Interleukin 12-based immunotherapy improves the antitumor effectiveness of a low-dose 5-Aza-2'-deoxycitidine treatment in L1210 leukemia and B16F10 melanoma models in mice.

PURPOSE: Recent findings indicating that many genes related to cancer development are silenced by an aberrant DNA methylation suggest that inhibitors of this process may be effective cancer therapeutics. In this study we investigated the efficacy of low-dose 5-aza-2'-deoxycitydine (DAC), a methylation inhibitor, with interleukin (IL) 12, one of the most potent cytokines with antitumor activity. Experimental Design: Mice inoculated with L1210 leukemia cells or with B16F10 melanoma cells were treated with 7 daily injections of low-dose DAC (0.2 mg/kg) and/or 7 daily doses of IL-12 (100 ng/dose). Scid/scid mice as well as monoclonal antibodies against CD4, CD8, and NK1.1 were used to investigate the mechanisms of the antitumor effects of the combination treatment. The activity of murine lymphocytes was measured with enzyme-linked immunospot and (51)Cr release assays. RESULTS: Treatment with DAC or IL-12 given alone produced moderate antitumor effects. In both tumor models combined treatment resulted in potentiated antitumor effects and produced 70% long-term survivors among mice inoculated with L1210 cells. The antitumor efficacy of combined treatment was abrogated in scid/scid mice, and after depletion of CD4(+) and CD8(+) T cells. Mice inoculated with B16F10 melanoma cells had significantly delayed tumor growth after combined treatment with DAC and IL-12. Strong antitumor effect correlated with a significant activation of lymph node-derived CD8(+) and CD4(+) cells. Transient neutropenia was observed in mice under treatment of DAC alone, but remarkably this effect was not potentiated by IL-12. CONCLUSIONS: This study provides the first evidence that antitumor effects of DAC can be strongly potentiated by IL-12 and could be beneficial in an effective low-dose-based antitumor therapy.     

Inhibition of cyclooxygenase-2 indirectly potentiates antitumor effects of photodynamic therapy in mice.

PURPOSE: The aim of the present study was to potentiate the antitumor effectiveness of photodynamic therapy (PDT). A cDNA microarray analysis was used to evaluate the gene expression pattern after Photofrin-mediated PDT to find more effective combination treatment with PDT and inhibitor(s) of the identified gene product(s) overexpressed in tumor cells. EXPERIMENTAL DESIGN: Atlas Mouse Stress Array was used to compare the expression profile of control and PDT-treated C-26 cells. The microarray results have been confirmed using Western blotting. Cytostatic/cytotoxic in vitro assay as well as in vivo tumor models were used to investigate the antitumor effectiveness of PDT in combination with cyclooxygenase (COX) 2 inhibitors. RESULTS: PDT induced the expression of 5 of 140 stress-related genes. One of these genes encodes for COX-2, an enzyme important in the tumor progression. Inhibition of COX-2 in vitro with NS-398, rofecoxib, or nimesulide, or before PDT with nimesulide did not influence the therapeutic efficacy of the treatment. Administration of a selective COX-2 inhibitor after PDT produced potentiated antitumor effects leading to complete responses in the majority of treated animals. CONCLUSIONS: COX-2 inhibitors do not sensitize tumor cells to PDT-mediated killing. However, these drugs can be used to potentiate the antitumor effectiveness of this treatment regimen when administered after tumor illumination.     

Inhibition of cell cycle and induction of apoptosis by 2‐oxoheksyl isothiocyanate and alyssin in cell lines carrying various inherited BRCA1 mutations

An important aspect of the chemopreventive activity of isothiocyanates (ITC) is their ability to induce cell growth inhibition and apoptosis. In this study, the effect of two sulforaphane analogues, 2‐oxoheksyl isothiocyanate and alyssin, on lymphoblastoid cells, derived from people carrying four different germ‐line mutations in BRCA1 gene, was tested and compared to the effect on wild type cells. The mutations studied were: C61G; 3819del5; 4153delA, and 5382INSC. Changes in cell viability and density after 2‐oxoheksyl isothiocyanate and alyssin treatment were evaluated, as well as cell cycle progression, mitochondrial membrane potential changes, and phosphatidylserine externalization. Both isothiocyanates were shown to reduce cell viability and density in all cell lines tested, as well as the change in cell cycle phase's distribution. The response of cells to two ITC tested was various, as well as mutation type‐modulated. We found that change of cellular maintenance by chemopreventive agents can be modulated by single allele BRCA1 mutation. Drug Dev. Res. 65:84–92, 2005. © 2005 Wiley‐Liss, Inc.     

Temperature in the Friction Couple Consisting of Functionally Graded and Homogeneous Materials

An analytical model was developed to determine the temperature of friction coupling, in which one element was made of a functionally graded material (FGM) and the other was homogeneous. First, for such a system, the boundary–value problem of heat conduction was formulated with consideration of the heat generation due to friction. Then, using the Laplace integral transform, an exact solution to this problem was obtained for uniform sliding, and braking with constant deceleration. A numerical analysis was performed for the selected friction pair consisting of the FGM (zircon dioxide + titanium alloy) and cast iron. It was established that the use of elements made of a FGM consisting of ZrO₂ and Ti-6Al-4V can significantly reduce the maximum temperature achieved in the friction system.     

