Study on the mechanism of Gualou Xiebai Guizhi decoction (GLXBGZD) in the treatment of coronary heart disease based on network pharmacology.

BACKGROUND: This study aims to analyze the mechanism of Gualou Xiebai Guizhi decoction (GLXBGZD) in treating coronary heart disease (CHD) utilizing network pharmacology. METHODS: The GLXBGZD effective components were searched on the pharmacological database platform of the Traditional Chinese Medicine Systems Pharmacol, and its potential target was predicted. The Online Mendelian Inheritance obtained CHD disease target in Man and GeneCards database. The Venn map of the intersection target for GLXBGZD and CHD was constructed by using Venn online website. The "drug-component-target-disease" network map was constructed by Cytoscape 3.7.2 software. The DAVID online platform was used to analyze the function of Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) at the intersection of targets of drugs and diseases. RESULTS: A total of 27 articles were searched for GLXBGZD, including 111 potential targets, 5521 disease targets, 100 drug and disease intersection targets. The core target network map shows that Interleukin (IL)-6, TNF, vascular endothelial growth factor (VEGFA), TP53, EGF, JUN, MAPK1, Catalase (CAT), and prostaglandin-endoperoxide synthase 2 (PTGS2) may be the key targets in CHD therapy. GO functional enrichment analysis revealed that the biological functions of GLXBGZD involved biological processes such as response to drugs, positive regulation of nitric oxide biosynthesis process, and response to hypoxia. KEGG pathway enrichment analysis showed that GLXBGZD might participate in CHD treatment through Hypoxia-inducible factor-1 (HIF-1), Tumor necrosis factor (TNF), PhosphoInositide-3 Kinase--Threonine protein kinase (PI3K-Akt), and the calcium signal pathway. CONCLUSIONS: This study reveals that the GLXBGZD mechanism in CHD treatment has the characteristics of multi-components, multi-targets, and multi-pathways, which provides a theoretical basis for its clinical application and subsequent experimental verification.

An "all-in-one" strategy based on the organic molecule DCN-4CQA for effective NIR-fluorescence-imaging-guided dual phototherapy.

Dual phototherapy combining photodynamic therapy (PDT) and photothermal therapy (PTT) is considered to be a more effective therapeutic method against cancer than single treatment. Therefore, the development of a single material with both near-infrared (NIR)-laser-triggered PDT and PTT abilities is highly desirable but remains a great challenge. A design philosophy for photosensitizers for integrated PDT and PTT treatment has been put forward: (1) a high molar extinction coefficient in the NIR region; (2) suitable LUMO and T1 energy levels to regulate intersystem crossing for effective singlet oxygen (1O2) generation for PDT; and (3) the suppression of fluorescence emission to enhance the process of nonradiative transition with appropriate chemical modifications. Herein, an "all-in-one" functional material, di-cyan substituted 5,12-dibutylquinacridone (DCN-4CQA), for diagnosis and therapy was obtained. DCN-4CQA possesses dual-functional phototherapeutic activity and NIR fluorescence and it was produced via a facile synthesis process from the classic organic photoelectric material quinacridone. We then prepared smart water-soluble nanoparticles (NPs), DCN-4CQA/F127, using Pluronic® 127 (F127) as a drug carrier. The NPs exhibited excellent biocompatibility, robust photostability, NIR fluorescence, a high photothermal conversion efficiency (η = 47.3%), and sufficient 1O2 generation (ΦΔ = 24.3%) under NIR laser irradiation. Remarkably, the DCN-4CQA/F127 NPs significantly inhibited tumor growth in mice subjected to NIR laser irradiation. This study provides a new route for the development of highly efficient, low-cytotoxicity photosensitizers for fluorescence-imaging-guided PTT/PDT.

Accuracy of half-way mucosa-supported implant guides for edentulous jaws: a retrospective study with a median follow-up of 2 years.

