Expression, Prognostic Value, and Biological Function of CTHRC1 in Different Types of Gliomas: A Bioinformatic Analysis and Experiment Validation.

Background: In recent years, abnormal expression of collagen triple helix repeat containing 1 (CTHRC1) has been found in some tumors, closely related to the poor prognosis of cancer patients. However, the clinical significance of CTHRC1 in gliomas is not completely understood. Methods: We investigated the expression, prognostic value, and potential biological function of CTHRC1 in different types of gliomas through bioinformatics analysis and experimental verification. Results: Bioinformatics analysis revealed several key findings regarding the expression and clinical significance of CTHRC1 in gliomas. First, the analysis demonstrated a positive correlation between CTHRC1 expression and the World Health Organization (WHO) grading of gliomas, a relationship that was validated through immunohistochemistry experiments. In addition, a trend was observed in which CTHRC1 expression increased with the extent of glioma invasion, as supported by Western blot experiments. Subsequent bioinformatics analysis identified the mesenchymal subtype of gliomas as having the highest levels of CTHRC1 expression, a finding reinforced by immunohistochemical staining. Moreover, high CTHRC1 expression was associated with poor prognosis in gliomas and emerged as an independent prognostic factor, with varying impacts on prognosis between low-grade gliomas (LGGs) and glioblastoma (GBM) subgroups. Notably, comparative analysis unveiled distinct patterns of immune infiltration of CTHRC1 in LGG and GBM. Furthermore, alterations in copy number variations and DNA methylation were identified as potential mechanisms underlying elevated CTHRC1 levels in gliomas. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that CTHRC1 and its associated genes mainly function in the extracellular matrix and participate in tumor-related signaling pathways. Conclusions: The CTHRC1 has shown significant clinical utility as a prognostic marker and mesenchymal subtype marker of glioma.

UBE2C enhances temozolomide resistance by regulating the expression of p53 to induce aerobic glycolysis in glioma.

UBE2C is overexpressed in gliomas, and its overexpression has been reported to be correlated with the drug resistance of gliomas to some extent. In this study, we explore the role of UBE2C in regulating temozolomide (TMZ) resistance in glioma and investigate the underlying mechanisms involved. Twenty normal brain tissues and 100 glioma tissues from 50 TMZ-resistant patients and 50 TMZ-sensitive patients are included in this study. TMZ-resistant cell lines are constructed to explore the role of UBE2C in regulating glioma cell viability and TMZ resistance. Our results show that both the mRNA and protein levels of UBE2C are significantly elevated in the brain tissues of glioma patients, especially in those of TMZ-resistant patients. Consistently, UBE2C expression is markedly upregulated in TMZ-resistant cell lines. Overexpression of UBE2C rescues glioma cells from TMZ-mediated apoptosis and enhances cell viability. In contrast, downregulation of UBE2C expression further enhances TMZ function, increases cell apoptosis and decreases cell viability. Mechanistically, UBE2C overexpression decreases p53 expression and enhances aerobic glycolysis level by increasing ATP level, lactate production, and glucose uptake. Downregulation of p53 level abolishes the role of UBE2C downregulation in inhibiting TMZ resistance and aerobic glycolysis in glioma cells. Moreover, an animal assay confirms that downregulation of UBE2C expression further suppresses tumor growth in the context of TMZ treatment. Collectively, this study reveals that downregulation of UBE2C expression enhances the sensitivity of glioma cells to TMZ by regulating the expression of p53 to inhibit aerobic glycolysis.

Comparison of subperiosteal or subgaleal drainage and subdural drainage in patients with chronic subdural hematoma: A systematic review and meta-analysis.

