Paraneoplastic thrombocytosis in ovarian cancer

<p>Background: The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear.</p> <p>Methods: We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained.</p> <p>Results: Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumorderived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti–interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis.</p> <p>Conclusions: These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. </p&gt

Liraglutide Treatment in a Morbidly Obese Adolescent with a MC4R Gene Variant: Side Effects Reduce Success

Variants of the melanocortin-4 receptor (MC4R) gene are the most common cause of monogenic obesity. It has been shown that, while obesity cannot be controlled with diet and exercise, glucagon-like-peptide-1 receptor agonists (GLP-1 RA) provide weight loss in the short term. In this paper, our experience with liraglutide treatment in an adolescent patient carrying a MC4R gene variant is presented. A female patient was admitted first at the age of 12.5 years with a complaint of progressive weight gain. She had marked excess of appetite since infancy. On physical examination of the pubertal female patient with a body mass index (BMI) of 36.1 kg/m2 (3.48 standard deviation score), there was no pathological finding except diffuse acanthosis nigricans. Laboratory examinations revealed only insulin resistance. Weight loss was not achieved with lifestyle changes, metformin and orlistat treatments. On genetic examination, a sporadic heterozygous c.206T>G(p.I69R) variant that had been reported previously, was found in MC4R gene. Treatment with the GLP-1 RA, liraglutide, was initiated and a 19.2% reduction was achieved in the body weight and BMI at the end of 32 weeks. However, the patient, whose treatment compliance was disrupted due to significant gastrointestinal complaints, returned to her former weight within a few months (13 weeks) after treatment was stopped. In this case with a known pathogenic variant in MC4R gene, decrease of appetite and weight loss were achieved with liraglutide treatment, but side-effects of this treatment led to discontinuation of therapy. In such cases, there is need for effective and tolerable treatment options

Novel Mutations in Obesity-related Genes in Turkish Children with Non-syndromic Early Onset Severe Obesity: A Multicentre Study

Objective: Non syndromic monogenic obesity is a rare cause of early onset severe obesity in the childhood period. This form may not be distinguishable from other forms of severe obesity without genetic analysis, particularly if patients do not exibit any physical abnormalities or developmental delay. The aim of this study was to screen 41 different obesity-related genes in children with nonsyndromic early onset severe obesity. Methods: Children with severe (body mass index-standard deviation score >3) and early onset (<7 years) obesity were screened by next-generation sequencing based, targeted DNA custom panel for 41 known-obesity-related genes and the results were confirmed by Sanger technique. Results: Six novel variants were identified in five candidate genes in seven out of 105 children with severe obesity; two in SIM1 (p.W306C and p.Q36X), one in POMC (p.Y160H), one in PCSK1 (p.W130G fs Ter8), two in MC4R (p.D126E) and one in LEPR (p.Q4H). Additionally, two previously known variations in MC4R were identified in four patients (p.R165W in three, and p.V166I in one). Conclusion: We identified six novel and four previously described variants in six obesity-related genes in 11 out of 105 childrens with early onset severe obesity. The prevalence of monogenic obesity was 10.4% in our cohort.Inonu University Research Fundation, Malatya, TurkeyInonu University [TSG-2018-1137]This project was supported by Inonu University Research Fundation, Malatya, Turkey, project number: TSG-2018-1137

Cytotoxic activity and apoptosis induction by a series Ag(I)-NHC complexes on human breast cancer cells and non-tumorigenic epithelial cell line

The main problems encountered in treatment with anticancer drugs, undesired side effects, and toxicity. One of the most important parameters in cell transport is the lipophilic and solubility property of the drug. Enough with the potential effects, side effects with minimal demand for new anti-cancer compounds, mechanisms of action of the compound can meet because of increased efforts to be clarified. In this case, scientists were encouraged to do new research. In particular, the organometallic compounds are one of the topics focused lately. Ag(I)-NHC complexes are one of the most important classes of organometallic compounds. Although the anticancer activity of Ag(I)-NHC complexes have been known recently times, the anticancer effects of 2-morpholino ethyl substituted benzimidazolium derivative, lipophilic, and solubility properties. Ag(I)-NHC complexes have not unknown yet. Therefore, we aimed to investigate of cytotoxic effect and apoptosis mechanism on breast cancer cell lines (MCF7), breast adenocarcinoma cell lines (MDA-MB-231), and non-tumorigenic epithelium cell lines (MCF 10A) of new Ag(I)-NHC complexes that derivative from morpholine-linked benzimidazole, were synthesized and antimicrobial activity was determined in our previous study. The cytotoxicity was determined by the MTS method, and the apoptosis mechanisms were determined the cell cycle, Annexin V, and caspase-3 analysis. A new benzimidazolium salt bearing morpholino ethyl substituent (2) was synthesized. This benzimidazolium salt was characterized by NMR and FT-IR spectroscopic method and elemental analysis technique. Also, the structure of the new benzimidazolium salt was confirmed by single-crystal X-ray diffraction. Ag(I)-NHC complexes inhibited the growth of MCF7 and MDA-MB-231 cells depending on the dosage and time. The complexes 3a and 3b exhibited a significant difference p < 0.05; p < 0.001; and p < 0.001 level depend on depending on the increase in concentration on cancer cells. All compound induced by apoptosis was associated with stopping the cell cycle in phase G1 and the caspase-3 activity exhibited. The complex 3c was the lowest number of caspase-activating cells (2.1%) compared with both the control and other complexes in MDA-MB-231 cells. But the complex 3a was the highest number of caspase-activating cells (% 9.6). These findings have shown that these new Ag(I)-NHC complexes can be important new anticancer agents for breast cancer treatments. (C) 2020 Elsevier B.V. All rights reserved