fos staining could only be observed in the striatum and thalamus in the lithium-pilocarpine-induced epilepsy model. In each brain region, prominent c-Fos labeling was observed 2 h and 4 h after the induction of SE or seizures and diminished at 24 h. During the lithium-pilocarpine-induced chronic epilepsy phase after SE induction, MFS was observed 7 days after SE and was accompanied by the dynamic evolution of epileptic EEG activities. These findings validated the lithium-pilocarpine-induced SE model as an epilepsy model with a specific spatial-temporal profile of neural activation. The EEG characteristics and c-Fos expression patterns differ from those presented in a previous study using a PTZ-induced seizure model. Hippocampal mossy fiber spouting might be associated with spontaneous seizures during the chronic phase and can be detected at least within 1 week by ZnT3 staining after stimulation.

Abstract Background Treatment of tuberculous-destroyed lung (TDL) with pleuropulmonary resection is challenging. Pulmonary hemorrhage is a frequent complication of this surgical procedure. Continuous efforts have been made to investigate clinical procedures that may reduce intraoperative bleeding effectively. In this study, we evaluated the feasibility and safety of regional arterial embolization before pleuropulmonary resection in patients with TDL. Methods The clinical data of 32 patients with TDL were retrospectively reviewed and analyzed. These patients were admitted to the hospital between July 2009 and November 2016. All of the patients had moderate to massive hemoptysis and received regional arterial embolization in affected areas. Then, these patients underwent pleuropulmonary resection within 1 week to 2 months after embolization. Results The results showed that 25 patients (78.1%) had bronchial artery, and all patients had non-bronchial systemic artery found in affected areas. Mild to moderate chest pain was reported in 6 patients, and fever was reported in 2 patients. Intraoperative blood loss during pleuropulmonary resection in patients who had received preoperative regional arterial embolization was 625.6 ± 352.6 ml. Duration of the operation was 120.3 ± 75.2 min. Bronchopleural fistulae and empyema were found in 3 cases (9.4%). Conclusion Performance of regional arterial embolization before pleuropulmonary resection offers a safe and feasible option that reduces intraoperative blood loss and shortens operative time in patients with TDL.

Abstract The rare decays $$\bar{B}\rightarrow X_s\gamma $$ B¯→Xsγ and $$B_s^0\rightarrow \mu ^+\mu ^-$$ Bs0→μ+μ- are important to research new physics beyond the standard model (SM). In this work, we investigate two loop electroweak corrections to $$\bar{B}\rightarrow X_s\gamma $$ B¯→Xsγ and $$B_s^0\rightarrow \mu ^+\mu ^-$$ Bs0→μ+μ- in the minimal supersymmetric extension of the SM with local $$B-L$$ B-L gauge symmetry (B-LSSM), under a minimal flavor violating assumption for the soft breaking terms. In this framework, new particles and new definition of squarks can affect the theoretical predictions of these two processes, with respect to the MSSM. Considering the constraints from updated experimental data, the numerical results show that the B-LSSM can fit the experimental data for the branching ratios of $$\bar{B}\rightarrow X_s\gamma $$ B¯→Xsγ and $$B_s^0\rightarrow \mu ^+\mu ^-$$ Bs0→μ+μ- . The results of the rare decays also further constrain the parameter space of the B-LSSM.

Fabrication of microlenses on a diamond surface is an important way to enhance the performance of the embedded nitrogen vacancy (NV) center which is a promising single light source for quantum communication and quantum-based detection. In this work, lenses with a micrometer diameter were fabricated on a diamond surface by using the inductively coupled plasma (ICP) etching technique with a mask of polystyrene (PS) balls. First, 1 µm diameter PS balls were dispersed on the surface of deionized water. Then, the balls were transferred onto a diamond surface. Third, the sample was treated using the ICP technique to form microlenses. By increasing ICP etching time, the surface of fabricated microlenses became smoother. The simulation results demonstrate that the microlenses can greatly improve the photon collection efficiency of the embedded NV center and focus more excitation light to the NV center than bulk diamond.

AIM: To investigate the effect of transplanted pigmented epithelium-derived factor(PEDF)on human umbilical cord-derived mesenchymal stem cells(hUCMSCs)in the treatment of retinitis pigmentosa in rat models. METHODS: The hUCMSCs were isolated and cultured, hUCMSCs were transfected with PEDF recombinant lentivirus. Experimental royal college of surgeon(RCS)rats were randomly divided into 3 groups, 8 rats in each group. The experimental group was injected with PEDF-hUCMSCs subcutaneously. The hUCMSCs control group was injected with the same amount of hUCMSCs. The PBS control group was injected with the same amount of PBS. At 4 and 8wk after injection, electroretinography(ERG), the thickness of retinal outer nuclear layer(ONL)and green fluorescent protein(GFP)staining were observed. Immunofluorescence staining of retinal sections and the phagocytosis of MERTK protein were evaluated to determine phagocytosis. RESULTS: PEDF gene carrying recombinant lentiviral vector could efficiently infect hUCMSCs. After infection, hUCMSCs were sub cultured and the lentivirus prolonged the expression in the cells of the target gene. At 8wk after transplantation, the amplitude of b-wave in ERG were significantly higher in the experimental group than in the control groups. At 4 and 8wk after transplantation, morphological changes of ONL thickness in the experimental group were significantly higher than those in the control groups(all PCONCLUSION: Transplantation of pigment epithelium-derived protein modified human umbilical cord-derived mesenchymal stem cells has a protective effect on the retina of RCS rats.

