Deep sequencing of circulating miRNAs and target mRNAs level in deep venous thrombosis patients.

Deep venous thrombosis is one of the most common peripheral vascular diseases that lead to major morbidity and mortality. The authors aimed to identify potential differentially expressed miRNAs and target mRNAs, which were helpful in understanding the potential molecule mechanism of deep venous thrombosis. The plasma samples of patients with deep venous thrombosis were obtained for the RNA sequencing. Differentially expressed miRNAs were identified, followed by miRNA-mRNA target analysis. Enrichment analysis was used to analyze the potential biological function of target mRNAs. GSE19151 and GSE173461 datasets were used for expression validation of mRNAs and miRNAs. 131 target mRNAs of 21 differentially expressed miRNAs were identified. Among which, 8 differentially expressed miRNAs including hsa-miR-150-5p, hsa-miR-326, hsa-miR-144-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-125a-5p, hsa-let-7e-5p and hsa-miR-381-3p and their target mRNAs (PRKCA, SP1, TP53, SLC27A4, PDE1B, EPHB3, IRS1, HIF1A, MTUS1 and ZNF652) were found associated with deep venous thrombosis for the first time. Interestingly, PDE1B and IRS1 had a potential diagnostic value for patients. Additionally, 3 important signaling pathways including p53, PI3K-Akt and MAPK were identified in the enrichment analysis of target mRNAs (TP53, PRKCA and IRS1). Identified circulating miRNAs and target mRNAs and related signaling pathways may be involved in the process of deep venous thrombosis.

CXCR4, regulated by HIF1A, promotes endometrial breakdown via CD45+ leukocyte recruitment in a mouse model of menstruation.

Menstruation is a specific physiological phenomenon in female humans that is regulated by complex molecular mechanisms. However, the molecular network involved in menstruation remains incompletely understood. Previous studies have suggested that C-X-C chemokine receptor 4 (CXCR4) is involved; however, how CXCR4 participates in endometrial breakdown remains unclear, as do its regulatory mechanisms. This study aimed to clarify the role of CXCR4 in endometrial breakdown and its regulation by hypoxia-inducible factor-1 alpha (HIF1A). We first confirmed that CXCR4 and HIF1A protein levels were significantly increased during the menstrual phase compared with the late secretory phase using immunohistochemistry. In our mouse model of menstruation, real-time PCR, western blotting, and immunohistochemistry showed that CXCR4 mRNA and protein expression levels gradually increased from 0 to 24 h after progesterone withdrawal during endometrial breakdown. HIF1A mRNA and HIF1A nuclear protein levels significantly increased and peaked at 12 h after progesterone withdrawal. Endometrial breakdown was significantly suppressed by the CXCR4 inhibitor AMD3100 and the HIF1A inhibitor 2-methoxyestradiol in our mouse model, and HIF1A inhibition also suppressed CXCR4 mRNA and protein expression. In vitro studies using human decidual stromal cells showed that CXCR4 and HIF1A mRNA expression levels were increased by progesterone withdrawal and that HIF1A knockdown significantly suppressed the elevation in CXCR4 mRNA expression. CD45+ leukocyte recruitment during endometrial breakdown was suppressed by both AMD3100 and 2-methoxyestradiol in our mouse model. Taken together, our preliminary findings suggest that endometrial CXCR4 expression is regulated by HIF1A during menstruation and may promote endometrial breakdown, potentially via leukocyte recruitment.

First American Cancer Patient to Receive Dicycloplatin (DCP) Chemotherapy Achieves Remission After Seven Weeks of DCP Capsules - A Case Report.

BACKGROUND: The majority of bladder cancer patients experience recurrence. Cisplatin is the standard chemotherapy for muscle-invasive bladder cancer though adverse effects are often severe. CASE REPORT: Intravenous (IV) dicycloplatin (DCP) sustained remission in an American bladder cancer patient for five years. A recurrent mass was observed in July 2021. The patient received DCP capsules for seven weeks with no significant side-effects. Complete blood count with differential and a basic metabolic panel showed no adverse effects of DCP capsules on the bone marrow, liver or renal parameters. Cystoscopy after oral DCP found no evident bladder tumors; cytology was negative for high-grade urothelial carcinoma. CONCLUSION: In this patient, DCP-capsules appeared to be as effective as DCP-IV for achieving bladder cancer remission. Both forms of DCP chemotherapy are convenient, active against several cancer types, with decreased adverse effects compared to cisplatin. Both have been available for treating cancer patients in China. A USA clinical trial of DCP in bladder and other cancers appears warranted.

