Characterization and prognostic value of LXR splice variants in triple-negative breast cancer

Activity of liver x receptor (LXR), the homeostatic regulator of cholesterol metabolism, is elevated in triple-negative breast cancer (BCa) relative to other BCa subtypes, driving drug resistance and metastatic gene signatures. The loci encoding LXRα and LXRβ produce multiple alternatively spliced proteins, but the true range of variants and their relevance to cancer remain poorly defined. Here, we report seven LXR splice variants, three of which have not previously been reported and five that were prognostic for disease-free survival. Expression of full-length LXRα splice variants was associated with poor prognosis, consistent with a role as an oncogenic driver of triple-negative tumor pathophysiology. Contrary to this was the observation that high expression of truncated LXRα splice variants or any LXRβ splice variant was associated with longer survival. These findings indicate that LXR isoform abundance is an important aspect of understanding the link between dysregulated cholesterol metabolism and cancer pathophysiology

Phytosterols Inhibit Side-Chain Oxysterol Mediated Activation of LXR in Breast Cancer Cells

Low fruit and vegetable consumption and high saturated fat consumption causes elevated circulating cholesterol and are breast cancer risk factors. During cholesterol metabolism, oxysterols form that bind and activate the liver X receptors (LXRs). Oxysterols halt breast cancer cell proliferation but enhance metastatic colonization, indicating tumour suppressing and promoting roles. Phytosterols and phytostanols in plants, like cholesterol in mammals, are essential components of the plasma membrane and biochemical precursors, and in human cells can alter LXR transcriptional activity. Here, a panel of breast cancer cell lines were treated with four dietary plant sterols and a stanol, alone or in combination with oxysterols. LXR activation and repression were measured by gene expression and LXR-luciferase reporter assays. Oxysterols activated LXR in all cell lines, but surprisingly phytosterols failed to modulate LXR activity. However, phytosterols significantly inhibited the ability of oxysterols to drive LXR transcription. These data support a role for phytosterols in modulating cancer cell behaviour via LXR, and therefore suggest merit in accurate dietary recordings of these molecules in cancer patients during treatment and perhaps supplementation to benefit recovery

Liver x receptor alpha drives chemoresistance in response to side-chain hydroxycholesterols in triple negative breast cancer

Triple negative breast cancer (TNBC) is challenging to treat successfully because targeted therapies do not exist. Instead, systemic therapy is typically restricted to cytotoxic chemotherapy, which fails more often in patients with elevated circulating cholesterol. Liver x receptors are ligand-dependent transcription factors that are homeostatic regulators of cholesterol, and are linked to regulation of broad-affinity xenobiotic transporter activity in non-tumor tissues. We show that LXR ligands confer chemotherapy resistance in TNBC cell lines and xenografts, and that LXRalpha is necessary and sufficient to mediate this resistance. Furthermore, in TNBC patients who had cancer recurrences, LXRalpha and ligands were independent markers of poor prognosis and correlated with P-glycoprotein expression. However, in patients who survived their disease, LXRalpha signaling and P-glycoprotein were decoupled. These data reveal a novel chemotherapy resistance mechanism in this poor prognosis subtype of breast cancer. We conclude that systemic chemotherapy failure in some TNBC patients is caused by co-opting the LXRalpha:P-glycoprotein axis, a pathway highly targetable by therapies that are already used for prevention and treatment of other diseases

Perancangan Aplikasi Pemesanan Makanan Vegetarian Berbasis Web pada PT. Malindo Vegetama

09110058- Penggunaan sistem informasi pada masa kini telah merambat ke berbagai bidang, Perancangan aplikasi pemesanan online merupakan salah satu bentuk penggunaan teknologi informasi dalam bidang pemesanan. Disesuaikan dengan keadaan sistem yang telah berjalan di PT. Malindo Vegetama, pemesanan dilakukan secara manual. Untuk itu penulis berkesempatan merancang sistem aplikasi pemesanan online di PT. Malindo Vegetama sehingga diharapkan dapat membantu proses pencatatan menjadi lebih baik.Metodelogi perangkat lunak yang digunakan adalah metodologi air terjun (waterfall) yang memiliki tahap - tahap dalam perancangan sistem aplikasi pemesanan barang yaitu tahap defmisi keperluan, sistem dan desain perangkat lunak.Akhirnya, setelah menyelesaikan rancangan sistem persediaan ini, penulis memperoleh kesimpulan bahwa rancangan aplikasi ini telah berhasil dibuat berdasarkan spesifikasi yang diinginkan seperti pemesanan makanan, pembuatan laporan yang terkait, dan status pengiriman.xii, 72 p; 30 c