OBJECTIVE: To assess the accuracy of half-way digital mucosa-supported implant guides (HDMIGs) for edentulous jaws. METHODS: Ninety-five consecutive patients (859 implants) with edentulous jaws who underwent implant placement using an HDMIG from July 2012 to June 2018 were retrospectively identified. The primary endpoint was implant-related complications (nerve injury and unexpected perforation), and the secondary endpoints were the faciolingual distance, mesiodistal distance, buccolingual angle, and mesiodistal angle. Follow-ups occurred at 1 month, 2 months, and then every 2 months following implant placement. RESULTS: Twenty-seven (28.4%) patients met the exclusion criteria, leaving 68 eligible patients (636 implants) for the final analysis. The median follow-up was 24 months (range, 18-27 months). No patients developed nerve injury, revision, or unexpected perforation. At the final follow-up, the mean faciolingual distance was 0.65 ± 0.16 mm, the mean mesiodistal distance was 1.16 ± 0.61 mm, the mean buccolingual angle was 4.04° ± 2.26°, and the mean mesiodistal angle was 3.75° ± 2.56°. In the comparison of the first month after surgery and the last follow-up, no significant differences were detected in any of the four measured variables. CONCLUSION: Use of an HDMIG may be a convenient and safe method to ensure correct implantation.

PHILOS Plate Plus Oblique Insertion of Autologous Fibula for 2-Part Proximal Humerus Fractures With Medial Column Disruption: A Retrospective Study.

INTRODUCTION: The aim of this retrospective study was to evaluate the outcomes of older patients with 2-part proximal humerus fractures (PHFs) with medial column disruption stabilized using a proximal humeral internal locking system (PHILOS) plate plus oblique insertion of autologous fibula as a primary procedure. MATERIALS AND METHODS: Data involving 112 patients (112 shoulders) sustaining 2-part PHFs with medial column disruption treated with PHILOS plate plus oblique insertion of autologous fibula as a primary procedure during 2012-2019 were identified. The median follow-up was 36 months (range: 11.2-43.5 months). The primary endpoint was the Constant scores and American Shoulder and Elbow Surgeons (ASES) scores. The secondary endpoint was the main orthopedic complication rate. RESULTS: The median Constant and ASES scores were 78 (range, 52-95) and 77 (range, 62-96) at the final follow-up, respectively. The main orthopedic complication rate was 10.7% (12/112). Twelve orthopedic complications in 8 patients were detected, and they involved loss of reduction, varus collapse, aseptic loosening, mal-union, revision, and intolerable shoulder pain. Of these complications, 3 (2.6%) involved loss of reduction, 2 (1.7%) involved varus collapse, 3 (2.6%) involved aseptic loosening, 1 (0.8%) involved mal-union, 2 (1.7%) required revision surgery, and 1 (0.8%) presented intolerable shoulder pain. CONCLUSION: PHILOS plate plus oblique insertion of autologous fibula as a primary procedure may yield good functional outcomes and a low rate of the main orthopedic complications.

Nivolumab plus ipilimumab versus nivolumab in individuals with treatment-naive programmed death-ligand 1 positive metastatic soft tissue sarcomas: a multicentre retrospective study.

BACKGROUND: Currently, the choice of treatment for individuals with metastatic soft tissue sarcomas (MSTS) presents a significant challenge to clinicians. The aim of this retrospective study was to assess the efficacy and safety of nivolumab plus ipilimumab (NPI) versus nivolumab alone (NIV) in individuals with treatment-naive programmed death-ligand 1 (PD-L1) positive MSTS. METHODS: Prospectively maintained databases were reviewed from 2013 to 2018 to assess individuals with treatment-naive PD-L1 MSTS who received NPI (nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every 2 weeks) or NIV (3 mg/kg every 2 weeks) until disease progression, withdrawal, unendurable [AEs], or death. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: The median follow-up was 16.0 months (IQR 14.4-18.5) after targeted intervention. The median OS was 12.2 months (95% confidence interval [CI], 6.1-13.7) and 9.2 months (95% CI, 4.2-11.5) for the NPI and NIV groups, respectively (hazard ratio [HR] 0.49, 95% CI, 0.33-0.73; p=0.0002); the median PFS was 4.1 months (95% CI, 3.2-4.5) and 2.2 months (95% CI, 1.1-3.4) for the NPI and NIV groups, respectively (HR 0.51, 95% CI, 0.36-0.71; p< 0.0001). Key grade 3-5 AEs occurred more frequently in the NPI group than in the NIV group (94 [72.9%] for NPI vs. 35 [27.1%], p< 0.001). CONCLUSIONS: For treatment-naive PD-L1 positive MSTS, NPI seems to be less tolerated but has a greater survival advantage than NIV as the primary therapy.