Adverse Effects Profile of Dicycloplatin (DCP) Offers Chemotherapeutic Advantage Over Cisplatin and Carboplatin.

BACKGROUND/AIM: Platinum-based chemotherapy often fails due to its severe adverse effects. The aim of this study was to examine the adverse effects profile and efficacy of dicycloplatin and compare them to those of cisplatin and carboplatin. MATERIALS AND METHODS: Cystoscopy surveillance of the first American cancer patient treated with dicycloplatin was performed quarterly. In vitro and in vivo studies were conducted using immunoblotting and flow cytometry to assess immune status of spleen and bone marrow of mice treated with dicycloplatin, cisplatin and carboplatin. RESULTS: The American patient did not suffer clinically significant myelosuppression; dicycloplatin has sustained remission in this patient to date. Experimental studies showed that dicycloplatin is less toxic to bone marrow and spleen of mice than cisplatin and carboplatin. CONCLUSION: Dicycloplatin is a promising drug in cancer chemotherapy with less aggressive side-effects than those typically associated with cisplatin and carboplatin. This is an important therapeutic advantage in cancer chemotherapy. Clinical investigation of dicycloplatin as an alternative to cisplatin or carboplatin is warranted.

Determination methods for the anticancer drug dicycloplatin, a supramolecule assembled through hydrogen bonding.

Dicycloplatin is a new generation supramolecular platinum-containing anti-cancer drug. Due to its structure, it is difficult to differentiate dicycloplatin from physical mixtures of carboplatin and cyclobutane dicarboxylate, and confounding results may arise during drug characterization. To solve this problem, this study aims to provide a reliable and reproducible standard for the determination of dicycloplatin. A simple method for dicycloplatin quality control has been developed using X-ray powder diffraction (XRPD) and high performance liquid chromatography (HPLC). XRPD allowed the control of impurities and dissociation of the dicycloplatin active ingredient to less than 1%, and HPLC allowed the monitoring and control of the relative molar ratio of carboplatin and cyclobutane dicarboxylate within the purity range. The study proved for the first time that the dicycloplatin supramolecule is substantially different from a physical mixture of carboplatin and cyclobutane dicarboxylate.

A double-blind, randomized phase II study of dicycloplatin plus paclitaxel versus carboplatin plus paclitaxel as first-line therapy for patients with advanced non-small-cell lung cancers.

INTRODUCTION: The aim of this study was to compare the efficacy and toxicity of dicycloplatin plus paclitaxel with those of carboplatin plus paclitaxel as first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS: In this study, 240 NSCLC patients with stage IIIB (with pleural effusion) and stage IV disease were randomly assigned (1: 1) to receive dicycloplatin 450 mg/m(2) or carboplatin AUC = 5, in combination with paclitaxel 175 mg/m(2) (D + P or C + P) every 3 weeks for up to 4 to 6 cycles. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. RESULTS: The response rates for the D + P and C + P arm were 36.44% and 30.51%, respectively (p = 0.33). The median PFS was 5.6 months in the D + P arm and 4.7 months in the C + P arm (p = 0.31). The median OS was 14.9 months for D + P and 12.9 months for C + P (p = 0.37). Adverse events in the two arms were well balanced. The most common grade 3/4 adverse event was hematologic toxicity. CONCLUSIONS: Patients treated with D + P had similar response and survival rates to those treated with C + P, and toxicities of both treatments were generally tolerable.

Dicycloplatin, a novel platinum analog in chemotherapy: synthesis of chinese pre-clinical and clinical profile and emerging mechanistic studies.

Dicycloplatin (DCP) has better solubility and stability than both cisplatin and carboplatin. Pre-clinical and phase I studies demonstrated significant antitumor activity and fewer adverse events than carboplatin. Phase II clinical trials in advanced non-small cell lung cancer found efficacy and safety of DCP-plus-paclitaxel comparable to carboplatin-plus-paclitaxel but better tolerability. This article summarizes and reviews pre-clinical and clinical data for dicycloplatin from the Chinese medical literature. We also report on new mechanistic findings in our laboratory in West Virginia, USA. Patient blood samples were collected for DCP-prototype determination by liquid chromatography mass spectrometry (LC-MS/MS). Molecular studies of ovarian cancer cells treated with DCP or cisplatin were carried out for gene-signature profiling using immunoblotting. Pharmacokinetic mass-spectrometry showed different spectrum profiles of DCP and carboplatin in plasma. Plasma concentration of DCP prototype was 17.1 µg/ml 2h after administration, with a peak concentration of 26.9 µg/ml at 0.5 h. Immunoblotting showed DCP-induced activation of DNA damage pathways, including double-phosphorylated checkpoint kinase 2 (CHK2) and breast cancer 1 (BRCA1) and triple-phosphorylated p53, compared to controls. Cisplatin produced a similar profile, with increased p53 protein. DCP and cisplatin activate DNA-damage response through similar pathways. DCP may be more soluble and stable, and better-tolerated.

