Single-cell RNA-seq reveals novel immune-associated biomarkers for predicting prognosis in AML patients with RUNX1::RUNX1T1.

Acute myeloid leukemia (AML) with t(8;21)(q22;q22);(RUNX1::RUNX1T1) is highly heterogeneous and malignant. It has a relapse rate of nearly 40 %, resulting in clinical resistance or refractoriness to chemotherapy. Immune cells, particularly CD4(+) T and CD8(+) T lymphocytes, have been discovered to be dysfunctional in this condition, and functional recovery shows promising efficiency in preclinical trials. Here, with single-cell transcriptomic data from de novo AML patients with RUNX1::RUNX1T1 and at various stages following disease progression, we investigated the genes correlated with T-cell proliferation and activation. In leukemia cells, ADA, AHCY, GPN3 and LTBR were markedly highly expressed compared to those in T-cell at diagnosis, and they tended to increase with disease progression. Additionally, we discovered that AHCY was an effective biomarker to predict the overall survival as well as relapse-free survival of AML patients with RUNX1::RUNX1T1. The correlation of AHCY with infiltrated immune cells and immune checkpoints was also investigated. AML cohorts from two other independent studies, TCGA LAML (n = 145) and the GEO dataset (n = 104), also demonstrated an inferior outcome for AML patients with high AHCY expression. In conclusion, our research revealed that AHCY might function as a novel indicator to predict the prognosis and efficiency of T-cell proliferation and activation in AML patients with RUNX1::RUNX1T1.

The claustrum-prelimbic cortex circuit through dynorphin/κ-opioid receptor signaling underlies depression-like behaviors associated with social stress etiology.

Ample evidence has suggested the stress etiology of depression, but the underlying mechanism is not fully understood yet. Here, we report that chronic social defeat stress (CSDS) attenuates the excitatory output of the claustrum (CLA) to the prelimbic cortex (PL) through the dynorphin/κ-opioid receptor (KOR) signaling, being critical for depression-related behaviors in male mice. The CSDS preferentially impairs the excitatory output from the CLA onto the parvalbumin (PV) of the PL, leading to PL micronetwork dysfunction by disinhibiting pyramidal neurons (PNs). Optogenetic activation or inhibition of this circuit suppresses or promotes depressive-like behaviors, which is reversed by chemogenetic inhibition or activation of the PV neurons. Notably, manipulating the dynorphin/KOR signaling in the CLA-PL projecting terminals controls depressive-like behaviors that is suppressed or promoted by optogenetic activation or inhibition of CLA-PL circuit. Thus, this study reveals both mechanism of the stress etiology of depression and possibly therapeutic interventions by targeting CLA-PL circuit.

A Four-Port MIMO Cylindrical DRA with High Isolation in Ultra-Compact Size for WLAN Applications.

A novel ultra-compact four-port multiple-input-multiple-output (MIMO) cylindrical dielectric resonator antenna (DRA) with improved isolation is proposed for WLAN applications in this paper. The antenna is originally radiated with the assistance of two different excitation mechanisms to generate decoupled orthogonal modes. To further diminish the coupling field and improve the isolation, a suitable U-shaped slot is created on the common ground plane. Two additional rectangular slits are also etched to adjust the impedance matching of other ports. To better reveal the operating mechanism of the decoupling scheme, the common mode (CM) and differential mode (DM) impedance analysis methods between DRA ports are presented. The etched U-shaped slot can tune the impedance of CM and DM to be consistent to realize the decoupling. The antenna is simulated, fabricated, and tested to verify the decoupling mechanism. The results demonstrate that the isolation between ports 1 and 2 is enhanced from 5 dB to 23 dB, and other ports exhibit low coupling of better than 12 dB. Moreover, the antenna with the full size of 30 × 30 × 8.1 mm3 can be used either as a four-port DRA with a bandwidth of 300 MHz or as a two-port DRA with a bandwidth of 700 MHz, at a center frequency of 5.6 GHz.

Multiple functions and regulatory network of miR-150 in B lymphocyte-related diseases.