Uptake and release of glucose is regulated by glucose-sensitive ion channels, but complexity of the system impedes investigation of the gating behavior under physiological conditions. Here the authors use a pillararene based artificial ion channel to mimic and investigate chirality driven switching of a glucose ion channel.

Hydrosilylation of alkenes poses substantial challenges in terms of regioselectivity. Here, the authors report iron complexes with 1,10-phenantroline ligand scaffolds which display benzylic selectivity in the hydrosilylation of internal alkenes and Markovnikov selectivity with terminal styrenes and 1,3-dienes.

AIM: To observe the visual quality after segmental Refractive multifocal intraocular lens(IOL)implantation.METHODS: Totally 50 cases(83 eyes)of cataract patients who receiving phacoemulsification and IOL implantation in our hospital from June 2016 to February 2017 were selected as the study object. Based on the IOL types, the patients were divided into two groups: 22 cases(37 eyes)in observation group implanted segmental refractive multifocal IOL, 28 cases(46 eyes)in control group implanted monofocal IOL. Three months after surgery, the uncorrected visual acuity was recorded. A double-pass optical quality analysis system(OQAS II)was used to evaluate the visual quality. The near spectacle independence, satisfaction, and symptoms of visual disturbance were assessed by a questionnaire.RESULTS: Three months after surgery, there were no statistical differences in uncorrected distance visual acuity(UCDVA)between the observation group and control group(P=0.273). The uncorrected intermediate visual acuity(UCIVA)and uncorrected near acuity(UCNVA)of observation group was better than control group(PPP>0.05).CONCLUSION: Segmental refractive multifocal intraocular lens provides wider objective amplitude of accommodation and good overall visual acuity, reduces spectacle dependency and provides high patient satisfaction.

Arc is an activity-regulated neuronal protein, but little is known about its interactions, assembly into multiprotein complexes, and role in human disease and cognition. We applied an integrated proteomic and genetic strategy by targeting a tandem affinity purification (TAP) tag and Venus fluorescent protein into the endogenous Arc gene in mice. This allowed biochemical and proteomic characterization of native complexes in wild-type and knockout mice. We identified many Arc-interacting proteins, of which PSD95 was the most abundant. PSD95 was essential for Arc assembly into 1.5-MDa complexes and activity-dependent recruitment to excitatory synapses. Integrating human genetic data with proteomic data showed that Arc-PSD95 complexes are enriched in schizophrenia, intellectual disability, autism, and epilepsy mutations and normal variants in intelligence. We propose that Arc-PSD95 postsynaptic complexes potentially affect human cognitive function.

AIM: To compare the effect of small incision extracapsular cataract extraction and phacoemulsification on corneal endothelial cells and explore the differences between these two most commonly used surgeries for grade Ⅱ-Ⅲ lens nucleus. METHODS: Retrospective study. We retrospectively evaluated the data of age-related cataract patients who had completed surgery in our hospital between June 2013 and December 2015. There were 84 eyes of 84 patients. The corneal endothelial cell density of all the patients were greater than 2000/mm2 and lens nucleus were grade Ⅱ-Ⅲ. The patients were divided into manual small incision cataract surgery(MSICS)group and phacoemulsification(Phaco)group. MSICS group included 42 cases(42 eyes)and Phaco group included 42 cases(42 eyes). Postoperative evaluations were performed at 1d, 1wk, 1mo and 6mo and included uncorrected visual acuity(UCVA), corneal endothelial cell density and the proportion of hexagonal cells.RESULTS: There were no statistically significant differences of the two groups in preoperative basic data, UCVA, corneal endothelial cell density and the proportion of hexagonal cells, nuclear classification. The postoperative UCVA were significantly improved in both groups(χ2=148.01, Pχ2=165.97, PF=37.74, P F=24.56, PP=0.002)after the operation and returned to baseline by 1wk(P=0.894)after surgery. There was no significant difference between the two groups in UCVA, corneal endothelial cell density and the proportion of hexagonal cells at each observation point (P>0.05). CONCLUSION: Manual small incision cataract surgery and phacoemulsification can indiscriminately improve UCVA and decrease the density of corneal endothelial cells. However, the change of hexagonal cells proportion was not obvious. These two surgeries for cataract patients with corneal endothelial cell density greater than 2000/mm2, grade Ⅱ-Ⅲ lens nucleus have similar efficacy and safety.

Hemoglobinopathies are among the most common autosomal-recessive disorders worldwide. A comprehensive next-generation sequencing (NGS) test would greatly facilitate screening and diagnosis of these disorders. An NGS panel targeting the coding regions of hemoglobin genes and four modifier genes was designed. We validated the assay by using 2522 subjects affected with hemoglobinopathies and applied it to carrier testing in a cohort of 10,111 couples who were also screened through traditional methods. In the clinical genotyping analysis of 1182 β-thalassemia subjects, we identified a group of additional variants that can be used for accurate diagnosis. In the molecular screening analysis of the 10,111 couples, we detected 4180 individuals in total who carried 4840 mutant alleles, and identified 186 couples at risk of having affected offspring. 12.1% of the pathogenic or likely pathogenic variants identified by our NGS assay, which were undetectable by traditional methods. Compared with the traditional methods, our assay identified an additional at-risk 35 couples. We describe a comprehensive NGS-based test that offers advantages over the traditional screening/molecular testing methods. To our knowledge, this is among the first large-scale population study to systematically evaluate the application of an NGS technique in carrier screening and molecular diagnosis of hemoglobinopathies.