A universal and scalable transformation of bulk metals into single-atom catalysts in ionic liquids.

Single-atom catalysts (SACs) with maximized metal atom utilization and intriguing properties are of utmost importance for energy conversion and catalysis science. However, the lack of a straightforward and scalable synthesis strategy of SACs on diverse support materials remains the bottleneck for their large-scale industrial applications. Herein, we report a general approach to directly transform bulk metals into single atoms through the precise control of the electrodissolution-electrodeposition kinetics in ionic liquids and demonstrate the successful applicability of up to twenty different monometallic SACs and one multimetallic SAC with five distinct elements. As a case study, the atomically dispersed Pt was electrodeposited onto Ni3N/Ni-Co-graphene oxide heterostructures in varied scales (up to 5 cm × 5 cm) as bifunctional catalysts with the electronic metal-support interaction, which exhibits low overpotentials at 10 mA cm-2 for hydrogen evolution reaction (HER, 30 mV) and oxygen evolution reaction (OER, 263 mV) with a relatively low Pt loading (0.98 wt%). This work provides a simple and practical route for large-scale synthesis of various SACs with favorable catalytic properties on diversified supports using alternative ionic liquids and inspires the methodology on precise synthesis of multimetallic single-atom materials with tunable compositions.

A pilot study of orelabrutinib treatment in three cases of refractory/relapsed autoimmune haemolytic anaemia/Evans syndrome.

Currently, there is no effective treatment for refractory/relapsed (R/R) autoimmune haemolytic anaemia (AIHA), associated with poor quality of life. Bruton tyrosine kinase inhibitors have begun to be used in some autoimmune diseases. We initiated the clinical trial of orelabrutinib treatment on R/R AIHA/Evans Syndrome, which is in progress. The preliminary results showed that nine of the 12 enrolled patients responded to orelabrutinib treatment. Here, we reported three cases who have completed the treatment and were followed up for 6 months, achieving complete or partial remission. Orelabrutinib is expected to become a new second-line treatment for R/R AIHA/Evans syndrome.

Role of transcriptional cofactors in cardiovascular diseases.

Cardiovascular disease is a main cause of mortality in the world and the highest incidence of all diseases. However, the mechanism of the pathogenesis of cardiovascular disease is still unclear, and we need to continue to explore its mechanism of action. The occurrence and development of cardiovascular disease is significantly associated with genetic abnormalities, and gene expression is affected by transcriptional regulation. In this complex process, the protein-protein interaction promotes the RNA polymerase II to the initiation site. And in this process of transcriptional regulation, transcriptional cofactors are responsible for passing cues from enhancers to promoters and promoting the binding of RNA polymerases to promoters, so transcription cofactors playing a key role in gene expression regulation. There is growing evidence that transcriptional cofactors play a critical role in cardiovascular disease. Transcriptional cofactors can promote or inhibit transcription by affecting the function of transcription factors. It can affect the initiation and elongation process of transcription by forming complexes with transcription factors, which are important for the stabilization of DNA rings. It can also act as a protein that interacts with other proteins to affect the expression of other genes. Therefore, the aim of this overview is to summarize the effect of some transcriptional cofactors such as BRD4, EP300, MED1, EZH2, YAP, SIRT6 in cardiovascular disease and to provide a promising therapeutic strategy for the treatment of cardiovascular disease.

The Zn Vacancy-Mediated De-Accumulation Based Process for Hydrogen Production Performance Promotion of 1D Zn─Cd─S Nanorods.

