Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

BACKGROUND: Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. METHODOLOGY/PRINCIPLE FINDINGS: EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). CONCLUSIONS/SIGNIFICANCE: Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted, doxorubicin-loaded minicells for effective treatment of human patients with recurrent glioblastoma

Sexual and Cardiovascular health.Factors Influencing on the Quality of Sexual Life of Coronary Heart Disease Patients - a Narrative Review

Magdalena Piegza,1 Joanna Smolarczyk,2 Jacek Piegza3 1Department of Psychiatry, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Tarnowskie Gory, Poland; 2Department of Psychoprophylaxis, Medical University of Silesia, Tarnowskie Góry, Poland; 3Third Department of Cardiology, Faculty of Medical Sciences in Zabrze, Silesian Center for Heart Diseases, Medical University of Silesia, Zabrze, PolandCorrespondence: Joanna Smolarczyk, Email [email protected]: Regular sexual activity is comparable to moderate exercise and may be safe for patients with cardiovascular disease (CVD). According to the recommendations of the Princeton III Conference (P3), people with a low risk of adverse cardiac events can undertake sexual activity safely, while other patients must first stabilise their cardiovascular status. Exercise testing is recommended to assess the safety of sexual activity in people with questionable or uncertain cardiac risk (P3). Patients after successful and uncomplicated treatment of myocardial infarction (MI) can return to sexual activity after 3 weeks if the stress test is negative. The 4th Princeton Conference (P4) recommends the use of the 2019 regimen developed by the American College of Cardiology (ACC) and American Heart Association (AHA) to assess the risk of atherosclerotic cardiovascular disease (ASCVD) in men with ED (ACC/AHA ASCVD 2019). Sexual health education plays an important role in the successful return to safe sexual activity, which should include post-MI patients and their relatives. The responsibility for counselling lies with cardiologists, general practitioner (GP) and nursing staff. Sexual rehabilitation should be an integral part of cardiac rehabilitation, and lifestyle modification and optimal treatment of underlying medical conditions are key to maintaining psychophysical well-being and a successful sex life.Keywords: sexual activity, cardiovascular risk factors, erectile dysfunction, Princeton consensus, myocardial infarctio

Combined Tumor Cell-Based Vaccination and Interleukin-12 Gene Therapy Polarizes the Tumor Microenvironment in Mice

Tumor progression depends on tumor milieu, which influences neovasculature formation and immunosuppression. Combining immunotherapy with antiangiogenic/antivascular therapy might be an effective therapeutic approach. The aim of our study was to elaborate an anticancer therapeutic strategy based on the induction of immune response which leads to polarization of tumor milieu. To achieve this, we developed a tumor cell-based vaccine. CAMEL peptide was used as a B16-F10 cell death-inducing agent. The lysates were used as a vaccine to immunize mice bearing B16-F10 melanoma tumors. To further improve the therapeutic effect of the vaccine, we combined it with interleukin (IL)-12 gene therapy. IL-12, a cytokine with antiangiogenic properties, activates nonspecific and specific immune responses. We observed that combined therapy is significantly more effective (as compared with monotherapies) in inhibiting tumor growth. Furthermore, the tested combination polarizes the tumor microenvironment, which results in a switch from a proangiogenic/immunosuppressive to an antiangiogenic/immunostimulatory one. The switch manifests itself as a decreased number of tumor blood vessels, increased levels of tumor-infiltrating CD4+, CD8+ and NK cells, as well as lower level of suppressor lymphocytes (Treg). Our results suggest that polarizing tumor milieu by such combined therapy does inhibit tumor growth and seems to be a promising therapeutic strategy

Thermal-Derivative Analysis and Precipitation Hardening of the Hypoeutectic Al-Si-Cu Alloys

The research focused on the influence of the solution temperature on the structure of precipitation hardening multi-component hypoeutectic aluminium alloys. The AlSi8Cu3 and AlSi6Cu4 alloys were used in the study and were subjected to a thermal-derivative analysis. The chemical composition and crystallization of phases and eutectics shift the characteristic points and the corresponding temperatures to other values, which affect to, for instance, the solution temperature. The alloys were supersaturated at 475°C (according to the determined temperature (TSol) and 505°C for 1.5 hours. Aging was performed at 180°C for 5 hours. The Rockwell hardness measurement, metallographic analysis of alloys by means of light microscopy as well as chemical and phase analysis using scanning electron microscopy and X-ray crystallography were carried out on alloys. The use of computer image analysis enabled the determination of the amount of the current Al2Cu phase in the alloys before and after heat treatment

Identification of Building Wall Orientation Angle with Multilook Synthetic Aperture Radars Processing

A new technique of identifying orientation angles of walls of buildings has been proposed in this paper. The present method is based on multilook processing. The aim of this work is to find the relationships between the received signals reflected from uniform targets (e.g. walls, parts of buildings, etc.) positioned at different orientation angles towards the radar platform. The technique is dedicated for synthetic aperture radars systems. It can be used to extend target identification in synthetic aperture radars images obtained by a single-channel antenna. In this paper, theoretical analysis is presented and verified with simulated radar data

Chronic Low Grade Inflammation in Pathogenesis of PCOS

Polycystic ovary syndrome (PCOS) is a one of the most common endocrine disorders, with a prevalence rate of 5–10% in reproductive aged women. It’s characterized by (1) chronic anovulation, (2) biochemical and/or clinical hyperandrogenism, and (3) polycystic ovarian morphology. PCOS has significant clinical implications and can lead to health problems related to the accumulation of adipose tissue, such as obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. There is also evidence that PCOS patients are at higher risk of cardiovascular diseases, atherosclerosis, and high blood pressure. Several studies have reported the association between polycystic ovary syndrome (PCOS) and low-grade chronic inflammation. According to known data, inflammatory markers or their gene markers are higher in PCOS patients. Correlations have been found between increased levels of C-reactive protein (CRP), interleukin 18 (IL-18), tumor necrosis factor (TNF-α), interleukin 6 (IL-6), white blood cell count (WBC), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) in the PCOS women compared with age- and BMI-matched controls. Women with PCOS present also elevated levels of AGEs and increased RAGE (receptor for advanced glycation end products) expression. This chronic inflammatory state is aggravating by obesity and hyperinsulinemia. There are studies describing mutual impact of hyperinsulinemia and obesity, hyperandrogenism, and inflammatory state. Endothelial cell dysfunction may be also triggered by inflammatory cytokines. Many factors involved in oxidative stress, inflammation, and thrombosis were proposed as cardiovascular risk markers showing the endothelial cell damage in PCOS. Those markers include asymmetric dimethylarginine (ADMA), C-reactive protein (CRP), homocysteine, plasminogen activator inhibitor-I (PAI-I), PAI-I activity, vascular endothelial growth factor (VEGF) etc. It was also proposed that the uterine hyperinflammatory state in polycystic ovary syndrome may be responsible for significant pregnancy complications ranging from miscarriage to placental insufficiency. In this review, we discuss the most importance evidence concerning the role of the process of chronic inflammation in pathogenesis of PCOS.</jats:p