Cisplatin plus paclitaxel chemotherapy with or without bevacizumab in postmenopausal women with previously untreated advanced cervical cancer: a retrospective study.

BACKGROUND: The aim of this study was to assess the survival outcomes of cisplatin-paclitaxel chemotherapy plus bevacizumab (CPB) versus cisplatin-paclitaxel chemotherapy alone (CPA) in postmenopausal women with previously untreated advanced cervical cancer (CC). METHODS: Consecutive postmenopausal women who experienced CPB or CPA were identified retrospectively from our medical centre during 2015-2019. Follow-up visits occurred 1 and 3 months after starting CPB or CPA. Afterwards, this assessment was conducted every 3 months for 1 year and then yearly thereafter. The primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints were the frequency and severity of adverse events (AEs). RESULTS: Two hundred forty-six postmenopausal women were included (CPB, n = 124; CPA, n = 122). The median follow-up for the entire cohort was 24 months (range, 2-32). At the final follow-up, a significant difference was detected in terms of median OS (16.4 months [95% CI, 15.3-17.1] for CPB vs. 12.3 months [95% CI, 10.2-13.5] for CPA; hazard ratio (HR) 0.69, 95% CI, 0.49-0.99; p = 0.001), and the median PFS was longer in the CPB group than in the CPA group (9.2 months [95% CI, 8.3-10.7] vs. 7.9 months (95% CI, 6.1-8.6) (HR 0.62, 95% CI, 0.47-0.82; p < 0.001). There were significant differences in the number of AEs between the groups (hypertension grade ≥ 2 [p < 0.001], neutropenia grade ≥ 4 [p < 0.001], and thrombosis/embolism grade ≥ 3 [p = 0.030]). CONCLUSIONS: Among postmenopausal women with previously untreated advanced CC, those who received CPB experienced superior survival benefits compared to those who received CPA. The safety profile for CPB was controllable despite the long duration of CPB use.

Revision of failed metal-on-metal total hip arthroplasty using cemented arthroplasty: a mean 10-year follow-up of 157 consecutive patients.

OBJECTIVE: This study was performed to assess the outcomes of Asian patients who underwent conversion from metal-on-metal total hip arthroplasty (MoM-THA) to cemented THA (CTHA). METHODS: One hundred and fifty-seven consecutive patients (157 hips) who underwent CTHA following primary MoM-THA from January 2005 to February 2015 were retrospectively analysed. The primary endpoints were the clinical outcomes. Follow-ups occurred at 3 months, 6 months, 1 year, 2 years, and then every 2 years following revision of MoM-THA. RESULTS: The mean follow-up after conversion was 10 years (range, 5-14 years). Statistically significant improvements in the mean Harris hip score were observed between the preoperative and final follow-up evaluations (62.71 ± 13.85 vs. 84.03 ± 16.21, respectively). The major orthopaedic complication rate was 16.5% (26/157). Six (3.8%) patients underwent revision at a mean of 3.5 ± 1.3 years after conversion, predominantly because of prosthesis loosening or recurrent dislocation. Nine (5.7%) patients developed prosthesis loosening at a mean of 2.6 ± 1.1 years following conversion, two of whom requested revision surgery. Eleven (7.0%) patients developed prosthesis dislocation, four of whom requested revision surgery. CONCLUSION: CTHA may yield favourable functional outcomes and a reduced rate of major orthopaedic complications.

Risk factors for thoracolumbar pain following percutaneous vertebroplasty for osteoporotic vertebral compression fractures.

