Citations

Ischemia-reperfusion injury (IRI) due to hypotension is a common cause of human acute kidney injury (AKI). Hypoxia-inducible transcription factors (HIFs) orchestrate a protective response in renal endothelial and epithelial cells in AKI models. As human mucin 1 (MUC1) is induced by hypoxia and enhances HIF-1 activity in cultured epithelial cells, we asked whether mouse mucin 1 (Muc1) regulates HIF-1 activity in kidney tissue during IRI. Whereas Muc1 was localized on the apical surface of the thick ascending limb, distal convoluted tubule, and collecting duct in the kidneys of sham-treated mice, Muc1 appeared in the cytoplasm and nucleus of all tubular epithelia during IRI. Muc1 was induced during IRI, and Muc1 transcripts and protein were also present in recovering proximal tubule cells. Kidney damage was worse and recovery was blocked during IRI in Muc1 knockout mice compared with congenic control mice. Muc1 knockout mice had reduced levels of HIF-1α, reduced or aberrant induction of HIF-1 target genes involved in the shift of glucose metabolism to glycolysis, and prolonged activation of AMP-activated protein kinase, indicating metabolic stress. Muc1 clearly plays a significant role in enhancing the HIF protective pathway during ischemic insult and recovery in kidney epithelia, providing a new target for developing therapies to treat AKI. Moreover, our data support a role specifically for HIF-1 in epithelial protection of the kidney during IRI as Muc1 is present only in tubule epithelial cells.

Key PointsThe NF-κB subunits p52 and RelB increase IRF4 promoter activity and expression in PTCL cells. A positive feedback loop involving CD30, NF-κB, and IRF4 drives PTCL cell proliferation and can be blocked by NF-κB inhibitors.

Background— The higher risk of adverse outcomes after transapical (TA) versus transfemoral (TF) transcatheter aortic valve replacement (TAVR) could be attributable to TA-TAVR being an open surgical procedure or to clinical differences between TA- and TF-TAVR patients. We compared outcomes after neutralizing patient differences using propensity score matching. Methods and Results— From April 2007 to February 2012, 1100 Placement of Aortic Transcatheter Valves (PARTNER)-I patients underwent TA-TAVR and 1521 underwent TF-TAVR with Edwards SAPIEN balloon-expandable bioprostheses. Propensity matching based on 111 preprocedural variables, exclusive of femoral access morphology, identified 501 well-matched patient pairs (46% of possible matches), 95% of whom had peripheral arterial disease. Matched TA-TAVR patients experienced more adverse procedural events, longer length of stay (5 versus 8 days; P <0.0001), and slower recovery (New York Heart Association class I, 31% versus 38% at 30 days, equalizing by 6 months at 51% versus 47%); stroke risk was similar (3.4% versus 3.3% at 30 days and 6.0% versus 6.7% at 3 years); mortality was elevated for the first 6 postprocedural months (19% versus 12%; P =0.01); but aortic regurgitation was less (34% versus 52% mild and 8.9% versus 12% moderate to severe at discharge, P =0.001; 36% versus 50% mild and 10% versus 15% moderate to severe at 6 months, P <0.0001). Conclusions— The likelihood of adverse periprocedural events and prolonged recovery is greater after TA-TAVR than TF-TAVR in vasculopathic patients after accounting for differences in cardiovascular risk factors, although stroke risk is equivalent and aortic regurgitation is less. As smaller delivery systems permit TF-TAVR in many of these patients, we recommend a TF-first access strategy for TAVR when anatomically feasible. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00530894.