Due to their anisotropy, 1D semiconductor nanorod-based materials have attracted much attention in the process of hydrogen production by solar energy. Nevertheless, the rational design of 1D heterojunction materials and the modulation of photo-generated electron-hole transfer paths remain a challenge. Herein, a ZnxCd1-xS@ZnS/MoS2 core-shell nanorod heterojunction is precisely constructed via in situ growth of discontinuous ZnS shell and MoS2 NCs on the Zn─Cd─S nanorods. Among them, the Zn vacancy in the ZnS shell builds the defect level, and the nanoroelded MoS2 builds the electron transport site. The optimized photocatalyst shows significant photocatalytic activity without Platinum as an auxiliary catalyst, mainly due to the new interfacial charge transfer channel constructed by the shell vacancy level, the vertical separation and the de-accumulation process of photo-generated electrons and photo-generated holes. At the same time, spectral analysis, and density functional theory (DFT) calculations fully prove that shortening difference of speed between the photogenerated electron and hole movement process is another key factor to enhance the photocatalytic performance. This study provides a new path for the kinetic design of enhanced carrier density by shortening the carrier retention time of 1D heterojunction photocatalysts with improved photocatalytic performance.

Dynamic regulation of phosphorylation of NMDA receptor GluN2B subunit tyrosine residues mediates ketamine rapid antidepressant effects.

The rapid antidepressant effects of ketamine depend on the N-methyl-D-aspartate (NMDA) receptor containing 2B subunit (NR2B), whose function is influenced by its phosphorylated regulation and distribution within and outside synapses. It remains unclear if ketamine's rapid onset of antidepressant effects relies on the dynamic phosphorylated regulation of NR2B within and outside synapses. Here, we show that ketamine rapidlyalleviated depression-like behaviors and normalized abnormal expression of pTyr1472NR2B and striatal-enriched protein tyrosine phosphatase (STEP) 61 within and outside synapses in the medial prefrontal cortex (mPFC) induced by chronic unpredictable stress (CUS) and conditional knockdown of STEP 61, a key phosphatase of NR2B, within 1 hour after administration Together, our results delineate the rapid initiation of ketamine's antidepressant effects results from the restoration of NR2B phosphorylation homeostasis within and outside synapses. The dynamic regulation of phosphorylation of NR2B provides a new perspective for developing new antidepressant strategies.

The Role of Depression and Anxiety in the Relationship Between Arthritis and Cognitive Impairment in Chinese Older Adults.

BACKGROUND: Mental disorders and cognitive impairment are common in older patients with arthritis. While it is recognized that mental conditions may play a role in the connection between arthritis and cognitive impairment, the precise underlying relationship remains uncertain. METHODS: The data was derived from the baseline survey of the Guangdong Mental Health Survey in South China, involving a sample of 3,764 citizens aged 65 and older. An array of aspects were explored, including socio-demographics, lifestyle behaviors, self-reported chronic conditions, depression, anxiety, and cognitive impairment. Logistic regression analyses examined the association between arthritis and cognitive impairment after adjustment for potential confounders. Serial mediation models were used to examine whether depression or anxiety played a mediating role in the arthritis-cognitive impairment linkage. RESULTS: The prevalence rates of cognitive impairment and arthritis of the older adults were 28.9% and 12.1%, respectively. Compared to those without arthritis, participants with arthritis were at a higher risk of cognitive impairment (OR = 1.322, 95%CI: 1.022-1.709) after adjustment for socio-demographics, lifestyle behaviors, and mental health conditions. Serial mediation analyses indicated that depressive and anxiety symptoms co-played a serial mediating role in the association between arthritis and cognitive impairment (B1 = 0.025, 95%CI: 0.005-0.052; B2 = 0.050, 95%CI: 0.021-0.086). CONCLUSIONS: Arthritis may heighten cognitive impairment risk in Chinese older adults, and the relationship was potentially mediated by depressive and anxiety symptoms. Future interventions should be considered, integrating mental health assessments into arthritis care frameworks and being alert to possible cognitive impairment.

Endothelial TIE1 Restricts Angiogenic Sprouting to Coordinate Vein Assembly in Synergy With Its Homologue TIE2.