OBJECTIVE: To explore possible risk factors for poor outcomes following percutaneous vertebroplasty (PV) for painful osteoporotic compression fractures of thoracolumbar vertebra. METHODS: This was a retrospective review of data from patients who underwent PV at our institution over a ten-year period to evaluate the association between possible risk factors and thoracolumbar pain (T11-L2). According to the difference between pre- and post-operative visual analogue scale (VAS) scores for pain, patients were separated into poor relief (PR; <4) and good relief (GR; ≥4) of pain. RESULTS: Of the 750 patients identified, 630 (PR group, n =310; GR group, n = 320) fulfilled the eligibility criteria. Multivariate binary logistic analysis showed that bone mineral density (BMD), >2 fractured vertebral bodies, maldistribution of bone cement, <5 ml bone cement injected into a single vertebral body and thoracolumbar fascia injury prior to surgery were independent risk factors associated with thoracolumbar pain following PV. CONCLUSION: Although prospective controlled studies are required to confirm our results, this review suggests that the above factors should be taken into account when selecting patients for PV.

Evaluation of Nonviral piggyBac and lentiviral Vector in Functions of CD19chimeric Antigen Receptor T Cells and Their Antitumor Activity for CD19+ Tumor Cells.

Nonviral transposon piggyBac (PB) and lentiviral (LV) vectors have been used to deliver chimeric antigen receptor (CAR) to T cells. To understand the differences in the effects of PB and LV on CAR T-cell functions, a CAR targeting CD19 was cloned into PB and LV vectors, and the resulting pbCAR and lvCAR were delivered to T cells to generate CD19pbCAR and CD19lvCAR T cells. Both CD19CAR T-cell types were strongly cytotoxic and secreted high IFN-γ levels when incubated with Raji cells. TNF-α increased in CD19pbCAR T cells, whereas IL-10 increased in CD19lvCAR T cells. CD19pbCAR and CD19lvCAR T cells showed similar strong anti-tumor activity in Raji cell-induced mouse models, slightly reducing mouse weight while enhancing mouse survival. High, but not low or moderate, concentrations of CD19pbCAR T cells significantly inhibited Raji cell-induced tumor growth in vivo. These CD19pbCAR T cells were distributed mostly in mesenteric lymph nodes, bone marrow of the femur, spleen, kidneys, and lungs, specifically accumulating at CD19-rich sites and CD19-positive tumors, with CAR copy number being increased on day 7. These results indicate that pbCAR has its specific activities and functions in pbCAR T cells, making it a valuable tool for CAR T-cell immunotherapy.

An efficient Screening System in Yeast to Select a Hyperactive piggyBac Transposase for Mammalian Applications.

As non-viral transgenic vectors, the piggyBac transposon system represents an attractive tool for gene delivery to achieve a long-term gene expression in immunotherapy applications due to its large cargo capacity, its lack of a trace of transposon and of genotoxic potential, and its highly engineered structure. However, further improvements in transpose activity are required for industrialization and clinical applications. Herein, we established a one-plasmid effective screening system and a two-step high-throughput screening process in yeast to isolate hyperactive mutants for mammalian cell applications. By applying this screening system, 15 hyperactive piggyBac transposases that exhibited higher transpose activity compared with optimized hyPBase in yeast and four mutants that showed higher transpose activity in mammalian cells were selected among 3000 hyPBase mutants. The most hyperactive transposase, bz-hyPBase, with four mutation sites showed an ability to yield high-efficiency editing in Chinese hamster ovarian carcinoma (CHO) cells and T cells, indicating that they could be expanded for gene therapy approaches. Finally, we tested the potential of this screening system in other versions of piggyBac transposase.

Triggered Immune Response Induced by Antigenic Epitopes Covalently Linked with Immunoadjuvant-Pulsed Dendritic Cells as a Promising Cancer Vaccine.

