MicroRNA-330-5p as a putative modulator of neoadjuvant chemoradiotherapy sensitivity in oesophageal adenocarcinoma

Oesophageal adenocarcinoma (OAC) is the sixth most common cause of cancer deaths worldwide, and the 5-year survival rate for patients diagnosed with the disease is approximately 17%. The standard of care for locally advanced disease is neoadjuvant chemotherapy or, more commonly, combined neoadjuvant chemoradiation therapy (neo-CRT) prior to surgery. Unfortunately, ~60-70% of patients will fail to respond to neo-CRT. Therefore, the identification of biomarkers indicative of patient response to treatment has significant clinical implications in the stratification of patient treatment. Furthermore, understanding the molecular mechanisms underpinning tumour response and resistance to neo-CRT will contribute towards the identification of novel therapeutic targets for enhancing OAC sensitivity to CRT. MicroRNAs (miRNA/miR) function to regulate gene and protein expression and play a causal role in cancer development and progression. MiRNAs have also been identified as modulators of key cellular pathways associated with resistance to CRT. Here, to identify miRNAs associated with resistance to CRT, pre-treatment diagnostic biopsy specimens from patients with OAC were analysed using miRNA-profiling arrays. In pre-treatment biopsies miR-330-5p was the most downregulated miRNA in patients who subsequently failed to respond to neo-CRT. The role of miR-330 as a potential modulator of tumour response and sensitivity to CRT in OAC was further investigated in vitro. Through vector-based overexpression the E2F1/p-AKT survival pathway, as previously described, was confirmed as a target of miR-330 regulation. However, miR-330-mediated alterations to the E2F1/p-AKT pathway were insufficient to significantly alter cellular sensitivity to chemotherapy (cisplatin and 5-flurouracil). In contrast, silencing of miR-330-5p enhanced, albeit subtly, cellular resistance to clinically relevant doses of radiation. This study highlights the need for further investigation into the potential of miR-330-5p as a predictive biomarker of patient sensitivity to neo-CRT and as a novel therapeutic target for manipulating cellular sensitivity to neo-CRT in patients with OAC

Method Effects and the Need for Cognition Scale

Individual differences in the need for cognition are typically assessed using the 18-item Need for cognition scale (NCS) developed by Cacioppo and Petty (1982). However, in contrast to the unidimensional model proposed by the scale developers, recent factor analyses have introduced two -and three- dimensional models of the scale. Confirmatory factor analyses were used in this study to evaluate different measurement models based on data provided by 590 (236 males, 354 females) young adult members of the general public. Although some alternative models showed promise, a single factor model with method effects associated with positively and negatively worded items provided best fit. Implications for the asses sment of need for cognition are considered

Understanding and Problematizing Contractual Tort Subrogation

The modern incarnation of tort subrogation allows an insurer to force its insured to turn over the litigation proceeds independently obtained by the insured against a third-party tortfeasor, even if the insured has not been made whole by such litigation. This Article demonstrates that such a result is the product of a subrogation-as-contract paradigm that has taken hold in the federal system, most notably by the United States Supreme Court in Sereboff v. Mid-Atlantic Services, 547 U.S. 356 (2006). More importantly, the Article illustrates the conceptual and historical roots of subrogation to demonstrate the extent to which subrogation-as-contract is divorced from the doctrine\u27s origins and to illustrate the serious negative consequences that flow from such a dramatic departure

Health Insurance and Federalism-in-Fact

The constitutional legitimacy of the Patient Protection and Affordable Care Act (“ACA”) received substantial attention. Less examined has been the legislation’s sub-constitutional effect on the regulatory power that states can and might exercise. Regarding a state\u27s ability to promulgate sickness rules, (those legal rules pertaining to the conditions or treatment an insurance policy covers) and non-sickness rules (those legal rules pertaining to insurance other than sickness rules), we scrutinize the ACA itself and contrast it with the other most significant statute governing private health insurance, the Employee Retirement Income Security Act of 1974 (“ERISA”). The authors would like to thank the participants at the 2012 Employee Benefits in an Era of Retrenchment conference at Washington University for their comments and criticism