BACKGROUND: Vascular growth followed by vessel specification is crucial for the establishment of a hierarchical blood vascular network. We have shown that TIE2 is required for vein development while little is known about its homologue TIE1 (tyrosine kinase with immunoglobulin-like and EGF [epithelial growth factor]-like domains 1) in this process. METHODS: We analyzed functions of TIE1 as well as its synergy with TIE2 in the regulation of vein formation by employing genetic mouse models targeting Tie1, Tek, and Nr2f2, together with in vitro cultured endothelial cells to decipher the underlying mechanism. RESULTS: Cardinal vein growth appeared normal in TIE1-deficient mice, whereas TIE2 deficiency altered the identity of cardinal vein endothelial cells with the aberrant expression of DLL4 (delta-like canonical Notch ligand 4). Interestingly, the growth of cutaneous veins, which was initiated at approximately embryonic day 13.5, was retarded in mice lack of TIE1. TIE1 deficiency disrupted the venous integrity, displaying increased sprouting angiogenesis and vascular bleeding. Abnormal venous sprouts with defective arteriovenous alignment were also observed in the mesenteries of Tie1-deleted mice. Mechanistically, TIE1 deficiency resulted in the decreased expression of venous regulators including TIE2 and COUP-TFII (chicken ovalbumin upstream promoter transcription factor, encoded by Nr2f2, nuclear receptor subfamily 2 group F member 2) while angiogenic regulators were upregulated. The alteration of TIE2 level by TIE1 insufficiency was further confirmed by the siRNA-mediated knockdown of Tie1 in cultured endothelial cells. Interestingly, TIE2 insufficiency also reduced the expression of TIE1. Combining the endothelial deletion of Tie1 with 1 null allele of Tek resulted in a progressive increase of vein-associated angiogenesis leading to the formation of vascular tufts in retinas, whereas the loss of Tie1 alone produced a relatively mild venous defect. Furthermore, the induced deletion of endothelial Nr2f2 decreased both TIE1 and TIE2. CONCLUSIONS: Findings from this study imply that TIE1 and TIE2, together with COUP-TFII, act in a synergistic manner to restrict sprouting angiogenesis during the development of venous system.

Lipid Metabolites as Potential Regulators of the Antibiotic Resistome in Tetramorium caespitum.

Antibiotic resistance genes (ARGs) are ancient but have become a modern critical threat to health. Gut microbiota, a dynamic reservoir for ARGs, transfer resistance between individuals. Surveillance of the antibiotic resistome in the gut during different host growth phases is critical to understanding the dynamics of the resistome in this ecosystem. Herein, we disentangled the ARG profiles and the dynamic mechanism of ARGs in the egg and adult phases of Tetramorium caespitum. Experimental results showed a remarkable difference in both gut microbiota and gut resistome with the development of T. caespitum. Meta-based metagenomic results of gut microbiota indicated the generalizability of gut antibiotic resistome dynamics during host development. By using Raman spectroscopy and metabolomics, the metabolic phenotype and metabolites indicated that the biotic phase significantly changed lipid metabolism as T. caespitum aged. Lipid metabolites were demonstrated as the main factor driving the enrichment of ARGs in T. caespitum. Cuminaldehyde, the antibacterial lipid metabolite that displayed a remarkable increase in the adult phase, was demonstrated to strongly induce ARG abundance. Our findings show that the gut resistome is host developmental stage-dependent and likely modulated by metabolites, offering novel insights into possible steps to reduce ARG dissemination in the soil food chain.

DIAGNOSTIC PATTERNS OF AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To characterize prevalence estimates by race, age, sex, and comorbidity (diabetes and hypertension) within the Medicare beneficiary demographic. METHODS: In this US population-based retrospective cohort analysis, the Vision and Eye Health Surveillance System was analyzed for a 100% sample of Medicare Fee-For-Service beneficiary populations of Asians and non-Hispanic Whites between 2014 and 2018. Exclusionary criteria included beneficiaries younger than 40 years. Prevalence rate ratios, defined as prevalence rate for Asians divided by prevalence rate for non-Hispanic Whites, were calculated using multivariate negative binomial regression or Pearson-scaled Poisson regression, stratified by age, sex, and comorbidity. RESULTS: A total of 21,892,200 Medicare beneficiaries fulfilled the inclusionary criteria in 2018. Of the entire cohort, 3.2% of the beneficiaries (N = 714,500) were Asian. For beneficiaries aged 40 to 64 years, Asian male (prevalence rate ratios 1.73, 95% confidence interval 1.64-1.83, P < 0.0001) and female (prevalence rate ratios 1.34, 95% confidence interval 1.28-1.41, P < 0.0001) beneficiaries had an increased prevalence rate of all age-related macular degeneration relative to non-Hispanic Whites. Significant time-wise increases in prevalence rate ratios were observed within several age groups, sexes, and comorbidities (race-time interaction coefficients P < 0.05 ). CONCLUSION: This analysis highlights increased age-related macular degeneration prevalence estimates within the Asian American demographic relative to non-Hispanic Whites. Furthermore, specific Asian subpopulations are experiencing accelerated prevalence rates over time.

