Factors associated with obesity alter matrix remodeling in breast cancer tissues

PubMed: 31983145Obesity is associated with a higher risk of developing breast cancer and with worse disease outcomes for women of all ages. The composition, density, and organization of the breast tissue stroma are also known to play an important role in the development and progression of the disease. However, the connections between obesity and stromal remodeling are not well understood. We sought to characterize detailed organization features of the collagen matrix within healthy and cancerous breast tissues acquired from mice exposed to either a normal or high fat (obesity inducing) diet. We performed second-harmonic generation and spectral two-photon excited fluorescence imaging, and we extracted the level of collagen-associated fluorescence (CAF) along with metrics of collagen content, three-dimensional, and two-dimensional organization. There were significant differences in the CAF intensity and overall collagen organization between normal and tumor tissues; however, obesity-enhanced changes in these metrics, especially when three-dimensional organization metrics were considered. Thus, our studies indicate that obesity impacts significantly collagen organization and structure and the related pathways of communication may be important future therapeutic targets.

Gemcitabine hydrochloride microspheres used for intravesical treatment of superficial bladder cancer: a comprehensive in vitro/ex vivo/in vivo evaluation

Sinem Yaprak Karavana,1 Zeynep Ay Şenyiğit,2 Çağrı Çalışkan,3 Gülnur Sevin,4 Derya İlem Özdemir,2 Yalçın Erzurumlu,5 Sait Şen,6 Esra Baloğlu1 1Department of Pharmaceutical Technology, Faculty of Pharmacy, Ege University, Izmir, Turkey; 2Department of Pharmaceutical Technology, Faculty of Pharmacy, Izmir Katip Çelebi University, Izmir, Turkey; 3Department of Radiopharmacy, Faculty of Pharmacy, Ege University, Izmir, Turkey; 4Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Turkey; 5Department of Biochemistry, Faculty of Pharmacy, Ege University, Izmir, Turkey; 6Department of Pathology, Faculty of Medicine, Ege University, Izmir, Turkey Introduction: Bladder cancer is responsible for more than 130,000 deaths annually worldwide. Intravesical delivery of chemotherapeutic agents provides effective drug localization to the target area to reduce toxicity and increase efficacy. This study aimed to develop an intravesical delivery system of gemcitabine HCl (Gem-HCl) to provide a sustained-release profile, to prolong residence time, and to enhance its efficiency in the treatment of bladder cancer. Materials and methods: For this purpose, bioadhesive microspheres were successfully prepared with average particle size, encapsulation efficiency, and loading capacity of 98.4 μm, 82.657%±5.817%, and 12.501±0.881 mg, respectively. For intravesical administration, bioadhesive microspheres were dispersed in mucoadhesive chitosan or in situ poloxamer gels and characterized in terms of gelation temperature, viscosity, mechanical, syringeability, and bioadhesive and rheological properties. The cytotoxic effects of Gem-HCl solution, Gem-HCl microspheres, and Gem-HCl microsphere-loaded gel formulations were evaluated in two different bladder cancer cell lines: T24 (ATCC HTB4TM) and RT4 (ATCC HTB2TM). Results: According to cell-culture studies, Gem-HCl microsphere-loaded poloxamer gel was more cytotoxic than Gem-HCl microsphere-loaded chitosan gel. Antitumor efficacy of newly developed formulations were investigated by in vivo studies using bladder-tumor-induced rats. Conclusion: According to in vivo studies, Gem-HCl microsphere-loaded poloxamer gel was found to be an effective and promising alternative for current intravesical delivery-system therapies. Keywords: gemcitabine HCl, intravesical chemotherapy, superficial bladder cancer microspheres, mucoadhesive gel, in situ ge

Design and evaluation of an intravesical delivery system for superficial bladder cancer: preparation of gemcitabine HCl-loaded chitosan–thioglycolic acid nanoparticles and comparison of chitosan/poloxamer gels as carriers

Zeynep Ay Şenyiğit,1 Sinem Yaprak Karavana,1 Derya İlem-Özdemir,2 Çağrı Çalışkan,2 Claudia Waldner,3 Sait Şen,4 Andreas Bernkop-Schnürch,5 Esra Baloğlu1 1Faculty of Pharmacy, Department of Pharmaceutical Technology, Ege University, Bornova, İzmir, Turkey; 2Faculty of Pharmacy, Department of Radiopharmacy, Ege University, Bornova, İzmir, Turkey; 3ThioMatrix, Forschungs-Beratungs GmbH, Innsbruck, Austria; 4Faculty of Medicine, Department of Pathology, Ege University, Bornova, İzmir, Turkey; 5Institute of Pharmacy, Department of Pharmaceutical Technology, University of Innsbruck, Innsbruck, AustriaAbstract: This study aimed to develop an intravesical delivery system of gemcitabine HCl for superficial bladder cancer in order to provide a controlled release profile, to prolong the residence time, and to avoid drug elimination via urination. For this aim, bioadhesive nanoparticles were prepared with thiolated chitosan (chitosan–thioglycolic acid conjugate) and were dispersed in bioadhesive chitosan gel or in an in situ gelling poloxamer formulation in order to improve intravesical residence time. In addition, nanoparticle-loaded gels were diluted with artificial urine to mimic in vivo conditions in the bladder and were characterized regarding changes in gel structure. The obtained results showed that chitosan-thioglycolic acid nanoparticles with a mean diameter of 174.5±3.762 nm and zeta potential of 32.100±0.575 mV were successfully developed via ionotropic gelation and that the encapsulation efficiency of gemcitabine HCl was nearly 20%. In vitro/ex vivo characterization studies demonstrated that both nanoparticles and nanoparticle-loaded chitosan and poloxamer gels might be alternative carriers for intravesical administration of gemcitabine HCl, prolonging its residence time in the bladder and hence improving treatment efficacy. However, when the gel formulations were diluted with artificial urine, poloxamer gels lost their in situ gelling properties at body temperature, which is in conflict with the aimed formulation property. Therefore, 2% chitosan gel formulation was found to be a more promising carrier system for intravesical administration of nanoparticles. Keywords: chitosan–TGA, nanoparticle, gemcitabine HCl, intravesical administration, chitosan, poloxamer, superficial bladder cance