The success of peptide-based dendritic cell (DC) cancer vaccines mainly depends on the utilized peptides and selection of an appropriate adjuvant. Herein, we aimed to evoke a broad immune response against multiple epitopes concurrently in the presence of immunoadjuvant. Three synthetic HLA-A∗0201-restricted peptides were separately linked with HMGB1-derived peptide (SAFFLFCSE, denoted as HB100-108) as immunoadjuvant via double arginine (RR) linker and loaded onto human monocyte-derived DCs. Peptide uptake was detected by immunofluorescence microscopy and flow cytometry. The maturation and activation status of pulsed DCs were monitored by detection of the expression of specific markers and released cytokines. The ability of peptide-pulsed DCs to activate allogeneic T cells has been assessed by a degranulation assay and detection of secreted cytokines. The lytic activity of effector T cells against cancer cells in vitro was analyzed by a lactate dehydrogenase (LDH) assay. Results revealed that DCs efficiently take up peptides+HB100-108 and expressed higher levels of surface markers (HLA-ABC, HLA-DR, CD80, CD86, CD83, CD40, and CCR7) and proinflammatory cytokines (IL-6, IFN-γ, TNF-α, and IL-12) than control DCs, free peptide-pulsed DCs, and free HB100-108-pulsed DC groups. Moreover, peptides+HB100-108/pulsed DCs were capable of activating allogeneic T cells and enhance their lytic activity against a pancreatic cancer cell line (PANC-1) in vitro. These findings suggest that antigenic peptides covalently linked with HB100-108/pulsed DCs could be a promising strategy to improve the current DC-based cancer vaccines.

Correction: Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PiggyBac-engineered T cells expressing a glypican-3-specific chimeric antigen receptor show potent activities against hepatocellular carcinoma.

Glypican-3 (GPC3) is an attractive target for chimeric antigen receptor (CAR)-T cell therapy, as it is overexpressed in most hepatocellular carcinoma (HCC) tissues but shows restricted expression in healthy adult tissues. Herein, we generated GPC3-specific CAR-T cells for HCC therapy by electroporation with plasmid DNA encoding the piggyBac (PB) transposon and the hyperactive piggyBac transposase simultaneously instead of by commonly-used viral vectors. Our results demonstrated that GPC3CAR gene was efficiently integrated into the genome of T cells utilizing the PB transposon system. Upon stimulation with GPC3 antigen, GPC3CAR-T cells could be effectively activated, proliferate strongly and secrete high levels of cytokines. It also was demonstrated that GPC3CAR-T cells displayed potent cytotoxicity against GPC3-positive HCC cell lines in vitro by using real-time cell analyser (RTCA) system and the JuLI™ Stage Cell History Recorder. More importantly, in a Huh-7 xenograft mouse model, GPC3CAR-T cells significantly reduced the tumour burden companied with the secretion of high levels of IFN-γ. Moreover, T cells in mice treated with GPC3CAR-T cells could infiltrate into tumour tissues and persist as effector memory T cells (TEM). Overall, our study suggests that the use of PB system-based GPC3CAR-T cell therapy could be a promising clinical strategy for patients with HCC.

Identification of novel methylated DNA marker ZNF569 for head and neck squamous cell carcinoma.

Aberrant DNA methylation pattern plays an indispensable role in the initiation and development of head and neck squamous cell carcinoma (HNSCC). It is well recognized that lymph node metastasis is closely with unfavorable prognosis of HNSCC. Therefore, exploring the methylation events accounting for the lymph node metastasis of HNSCC is very important for improving the clinical outcome of HNSCC. Methylation data, RNA-seq data and clinical data were downloaded from The Cancer Genome Atlas (TCGA) and processed using the R package TCGA-Assembler. MethylMix was use for data analysis by integrating both methylation and gene expression data on HNSCC patients with lymph node metastasis and without lymph node metastasis. Pathway analysis was performed on significantly altered genes using ConsensusPathDB. The role of our interested gene zinc figure protein 569 (ZNF569) in HNSCC was further evaluated. Our results identified many novel hypermethylated/hypomethylated genes that might be closely associated with the lymph node metastasis of HNSCC. Pathway analysis revealed that increase in methylation of genes involved in generic transcription pathway including zinc figure proteins. ZNF569 was hypermethylated in HNSCC tissues especially those with lymph node metastasis. In addition, the expression levels of ZNF569 mRNA and protein were significantly lower in HNSCC tissues and cell lines compared to their respective controls. Moreover, overexpression of ZNF569 inhibited the proliferation, migration and invasion of HNSCC cells. HNSCC patients with lower ZNF569 expression suffered a significantly shorter overall survival than those with higher ZNF569 expression. In conclusion, we have identified many novel differentially methylated genes that might be important for the lymph node metastasis of HNSCC. In addition, ZNF569 might play a tumor suppressive role in carcinogenesis of HNSCC.

Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor.

Mesothelin (MSLN) is an attractive antigen for chimeric antigen receptor (CAR) T therapy and the epitope selection within MSLN is essential. In this study, we constructed two types of CARs targeting either region I of MSLN (meso1 CAR, also known as a membrane-distal region) or region III of MSLN (meso3 CAR, also known as a membrane-proximal region) using a modified piggyBac transposon system. We reported that, compared with meso1 CAR T cells, meso3 CAR T cells express higher levels of CD107α upon activation and produce increased levels of interleukin-2, TNF-α, and IFN-γ against multiple MSLN-expressing cancer cells in vitro. In a real-time cell analyzer system and a three-dimensional spheroid cancer cell model, we also demonstrated that meso3 CAR T cells display an enhanced killing effect compared with that of meso1 CAR T cells. More importantly, in a gastric cancer NSG mice model, meso3 CAR T cells mediated stronger antitumor responses than meso1 CAR T cells did. We further identified that meso3 CAR T cells can effectively inhibit the growth of large ovarian tumors in vivo. Collectively, our study provides evidences that meso3 CAR T-cell therapy performs as a better immunotherapy than meso1 CAR T-cell therapy in treating MSLN-positive solid tumors.

A three miRNAs signature for predicting the transformation of oral leukoplakia to oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) remains to be a global health problem. However, the underlying molecular mechanisms regulating the oral leukoplakia (OLK) to OSCC remain poorly known. MicroRNAs (miRNAs) expression profiles of GSE33299 and GSE62809 were downloaded from gene expression omnibus (GEO) respectively. R software and bioconductor packages were used to compare and identify the differentially expressed miRNAs between OLK tissues and OLK transformed OSCC (OLK-OSCC). The target genes of commonly changed miRNAs were then subjected to gene ontology (GO) enrichment analysis, pathway analysis and miRNA-target genes network analysis. The prediction power of commonly changed miRNAs was further tested in an independent cohort. In total, 161 (88 upregulated and 73 downregulated) and 68 (19 upregulated and 49 downregulated) markedly altered miRNAs were identified from GSE33299 and GSE62809 respectively. The downstream targets of these differentially expression miRNAs in the two cohorts shared many top enriched GO and KEGG pathways. A set of three miRNAs signature including miR-129-5p, miR-296-5p and miR-450b-5p was commonly changed in both GSE33299 and GSE62809. Functional analysis revealed that the downstream target genes of the miRNA signature were associates with transcriptional regulation, estrogen signaling pathway, p53 signaling pathway and RIG-I-like receptor signaling pathway. This three-gene signature was further successfully validated in another independent cohort. The expression levels of miR-129-5p and miR-296-5p were significantly downregulated in OLK-OSCC tissues compared to OLK tissues, while miR-450b-5p levels were higher in OLK-OSCC tissues. In addition, this three miRNAs signature could discriminate OLK from OLK-OSCC with high accuracy. In conclusion, our study has identified a three miRNAs signature that might help predict the transformation of OLK to OSCC. Which will provide useful guidance for therapeutic applications.

JMJD3 facilitates C/EBPß-centered transcriptional program to exert oncorepressor activity in AML.

JMJD3, a stress-inducible H3K27 demethylase, plays a critical regulatory role in the initiation and progression of malignant hematopoiesis. However, how this histone modifier affects in a cell type-dependent manner remains unclear. Here, we show that in contrast to its oncogenic effect in preleukemia state and lymphoid malignancies, JMJD3 relieves the differentiation-arrest of certain subtypes (such as M2 and M3) of acute myeloid leukemia (AML) cells. RNA sequencing and ChIP-PCR analyses revealed that JMJD3 exerts anti-AML effect by directly modulating H3K4 and H3K27 methylation levels to activate the expression of a number of key myelopoietic regulatory genes. Mechanistic exploration identified a physical and functional association of JMJD3 with C/EBPß that presides the regulatory network of JMJD3. Thus, the leukemia regulatory role of JMJD3 varies in a disease phase- and lineage-dependent manner, and acts as a potential oncorepressor in certain subsets of AML largely by coupling to C/EBPß-centered myelopoietic program.