Perbaikan Tata Letak Gudang Kaleng Di Surabaya

PT.JAYA merupakan perusahaan yang bergerak di bidang manufaktur pembuatan kaleng berbagai ukuran untuk lem, thinner, dan cat. Meskipun memiliki gudang yang cukup luas, tata letak gudang kurang baik karena mencampur beberapa barang di satu area sehingga tidak dapat diketahui jumlah stok dan lokasi penyimpanan. Selain itu, lebar jalan menjadi terasa sempit karena barang jadi dan retur diletakkan di area distribusi. Akibat lainnya adalah terhambatnya proses produksi karena waktu pencarian dan pemindahan yang lama. Metode usulan untuk penataan gudang adalah metode dedicated storage dengan prioritas penyimpanan untuk seluruh bahan baku, retur dan stok tutup dan alas kaleng, serta prioritas pengambilan untuk barang jadi. Ada beberapa area yang diuji coba untuk area penyimpanan untuk mendapatkan jarak terpendek sesuai dengan prioritas masing-­‐masing barang. Penyimpanan bahan baku plat yang awalnya menempuh jarak 23.870 m menjadi 13.629 m. Untuk penyimpanan bahan baku kawat berubah dari 1.150,2 m menjadi 109,2 m. Untuk pengambilan bahan baku terdapat perubahan dari semula total jarak 1.574,6 m menjadi 1.583 m. Untuk penyimpanan barang jadi semula menempuh jarak 2.244,5 m menjadi 3312,2 m. Untuk pengambilan barang jadi semula jaraknya 37.884 m menjadi 17.046,8 m

Vertical etching with isolated catalysts in metal-assisted chemical etching of silicon

10.1039/c2nr32350hNanoscale4237532-753

Associations between liver X receptor polymorphisms and blood lipids: a systematic review and meta-analysis

Genetic susceptibility to dyslipidaemia remains incompletely understood. The liver X receptors (LXRs), members of the nuclear receptor superfamily of ligand dependent transcription factors, are homeostatic regulators of lipid metabolism. Multiple single nucleotide polymorphisms (SNPs) have been identified previously in the coding and regulatory regions of the LXRs. The aim of this systematic review and meta-analysis was to summarise associations between SNPs of LXRs (α and β isoforms) with blood lipid and lipoprotein traits. Five databases (PubMed, Ovid Embase, Scopus, Web of Science, and the Cochrane Library) were systematically searched for population-based studies that assessed associations between one or more blood lipid/lipoprotein traits and LXR SNPs. Of seventeen articles included in the qualitative synthesis, ten were eligible for meta-analysis. Nine LXRα SNPs and five LXRβ SNPs were identified, and the three most studied LXRα SNPs were quantitatively summarised. Carriers of the minor allele A of LXRα rs12221497 (-115G>A) had higher TG levels than GG homozygotes (0.13 mmol/L; 95%CI: [0.03, 0.23], P=0.01). Heterozygote carriers of LXRα rs2279238 (297C/T) had higher TC levels (0.12 mmol/L; (95%CI: [0.01, 0.23], P=0.04) than either CC or TT homozygotes. For LXRα rs11039155 (-6G>A), no significant differences in blood levels of either TG (P=0.39) or HDL-C (P=0.98) were detected between genotypes in meta-analyses. In addition, there were no strong associations for other SNPs of LXRα and LXRβ. This study provides the evidence of an association between LXRα, but not LXRβ, SNPs and blood-lipid traits. Systematic review registration: PROSPERO No. CRD4202124615

ER-Negative Breast Cancer Is Highly Responsive to Cholesterol Metabolite Signalling

Interventions that alter cholesterol have differential impacts on hormone receptor positive- and negative-breast cancer risk and prognosis. This implies differential regulation or response to cholesterol within different breast cancer subtypes. We evaluated differences in side-chain hydroxycholesterol and liver X nuclear receptor signalling between Oestrogen Receptor (ER)-positive and ER-negative breast cancers and cell lines. Cell line models of ER-positive and ER-negative disease were treated with Liver X Receptor (LXR) ligands and transcriptional activity assessed using luciferase reporters, qPCR and MTT. Publicly available datasets were mined to identify differences between ER-negative and ER-positive tumours and siRNA was used to suppress candidate regulators. Compared to ER-positive breast cancer, ER-negative breast cancer cells were highly responsive to LXR agonists. In primary disease and cell lines LXRA expression was strongly correlated with its target genes in ER-negative but not ER-positive disease. Expression of LXR’s corepressors (NCOR1, NCOR2 and LCOR) was significantly higher in ER-positive disease relative to ER-negative, and their knock-down equalized sensitivity to ligand between subtypes in reporter, gene expression and viability assays. Our data support further evaluation of dietary and pharmacological targeting of cholesterol metabolism as an adjunct to existing therapies for ER-negative and ER-positive breast cancer patients

Interference lithographically defined and catalytically etched, large-area silicon nanocones from nanowires

10.1088/0957-4484/21/20/205305Nanotechnology2120-NNOT