BACKGROUND: Chronic subdural hematoma (CSDH) is a relatively common disease, especially in the elderly, for which there is no clear standard of treatment available. The authors systematically evaluated the efficacy of various surgical procedures for the treatment of chronic subdural hematoma. METHODS: Electronic databases of PubMed, EmBase, Web of Science, Medicine, and the Cochrane Library were searched systematically. Based on the PRISMA template, we finally selected and analyzed 13 eligible papers to evaluate the effect of different drainage methods on CSDH. The primary outcomes were recurrence and clinical outcomes. Secondary outcomes were mortality and postoperative complications and other parameters. RESULTS: The meta-analysis included 3 randomized controlled trials and 10 retrospective studies (non-randomized controlled trials) involving 3619 patients. The pooled results showed no statistically significant difference between non-subdural drainage (NSD) and subdural drainage (SD) in mortality and complication rates (P > 0.05). Additionally, overall pooled results showed that the use of NSD (10.9%) has a lower recurrence rate than the use of SD (11.7%), but the results were not statistically significant (relative risk ratio [RR] = 0.98; 95% confidence interval [CI] = 0.70-1.45; I2 = 47%; P = .92). However, the difference between NSD and SD in postoperative bleeding rate reached statistical significance (RR = 2.39; 95% CI = 1.31-4.36; I2 = 0 %; P = .004). Subgroup analysis showed that SD was associated with similar recurrent CSDH (RR = 0.75; 95% CI = 0.52-1.09; I2 = 0%; P = .14), good recovery (RR = 0.98; 95% CI = 0.93-1.04; I2 = 0%; P = .50), and mortality (RR = 0.98; 95% CI = 0.37-2.57; I2 = 0%; P = .96), compared to NSD. CONCLUSIONS: These results suggest that NSD and SD are equally effective in the treatment of patients with CSDH, with no difference in final clinical characteristics and radiologic outcomes. However, in patients with limited subdural space after evacuation of a hematoma, NSD may be the preferred strategy to avoid iatrogenic brain injury.

BODIPY-based fluorescent probe for cysteine detection and its applications in food analysis, test strips and biological imaging.

Cysteine, as one of semi-essential amino acids, which is absorbed from protein-rich foods and acts considerable role in various physiological processes. Here, we designed and synthesized a BODIPY-based turn-on fluorescent probe BDP-S for detecting Cys. The probe displayed short reaction time (10 min), distinct color response (from blue to pink), large signal noise ratio (3150-fold), high selectivity and sensitivity (LOD = 11.2 nM) toward Cys. Moreover, BDP-S could not only be used for quantitative determination of Cys in food samples, but also be conveniently deposited on the test strips for qualitative detection of Cys. Notably, BDP-S was successfully used for imaging Cys in living cells and in vivo. Consequently, this work provided a hopefully powerful tool for detecting Cys in food samples and complex biological systems.

Craniopharyngioma involving the anterior, middle, and posterior cranial fossa in adults: A case report.

Craniopharyngioma (CP) is a rare benign tumor that develops from the residual epithelial cells of the craniopharynx, accounting for < 5% of intracranial tumors. It is common for CPs to grow in the sellar/parasellar region and extend suprasellar. The pathology classifies CPs into adamantinomatous craniopharyngiomas (ACP) and papillary craniopharyngiomas (PCP). The PCP is mainly solid and occurs only in adults. ACP is predominantly cystic and more common in childhood and adolescent. Multilocular cystic ACP involving the anterior, middle, and posterior cranial fossa is rare in adults. Here, we report a case of a 46-year-old adult male patient who presented with recurrent headaches for 1 year with choking and hoarseness. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed multiple cystic masses in the anterior, middle, and posterior cranial fossa. Initial hypotheses included the following: CP, colloid cyst, enterogenous cyst, epidermoid cyst, and dermoid cyst. Subsequently, the patient underwent surgery and postoperative histopathology diagnosed ACP. Adults with ACP involving the anterior, middle, and posterior cranial fossae are uncommon. This is a rare condition that radiologists should be aware of.

Endoscopic surgery versus craniotomy in the treatment of spontaneous intracerebral hematoma: a systematic review and meta-analysis.