From Inflammation to Oncogenesis: Tracing Serum DCLK1 and miRNA Signatures in Chronic Liver Diseases.

Chronic liver diseases, fibrosis, cirrhosis, and HCC are often a consequence of persistent inflammation. However, the transition mechanisms from a normal liver to fibrosis, then cirrhosis, and further to HCC are not well understood. This study focused on the role of the tumor stem cell protein doublecortin-like kinase 1 (DCLK1) in the modulation of molecular factors in fibrosis, cirrhosis, or HCC. Serum samples from patients with hepatic fibrosis, cirrhosis, and HCC were analyzed via ELISA or NextGen sequencing and were compared with control samples. Differentially expressed (DE) microRNAs (miRNA) identified from these patient sera were correlated with DCLK1 expression. We observed elevated serum DCLK1 levels in fibrosis, cirrhosis, and HCC patients; however, TGF-ß levels were only elevated in fibrosis and cirrhosis. While DE miRNAs were identified for all three disease states, miR-12136 was elevated in fibrosis but was significantly increased further in cirrhosis. Additionally, miR-1246 and miR-184 were upregulated when DCLK1 was high, while miR-206 was downregulated. This work distinguishes DCLK1 and miRNAs' potential role in different axes promoting inflammation to tumor progression and may serve to identify biomarkers for tracking the progression from pre-neoplastic states to HCC in chronic liver disease patients as well as provide targets for treatment.

Gene therapy with B-cell maturation antigen/CD3 bispecific antibody encoding plasmid DNA for treating multiple myeloma.

The delivery of bispecific antibodies (BsAbs) targeting B-cell maturation antigen (BCMA) and CD3 using the gene therapy approach is a promising alternative for BsAb administration in patients with multiple myeloma (MM). In the present study, we evaluated the efficacy of this approach using a xenograft model. Tumour growth was significantly delayed in mice treated with single electroporation-enhanced intramuscular injection of plasmid DNA encoding BCMA/CD3 BsAb in contrast to the vehicle control-treated group. Limited toxicity was observed following treatment. This study demonstrates that the gene therapy-based approach for the delivery of BCMA/CD3 BsAb is effective and safe for the treatment of MM.

Pressure-Gradient Counterwork of Dual-Fuel Driven Nanocarriers in Abnormal Interstitial Fluids for Enhancing Drug Delivery Efficiency.

The abnormal pressure in tumor tissue is a significant limitation on the drug delivery efficiency of tumor therapy. This work reports a gradient-driven nanomotor as drug nanocarrier with the pressure-counterworking function. The dual-fuel nanomotors are formed by co-electrospinning of the photosensitive polymers with calcium peroxide (CaO2 ) and catalase (CAT), followed by ultraviolet (UV) irradiation and bovine serum albumin (BSA) incubation. The UV-responsive cleavage nanomotors can effectively release O2 molecules at the fractures as a driving force to increase the delivery speed and escape the phagocytosis of macrophage system in normal tissues. Furthermore, CAT catalyzes H2 O2 produced by CaO2 and the tumor interstitial fluids to provide stronger power for the nanomotors. Additionally, according to the analysis of directional motions of the nanomotors, the functional relationship between the rotational diffusion coefficient (DR ) and the physiological viscosity is constructed. The dual-fuel nanocarriers enable up to 13.25% of the injected dose (ID)/per gram tissue and significantly improve the penetration in deep tumor. It is of vital importance to design and obtain the adaptive pressure-gradient counterworking nanomotors, which can effectively improve the drug delivery efficiency in vitro and in vivo.