Background and aim Although Non-steroidal anti-inflammatory drugs reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), the utility of combining chemopreventive agents in FAP is not known. We conducted a randomised trial of celecoxib (CXB) versus CXB+diflouromethylornithine (DFMO) to determine the synergistic effect, if any. Methods The primary endpoint was % change in adenoma count in a defined field. Secondary endpoints were adenoma burden (weighted by adenoma diameter) and video review of entire colon/rectal segments. Adverse event (AEs) were monitored by National Cancer Institution toxicity criteria. Results 112 subjects were randomised: 60 men and 52 women at a mean age of 38 years. For the 89 patients who had landmark-matched polyp counts available at baseline and 6 months, the mean % change in adenoma count over the 6 months of trial was −13.0% for CXB+DFMO and −1.0% for CXB (p=0.69). Mean % change in adenoma burden was −40% (CXB+DFMO) vs −27% (CXB) (p=0.13). Video-based global polyp change was −0.80 for CXB+DFMO vs −0.33 for CXB (p=0.03). Fatigue was the only significant AE, worse on the CXB arm (p=0.02). Conclusions CXB combined with DFMO yielded moderate synergy according to a video-based global assessment. No significant difference in adenoma count, the primary endpoint, was seen between the two study arms. No evidence of DFMO-related ototoxicity was seen. There were no adverse cardiovascular outcomes in either trial arm and no significant increase in AEs in the CXB+DFMO arm of the trial. Differences in outcomes between primary and secondary endpoints may relate to sensitivity of the endpoint measures themselves. Trial registration number ClinicalTrials.gov number N01-CN95040.

AbstractThe many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach. Clin Cancer Res; 21(13); 2911–5. ©2015 AACR.

AbstractBackgroundIncreasing evidence suggests that genetic factors play a role in the variability associated with cognitive performance in Parkinson's disease (PD). Mutations in the LRRK2 gene are the most common cause of monogenic PD; however, the cognitive profile of LRRK2‐related PD is not well‐characterized.MethodsA cohort of 1,447 PD patients enrolled in the PD Cognitive Genetics Consortium was screened for LRRK2 mutations and completed detailed cognitive testing. Associations between mutation carrier status and cognitive test scores were assessed using linear regression models.ResultsLRRK2 mutation carriers (n = 29) demonstrated better performance on the Mini Mental State Examination (P = 0.03) and the Letter‐Number Sequencing Test (P = 0.005). A smaller proportion of LRRK2 carriers were demented (P = 0.03).ConclusionsOur cross‐sectional study demonstrates better performance on certain cognitive tests, as well as lower rates of dementia in LRRK2‐related PD. Future longitudinal studies are needed to determine whether LRRK2 mutation carriers exhibit slower cognitive decline. © 2015 International Parkinson and Movement Disorder Society

Background and Purpose— The relationships between cerebrovascular lesions visible on imaging and cognition are complex. We explored the possibility that the cerebral cortical volume mediated these relationships. Methods— Total of 1906 nondemented participants (59% women; 25% African–American; mean age, 76.6 years) in the Atherosclerosis Risk in Communities (ARIC) study underwent cognitive assessments, risk factor assessments, and quantitative MRI for white matter hyperintensities (WMH) and infarcts. The Freesurfer imaging analysis pipeline was used to determine regional cerebral volumes. We examined the associations of cognitive domain outcomes with cerebral volumes (hippocampus and separate groups of posterior and frontal cortical regions of interest) and cerebrovascular imaging features (presence of large or small cortical/subcortical infarcts and WMH volume). We performed mediation pathway analyses to assess the hypothesis that hippocampal and cortical volumes mediated the associations between cerebrovascular imaging features and cognition. Results— In unmediated analyses, WMH and infarcts were both associated with worse psychomotor speed/executive function. In mediation analyses, WMH and infarct associations on psychomotor speed/executive function were significantly attenuated, but not abolished, by the inclusion of the posterior cortical regions of interest volume in the models, and the infarcts on psychomotor speed/executive function association were attenuated, but not abolished, by inclusion of the frontal cortical regions of interest volume. Conclusions— Both WMH and infarcts were associated with cortical volume, and both lesions were also associated with cognitive performance, implying shared pathophysiological mechanisms. Although cross-sectional, our findings suggest that WMH and infarcts could be proxies for clinically covert processes that directly damage cortical regions. Microinfarcts are 1 candidate for such a clinically covert process.

We used whole‐exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in‐silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole‐brain analysis and meta‐analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next‐generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets. Ann Neurol 2015;77:547–552