MicroRNAs (miRNAs) play vital roles in the post-transcriptional regulation of gene expression. Previous studies have shown that miR-150 is a crucial regulator of B cell proliferation, differentiation, metabolism, and apoptosis. miR-150 regulates the immune homeostasis during the development of obesity and is aberrantly expressed in multiple B-cell-related malignant tumors. Additionally, the altered expression of MIR-150 is a diagnostic biomarker of various autoimmune diseases. Furthermore, exosome-derived miR-150 is considered as prognostic tool in B cell lymphoma, autoimmune diseases and immune-mediated disorders, suggesting miR-150 plays a vital role in disease onset and progression. In this review, we summarized the miR-150-dependent regulation of B cell function in B cell-related immune diseases.

Natural flavonoids derived from herbal medicines are potential anti-atherogenic agents by inhibiting oxidative stress in endothelial cells.

As the common pathological basis of various cardiovascular diseases, the morbidity and mortality of atherosclerosis (AS) have increased in recent years. Unfortunately, there are still many problems in the treatment of AS, and the prevention and treatment of the disease is not ideal. Up to now, the occurrence and development of AS can roughly include endothelial cell dysfunction, vascular smooth muscle cell proliferation, inflammation, foam cell production, and neoangiogenesis. Among them, endothelial dysfunction, as an early event of AS, plays a particularly important role in promoting the development of AS. In addition, oxidative stress occurs throughout the causes of endothelial dysfunction. Some previous studies have shown that flavonoids derived from herbal medicines are typical secondary metabolites. Due to its structural presence of multiple active hydroxyl groups, it is able to exert antioxidant activity in diseases. Therefore, in this review, we will search PubMed, Web of Science, Elesvier, Wliey, Springer for relevant literature, focusing on flavonoids extracted from herbal medicines, and summarizing how they can prevent endothelial dysfunction by inhibiting oxidative stress. Meanwhile, in our study, we found that flavonoid represented by quercetin and naringenin showed superior protective effects both in vivo and in vitro, suggesting the potential of flavonoid compounds in the treatment of AS.

Identification of the Thyrotropin-Releasing Hormone (TRH) as a Novel Biomarker in the Prognosis for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a biologically and genetically heterogeneous hematological malignance with an unsatisfactory risk stratification system. Recently, through the novel single-cell RNA sequencing technology, we revealed heterogeneous leukemia myeloblasts in RUNX1-RUNX1T1 AML. Thyrotropin-releasing hormone (TRH), as biomarkers of CD34+CD117bri myeloblasts, were found to be prognostic in RUNX1-RUNX1T1 AML. However, the clinical and genetic features of TRH in AML patients are poorly understood. Here, with data from TCGA AML, TRH was found to be downregulated in patients older than 60 years old, with DNMT3A and NPM1 mutations, while overexpressed in patients with KIT mutations. This was further validated in three other cohorts of primary AML including Beat AML (n = 223), GSE6891 (n = 461), and GSE17855 (n = 237). Furthermore, we demonstrated that the expression of TRH in AML could be used to improve the ELN 2017 risk stratification system. In conclusion, our preliminary analysis revealed that TRH, a novel biomarker for AML patients, could be used to evaluate the survival of AML.

Comprehensive analysis of tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2): A potential novel pan-cancer immune checkpoint.

Tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2) is encoded by TNFAIP8L2 and is a newly identified negative regulator of natural and acquired immunity that plays a critical function in maintaining immune homeostasis. Recently, CAR-NK immune cell therapy has been a focus of major research efforts as a novel cancer therapeutic strategy. TIPE2 is a potential checkpoint molecule for immune cell maturation and antitumor immunity that could be used as a novel NK cell-based immunotherapeutic approach. In this study, we explored the expression of TNFAIP8L2 across various tumor types and found that TNFAIP8L2 was highly expressed in most tumor types and correlated with prognosis. Survival analysis showed that TNFAIP8L2 expression was predictive of improved survival in cervical-squamous-cell-carcinoma (CESC), sarcoma (SARC) and skin-cutaneous-melanoma (SKCM). Conversely, TNFAIP8L2 expression predicted poorer survival in acute myeloid leukemia (LAML), lower-grade-glioma (LGG), kidney-renal-clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). Analysis of stemness features and immune cell infiltration indicated that TNFAIP8L2 was significantly associated with cancer stem cell index and increased macrophage and dendritic cell infiltration. Our data suggest that TNFAIP8L2 may be a novel immune checkpoint biomarker across different tumor types, particularly in LAML, LGG, KIRC and UVM, and may have further utility as a potential target for immunotherapy.