A Design and Evaluation of Layered Matrix Tablet Formulations of Metoprolol Tartrate

The aim of this paper was to evaluate the performance of different swellable polymers in the form of layered matrix tablets to provide controlled therapeutic effect of metoprolol tartrate for twice daily administration. Seven different swellable polymers (carrageenan, hydroxypropylmethyl cellulose, pectin, guar gum, xanthan gum, chitosan, and ethyl cellulose) were evaluated alone or in combination as release-retardant layer. Tablets were tested for weight variation, hardness, diameter/thickness ratio, friability, and drug content uniformity and subjected to in vitro drug-release studies. In addition, the target-release profile of metoprolol tartrate was plotted using its clinical pharmacokinetic data, and the release profiles of the tablets were evaluated in relation to the plotted target release profile. Carrageenan was determined as the best polymer in two-layered matrix tablet formulations due to its better accordance to the target release profile and was selected for preparing three-layered matrix tablets. Carrageenan formulations exhibited super case II release mechanism. Accelerated stability testing was performed on two- and three-layered matrix tablet formulations of carrageenan. The tablets were stored at 25°C/60% relative humidity and 40°C/75% relative humidity for 6 months and examined for physical appearance, drug content, and release characteristics. At the end of the storage time, formulations showed no change either in physical appearance, drug content, or drug-release profile. These results demonstrated the suitability of three-layered tablet formulation of carrageenan to provide controlled release and improved linearity for metoprolol tartrate in comparison to two-layered tablet formulation

Individual Differences In The Relationship Between Attachment And Nomophobia Among College Students: The Mediating Role Of Mindfulness

Background There is a growing interest in nomophobia, which is defined as the fear of being out of cellular phone contact, or "feelings of discomfort or anxiety experienced by individuals when they are unable to use their mobile phones or utilize the affordances these devices provide”. However, only limited research can be found in terms of its determinants at present. Contemporary literature suggests that the relationships among attachment styles, mindfulness, and nomophobia have not been investigated. Objective This study aims to investigate the mediating effect of mindfulness on the relationship between attachment and nomophobia. In addition, the study also focuses on gender differences in attachment, mindfulness, and nomophobia. A theory-based structural model was tested to understand the essentials of the associations between the constructs. Methods The Experiences in Close Relationships Scale, Nomophobia Questionnaire, and Mindful Attention Awareness Scale were used to collect data from undergraduate students (N=450; 70.9% women [319/450]; mean age=21.94 years [SD 3.61]). Two measurement models (ie, attachment and mindfulness) and a structural model were specified, estimated, and evaluated. Results The structural equation model shows that the positive direct effects of avoidant (.13, P=.03) and anxious attachment (.48, P<.001) on nomophobia were significant. The negative direct effects of avoidant (?.18, P=.01) and anxious attachment (?.33, P<.001) on mindfulness were also significant. Moreover, mindfulness has a significant negative effect on nomophobia for women only (?.13, P=.03). Finally, the Sobel test showed that the indirect effects of avoidant and anxious attachment on nomophobia via mindfulness were significant (P<.001). The direct and indirect effects of anxious attachment, avoidant attachment, and mindfulness altogether accounted for 33% of the total variance in nomophobia. Gender comparison results show that there is a significant difference in attachment based on gender (F2,447=6.97, P=.01, Wilk ?=.97, partial ?2=.03). Women (mean 68.46 [SD 16.96]) scored significantly higher than men (mean 63.59 [SD 15.97]) in anxious attachment (F1=7.93, P=.01, partial ?2=.02). Gender differences in mindfulness were not significant (F4,448=3.45, P=.69). On the other hand, results do show significant gender differences in nomophobia (F4,445=2.71, P=.03, Wilk ?=.98, partial ?2=.02) where women scored significantly higher than men. Conclusions In general, individuals who are emotionally more dependent and crave more closeness and attention in the relationship tend to display higher levels of fear or discomfort when they have no access to their mobile phones. However, gender has a differential impact on the relationship between avoidant attachment and nomophobia. This study establishes the impact of mindfulness on nomophobia for women; therefore, future studies should test the effectiveness of mindfulness-based therapy approaches and confirm whether they are effective and efficient. On the basis of significant gender difference in nomophobia and attachment, we conclude that gender should be taken into account in mindfulness-based treatments dealing with nomophobia.PubMedWoSScopu