Enough About the Constitution: How States Can Regulate Health Insurance Under the ACA

Last term, the United States Supreme Court upheld the constitutionality of the Affordable Care Act in a landmark decision. It is a forceful reminder that America’s oldest question — how power should be shared between federal and state sovereigns — retains powerful political salience. Critics have reflexively attacked the decision as an assault on states’ rights, while supporters have celebrated the result. Regrettably, insufficient attention has been paid to how, in actuality, health care regulatory authority has been and will be divided between federal and state governments. In this Article, we fill that gap. To do so, we apply “federalism-in-fact,” a theory that seeks to measure the real-world, as opposed to theoretical, apportionment of power between sovereigns. We conclude that the Affordable Care Act has in important ways increased states’ power to regulate private health insurance when viewed in proper contrast to the previously exclusive ERISA regulatory regime. In addition, we offer recommendations on how states can use their freedom under the Affordable Care Act to grow their regulatory markets, and we explain why collateral forces are likely to increase state regulatory power even if states do nothing

Enough About the Constitution: How States Can Regulate Health Insurance Under the ACA

Last Term, the United States Supreme Court upheld the constitutionality of the Affordable Care Act (ACA). The Court\u27s landmark decision is a forceful reminder that America\u27s oldest question-how power should be shared between state and federal sovereigns-retains powerful political salience. The ACA has been hotly criticized as an affront to state power. It is now settled that the ACA is constitutional. But that is the end of the beginning rather than the beginning of the end

A putative resistant DNA marker for wool yellowing susceptibility in sheep.

An Australian Merino flock was screened for low (resistant) and high (susceptible) yellow predictive colour (YPC) breeding values in order to compare extreme individuals using the differential display of mRNA technique. One differentially expressed cDNA band was visualised only in the resistant group. This band showed no identity with the DNA sequences of public databases; however, they showed short homologies with three database sequences related to transmembrane signalling functions. The use of these candidate genes as DNA markers needs to be confirmed against sheep with a wide range of susceptibility to wool yellowing to verify the results

The environmental contaminant DDE fails to influence the outcome of sexual differentiation in the marine turtle Chelonia mydas.

In many turtles, the temperature experienced during the middle of egg incubation determines the sex of the offspring. The implication of steroid sex hormones as the proximate trigger for sex determination opens the possibility that endocrine-disrupting contaminants may also influence the outcome of sexual differentiation. In this study we investigate the potential effects of DDE (a common DDT metabolite) on sexual differentiation of Chelonia mydas (green sea turtle). Four clutches of eggs collected from Heron Island, Queensland, Australia, were treated with DDE at the beginning of the thermosensitive period for sexual determination. An incubation temperature of 28 degrees C or less produces male hatchlings in this species, whereas 30 degrees C or more produces female hatchlings. Dosed eggs were consequently incubated at two temperatures (27.6 degrees C and 30.4 degrees C) on the upper and lower boundaries of the sex determination threshold for this species. DDE, ranging from 3.3 to 66.5 microg, was dissolved in 5, 10, and 25 microl ethanol and applied to eggshells above the embryo. Less than 2.5 ng/g DDE was present in eggs prior to dosing. Approximately 34% of the applied DDE was absorbed in the eggs, but only approximately 8% of applied DDE was found in embryos. Thus, treated eggs, corrected for background DDE, had up to 543 ng/g DDE. The sex ratio at these doses did not differ from what would be expected on consideration of temperature alone. Incubation time, hatching success, incidence of body deformities, hatching size, and weight were also within the limits of healthy developed hatchlings. This indicates that the eggs of C. mydas in the wild with concentrations of DDE less than 543 ng/g should produce hatchlings with relatively high hatching success, survival rate, and normally differentiated gonads