Frequently expressed glypican-3 as a promising novel therapeutic target for osteosarcomas.

Osteosarcoma (OS) is the most common bone malignancy without a reliable therapeutic target. Glypican-3 (GPC3) mutation and upregulation have been detected in multidrug resistant OS, and anti-GPC3 immunotherapy can effectively suppress the growth of organoids. Further profiling of GPC3 mutations and expression patterns in OS is of clinical significance. To address these issues, fresh OS specimens were collected from 24 patients for cancer-targeted next-generation sequencing (NGS) and three-dimensional patient-derived organoid (PDO) culture. A tumor microarray was prepared using 37 archived OS specimens. Immunohistochemical (IHC) staining was performed on OS specimens and microarrays to profile GPC3 and CD133 expression as well as intratumoral distribution patterns. RT-PCR was conducted to semiquantify GPC3 and CD133 expression levels in the OS tissues. Anti-GPC3 immunotherapy was performed on OS organoids with or without GPC3 expression and its efficacy was analyzed using multiple experimental approaches. No OS cases with GPC3 mutations were found, except for the positive control (OS-08). IHC staining revealed GPC3 expression in 73.77% (45/61) of OSs in weak (+; 29/45), moderate (++; 8/45), and strong (+++; 8/45) immunolabeling densities. The intratumoral distribution of GPC3-positive cells was variable in the focal (+; 10%-30%; 8/45), partial (++; 31%-70%; 22/45), and the most positive patterns (+++; >71%; 15/45), which coincided with CD133 immunolabeling (P = 9.89 × 10-10 ). The anti-GPC3 antibody efficiently inhibits Wnt/ß-catenin signaling and induces apoptosis in GPC3-positive PDOs and PDXs, as opposed to GPC3-negative PDOs and PDXs. The high frequency of GPC3 and CD133 co-expression and the effectiveness of anti-wild-type GPC3-Ab therapy in GPC3-positive OS models suggest that GPC3 is a novel prognostic parameter and a promising therapeutic target for osteosarcoma.

Identification of GPC3 mutation and upregulation in a multidrug resistant osteosarcoma and its spheroids as therapeutic target.

BACKGROUND: Drug resistance and the lack of molecular therapeutic target are the main challenges in the management of osteosarcomas (OSs). Identification of novel genetic alteration(s) related with OS recurrence and chemotherapeutic resistance would be of scientific and clinical significance. METHODS: To identify potential genetic alterations related with OS recurrence and chemotherapeutic resistance, the biopsies of a 20-year-old male osteosarcoma patient were collected at primary site (p-OS) and from its metastatic tumor (m-OS) formed after 5 months of adjuvant chemotherapy. Both OS specimens were subjected to cancer-targeted next generation sequencing (NGS) and their cell suspensions were cultured under three-dimensional condition to establish spheroid therapeutic model. Transcript-oriented Sanger sequencing for GPC3, the detected mutated gene, was performed on RNA samples of p-OS and m-OS tissues and spheroids. The effects of anti-GPC3 antibody and its combination with cisplatin on m-OS spheroids were elucidated. RESULTS: NGS revealed 4 mutations (GPC3, SOX10, MDM4 and MAPK8) and 6 amplifications (MDM2, CDK4, CCND3, RUNX2, GLI1 and FRS2) in p-OS, and 3 mutations (GPC3, SOX10 and EGF) and 10 amplifications (CDK4, CCND3, MDM2, RUNX2, GLI1, FRS2, CARD11, RAC1, SLC16A7 and PMS2) in m-OS. Among those alterations, the mutation abundance of GPC3 was the highest (56.49%) in p-OS and showed 1.54 times increase in m-OS. GPC3 transcript-oriented Sanger sequencing confirmed the mutation at 1046 in Exon 4, and immunohistochemical staining showed increased GPC3 production in m-OS tissues and its spheroids. EdU cell proliferation and Calcein/PI cell viability assays revealed that of the anti-OS first line drugs (doxorubicin, cisplatin, methotrexate, ifosfamide and carboplatin), 10 µM carboplatin exerted the best inhibitory effects on the p-OS but not the m-OS spheroids. 2 µg/mL anti-GPC3 antibody effectively committed m-OS spheroids to death by itself (76.43%) or in combination with cisplatin (92.93%). CONCLUSION: This study demonstrates increased abundance and up-regulated expression of mutant GPC3 in metastatic osteosarcoma and its spheroids with multidrug resistance. As GPC3-targeting therapy has been used to treat hepatocellular carcinomas and it is also effective to OS PDSs, GPC3 would be a novel prognostic parameter and therapeutic target of osteosarcomas.

Risk of Cardiovascular and Cerebrovascular Events in Polycystic Ovarian Syndrome Women: A Meta-Analysis of Cohort Studies.