BACKGROUND: Spontaneous intracerebral hemorrhage (SICH) has high morbidity and mortality, with no clear standard of treatment available. Compared with the craniotomy approach, neuroendoscopy is a relatively minimally invasive treatment method, and may be an efficient alternative. Therefore, this meta-analysis aimed to assess the clinical efficacy of neuroendoscopy and craniotomy in SICH patients. METHODS: The electronic databases Web of Science, PubMed, EmBase, MEDLINE, and the Cochrane Library were systematically searched. According to the PRISMA template, we finally selected and analyzed 14 eligible studies that evaluated neuroendoscopy versus craniotomy. Primary outcomes included operation time, intraoperative blood loss volume, evacuation rate, residual hematoma, complications, hospital stay duration, clinical outcomes, and other parameters. RESULTS: A total of 4 randomized controlled trials (RCTs) and 10 retrospective studies (non-RCTs) involving 1652 patients were included in the final analysis. In the neuroendoscopy (NE) group, operation time (p < 0.00001), intraoperative blood loss volume (p < 0.0001), hematoma evacuation rate (p = 0.0002), complications (p < 0.00001), hospitalization days (p = 0.004), and mortality (p < 0.0001) were significantly different from those of the craniotomy (C) group, with a higher rate of good recovery compared with the craniotomy group (P < 0.00001). CONCLUSIONS: These findings suggest that patients with SICH and physicians may benefit more from neuroendoscopic surgery than craniotomy.

Mesenchymal stem cells-derived exosomal miR-24-3p ameliorates non-alcohol fatty liver disease by targeting Keap-1.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with ill-defined etiology and pathogenesis, and no approved effective therapy is presently available. Exosome-dependent intercellular communication has been identified as a potential signaling involved in tissue repair. Unfortunately, the exact influence and underlying mechanism of mesenchymal stem cells (MSCs)-derived exosome (Exo) in modulating fatty liver have not been well determined. Here in our study, in vitro results initially showed that human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)-derived Exo treatment significantly suppressed lipid accumulation, reactive oxygen species (ROS) generation and inflammatory response in palmitate (PA)-stimulated mouse hepatocytes. Consistently, MSCs-derived Exo administration strongly ameliorated metabolic disorders, hepatic dysfunction and steatosis in high fat diet (HFD)-induced mouse model with NAFLD. Furthermore, Exo derived from MSCs significantly alleviated hepatic lipid metabolism disturbance, inflammation and oxidative stress induced by HFD. Exo treatment resulted in a stronger increase in miR-24-3p expression in hepatocytes. Reducing miR-24-3p in MSCs markedly abrogated the protective effects of Exo in hepatocytes under PA stimulation. Mechanistically, miR-24-3p directly targeted Kelch-like ECH-associated protein 1 (Keap-1), and suppressed its expression. In addition, the effects of MSCs-derived exosomal miR-24-3p to restrain lipid accumulation, ROS generation and inflammation in vitro were largely Keap-1 dependent via Keap-1 depression. Collectively, our study demonstrated that MSCs-derived exosomal miR-24-3p had hepaprotective effects through targeting Keap-1 signaling, providing a potential therapeutic value for NAFLD treatment.

Genetic Analysis of Adult Plant Resistance to Stripe Rust in Common Wheat Cultivar "Pascal".