Semi-deconvolution of bulk and single-cell RNA-seq data with application to metastatic progression in breast cancer.

MOTIVATION: Identifying cell types and their abundances and how these evolve during tumor progression is critical to understanding the mechanisms of metastasis and identifying predictors of metastatic potential that can guide the development of new diagnostics or therapeutics. Single-cell RNA sequencing (scRNA-seq) has been especially promising in resolving heterogeneity of expression programs at the single-cell level, but is not always feasible, e.g. for large cohort studies or longitudinal analysis of archived samples. In such cases, clonal subpopulations may still be inferred via genomic deconvolution, but deconvolution methods have limited ability to resolve fine clonal structure and may require reference cell type profiles that are missing or imprecise. Prior methods can eliminate the need for reference profiles but show unstable performance when few bulk samples are available. RESULTS: In this work, we develop a new method using reference scRNA-seq to interpret sample collections for which only bulk RNA-seq is available for some samples, e.g. clonally resolving archived primary tissues using scRNA-seq from metastases. By integrating such information in a Quadratic Programming framework, our method can recover more accurate cell types and corresponding cell type abundances in bulk samples. Application to a breast tumor bone metastases dataset confirms the power of scRNA-seq data to improve cell type inference and quantification in same-patient bulk samples. AVAILABILITY AND IMPLEMENTATION: Source code is available on Github at https://github.com/CMUSchwartzLab/RADs.

Long noncoding RNA FAM157C contributes to clonal proliferation in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease of hematopoietic stem cells (HSCs). Long noncoding RNAs (lncRNAs) perform a wide range of biological functions, including the regulation of gene expression, cell differentiation, and proliferation, but their role in PNH remains unclear.CD59- and CD59+ granulocytes and monocytes from 35 PNH patients were sorted. High-throughput sequencing was analyzed in 5 PNH patients, and differentially expressed lncRNAs and mRNAs were identified. The mRNAs with fragments per kilobase of exon model per million mapped fragments (FPKM) > 10 in at least 3 patients were selected, and experiments were performed to identify their upstream regulatory lncRNAs. The expression of selected mRNAs and lncRNAs was verified by qRT‒PCR, and the correlation of these expression patterns with clinical data from other 30 PNH patients was analyzed. Then, the functions of the lncRNAs were studied in the PIGA-KO-THP-1 cell line.Transcription analysis revealed 742 upregulated and 1376 downregulated lncRNAs and 3276 upregulated and 213 downregulated mRNAs. After deep screening, 8 highly expressed mRNAs that were related to the NF-κB pathway were analyzed to determine coexpression patterns. LINC01002, FAM157C, CTD-2530H12.2, XLOC-064331 and XLOC-106677 were correlated with the 8 mRNAs. After measuring the expression of these molecules in 30 PNH patients by qRT‒PCR, lncRNA FAM157C was verified to be upregulated in the PNH clone, and its expression levels were positively correlated with the LDH levels and CD59- granulated and monocyte cell ratios. After knockdown of the FAM157C gene in the PIGA-KO-THP-1 cell line, we found that the cells were arrested in the G0/G1 phase and S phase, the apoptosis rate increased, and the cell proliferation decreased.LncRNA FAM157C was proven to promote PNH clone proliferation, and this is the first study to explore the role of lncRNAs in PNH.

Novel 1,2,4-triazoles derived from Ibuprofen: synthesis and in vitro evaluation of their mPGES-1 inhibitory and antiproliferative activity.

