Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature

<p>Abstract</p> <p>Background</p> <p>Given the large number of genes purported to be prognostic for breast cancer, it would be optimal if the genes identified are not confounded by the continuously changing systemic therapies. The aim of this study was to discover and validate a breast cancer prognostic expression signature for distant metastasis in untreated, early stage, lymph node-negative (N-) estrogen receptor-positive (ER+) patients with extensive follow-up times.</p> <p>Methods</p> <p>197 genes previously associated with metastasis and ER status were profiled from 142 untreated breast cancer subjects. A "metastasis score" (MS) representing fourteen differentially expressed genes was developed and evaluated for its association with distant-metastasis-free survival (DMFS). Categorical risk classification was established from the continuous MS and further evaluated on an independent set of 279 untreated subjects. A third set of 45 subjects was tested to determine the prognostic performance of the MS in tamoxifen-treated women.</p> <p>Results</p> <p>A 14-gene signature was found to be significantly associated (p < 0.05) with distant metastasis in a training set and subsequently in an independent validation set. In the validation set, the hazard ratios (HR) of the high risk compared to low risk groups were 4.02 (95% CI 1.91–8.44) for the endpoint of DMFS and 1.97 (95% CI 1.28 to 3.04) for overall survival after adjustment for age, tumor size and grade. The low and high MS risk groups had 10-year estimates (95% CI) of 96% (90–99%) and 72% (64–78%) respectively, for DMFS and 91% (84–95%) and 68% (61–75%), respectively for overall survival. Performance characteristics of the signature in the two sets were similar. Ki-67 labeling index (LI) was predictive for recurrent disease in the training set, but lost significance after adjustment for the expression signature. In a study of tamoxifen-treated patients, the HR for DMFS in high compared to low risk groups was 3.61 (95% CI 0.86–15.14).</p> <p>Conclusion</p> <p>The 14-gene signature is significantly associated with risk of distant metastasis. The signature has a predominance of proliferation genes which have prognostic significance above that of Ki-67 LI and may aid in prioritizing future mechanistic studies and therapeutic interventions.</p

Severe varicella in persons vaccinated with varicella vaccine (breakthrough varicella): a systematic literature review

Introduction: Varicella vaccines are highly effective at preventing disease, but varicella may occur among vaccinated persons (termed breakthrough varicella). Breakthrough varicella is generally mild, but severe cases have been reported. The objective of this review is to describe severe breakthrough varicella. Areas covered: We conducted a systematic review of articles published during 1974–2016. A total of 34 articles were included in our review: 21 described breakthrough varicella with disseminated varicella-zoster virus (VZV) infection with other organ involvement in addition to skin (none among two-dose vaccinees); 9 described hospitalized breakthrough varicella without mention of other organ involvement in addition to skin (of which 2 reported 4 two-dose vaccinees); and 4 described both. A total of 52–60 unique breakthrough varicella cases with disseminated VZV infection with other organ involvement in addition to skin reported with the following complications, not mutually exclusive: pneumonia (n = 8–9 cases), neurologic (n = 18–24 cases), hematologic (n = 10–11 cases), ocular (n = 5 cases), renal (n = 2 cases), hepatic (n = 3 cases), secondary infection with bacteremia or sepsis (n = 8 cases), and other complication (n = 4 cases). There were 6 cases of fatal breakthrough varicella. Expert commentary: With >31 million doses distributed annually worldwide since 2007, severe breakthrough varicella can occur but they appear to be uncommon

Differential utilization of CCR5 by macrophage and T cell tropic simian immunodeficiency virus strains

Certain chemokine receptors serve as cofactors for HIV type 1 envelope (env)-mediated cell–cell fusion and virus infection of CD4-positive cells. Macrophage tropic (M-tropic) HIV-1 isolates use CCR5, and T cell tropic (T-tropic) strains use CXCR4. To investigate the cofactors used by simian immunodeficiency viruses (SIV), we tested four T-tropic and two M-tropic SIV env proteins for their ability to mediate cell–cell fusion with cells expressing CD4 and either human or nonhuman primate chemokine receptors. Unlike HIV-1, both M- and T-tropic SIV envs used CCR5 but not CXCR4 or the other chemokine receptors tested. However, by testing a panel of CCR5/CCR2b chimeras, we found that the structural requirements for CCR5 utilization by M-tropic and T-tropic SIV strains were different. T-tropic SIV strains required the second extracellular loop of CCR5 whereas a closely related M-tropic SIV strain could, like M-tropic HIV-1 strains, use the amino-terminal domain of CCR5. As few as two amino acid changes in the SIV env V3 domain affected the regions of CCR5 that were critical for fusogenic activity. Receptor signaling was not required for either fusion or infection. Our results suggest that viral tropism may be influenced not only by the coreceptors used by a given virus strain but also by how a given coreceptor is used

Supplemental Material, AUT766238_Lay_Abstract – Implementing systems-based innovations to improve access to early screening, diagnosis, and treatment services for children with autism spectrum disorder: An Autism Spectrum Disorder Pediatric, Early Detection, Engagement, and Services network study

<p>Supplemental Material, AUT766238_Lay_Abstract for Implementing systems-based innovations to improve access to early screening, diagnosis, and treatment services for children with autism spectrum disorder: An Autism Spectrum Disorder Pediatric, Early Detection, Engagement, and Services network study by Sarabeth Broder Fingert, Alice Carter, Karen Pierce, Wendy L Stone, Amy Wetherby, Chris Scheldrick, Christopher Smith, Elizabeth Bacon, Stephen N James, Lisa Ibañez and Emily Feinberg in Autism</p