Engineered CAR T cells targeting mesothelin by piggyBac transposon system for the treatment of pancreatic cancer.

Patients with pancreatic cancer have a poor prognosis largely due to the poor efficacy of the available treatment modalities. In this study, we engineered mesothelin-targeting chimeric antigen receptor T cells (mesoCAR T) using the piggyBac transposon based plasmid electroporation technique for specific targeting of pancreatic cancer cells expressing mesothelin. In vitro, mesoCAR T cells exhibited rapid and robust killing effect against ASPC1 cells with high expression levels of mesothelin with high production of IFN-γ; the cytotoxic effect on PANC1 cells with low expressions of mesothelin was relatively attenuated. In the ASPC1 xenograft mice model, mesoCAR T cells significantly suppressed the tumor growth accompanied with higher-level IFN-γ secretion as compared to control T cells. Besides, more mesoCAR T cells differentiated into memory T cells after tumor remission, whilst causing minimal lesions in major organs. Our study suggests promising efficacy of piggyBac transposon-based mesoCAR T cell therapy for pancreatic cancer, which is a potential candidate for clinical translation.

All-trans retinoic acid and arsenic trioxide fail to derepress the monocytic differentiation driver Irf8 in acute promyelocytic leukemia cells.

All-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) administration leads to granulocytic maturation and/or apoptosis of acute promyelocytic leukemia (APL) cells mainly by targeting promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα). Yet, ~10-15% of APL patients are not cured by ATRA- and ATO-based therapies, and a potential failure of ATRA and ATO in completely reversing PML/RARα-driven oncogenic alterations has not been comprehensively examined. Here we characterized the in vivo primary responses of dysregulated genes in APL cells treated with ATRA and ATO using a GFP-labeled APL model. Although induced granulocytic differentiation of APL cells was evident after ATRA or ATO administration, the expression of the majority of dysregulated genes in the c-Kit+ APL progenitors was not consistently corrected. Irf8, whose expression increased along with spontaneous differentiation of the APL progenitors in vivo, represented such a PML/RARα-dysregulated gene that was refractory to ATRA/ATO signaling. Interestingly, Irf8 induction, but not its knockdown, decreased APL leukemogenic potential through driving monocytic maturation. Thus, we reveal that certain PML/RARα-dysregulated genes that are refractory to ATRA/ATO signaling are potentially crucial regulators of the immature status and leukemogenic potential of APL cells, which can be exploited for the development of new therapeutic strategies for ATRA/ATO-resistant APL cases.

Placental characteristics in monochorionic twins with selective intrauterine growth restriction assessed by gradient angiography and three-dimensional reconstruction.

OBJECTIVE: To investigate the placental characteristics in selective intrauterine growth restriction (sIUGR) using gradient angiography and three-dimensional (3D) reconstruction from computed tomography (CT) scan data. METHODS: This study included 23 sIUGR cases and 16 monochorionic twin-pregnancies without sIUGR. We injected nonionic iodinated contrast agents into the umbilical arteries and veins. Placental characteristics were analyzed after CT scanning and 3D reconstruction. RESULTS: 73.9% of smaller twins in sIUGR cases had marginal or velamentous cord insertions and less placental sharing. The terminal branch of the arterial tree was scored III-IV in smaller sIUGR twins, while it was scored V-VII in normal monochorionic twins and larger sIUGR twins. Arterio-arterial (A-A) anastomoses presented in all monochorionic placentas. Veno-venous (V-V) anastomoses present in 83.3% (5/6) of Type III sIUGR cases, which was higher than observed in Type I-II cases. The mean diameters of A-A and V-V anastomoses were larger in Type III sIUGR cases. CONCLUSIONS: Gradient angiography and 3D placental models displayed different placental angioarchitectures and voluminal placental sharing among three types of sIUGR cases. Placental dysplasia in the smaller twin may cause abnormal cord insertion and unequal placental sharing. The inter-twin anatomoses influence the umbilical cord artery (UA) Doppler and natural pathogenesis of sIUGR.