Some novel triazole-bearing ketone and oxime derivatives were synthesized from Ibuprofen. In vitro cytotoxic activities of all synthesized molecules against five cancer lines (human breast cancer MCF-7, human lung cancer A549, human prostate cancer PC-3, human cervix cancer HeLa, and human chronic myelogenous leukemia K562 cell lines) were evaluated by MTT assay. In addition, mouse embryonic fibroblast cells (NIH/3T3) were also evaluated to determine the selectivity. Compounds 18, 36, and 45 were found to be the most cytotoxic, and their IC50 values were in the range of 17.46-68.76 µM, against the tested cancer cells. According to the results, compounds 7 and 13 demonstrated good anti-inflammatory activity against the microsomal enzyme prostaglandin E2 synthase-1 (mPGES-1) enzyme at IC50 values of 13.6 and 4.95 µM. The low cytotoxicity and non-mutagenity of these compounds were found interesting. Also, these compounds significantly prevented tube formation in angiogenesis studies. In conclusion, the anti-inflammatory and angiogenesis inhibitory activities of these compounds without toxicity suggested that they may be promising agents in anti-inflammatory treatment and they may be supportive agents for the cancer treatment.

Biomimetic nanovesicle co-delivery system impairs energy metabolism for cancer treatment.

Metabolic reprogramming in cancer cells plays a crucial role in cancer development, metastasis and invasion. Cancer cells have a unique metabolism profile that could switch between glycolysis and oxidative phosphorylation (OXPHOS) in order to satisfy a higher proliferative rate and enable survival in tumor microenvironment. Although dietary-based cancer starvation therapy has shown some positive outcomes for cancer treatment, it is difficult for patients to persist for a long time due to the adverse effects. Here in this study, we developed a specific M1 macrophage-derived membrane-based drug delivery system for breast cancer treatment. Both metformin and 3-Bromopyruvate were loaded into the engineered cell membrane-based biomimetic carriers (Met-3BP-Lip@M1) for the shutdown of energy metabolism in cancer cells via simultaneous inhibition of both glycolysis and oxygen consumption. The in vitro studies showed that Met-3BP-Lip@M1 had excellent cancer cell uptake and enhanced cancer cell apoptosis via cell cycle arrest. Our results also demonstrated that this novel biomimetic nanomedicine-based cancer starvation therapy synergistically improved the therapeutic efficiency against breast cancer cells by blocking energy metabolic pathways, which resulted in a significant reduction of cancer cell proliferation, 3D tumor spheroid growth as well as in vivo tumor growth.

Dry eye in the upper blepharoplasty patient: a study comparing orbicularis-sparing versus orbicularis-excising techniques.

PURPOSE: To compare subjective and objective dry eye syndrome (DES) metrics preoperatively and postoperatively in patients undergoing bilateral upper eyelid blepharoplasty (ULB) using orbicularis-sparing versus orbicularis-excising techniques. METHODS: A double-blind, randomized clinical trial was conducted on patients without prior DES or other severe conditions who presented to our institution between 2017 and 2019 for routine functional ULB. Patients were randomized into two treatment arms: bilateral ULB using the orbicularis-sparing technique or bilateral ULB using the orbicularis-excising technique. One subjective and seven objective DES assessments were performed on all patients preoperatively and 1 month and 1 year after surgery. RESULTS: A total of 63 patients were recruited for the study. Standard Patient Evaluation of Eye Dryness (SPEED) scores decreased in both treatment groups at 1 month and 1 year postoperatively. This change did not significantly vary based on surgical technique. Objective DES assessments were not significantly changed at both postoperative time points for either group. There was a correlation between the severity of preoperative DES symptoms and the subjective improvement of DES symptoms postoperatively in both groups. CONCLUSIONS: ULB with an orbicularis-sparing or orbicularis-excising technique does not worsen subjective or objective DES metrics and so, surgeons may confidently use either surgical technique. These findings may impact postoperative expectations for surgeons and patients alike.

Applying struvite as a N-fertilizer to mitigate N2O emissions in agriculture: Feasibility and mechanism.

