Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1)

Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark cancer phenotypes. This has led to the identification and development of small molecules with spliceosome-modulating activity as potential anticancer agents. Jerantinine A (JA) is a novel indole alkaloid which displays potent anti-proliferative activities against human cancer cell lines by inhibiting tubulin polymerization and inducing G2/M cell cycle arrest. Using a combined pooled-genome wide shRNA library screen and global proteomic profiling, we showed that JA targets the spliceosome by up-regulating SF3B1 and SF3B3 protein in breast cancer cells. Notably, JA induced significant tumor-specific cell death and a significant increase in unspliced pre-mRNAs. In contrast, depletion of endogenous SF3B1 abrogated the apoptotic effects, but not the G2/M cell cycle arrest induced by JA. Further analyses showed that JA stabilizes endogenous SF3B1 protein in breast cancer cells and induced dissociation of the protein from the nucleosome complex. Together, these results demonstrate that JA exerts its antitumor activity by targeting SF3B1 and SF3B3 in addition to its reported targeting of tubulin polymerization

Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73.

Recent gene expression profiling studies have identified five breast cancer subtypes, of which the basal-like subtype is the most aggressive. Basal-like breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it. Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin, its success is often compromised due to its dose-limiting nephrotoxicity and the development of drug resistance. To overcome this limitation, our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies. Using a validated kinase inhibitor library, we showed that inhibition of the mTOR, TGFβRI, NFκB, PI3K/AKT, and MAPK pathways sensitized basal-like MDA-MB-468 cells to cisplatin treatment. Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basal-like MDA-MB-468, MDA-MB-231, and HCC1937 cells but not in luminal-like T47D or MCF-7 cells. We further showed that the synergistic effect of rapamycin plus cisplatin on basal-like breast cancer cells was mediated through the induction of p73. Depletion of endogenous p73 in basal-like cells abolished these synergistic effects. In conclusion, combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basal-like breast cancers

A review of the Internet as a alternative consumer banking channel.

In recent years, the explosion of the Internet looks set to make it an important tool not just for gathering or dissemination of information but also for the conducting of business. One of the business sectors that looks to experience great change as a results of the growth of the Internet is consumer banking. The objective of this project is to examine the possible impact of the Internet as a delivery channel on consumer banking in Singapore. Special attention is paid on the effects of Internet Banking on the way traditional delivery channels such as bank branches, telephone banking and Automated Teller Machines will be used be consumers to carry out their banking transactions and employed by banks to deliver their products

Service quality of 5 major sectors in Singapore.

Identification of the weaknesses in service of the 5 sectors; Banking, Food & Beverage, Healthcare, Public Transport and Retail. An analysis of the root causes to these weaknesses. Re-enactments of bad and good services in video

Numerical simulation of backgating suppression in high electron mobility transistors (HEMTs) with a low temperature molecular beam epitaxy (MBE)-grown gallium arsenide buffer layer between the substrate and active layers

Japanese Journal of Applied Physics, Part 2: Letters336 BL826-L829JAPL

Corneal ectasia risk and percentage tissue altered in myopic patients presenting for refractive surgery

Purpose: A percentage tissue altered (PTA) score of ≥40% has been advocated as an independent indicator of post-operative ectasia risk following laser in-situ keratomileusis (LASIK). This study was performed to test the hypothesis that refractive procedures, such as laser-assisted subepithelial keratectomy (LASEK) or small incision lenticule extraction (SMILE), may alter the range of PTA, within which refractive corneal surgery can be safely performed. Setting: Refractive department, tertiary ophthalmic hospital. Design: Retrospective observational study. Methods: Review of case notes was performed for patients who presented for refractive surgeries, other than LASIK. To determine the risk of corneal ectasia for each patient prior to refractive surgery, we estimated what each patient’s PTA would have been if they had undergone LASIK. The Randleman Ectasia Risk Score System (ERSS) was also calculated. Results: 114 eyes (66 patients) were included. 94 eyes underwent SMILE. 20 eyes underwent LASEK. A significant proportion of eyes had PTA ≥40% – SMILE eyes: up to 31.9%, LASEK eyes: up to 60.0% (at presumed LASIK flap of 120 μm). The maximum calculated PTAwas up to 47.9% in the SMILE group and up to 51.5% in the LASEK group. Using ERSS, 12.8–16% of SMILE eyes and 15.0–80.0% of LASEK eyes would have been considered to have moderate-tohigh ectasia risk. No post-surgical ectasia was observed at 3 years. Conclusion: SMILE and LASEK alter the range of PTA, within which corneal refractive surgery may be performed with a lower risk of developing post-operative corneal ectasia; a safe PTA threshold needs to be determined for these procedures before recommendations for clinical practice can be made.Published versio

Fibroblast growth factor receptor 4 (FGF4) and fibroblast growth factor 19 (FGFR19) autocrine enhance brest cancer cells survival

Basal-like breast cancer is an aggressive tumor subtype with poor prognosis. The discovery of underlying mechanisms mediating tumor cell survival, and the development of novel agents to target these pathways, is a priority for patients with basal-like breast cancer. From a functional screen to identify key drivers of basal-like breast cancer cell growth, we identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of cell survival. We found that FGFR4 mediates cancer cell survival predominantly via activation of PI3K/AKT. Importantly, a subset of basal-like breast cancer cells also secrete fibroblast growth factor 19 (FGF19), a canonical ligand specific for FGFR4. siRNA-mediated silencing of FGF19 or neutralization of extracellular FGF19 by anti-FGF19 antibody (1A6) decreases AKT phosphorylation, suppresses cancer cell growth and enhances doxorubicin sensitivity only in the FGFR4+/FGF19+ breast cancer cells. Consistently, FGFR4/FGF19 co-expression was also observed in 82 out of 287 (28.6%) primary breast tumors, and their expression is strongly associated with AKT phosphorylation, Ki-67 staining, higher tumor stage and basal-like phenotype. In summary, our results demonstrated the presence of an FGFR4/FGF19 autocrine signaling that mediates the survival of a subset of basal-like breast cancer cells and suggest that inactivation of this autocrine loop may potentially serve as a novel therapeutic intervention for future treatment of breast cancers

'Lnc'-ing Wnt in female reproductive cancers: therapeutic potential of long non-coding RNAs in Wnt signalling

10.1111/bph.13958BRITISH JOURNAL OF PHARMACOLOGY174244684-470

BREAst screening Tailored for HEr (BREATHE)-A study protocol on personalised risk-based breast cancer screening programme

10.1371/journal.pone.0265965PLOS ONE17