Comprehensive Analysis of CRIP1 Expression in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy that imposes great challenges in terms of drug resistance and relapse. Previous studies revealed heterogeneous leukemia cells and their relevant gene markers, such as CRIP1 as clinically prognostic in t (8;21) AML patients. However, the expression and role of CRIP1 in AML are poorly understood. We used the single-cell RNA sequencing and gene expression data from t (8;21) AML patients to analyze the immune and regulation networks of CRIP1. Two independent cohorts from GSE37642 and The Cancer Genome Atlas (TCGA) datasets were employed as validation cohorts. In addition, the methylation data from TCGA were used to analyze the methylation effect of the CRIP1 expression. Gene expression profile from t (8;21) AML patients showed that the CRIP1-high group exhibited an enrichment of immune-related pathways, including tumor necrosis factor (TNF)α signaling via nuclear factor kappa B (NFκB) pathways. Further studies using CIBERSORT showed that the CRIP1-high group had a significantly higher infiltration of exhausted CD8 T cells and activated mast cells. The CRIP1 expression was validated in the GSE37642-GPL96, GSE37642-GPL570, and TCGA datasets. In addition, with the methylation data, four CpG probes of CRIP1 (cg07065217, cg04411625, cg25682097, and 11763800) were identified as negatively associated with the CRIP1 gene expression in AML patients. Our data provide a comprehensive overview of the regulation of CRIP1 expression in AML patients. The evaluation of the TNFα-NFκB signaling pathway as well as the immune heterogeneity might provide new insights for exploring improvements in AML treatment.

Integration of CD34+CD117dim population signature improves the prognosis prediction of acute myeloid leukemia.

BACKGROUND: Acute Myeloid Leukemia (AML) is a hematological cancer characterized by heterogeneous hematopoietic cells. Through the use of multidimensional sequencing technologies, we previously identified a distinct myeloblast population, CD34+CD117dim, the proportion of which was strongly associated with the clinical outcome in t (8;21) AML. In this study, we explored the potential value of the CD34+CD117dim population signature (117DPS) in AML stratification. METHODS: Based on the CD34+CD117dim gene signature, the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to construct the 117DPS model using the gene expression data from Gene Expression Omnibus (GEO) database (GSE37642-GPL96 was used as training cohort; GSE37642-GPL570, GSE12417-GPL96, GSE12417-GPL570 and GSE106291 were used as validation cohorts). In addition, the RNA-seq data from The Cancer Genome Atlas (TCGA)-LAML and Beat AML projects of de-novo AML patients were also analyzed as validation cohorts. The differences of clinical features and tumor-infiltrating lymphocytes were further explored between the high-risk score group and low-risk score group. RESULTS: The high-risk group of the 117DPS model exhibited worse overall survival than the low-risk group in both training and validation cohorts. Immune signaling pathways were significantly activated in the high-risk group. Patients with high-risk score had a distinct pattern of infiltrating immune cells, which were closely related to clinical outcome. CONCLUSION: The 117DPS model established in our study may serve as a potentially valuable tool for predicting clinical outcome of patients with AML.

Comprehensive analysis of the novel omicron receptor AXL in cancers.