Nitrous oxide (N2O) is an effective ozone-depleting substance and an important greenhouse gas in the atmosphere. Fertilization is a major factor that dictates agricultural N2O emissions. In this work, as opposed to the commonly-seen highly-soluble nitrogen (N) fertilizers, the feasibility of using struvite as a slow-releasing N-fertilizer and its mechanism for mitigating N2O emissions were investigated. During the 149-d field cultivation of water spinach (Ipomoea Aquatica Forsk), struvite exhibited comparable crop yields, with a 40.8-58.1% N2O reduction compared with commercial fertilizers. In addition, struvite fertilization increased soil bacterial diversity and denitrification genes levels (narG, nirS, nirK, norB and nosZ) effectively, but decreased nitrification genes contents (amoA). By conducting partial least-square path modeling, it was found that the use of struvite would satisfy the soil N control and pH regulation, which altered N-cycling related bacteria and ultimately mitigated N2O emissions. From an economic aspect, using struvite as a N-fertilizer may increase the struvite market price from 50 to 131.7 €/ton. These findings help change the inherent impression that struvite is only suitable as a P-fertilizer, the application of struvite as N-fertilizer could effectively mitigate the agriculture N2O emission and inspire the application of struvite-based P-recovery technologies.

Selinexor synergizes with azacitidine to eliminate myelodysplastic syndrome cells through p53 nuclear accumulation.

Myelodysplastic syndromes (MDS) are clonal malignancies of multipotent hematopoietic stem cells, characterized by ineffective hematopoiesis leading to cytopenia. Hypomethylating agents, including azacitidine, have been used for treating MDS with some success; however, the overall survival rate remains poor and, therefore, finding new therapies is necessary. Selinexor, which exerts anticancer effects against some hematologic tumors, is a nuclear export protein inhibitor that blocks cell proliferation and induces apoptosis in various cancer cell lines. We investigated the effects of combined selinexor and azacitidine administration on two MDS cell lines, namely SKM-1 and MUTZ-1. Cells were subjected to a proliferation assay, and the effects of each drug alone, and in combination, were compared. Changes in apoptosis and the cell cycle between groups were also analyzed. Western blotting was conducted to identify the underlying mechanism of action of combined selinexor and azacitidine therapy. The results revealed that the combination of selinexor and azacitidine synergistically inhibited MDS cell proliferation and arrested the cell cycle at the G2/M phase. This combination also promoted MDS cell apoptosis and enhanced p53 accumulation in the nucleus, thereby allowing p53 to be activated and to function as a tumor suppressor. Overall, our results indicate that the combination of selinexor and azacitidine may be a promising approach for treating MDS.

Deletion of Sox9 in the liver leads to hepatic cystogenesis in mice by transcriptionally downregulating Sec63.

Hepatic cysts are found in heterogeneous disorders with different pathogeneses, of which simple hepatic cysts and polycystic liver diseases are two major types. The process of hepatic cytogenesis for these two diseases is caused by defects in remodelling of the ductal plate during biliary tract development, which is called ductal plate malformation. SOX9 is a transcription factor participating in the process of bile duct development, and thus, its dysregulation may play important roles in hepatic cystogenesis. SEC63 encodes an endoplasmic reticulum membrane protein that is mutated in human autosomal dominant polycystic liver disease. However, the transcriptional regulation of SEC63 is largely unknown. In the present study, a liver-specific Sox9 knockout (Sox9LKO ) mouse was generated to investigate the roles and underlying mechanism of SOX9 in hepatic cystogenesis. We found that hepatic cysts began to be observed in Sox9LKO mice at 6 months of age. The number and size of cysts increased with age in Sox9LKO mice. In addition, the characteristics of hepatic cytogenesis, including the activation of proliferation, absence of primary cilium, and disorder of polarity in biliary epithelial cells, were detected in the livers of Sox9LKO mice. RNAi silencing of SOX9 in human intrahepatic biliary epithelial cells (HIBEpic) resulted in increased proliferation and reduced formation of the primary cilium. Moreover, Sec63 was downregulated in primary biliary epithelial cells from Sox9LKO mice and SEC63 in HIBEpic transfected with siSOX9. Chromatin immunoprecipitation assays and luciferase reporter assays further demonstrated that SOX9 transcriptionally regulated the expression of SEC63 in biliary epithelial cells. Importantly, the overexpression of SEC63 in HIBEpic partially reversed the effects of SOX9 depletion on the formation of primary cilia and cell proliferation. These findings highlight the biological significance of SOX9 in hepatic cytogenesis and elucidate a novel molecular mechanism underlying hepatic cytogenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.