Aim: This systematic review and meta-analysis aimed to investigate the risk of cardiovascular disease (CVD) and cerebrovascular disease (CeVD) events in women with polycystic ovary syndrome (PCOS). Methods: We searched the literatures in Pubmed, Embase, and Web of Science to identify cohort studies reporting the association between PCOS and CVD/CeVD events from 1964 to June 1, 2020. Outcome variables, such as all-cause mortality, cardiovascular death, any cardiovascular diseases, myocardial infarction, ischemic heart disease, and stroke, were extracted from the identified literatures, and we reported the outcomes of the association in hazard ratios (HR) and odds ratios (OR). Results: Ten cohort studies comprising 166,682 samples are included in the review. Compared to non-PCOS women, the pooled risk of CVD events in PCOS women (OR: 1.66, 95% CI: 1.32-2.08). In addition, the risk of myocardial infarction (OR: 2.57, 95% CI: 1.37-4.82), ischemic heart disease (OR: 2.77, 95% CI: 2.12-3.61), and stroke (OR: 1.96, 95% CI: 1.56-2.47) are higher in the PCOS group. However, no significant difference in the overall mortality (HR: 1.04, 95% CI: 0.57-1.86) and CVD-related death (HR: 1.49, 95% CI: 0.99-2.23) was observed. Funnel plots of all outcomes are roughly symmetric, and no significant publication bias was found. Conclusion: Though this study identified an increased risk of CVD and CeVD among women with PCOS, including occurrence of myocardial infarction, ischemic heart disease, and stroke, there was no difference in the all-cause or CVD-related mortality observed. Further large-scale studies are warranted to strengthen the association between PCOS and CV events. Our study may require a larger sample size to further verify the conclusions.

Early-TIPS Versus Current Standard Therapy for Acute Variceal Bleeding in Cirrhosis Patients: A Systemic Review With Meta-analysis.

BACKGROUND: The survival of early placement (within 72h after admission) of transjugular intrahepatic portosystemic shunts (early-TIPS) in patients with cirrhosis and acute variceal bleeding (AVB) is controversial. OBJECTIVES: We performed a systemic review and meta-analysis to assess whether early-TIPS could improve survival in patients with cirrhosis and acute variceal bleeding. METHODS: A systematic search of the literature was conducted in PubMed, EMBASE, and Cochrane Library published before 25 June 2019 for eligible studies that compared early-TIPS with a combination of endoscopic variceal ligation (EVL) and pharmacotherapy in the therapeutic effect in AVB patients. RESULTS: A total of five studies with 1,754 participants were enrolled. The early-TIPS demonstrated a significant improvement in prevention of treatment failure (OR=0.11,95%CI=0.05-0.23), 6-weeks mortality (OR=0.24,95%CI=0.13-0.46), rebleeding within 6 weeks (OR=0.21,95%CI=0.12-0.36), rebleeding within 1 year (OR=0.16,95%CI=0.07-0.36), new or worsening ascites (OR=0.33,95%CI=0.21-0.53), except in encephalopathy (OR=1.29,95%CI=0.996-1.67). For 1-year mortality, a significant prior effect was also observed in early-TIPS (OR=0.64,95%CI=0.46-0.90), and the beneficial effect in Child-Pugh C patients (OR=0.35,95%CI=0.18-0.68) was equal to Child-Pugh B patients (OR=0.34,95%CI=0.25-0.58). No difference in liver transplantation and mortality caused by liver failure was observed. CONCLUSIONS: Early covered-TIPS could be recommended for the management of AVB patients in cirrhosis demonstrating a significant improvement in treatment failure, both short- and long-term mortality, rebleeding risk, and new or worsening ascites compared to standard therapy, especially for high-risk AVB patients. It will also apply to patients with Child-Pugh A until solutions to prevent hepatic encephalopathy in future research are found.

Synthesis, characterization and applications of copper(II) complexes with Schiff bases derived from chitooligosaccharide and iodosubstituted salicylaldehyde.

Cu(II) complexes with Schiff bases derived from chitooligosaccharide and iodosubstituted salicylaldehyde (I-SCOS) were synthesized and characterized by EA, ICP, FTIR and SEM. The Cu(II) was coordinated by the imino N atoms and phenolic hydroxyl O atoms from I-SCOS. The antimicrobial activities of I-SCOS and their Cu(II) complexes were investigated against Enterobacter cloacae, Staphylococcus aureus, Staphylococcus epidermidis and Staphylococcus saprophyticus. The results indicated that the introduction of the iodosubstituted and the imine groups of Schiff bases increased the antimicrobial activity of I-SCOS and exhibited a superposition effect of molecular structure. The coordination interaction between I-SCOS and Cu(II) further enhanced the antimicrobial activities. The scavenging superoxide anion radical activity of I-SCOS derivatives was estimated by using NBT/VB2/methionine superoxide anion radical producing system. When the concentration of the complexes was more than 0.3 mg/mL, their antioxidant activity was higher than that of I-SCOS.

Hydrothermal Synthesis, Structural Characterization, and Interaction Mechanism with DNA of Copper(II) Complex Containing 2,2'-Bipyridine.