The SARS-CoV-2 is constantly mutating, and the new coronavirus such as Omicron has spread to many countries around the world. Anexelekto (AXL) is a transmembrane protein with biological functions such as promoting cell growth, migration, aggregation, metastasis and adhesion, and plays an important role in cancers and coronavirus disease 2019 (COVID-19). Unlike angiotensin-converting enzyme 2 (ACE2), AXL was highly expressed in respiratory system cells. In this study, we verified the AXL expression in cancer and normal tissues and found AXL expression was strongly correlated with cancer prognosis, tumor mutation burden (TMB), the microsatellite instability (MSI) in most tumor types. Immune infiltration analysis also demonstrated that there was an inextricable link between AXL expression and immune scores in cancer patients, especially in BLCA, BRCA and CESC. The NK-cells, plasmacytoid dendritic cells, myeloid dendritic cells, as one of the important components of the tumor microenvironment, were highly expressed AXL. In addition, AXL-related tumor neoantigens were identified and might provide the novel potential targets for tumor vaccines or SARS-Cov-2 vaccines research in cancer patients.

A Double-Layer Patch Antenna for 5-6 GHz Wireless Communication.

This paper proposes a compact double-layer microstrip patch antenna with a wide bandwidth of 4.83-6.1 GHz and a gain reaching 4.7 dBi. By folding its mirror image through the electric field symmetry principle of the microstrip antenna, its electrical properties are maintained, and the physical size is halved to the compact size of only 25 × 40 mm2. The proposed antenna has the radiation characteristics of a planar inverted-F antenna (PIFA), which can generate the first resonant frequency and realize omnidirectional radiation characteristics. By coupling and feeding the upper patch, the second resonant frequency of the proposed antenna is produced and the directional radiation characteristics of the microstrip patch antenna can be achieved. The consistency of the results between the simulation and test indicates that the proposed antenna design is an ideal potential choice for home wireless local area network (WLAN) communication.

Drug resistance biomarker ABCC4 of selinexor and immune feature in multiple myeloma.

The treatment of relapse or refractory multiple myeloma (RRMM) is still a big challenge in clinic. Recently, several clinical trials indicated that the XPO1 inhibitor, selinexor could significantly improve the remission rate in MM patients. However, the heterogeneous genetic background greatly influenced the efficiency of selinexor among MM. Here, we tried to characterized the biomarkers associated with selinexor sensitivity by analyzing gene expression data in MM patients. We found the cytogenetic background of selinexor sensitive MM patients was not limited to specific cytogenetic subtypes. In addition, by weighted gene co-expression network analysis (WGCNA), we obtained 10 key genes which showed a strong correlation with the selinexor sensitivity in MM patients. Notably, ABCC4 (MRP4) was the only gene which was both differentially expressed and proved to be clinical prognostic valuable (both for event-free survival and overall survival) in MM patients. We further validated the heterogenous expression of ABCC4 in MM cell lines and its value as a novel indicator for selinexor sensitivity. Moreover, immune infiltration analysis showed that ABCC4 expression had a significantly positive correlation with NK infiltration as well as immunotherapy target TIM-3 (HAVCR2) expression. Collectively, our findings indicated that ABCC4 might be a predictive biomarker of selinexor sensitivity in MM patients, which could be enhanced if combined with immunotherapy drugs such as TIM-3 inhibitor.

Efficacy and safety of switching from brand-name to domestic generic levetiracetam in children with epilepsy. / å·¦ä¹™æ‹‰è¥¿å¦çš„å›½äº§ä»¿åˆ¶è¯æ›¿æ¢æ²»ç–—å„¿ç«¥ç™«ç—«çš„ç–—æ•ˆåŠå®‰å ¨æ€§ç ”ç©¶.

OBJECTIVES: To study the efficacy and safety of domestic generic levetiracetam in replacement of brand-name levetiracetam in the treatment of children with epilepsy. METHODS: A retrospective analysis was performed on the medical data of 154 children with epilepsy who received domestic generic levetiracetam in the inpatient or outpatient service of Guangdong Provincial People's Hospital from May 2019 to December 2020. Domestic generic levetiracetam and brand-name levetiracetam were compared in terms of efficacy and safety. RESULTS: For these 154 children, the epilepsy control rate was 77.3% (119/154) at baseline. At 6 months after switching to domestic generic levetiracetam, the epilepsy control rate reached 83.8% (129/154), which showed a significant increase (P<0.05). There was no significant change in the frequency of seizures from baseline to 6 months after switching (P>0.05). The incidence of refractory epilepsy in children with no response after switching treatment was significantly higher than that in children with response (P<0.05). Before switching, only 1 child (0.6%) experienced somnolence, while after switching, 3 children (1.9%) experienced mild adverse drug reactions, including dizziness, somnolence, irritability, and bad temper. CONCLUSIONS: Switching from brand-name to generic levetiracetam is safe and effective and holds promise for clinical application, but more prospective randomized controlled trials are required in future.