Wheat stripe rust is an important foliar disease that affects the wheat yield globally. Breeding for resistant wheat varieties is one of the most economically and environmentally effective ways to control this disease. The common wheat (Triticum aestivum L.) cultivar "Pascal" exhibited susceptibility to stripe rust at the seedling stage but it showed high resistance to stripe rust at the adult plant stage over 20 years in Gansu, a hotspot of the disease in northwestern China. To understand the genetic mechanism of stripe rust resistance in this cultivar, a 55K SNP array was used to analyze the two parents and the 220 recombinant inbred lines (RILs) derived from the cross of "Huixianhong" × "Pascal." We detected three new stripe rust adult plant resistance (APR) quantitative trait locus (QTL) contributed by Pascal, viz. QYr.gaas-1AL, QYr.gaas-3DL, and QYr.gaas-5AS, using the inclusive composite interval mapping method. They were flanked by SNP markers AX-111218361-AX-110577861, AX-111460455-AX-108798599, and AX-111523523-AX-110028503, respectively, and explained the phenotypic variation ranging from 11.0 to 23.1%. Bulked segregant exome capture sequencing (BSE-Seq) was used for fine mapping of QYr.gaas-1AL and selection of candidate genes, TraesCS1A02G313700, TraesCS1A02G313800, and TraesCS1A02G314900 for QYr.gaas-1AL. KASP markers BSE-1A-12 and HXPA-3D for QYr.gaas-1AL and QYr.gaas-3DL were developed for breeders to develop durable stripe rust-resistant wheat varieties.

Near-Infrared Fluorescent Probe with a Large Stokes Shift for Detection of Hydrogen Sulfide in Food Spoilage, Living Cells, and Zebrafish.

Hydrogen sulfide (H2S) is a significant component of various physiological processes, and it can also cause a negative effect on foodstuffs. In this work, we designed and synthesized an NIR fluorescent turn-on responding probe (DDM-H2S) with a large Stokes shift (190 nm) for the detection of H2S. DDM-H2S exhibited high selectivity and sensitivity, obvious color changes, and a fast response time for tracing H2S. When DDM-H2S reacted with H2S, the PET process was eliminated, and the recovered ICT process and NIR fluorescence were observed. Moreover, DDM-H2S could image endogenous and exogenous H2S in living HeLa cells and zebrafish. What is more, the probe DDM-H2S could be deposited easily to test paper strips, which were able to detect the H2S gas produced during food spoilage (such as eggs, raw meat, and fishes) by the color of test paper strips changing from pink to purple. Therefore, this work provides a promising approach for monitoring H2S in complicated biological systems and practical food samples.

Polysaccharide conjugates from Chin brick tea (Camellia sinensis) improve the physicochemical stability and bioaccessibility of ß-carotene in oil-in-water nanoemulsions.

A natural antioxidant emulsifier, tea polysaccharide conjugate (TPC), was isolated from Chin brick tea. The impact of TPC on ß-carotene stability and bioaccessibility in oil-in-water nanoemulsions was assessed. TPC exhibited strong antioxidant activity and could be used to fabricate stable nanoemulsions (d < 140 nm). The extent of lipid digestion was considerably lower for lipid droplets coated by TPC (68%) than Tween 80 (94%) or whey protein isolate (WPI) (89%), probably because TPC formed interfacial layers that hindered the access of lipases to lipids. The chemical stability of ß-carotene in TPC-nanoemulsions was markedly higher than in those formulated with Tween 80 or WPI due to the high antioxidant activity of TPC. The bioaccessibility of ß-carotene (20-30%) was independent of emulsifier type. TPC from Chin brick tea can therefore be used as a dual-purpose functional ingredient in emulsified foods.

The effects of Intensive Supervision Mechanism on air quality improvement in China.