A Cu(II) complex [Cu(bipy)(H2O)2(SO4)] n (bipy = 2,2'-bipyridine) was synthesized by hydrothermal method and characterized structurally by elemental analyses, single crystal X-ray diffraction, infrared spectra, and thermogravimetry and differential scanning calorimetry. The Cu(II) was hexacoordinated by two N atoms from bipy, two O atoms from different sulfate radical anions, and two O atoms from two water molecules, forming a slightly distorted octahedral geometry, and bridged by sulfato groups into polymeric chains. Under the condition of physiological pH, the interaction mechanism between the complex and hsDNA was explored with acridine orange as a fluorescence probe by spectroscopic methods. The binding modes between the complex and hsDNA were the electrostatic and embedded modes.

Synthesis, Structural Characterization, and Antibacterial Activity of Novel Erbium(III) Complex Containing Antimony.

The novel 3D edta-linked heterometallic complex [Sb2Er(edta)2(H2O)4]NO3·4H2O (H4edta = ethylenediaminetetraacetic acid) was synthesized and characterized by elemental analyses, single-crystal X-ray diffraction, powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and thermal analysis. The complex crystallizes in the monoclinic system with space group Pm. In the complex, each erbium(III) ion is connected with antimony(III) ions bridging by four carboxylic oxygen atoms, and in each [Sb(edta)]- anion, the antimony(III) ion is hexacoordinated by two nitrogen atoms and four oxygen atoms from the edta4- ions, together with a lone electron pair at the equatorial position. The erbium(III) ion is octacoordinated by four oxygen atoms from four different edta4- ions and four oxygen atoms from the coordinated water molecules. The carboxylate bridges between antimony and erbium atoms form a planar array, parallel to the (1 0 0) plane. There is an obvious weak interaction between antimony atom and oxygen atom of the carboxyl group from the adjacent layer. The degradation of the complex proceeds in several steps and the water molecules and ligands are successively emitted, and the residues of the thermal decomposition are antimonous oxide and erbium(III) oxide. The complex was evaluated for its antimicrobial activities by agar diffusion method, and it has good activities against the test bacterial organisms.

Synthesis and Crystal Structure of the Bioinorganic Complex [Sb(Hedta)]·2H2O.

The antimony(III) complex [Sb(Hedta)]·2H2O was synthesized with ethylenediaminetetraacetic acid (H4edta) and antimonous oxide as main raw materials in aqueous solution. The composition and structure of the complex were characterized by elemental analysis, infrared spectra, single crystal X-ray diffraction, X-ray powder diffraction, thermogravimetry, and differential scanning calorimetry. The crystal structure of the antimony(III) complex belongs to orthorhombic system, space group Pna2(1), with cell parameters of a = 18.4823(18) Å, b = 10.9408(12) Å, c = 7.3671(5) Å, V = 1489.7(2) Å(3), Z = 4, and D c = 1.993 g cm(-3). The Sb(III) ion is five-coordinated by two amido N atoms and three carboxyl O atoms from a single Hedta(3-) ligand, forming a distorted trigonal bipyramid geometry. The thermal decomposition processes of the complex include dehydration, oxidation, and pyrolysis of the ligand, and the last residue is Sb2O3 at the temperature of 570°C.

Synthesis, crystal structure, and thermal decomposition of the cobalt(II) complex with 2-picolinic acid.

The cobalt(II) complex of 2-picolinic acid (Hpic), namely, [Co(pic)2(H2O)2] · 2H2O, was synthesized with the reaction of cobalt acetate and 2-picolinic acid as the reactants by solid-solid reaction at room temperature. The composition and structure of the complex were characterized by elemental analysis, infrared spectroscopy, single crystal X-ray diffraction, and thermogravimetry-differential scanning calorimetry (TG-DSC). The crystal structure of the complex belongs to monoclinic system and space group P2(1)/n, with cell parameters of a = 9.8468(7) Å, b = 5.2013(4) Å, c = 14.6041(15) Å, ß = 111.745(6)°, V = 747.96(11) ų, Z = 2, D(c) = 1.666 g cm⁻³, R1 = 0.0297, and wR2 = 0.0831. In the title complex, the Co(II) ion is six-coordinated by two pyridine N atoms and two carboxyl O atoms from two 2-picolinic acid anions, and two O atoms from two H2O molecules, and forming a slightly distorted octahedral geometry. The thermal decomposition processes of the complex under nitrogen include dehydration and pyrolysis of the ligand, and the final residue is cobalt oxalate at about 450°C.

Preparation of soft magnetic Fe-Ni-Pb-B alloy nanoparticles by room temperature solid-solid reaction.

The Fe-Ni-Pb-B alloy nanoparticles was prepared by a solid-solid chemical reaction of ferric trichloride, nickel chloride, lead acetate, and potassium borohydride powders at room temperature. The research results of the ICP and thermal analysis indicate that the resultants are composed of iron, nickel, lead, boron, and PVP, and the component of the alloy is connected with the mole ratio of potassium borohydride and the metal salts. The TEM images show that the resultants are ultrafine and spherical particles, and the particle size is about a diameter of 25 nm. The largest saturation magnetization value of the 21.18 emu g(-1) is obtained in the Fe-Ni-Pb-B alloy. The mechanism of the preparation reaction for the Fe-Ni-Pb-B multicomponent alloys is discussed.