Multi-omics analyses of tumor-associated immune-infiltrating cells with the novel immune checkpoint protein tyrosine phosphatase 1B (PTP1B) in extracellular matrix of brain-lower-grade-glioma (LGG) and uveal-melanoma (UVM).

Immune checkpoint inhibitors represented by PD-1 have greatly changed the way cancer is treated. In addition to PD-1, new immune checkpoints are constantly excavated to better treat cancer. Recently, protein tyrosine phosphatase 1B (PTP1B) was identified as a new immune checkpoint and played a critical role in the treatment of tumors by inhibiting the proliferation and cytotoxicity of T cells induced by tumor antigen. To explore the targeting role of PTP1B in precision tumor therapy, we deeply analyzed the expression and prognosis of PTP1B in all tumors. Survival analysis results indicated that PTP1B was highly expressed in most tumor tissues and indicated poor prognosis in acute-myeloid-leukemia (LAML), brain-lower-grade-glioma (LGG), kidney-renal clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). The methylation status of PTP1B in these four tumors exhibited hypomethylation and mutation landscape showed that PTP1B had its specific characteristics in genomic instability and heterogeneity. The homologous recombination deficiency (HRD) and loss of heterozygosity (LOH) were positive related to PTP1B expression in liver-hepatocellular-carcinoma (LIHC) and kidney-chromophobe (KICH), while the immunescore and immune infiltration displayed a significant positive correlation with PTP1B expression in LGG and UVM. Drug sensitivity tests showed that the PTP1B inhibitor MSI-1436 had a sensitivity effect suppressing tumor cell viability and suggested it enhanced the efficacy of PD-1 inhibitors in cancers.

Amygdalar κ-opioid receptor-dependent upregulating glutamate transporter 1 mediates depressive-like behaviors of opioid abstinence.

Opiates produce a strong rewarding effect, but abstinence from opiate use emerges with severe negative emotions. Depression is one of the most frequent emotion disorders associated with opiate abstinence, which is thought to be a main cause for relapse. However, neurobiological bases of such an aversive emotion processing are poorly understood. Here, we find that morphine abstinence activates κ-opioid receptors (KORs) by increasing endogenous KOR ligand dynorphin expression in the amygdala, which in turn facilitates glutamate transporter 1 (GLT1) expression by activation of p38 mitogen-activated protein kinase (MAPK). Upregulation of GLT1 expression contributes to opiate-abstinence-elicited depressive-like behaviors through modulating amygdalar glutamatergic inputs to the nucleus accumbens (NAc). Intra-amygdala injection of GLT1 inhibitor DHK or knockdown of GLT1 expression in the amygdala significantly suppresses morphine-abstinence-induced depressive-like behaviors. Pharmacological and pharmacogenetic activation of amygdala-NAc projections prevents morphine-abstinence-induced behaviors. Overall, our study provides key molecular and circuit insights into the mechanisms of depression associated with opiate abstinence.

Compact TSA with Anti-Spiral Shape and Lumped Resistors for UWB Applications.

A novel compact tapered-slot-fed antenna (TSA) with anti-spiral shape and lumped resistors is presented for ultra-wideband (UWB) applications. Unique coplanar waveguide (CPW) to coplanar strip (CPS) feeding structure and exponential slot are designed to ensure the continuous current propagation and good impedance matching. With a pair of anti-spiral-shaped structure loadings at the end of the antenna, the radiation performance in lower operating band can be enhanced obviously. The typical resistor loading technique is applied to improve the time domain characteristics and expand the bandwidth. The fabricated prototype of this proposed antenna with a size of 53 × 63.5 mm2 was measured to confirm simulated results. The proposed antenna has S11 less than -10 dB in the range of 1.2-9.8 GHz, and the group delay result is only 0.4 ns. These findings indicate the proposed antenna can be taken as a promising candidate in UWB communication field.