Comparative Analysis of Postoperative Complications of Sentinel Node Identification Using the SentiMag® Method and the Use of a Radiotracer in Patients with Breast Cancer

(1) Background: The purpose of the study was a retrospective, comparative assessment of complications of the surgical sentinel node biopsy (SNB) procedure in breast cancer using the radiotracer method and the SentiMag^® method on groups of patients after 3.5 years of use. (2) Methods: The material was a group of 345 patients with primary surgical breast cancer who underwent the SNB procedure with the use of a radiotracer in combination with wide local excision (WLE), simple amputation (SA) with SNB and an independent SNB procedure in the period from May 2018 to January 2021 in the Department of Oncological Surgery. Of the patients who were monitored in the Hospital Outpatient Clinic, 300 were enrolled. The analyzed group was compared in terms of the occurrence of the same complications with the group of 303 patients also operated on in our center in the period from January 2014 to September 2017, in which SN identification was performed using the SentiMag^® method. (3) Results: The most common complications found were sensation disorders in the arm, which occurred in 16 (14.1%) patients using the radiotracer method, SentiMag^®-11 (9.9%). By comparing the complication rate between the methods with the radiotracer (n = 300) and SentiMag^® (n = 303), no significant differences were found. (4) Conclusions: Sentinel node (SN) identification using the radiotracer method and the SentiMag^® method are comparable diagnostic methods in breast cancer, with a low risk of complications.     

Conductive Layers on a Shrinkable PET Film by Flexographic Printing

In this study, the extremely important and difficult topic of flexographic printing on a heat-shrinkable substrate was taken up. Six commercially available, electrically conductive inks based on silver, copper and graphite nanoparticles were selected and tested upon their applicability for printing on the temperature-sensitive PET material. As a printing substrate, the one-direction heat-shrinkable PET film, with a maximum shrinkage of 78%, was selected. All of the examined inks were subjected to the printing process throughout three different anilox line screens. The tested inks, along with the electric paths printed with them, were subjected to various tests. The main parameters were evaluated, such as printability combined with the rheology tests and ink adhesion to the examined PET substrate together with the electrical conductivity before and after the shrinkage.     

Analgesic and anticonvulsant activity of new derivatives of 2-substituted 4-hydroxybutanamides in mice

Earlier in vitro studies of the compounds marked as GT27, GT28, GT29 and BM128 revealed their inhibitory action towards murine γ-aminobutyric acid (GABA) transporters (mGAT1-mGAT4). In the present paper, the pharmacological activity of four γ-hydroxybutyric acid (GHB) amide derivatives was investigated. The following procedures were involved: locomotor activity, hot plate and electroconvulsive threshold tests. The compounds' influence on motor coordination was evaluated in the chimney test, as well. Intraperitoneal (i.p.) administration of the GHB derivatives decreased animals' locomotor activity (ED(50) values ranged between 23.79 and 26.37 mg/kg). At a dose of 25 mg/kg (i.p.) the compounds prolonged the nociceptive reaction time latency in the hot plate assay to various degree and GT28 and GT29 were the most potent ones in this respect. Their analgesic efficacy was particularly pronounced 30 min after their administration [percent of maximal possible effect (%MPE) = 16.93 and 22.72, respectively]. The investigated GHB derivatives, except for GT29 at 100 mg/kg, increased the electroconvulsive threshold by approximately 4-11 mA as compared to the vehicle-treated mice. In the chimney test they impaired the animals' motor coordination to various degree. We suggest further investigations of the compounds to estimate their biological activity.     

An Evaluation of Nutritional Status and Problems with Dietary Compliance in Polish Patients with Celiac Disease

Celiac disease (CD, enteropathy) is a genetic autoimmune disease (abnormal immune response that attacks healthy tissues) associated with gluten intolerance. The aim of this study was to evaluate and monitor the nutritional status of CD patients, explore the problems associated with diet planning and dietary adherence among children and adults, and assess the impact of these factors on the persistence of CD symptoms. This study was carried out as part of the project entitled “A gluten-free diet without obstacles—eating well and healthy” (POWR 03.01.00-00-T153/18), conducted in Lublin Voivodeship. The study involved 87 persons, including 23 children younger than 18. At the beginning of the study and after nine months, all adult participants (older than 18) were subjected to a body composition analysis with the SECA mBCA 515 analyzer. During the project, the participants attended three consultations with a dietician. During each visit, the subjects’ body weight, nutritional status and diets were evaluated; their diets were modified, and problems relating to dietary adherence were resolved. The initial body composition analysis revealed a risk of sarcopenic obesity in 30% of adult participants, in particular in women (p = 0.003) older than 45 (p = 0.001). The risk of being underweight was diagnosed in 25% of the subjects, in particular, in women younger than 35 (p = 0.0023) and in participants who had been affected by short stature and underweight in childhood, i.e., before CD diagnosis (p = 0.0024). The analysis demonstrated that patients with gastrointestinal symptoms (abdominal pain, diarrhea, vomiting) of CD were significantly more likely to avoid even accidental exposure to gluten and were more likely to strictly follow GFD recommendations (1.97; 95CI:1.56–2.12, p = 0.0001) and safety guidelines when preparing meals at home (1.76; 95CI: 1.34–192, p = 0.0023). Parents, in particular, parents of toddlers and preschoolers who are at significantly higher risk of CD, adhered strictly to dietary guidelines and did not allow for any exceptions when preparing meals (1.88; 95CI: 1.53–2.09, p = 0.001). Persons at risk of malnutrition were also far less likely to deliberately choose gluten-containing foods (0.74; 95CI: 0.53–0.91, p = 0.021), in particular, patients with Marsh type 3a and 3b classification (p = 0.01) and persons whose intestinal histology scores did not fully improve after switching to a GFD. An assessment of the effectiveness of diet therapy based on the phase angle revealed that dietary recommendations had a positive impact on patients who had been recently diagnosed with CD. In all age groups, the main problem was accidental exposure to gluten, in particular in foods that were not labeled with the crossed grain symbol. A comparative analysis of CDAT questionnaires revealed that dietary advice on eating out significantly improved adherence to a GFD and reduced the frequency of unintentional gluten exposure in all age groups.