Phase I clinical trial of the novel platin complex dicycloplatin: clinical and pharmacokinetic results.

UNLABELLED: TRANSLATIONAL RELEVANCE: Dicycloplatin (DCP) is a novel super molecule composed of carboplatin (CBP) and 1,1-cyclobutane dicarboxylate (CBDCA) joined by a strong hydrogen bond. The solubility and stability of platinum complexes have a direct bearing on their activity, toxicity and pharmacokinetics. Preclinical studies have shown that DCP overcomes the problem of CBP instability in aqueous solution and maintains anticancer effects. Clinical evaluation in a Phase I dose-escalation study in patients with tumors showed that DCP was tolerated at doses ranging from 100 to 550 mg/m(2) and had potential efficacy in Chinese cancer patients. DCP showed favourable bioavailability and stability in vivo, and the recommended Phase II dosage for DCP-containing chemotherapy is 450 mg/m(2). DCP is currently being investigated as a monotherapy in several cancer types, such as prostatic carcinoma, and in combination with paclitaxel in a Phase II non-lung cancer study. PURPOSE: Dicycloplatin (DCP) is a novel supramolecule composed of carboplatin (CBP) and 1,1-cyclobutane dicarboxylate (CBDCA) joined by a strong hydrogen bond. DCP is stable in aqueous solution unlike CBP alone. The purpose of this study was to assess the maximally tolerated dose, safety, and pharmacokinetics of DCP in Chinese cancer patients. EXPERIMENTAL DESIGN: 29 patients were included in this study. DCP was administered by intravenous infusion over 1 hour once every 21 days. The dose of DCP was escalated from 50 mg/m(2) to 650 mg/m(2) using a modified Fibonacci scheme. Pharmacokinetic analysis was performed in 26 patients to determine the total and ultrafiltered platinum concentrations in plasma. RESULTS: 29 and 20 patients were evaluated for toxicities and response, respectively. The primary adverse effects were nausea/vomiting (58.6%), thrombocytopenia (24.1%), neutropenia (17.2%), anemia (20.7%), fatigue (10.3%), anorexia (10.3%), liver enzyme elevation (10.3%) and alopecia (3.5%). There was no significant toxicity with doses up to 350 mg/m(2). At higher doses, a variety of dose-limiting toxicities (DLTs) were observed, including Grade 3/4 anemia, Grade 3/4 thrombocytopenia, and Grade 3/4 emesis under antiemetic treatment. The maximum tolerated dose of DCP was 550 mg/m(2). Two partial responses occurred in patients with non-cell lung cancer who had received cisplatin- or carboplatin-based chemotherapy. Plasma decay of total and free platinum concentrations was best fitted by using a twocompartment analysis. The terminal plasma half-life of total platinum after DCP administration ranged from 41.86 to 77.20 hours without significant dose dependency. However, the terminal plasma half-life of free platinum concentrations ranged from 42.34 to 61.07 hours. CONCLUSIONS: DCP displayed a favorable safety profile at doses between 50 mg/m(2) and 550 mg/m(2), and first efficacy signals were observed. DLTs were thrombocytopenia, anemia and emesis. The recommended starting dose for a subsequent Phase II study is 450 mg/m(2) once every 3 weeks.

[Study on spectra properties of novel octa-substituted phthalocyanines].

The spectrum properties of four novel 1, 4, 8, 11, 15, 18, 22, 25-octaoxybutyl copper phthalocyanine; 1,4,8,11,15,18, 22, 25-octamethoxybutanoate manganese phthalocyanine; 1, 4, 8, 11, 15, 18, 22, 25-octamethoxybutanoate copper phthalocyanine; 1, 4, 8, 11, 15, 18, 22, 25-octamethoxybutanoate zinc phthalocyanine were investigated by infrared, fluorescence and UV-visible spectrum in the the paper. There is no rule in the infrared spectrum of these octa-substituted phthalocyanines. The orders of the Q band, B band and Pc dimer band are different among the above Octa-substituted Phthalocyanines in the UV and fluorescence spectra. The reason is related to the interaction between the ligand and the central metal of these octa-substituted phthalocyanines.