The Intensive Supervision Mechanism (hereafter referred to as ISM) is one of the most important institutional management innovations for air pollution control in China, but there is currently no consensus on the effects of the ISM on air quality improvement. In this study, a reliable quantitative model based on the Difference-in-Differences (DID) analysis was designed to evaluate the impacts of ISM on air quality (as indicated by good air quality days (hereafter referred to as GAD) and the concentrations of six major air pollutants (i.e. PM2.5, PM10, O3_8H, NO2, SO2, and CO)), in China with focuses on the implementation cities of Henan Province. To optimize the model design, six meteorological factors, five socio-economic indicators, and VIIRS (Visible Infrared Imaging Radiometer Suite) data were also considered as alternative control variables for more comprehensive and effective results. In addition, the redundancy analysis (RDA) and Monte Carlo simulation were conducted to determine the optimal combination of those control variables which can best reflect the changes in explanatory variables. The main findings are as follows: (1) the statistical model applied in this study can well evaluate the impacts of ISM; (2) the implementation of ISM can significantly reduce the concentrations of SO2, CO, and NO2, but the improvements for PM2.5, PM10, GAD and O3_8H were not significant. (3) the potential for air quality improvement due to ISM tends to be reduced over time, and thus the positive effects of ISM at its second stage were not increased significantly compared with those observed during its first stage. In general, those results not only demonstrate the effectiveness of ISM on air quality improvement, but also provide insights into how the ISM can be optimized to gain a sustained improvement of the ambient air quality in the future.Implications: As a policy measure implemented by the Chinese government, the Intensive Supervision Mechanism (ISM) has significantly contributed to the improvement of air quality since its execution. However, the potential for air quality improvement due to ISM tends to be reduced over time, and thus the positive effects of ISM at its second stage were not increased significantly compared with those observed during its first stage. In addition, the implementation of ISM requires a large amount of financial investment, and thus has limited sustainability. Considering the increased difficulty of this policy instrument, whether to insist on the ISM warrants further analyses on its cost and effectiveness. More importantly, more targeted measures of ISM should be applied to decrease the ozone concentration in the future.

Adsorption of miR-218 by lncRNA HOTAIR regulates PDE7A and affects glioma cell proliferation, invasion, and apoptosis.

OBJECTIVE: To evaluate the role of targeted adsorption of miR-218 by long-chain non-coding RNAHOTAIR to regulate PDE7A on glioma cell proliferation, invasion, and apoptosis. METHODS: The expressions of lncRNA HOTAIR, miR-218, and PDE7A in glioma tissues and normal parcancer tissues, NHA and glioma cell lines were determined, and correlations among the three genes were analyzed. The subcellular localization of lncRNA HOTAIR was determined by fluorescent in situ hybridization. Dual-luciferase reporter assay was used to validate the targeted relationship between lncRNA HOTAIR/miR-218/PDE7A. Glioma cells were grouped to receive intervention of lncRNA HOTAIR or miR-218. MTT, transwell, and flow cytometry were performed to determine the proliferation, invasion, and apoptosis of cells. RESULTS: Compared with the normal tissues and cells, the expression of lncRNA HOTAIR was increased while miR-218 was suppressed in glioma tissues samples and cells (all P<0.05). Inhibition of lncRNA HOTAIR expression, was able to induce apoptosis and suppress the proliferation and invasion of cells (all P<0.05). LncRNA HOTAIR is mainly localized in the cytoplasm, and is able to adsorb miR-218 as ceRNA. The effect of knockdown of HOTAIR on glioma cells could be partially rescued by miR-218 inhibitor. The expression of PDE7A was enhanced in glioma tissues and cells compared to normal tissues and cells (all P<0.05), which positively correlated with the expression of HOTAIR (r=0.546, P<0.05) and negatively correlated with the expression of miR-218 (r=0.363, P<0.05). The targeted relationship between miR-218 and PDE7A was validated: Overexpression of miR-218 was able to suppress the proliferation and invasion of glioma cells and restrain apoptosis compared to the miR-NC group (all P<0.05). The effect of miR-218 on glioma cells could be partially rescued by PDE7A. CONCLUSION: lncRNA HOTAIR can adsorb miR-218 to regulate expression of PDE7A and promote the malignant biologic behavior of glioma cells.

Anchor Link Prediction across Attributed Networks via Network Embedding.

Presently, many users are involved in multiple social networks. Identifying the same user in different networks, also known as anchor link prediction, becomes an important problem, which can serve numerous applications, e.g., cross-network recommendation, user profiling, etc. Previous studies mainly use hand-crafted structure features, which, if not carefully designed, may fail to reflect the intrinsic structure regularities. Moreover, most of the methods neglect the attribute information of social networks. In this paper, we propose a novel semi-supervised network-embedding model to address the problem. In the model, each node of the multiple networks is represented by a vector for anchor link prediction, which is learnt with awareness of observed anchor links as semi-supervised information, and topology structure and attributes as input. Experimental results on the real-world data sets demonstrate the superiority of the proposed model compared to state-of-the-art techniques.