Rehabilitation and pharmacotherapy of neuromyelitis optica spectrum disorder: A case report.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating autoimmune disease that affects the central nervous system. It typically manifests as optic neuritis or extensive longitudinal myelitis, with or without the presence of anti-aquaporin protein 4 autoantibodies (immunoglobulin G). CASE SUMMARY: We report the case of a 45-year-old woman with a history of Sjogren's syndrome who was diagnosed with NMOSD accompanied by spinal cord injury and left calf intermuscular vein thrombosis. The patient received hormone shock and gamma globulin therapy in the acute phase and standard rehabilitation treatment during convalescence. Upon discharge, the patient was able to control urination and defecation, stand independently, and walk short distances with the aid of a walker. CONCLUSION: This case suggests that pharmacotherapy and standard rehabilitation treatment can improve the prognosis of NMSOD patients.

Bone marrow infiltrated natural killer cells predicted the anti-leukemia activity of MCL1 or BCL2 inhibitors in acute myeloid leukemia.

Acute myeloid leukemia (AML) is still incurable due to its heterogeneity and complexity of tumor microenvironment. It is imperative therefore to understand the molecular pathogenesis of AML and identify leukemia-associated biomarkers to formulate effective treatment strategies. Here, we systematically analyzed the clinical characters and natural killer (NK) cells portion in seventy newly-diagnosis (ND) AML patients. We found that the proportion of NK cells in the bone marrow of ND-AML patients could predict the prognosis of patients by analyzing the types and expression abundance of NK related ligands in tumor cells. Furthermore, MCL1 inhibitor but not BCL2 inhibitor combined with NK cell-based immunotherapy could effectively improve the therapeutic efficiency via inhibiting proliferation and inducing apoptosis of AML primary cells as well as cell lines in vitro. There results provide valuable insights that could help for exploring new therapeutic strategies for leukemia treatment.

Multidimensional study of the heterogeneity of leukemia cells in t(8;21) acute myelogenous leukemia identifies the subtype with poor outcome.

t(8;21)(q22;q22) acute myelogenous leukemia (AML) is morphologically characterized by a continuum of heterogeneous leukemia cells from myeloblasts to differentiated myeloid elements. Thus, t(8;21) AML is an excellent model for studying heterogeneous cell populations and cellular evolution during disease progression. Using integrative analyses of immunophenotype, RNA-sequencing (RNA-seq), and single-cell RNA-sequencing (scRNA-seq), we identified three distinct intrapatient leukemic cell populations that were arrested at different stages of myeloid differentiation: CD34+CD117dim blasts, CD34+CD117bri blasts, and abnormal myeloid cells with partial maturation (AM). CD117 is also known as c-KIT protein. CD34+CD117dim cells were blocked in the G0/G1 phase at disease onset, presenting with the regular morphology of myeloblasts showing features of granulocyte-monocyte progenitors (GMP), and were drug-resistant to chemotherapy. Genes associated with cell migration and adhesion (LGALS1, EMP3, and ANXA2) were highly expressed in the CD34+CD117dim population. CD34+CD117bri blasts were blocked a bit later than the CD34+CD117dim population in the hematopoietic differentiation stage and displayed high proliferation ability. AM cells, which bear abnormal myelocyte morphology, especially overexpressed granule genes AZU1, ELANE, and PRTN3 and were sensitive to chemotherapy. scRNA-seq at different time points identified CD34+CD117dim blasts as an important leukemic cluster that expanded at postrelapse refractory stage after several cycles of chemotherapy. Patients with t(8;21) AML with a higher proportion of CD34+CD117dim cells had significantly worse clinical outcomes than those with a lower CD34+CD117dim proportion. Univariate and multivariate analyses identified CD34+CD117dim proportion as an independent factor for poor disease outcome. Our study provides evidence for the multidimensional heterogeneity of t(8;21)AML and may offer new tools for future disease stratification.