Light Directed Targeted Photodynamic Therapy of Breast Cancer

Breast cancer is the most prevalent cancer among women besides non-melanoma skin cancer. Even when caught in early stages, the treatment for breast cancer is often accompanied by harsh and debilitating side effects. For better quality of life, treatment options that have minimal side effects but maintain effectiveness are invaluable. If such a treatment option is a targeted form of therapy, it could selectively treat cancerous cells and not healthy cells. Photodynamic therapy (PDT) is a relatively new light-based therapy that utilizes inherent photochemical properties of certain dyes called photosensitizers (PS) in order to kill cancerous cells. It shows great promise as an alternative therapy for breast cancer with temporary photosensitivity as the only main side effect. The goal of this research was to make a molecularly targeted agent for photodynamic therapy of breast cancer by reliable and replicable methods. This was done through the use of a breast cancer targeting peptide called 18-4 discovered by Dr. Kamaljit Kaur, the synthesis of which was modified within our lab to be done on Sieber resin by solid phase peptide synthesis (SPPS). To this peptide, a tetra-pyrrole dye based on 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), was conjugated to form a molecularly targeted photosensitizer (MTPS). This was accomplished by two different approaches, the first by conjugation at the third residue of lysine on the 18-4 decapeptide. The second was by the addition of a puzzle piece based on a modular method developed earlier in our lab, which was the PS dye attached to side chain of a lysine residue. These two single modal compounds are the first reported MTPS agents that utilize 18-4 for the molecularly targeted photodynamic therapy of breast cancer and will be tested, along with a Cy5.5-3S analog of the MTPS agents, by our collaborators at the University of Rochester in the PDT of breast cancer models in mice

FAKTOR PERTIMBANGAN KONSUMEN DALAM PEMBELIAN SUSU BUBUK DI KOTA PADANG

ABSTRAK Penelitian ini bertujuan untuk mengetahui karakteristik pembelian konsumen dan atribut bauran pemasaran yang dipertimbangkan konsumen dalam keputusan pembelian susu bubuk di Kota Padang. Metode pengumpulan data menggunakan metode survei. Data yang digunakan adalah data primer dan data sekunder. Variabel yang diukur adalah karakteristik konsumen , karakteristik pembelian dan atribut bauran pemasaran yang dipertimbangkan dalam keputusan pembelian susu bubuk di Kota Padang. Metode analisis yang digunakan adalah deskriptif. Berdasarkan hasil penelitian bahwa karakteristik pembelian yaitu : Merek Susu bubuk yang banyak digunakan adalah Milo 28,00%, Frisian Flag 20,00%, Indomilk dan Dancow 12,00%, Anlene 10,00%, L Men 8,00%, WRP 5,00%, Prenagen 3,00% dan Lactamil 2,00%. Rasa susu bubuk yang banyak digunakan antara coklat dan vanila adalah sama yaitu 50,00%. Frekuensi pembelian susu perbulan yaitu satu kali 52,00%,dua kali perbulan 29,00%, tiga kali perbulan 13,00%, empat kali perbulan 6,00% dan alasan pembelian terbanyak adalah rasa enak 40,00%, nilai gizi tinggi 30,00%, kebiasaan mengkonsumsi 21,00%, harga terjangkau 9,00%. Sedangkan atribut bauran pemasaran yang dipertimbangkan dalam keputusan pembelian susu bubuk adalah 1). Harga, dengan persentase paling dipertimbangkan pada pertanyaan ketiga 60,00%. 2). Tempat pembelian, dengan persentase paling dipertimbangkan pada pertanyaan kedua 74,00%. 3). Produk, (rasa) dengan persentase paling dipertimbangkan pada pertanyaan kedua 100,00%, (kemasan) dengan persentase paling dipertimbangkan pada pertanyaan kedua 90,00%, (label) dengan persentase paling dipertimbangkan pada pertanyaan keempat 100,00%. 4). Promosi, dengan persentase paling dipertimbangkan pada pertanyaan ketiga 71,00%. Kata kunci : Karakteristik Pembelian, Atribut Bauran Pemasaran, Susu Bubuk

HOXA13 Is Essential for Placental Vascular Patterning and Labyrinth Endothelial Specification

In eutherian mammals, embryonic growth and survival is dependent on the formation of the placenta, an organ that facilitates the efficient exchange of oxygen, nutrients, and metabolic waste between the maternal and fetal blood supplies. Key to the placenta's function is the formation of its vascular labyrinth, a series of finely branched vessels whose molecular ontogeny remains largely undefined. In this report, we demonstrate that HOXA13 plays an essential role in labyrinth vessel formation. In the absence of HOXA13 function, placental endothelial cell morphology is altered, causing a loss in vessel wall integrity, edema of the embryonic blood vessels, and mid-gestational lethality. Microarray analysis of wild-type and mutant placentas revealed significant changes in endothelial gene expression profiles. Notably, pro-vascular genes, including Tie2 and Foxf1, exhibited reduced expression in the mutant endothelia, which also exhibited elevated expression of genes normally expressed in lymphatic or sinusoidal endothelia. ChIP analysis of HOXA13–DNA complexes in the placenta confirmed that HOXA13 binds the Tie2 and Foxf1 promoters in vivo. In vitro, HOXA13 binds sequences present in the Tie2 and Foxf1 promoters with high affinity (Kd = 27–42 nM) and HOXA13 can use these bound promoter regions to direct gene expression. Taken together, these findings demonstrate that HOXA13 directly regulates Tie2 and Foxf1 in the placental labyrinth endothelia, providing a functional explanation for the mid-gestational lethality exhibited by Hoxa13 mutant embryos as well as a novel transcriptional program necessary for the specification of the labyrinth vascular endothelia

EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice

Background We have previously shown that EphrinA1/EphA expression profile changes in response to myocardial infarction (MI), exogenous EphrinA1-Fc administration following MI positively influences wound healing, and that deletion of the EphA2 Receptor (EphA2-R) exacerbates injury and remodeling. To determine whether or not ephrinA1-Fc would be of therapeutic value in the hyperglycemic infarcted heart, it is critical to evaluate how ephrinA1/EphA signaling changes in the hyperglycemic myocardium in response to MI. Methods Streptozotocin (STZ)-induced hyperglycemia in wild type (WT) and EphA2-receptor mutant (EphA2-R-M) mice was initiated by an intraperitoneal injection of STZ (150 mg/kg) 10 days before surgery. MI was induced by permanent ligation of the left anterior descending coronary artery and analyses were performed at 4 days post-MI. ANOVAs with Student-Newman Keuls multiple comparison post-hoc analysis illustrated which groups were significantly different, with significance of at least p < 0.05. Results Both WT and EphA2-R-M mice responded adversely to STZ, but only hyperglycemic EphA2-R-M mice had lower ejection fraction (EF) and fractional shortening (FS). At 4 days post-MI, we observed greater post-MI mortality in EphA2-R-M mice compared with WT and this was greater still in the EphA2-R-M hyperglycemic mice. Although infarct size was greater in hyperglycemic WT mice vs normoglycemic mice, there was no difference between hyperglycemic EphA2-R-M mice and normoglycemic EphA2-R-M mice. The hypertrophic response that normally occurs in viable myocardium remote to the infarct was noticeably absent in epicardial cardiomyocytes and cardiac dysfunction worsened in hyperglycemic EphA2-R-M hearts post-MI. The characteristic interstitial fibrotic response in the compensating myocardium remote to the infarct also did not occur in hyperglycemic EphA2-R-M mouse hearts to the same extent as that observed in the hyperglycemic WT mouse hearts. Differences in neutrophil and pan-leukocyte infiltration and serum cytokines implicate EphA2-R in modulation of injury and the differences in ephrinA1 and EphA6-R expression in governing this are discussed. Conclusions We conclude that EphA2-mutant mice are more prone to hyperglycemia-induced increased injury, decreased survival, and worsened LV remodeling due to impaired wound healing

The genome-defence gene Tex19.1 suppresses LINE-1 retrotransposons in the placenta and prevents intra-uterine growth retardation in mice

DNA methylation plays an important role in suppressing retrotransposon activity in mammalian genomes, yet there are stages of mammalian development where global hypomethylation puts the genome at risk of retrotransposition-mediated genetic instability. Hypomethylated primordial germ cells appear to limit this risk by expressing a cohort of retrotransposon-suppressing genome-defence genes whose silencing depends on promoter DNA methylation. Here, we investigate whether similar mechanisms operate in hypomethylated trophectoderm-derived components of the mammalian placenta to couple expression of genome-defence genes to the potential for retrotransposon activity. We show that the hypomethylated state of the mouse placenta results in activation of only one of the hypomethylation-sensitive germline genome-defence genes: Tex19.1. Tex19.1 appears to play an important role in placenta function as Tex19.1(−/−) mouse embryos exhibit intra-uterine growth retardation and have small placentas due to a reduction in the number of spongiotrophoblast, glycogen trophoblast and sinusoidal trophoblast giant cells. Furthermore, we show that retrotransposon mRNAs are derepressed in Tex19.1(−/−) placentas and that protein encoded by the LINE-1 retrotransposon is upregulated in hypomethylated trophectoderm-derived cells that normally express Tex19.1. This study suggests that post-transcriptional genome-defence mechanisms are operating in the placenta to protect the hypomethylated cells in this tissue from retrotransposons and suggests that imbalances between retrotransposon activity and genome-defence mechanisms could contribute to placenta dysfunction and disease

Trophoblast attachment to the endometrial epithelium elicits compartment-specific transcriptional waves in an in-vitro model

Implantation is a major bottleneck in human reproduction (Polanski et al., 2014). The average implantation rate for an embryo ranges from 30% to 40% (Coughlan et al., 2014). Recurrent implantation failure (RIF) is estimated to occur in approximately 4% of IVF cycles (Koot et al., 2012), although estimates vary because there are several somewhat different definitions of RIF in the literature. Implantation of the blastocyst in the receptive endometrium is a sequential process involving apposition, attachment and invasion that precedes the establishment of pregnancy (Wang and Dey, 2006). Successful implantation requires embryo competence and endometrial receptivity, both of which are dynamic and highly regulated states (Wang and Dey, 2006). In addition to genetic disorders (which are a major cause of implantation failure and miscarriage), embryo competence, quality and ultimately developmental potential depend on the embryo achieving the correct regulatory, signalling and metabolic states (Fu et al., 2009; Hourvitz et al., 2006; Lundin et al., 2001; Simon and Laufer, 2012; Sjoblom et al., 2006). A key determinant of these embryonic states is their underlying transcriptional dynamics; for instance, waves of embryonic transcriptional activation direct early development and the symmetry breaking needed for cell fate specification (Shi et al., 2015; Vassena et al., 2011).info:eu-repo/semantics/publishedVersio