Self-assembly of anisotropic red blood cell (RBC)-like colloidal particles.

Non-spherical colloidal particles, as basic building blocks, exhibit special capability in constructing novel materials. In this work, red blood cell (RBC)-like, anisotropic particles were synthesized and the self-assembly of the RBC-like particles was then carried out at the air-water interface. Subsequently, multilayer 3D structured colloidal crystals were also fabricated. The as-prepared colloidal crystal film displays beautiful Bragg diffraction, which can be used to construct a photonic crystal. After that, the self-assembly of binary colloidal particles was explored to design well-patterned binary colloidal crystals. This facile self-assembly approach to prepare colloidal crystals may extend to other anisotropic building blocks, providing guidance for the fabrication of more complex and flexible materials.

Histological analysis of oogenesis and ovarian development of the freshwater crab Sinopotamon henanense.

The morphological and cytological changes of oogenesis and ovarian development were described in the freshwater crab Sinopotamon henanense through macroscopic and microscopic examinations. Serial histological dissections of the ovaries demonstrated that oocyte development was asynchronous. Oogenesis was divided into four distinct stages including six phases: oogonium stage, the first phase (OI) and the second phase (OII) comprising the previtellogenic stage, the third phase (OIII), the fourth phase (OIV) and the fifth phase (OV), comprising the vitellogenic stage and the sixth phase representing the mature stage. Furthermore, examining and analyzing the gonadosomatic indices showed that the developmental cycle of the ovary was closely related to season, and indicated that the breeding season of S. henanense was between May and June. Ovarian development was classified into six stages: proliferation stage, small growth stage, large growth stage, pre-maturation stage, mature stage and spawning stage. Ovaries varied in size and color during each developmental stage, which were closely related to the status and proportions of oogonia and primary oocytes. Although there were cases that oocytes at two or more phases were present at each stage, ovary developmental stages were substantially different. These results provide an important base for studies of the regulatory mechanisms of oogenesis in this compared to other brachyuran species, and will be useful for the aquaculture of S. henanense and related species.

Combined Chemical Groups and Topographical Nanopattern on the Poly(ε-Caprolactone) Surface for Regulating Human Foreskin Fibroblasts Behavior.

Surface chemistry and substrate topography could contribute significantly to providing a biochemical and topographical cues for governing the fate of cells on the cell-material interface. However, the synergies between these two properties have not been exploited extensively for biomaterial design. Herein, we achieved spatial-controlled patterning of chemical groups on the poly(ε-caprolactone) (PCL) surface by elegant UV-nanoimprint lithography (UN-NIL). The introduction of chemical groups on the PCL surface was developed by our newly 6-benzyloxycarbonylmethyl-ε-caprolactone (BCL) monomer, which not only solved the lack of functional groups along the PCL chain but also retained the original favorable properties of PCL materials. The synergetic effect of the chemical groups and nanopatterns on the human foreskin fibroblasts (HFFs) behaviors was evaluated in detail. The results revealed that the patterned functional PCL surfaces could induce enhanced cell adhesion and proliferation, further trigger changes in HFFs morphology, orientation and collagen secretion. Taken together, this study provided a method for straightforward fabrication of reactive PCL surfaces with topographic patterns by one-step process, and they would facilitate PCL as potential candidate for cell cultivation and tissue engineering.

A novel small molecule agent displays potent anti-myeloma activity by inhibiting the JAK2-STAT3 signaling pathway.

The oncogenic STAT3 signaling pathway is emerging as a promising target for the treatment of multiple myeloma (MM). In the present study, we identified a novel STAT3 inhibitor SC99 in a target-based high throughput screen. SC99 inhibited JAK2-STAT3 activation but had no effects on other transcription factors such as NF-κB, and kinases such as AKT, ERK, and c-Src that are in association with STAT3 signaling pathway. Furthermore, SC99 downregulated the expression of STAT3-modulated genes, including Bcl-2, Bcl-xL, VEGF, cyclin D2, and E2F-1. By inhibiting the STAT3 signaling, SC99 induced MM cell apoptosis which could be partly abolished by the ectopic expression of STAT3. Furthermore, SC99 displayed potent anti-MM activity in two independent MM xenograft models in nude mice. Oral administration of SC99 led to marked decrease of tumor growth within 10 days at a daily dosage of 30 mg/kg, but did not raise toxic effects. Taken together, this study identified a novel oral JAK2/STAT3 inhibitor that could be developed as an anti-myeloma agent.

CDX2 inhibits pancreatic adenocarcinoma cell proliferation via promoting tumor suppressor miR-615-5p.

CDX2 has recently been identified as a prognostic marker for pancreatic adenocarcinoma. However, the role and mechanism of CDX2 in progression of pancreatic adenocarcinoma are still elusive. In this study, we observed that CDX2 expression was much lower in mouse pancreatic adenocarcinoma tissues and pancreatic cancer cells. A network integrated by ChIPBase platform hinted that miR-615-5p, a most newly discovered tumor suppressor, was probably bound by CDX2 in the promoter region. Chromatin immunoprecipitation (ChIP)-qPCR assay showed that CDX2 exhibited a high capacity of binding to miR-615-5p promoter region compared to the negative control. Real-time PCR and western blotting analyses revealed that CDX2 overexpression caused inflation of miR-615-5p and depression of insulin-like growth factor 2 (IGF2), a direct target of miR-615-5p. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and EdU approaches showed that CDX2 overexpression markedly suppressed pancreatic adenocarcinoma cell proliferation. CDX2 small interfering RNA (siRNA) transfection showed an opposite effect on gene expression and cell proliferation to that of CDX2 overexpression. Collectively, CDX2 inhibited pancreatic adenocarcinoma cell proliferation via promoting tumor suppressor miR-615-5p. Our findings suggested a potential molecular target for pancreatic adenocarcinoma therapy.

Identification of a promising PI3K inhibitor for the treatment of multiple myeloma through the structural optimization.

BACKGROUND: We previously reported a PI3K inhibitor S14161 which displays a promising preclinical activity against multiple myeloma (MM) and leukemia, but the chiral structure and poor solubility prevent its further application. METHODS: Six S14161 analogs were designed based on the structure-activity relationship; activity of the compounds in terms of cell death and inhibition of PI3K were analyzed by flow cytometry and Western blotting, respectively; anti-myeloma activity in vivo was performed on two independent xenograft models. RESULTS: Among the six analogs, BENC-511 was one of the most potent compounds which significantly inhibited PI3K activity and induced MM cell apoptosis. BENC-511 was able to inactivate PI3K and its downstream signals AKT, mTOR, p70S6K, and 4E-BP1 at 1 µM but had no effects on their total protein expression. Consistent with its effects on PI3K activity, BENC-511 induced MM cell apoptosis which was evidenced by the cleavage of Caspase-3 and PARP. Notably, addition of insulin-like growth factor 1 and interleukin-6, two important triggers for PI3K activation in MM cells, partly blocked BENC-511-induced MM cell death, which further demonstrated that PI3K signaling pathway was critical for the anti-myeloma activity of BENC-511. Moreover, BENC-511 also showed potent oral activity against myeloma in vivo. Oral administration of BENC-511 decreased tumor growth up to 80% within 3 weeks in two independent MM xenograft models at a dose of 50 mg/kg body weight, but presented minimal toxicity. Suppression of BENC-511 on MM tumor growth was associated with decreased PI3K/AKT activity and increased cell apoptosis. CONCLUSIONS: Because of its potent anti-MM activity, low toxicity (LD50 oral >1.5 g/kg), and easy synthesis, BENC-511 could be developed as a promising agent for the treatment of MM via suppressing the PI3K/AKT signaling pathway.