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The hypoxia-inducible factor (HIF)-1 and β-catenin protective pathways represent the two most significant cellular responses that are activated in response to acute kidney injury. We previously reported that murine mucin (Muc)1 protects kidney function and morphology in a mouse model of ischemia-reperfusion injury (IRI) by stabilizing HIF-1α, enhancing HIF-1 downstream signaling, and thereby preventing metabolic stress (Pastor-Soler et al. Muc1 is protective during kidney ischemia-reperfusion injury. Am J Physiol Renal Physiol 308: F1452–F1462, 2015). We asked if Muc1 regulates the β-catenin protective pathway during IRI as 1) β-catenin nuclear targeting is MUC1 dependent in cultured human cells, 2) β-catenin is found in coimmunoprecipitates with human MUC1 in extracts of both cultured cells and tissues, and 3) MUC1 prevents β-catenin phosphorylation by glycogen synthase kinase (GSK)3β and thereby β-catenin degradation. Using the same mouse model of IRI, we found that levels of active GSK3β were significantly lower in kidneys of control mice compared with Muc1 knockout (KO) mice. Consequently, β-catenin was significantly upregulated at 24 and 72 h of recovery and appeared in the nuclear fraction at 72 h in control mouse kidneys. Both β-catenin induction and nuclear targeting were absent in Muc1 KO mice. We also found downstream induction of β-catenin prosurvival factors (activated Akt, survivin, transcription factor T cell factor 4 (TCF4), and its downstream target cyclin D1) and repression of proapoptotic factors (p53, active Bax, and cleaved caspase-3) in control mouse kidneys that were absent or aberrant in kidneys of Muc1 KO mice. Altogether, the data clearly indicate that Muc1 protection during acute kidney injury proceeds by enhancing both the HIF-1 and β-catenin protective pathways.

AbstractIntroductionWe examined prevalence of mild cognitive impairment (MCI) and dementia in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive study.MethodsBeginning in June, 2011, we invited all surviving ARIC participants to undergo cognitive, neurologic, and brain imaging assessments to diagnose MCI or dementia and assign an etiology for the cognitive disorder.ResultsOf 10,713 surviving ARIC participants (age range, 69–88 years), we ascertained cognitive diagnoses in 6471 in person, 1966 by telephone interviews (participant or informant), and the remainder by medical record review. The prevalence of dementia was 9.0% and MCI 21%. Alzheimer's disease (AD) was the primary or secondary etiology in 76% of dementia and 75% of MCI participants. Cerebrovascular disease was the primary or secondary etiology in 46% of dementia and 32% of MCI participants.DiscussionMCI and dementia were common among survivors from the original ARIC cohort. Nearly 30% of the ARIC cohort received diagnoses of either dementia or MCI, and for the majority of these individuals, the etiologic basis was attributed to AD.

Background: The outcome for arthroscopic treatment of femoroacetabular impingement (FAI) can worsen with increasing arthritis. However, there remains a subset of hips with relatively maintained joint space but with acetabular subchondral edema and cystic change with unknown outcome on magnetic resonance imaging (MRI). Purpose: (1) To correlate MRI findings of subchondral acetabular edema/cystic change with arthroscopy grading of articular cartilage and (2) to determine whether postoperative outcome was worse for patients with subchondral edema/cystic change compared with a matched control group. Study Design: Cohort study; Level of evidence, 3. Methods: The records of all patients who underwent arthroscopic hip surgery for FAI at a single institution between 2007 and 2013 were reviewed for subchondral edema/cyst on preoperative MRI. Lesions were characterized by grade using an established classification system and were correlated with arthroscopic articular cartilage changes. A matched cohort of patients without evidence of subchondral edema or cyst was identified. Minimum 2-year outcomes were compared using prospectively collected Hip Outcome Score (HOS) activities of daily living and sport subscales as well as the modified Harris Hip Score (mHHS). Results: Overall, 104 patients were included. Thirty-six patients (18 men, 18 women) with a mean age of 41 years (range, 19-67 years) had subchondral edema, with or without the presence of cystic acetabular changes, at minimum 2-year follow-up (range, 24-60 months). Two patients who underwent total hip replacement were excluded in the outcome score comparison. Thirty-one of 34 patients (91%) had a grade 4 full-thickness cartilage lesion at the time of diagnostic arthroscopy. The mean mHHS was inferior for all patients with subchondral edema/cystic change (79.9 ± 18.7 vs 86.6 ± 12.5; P = .03), and the HOS was also lower (69.1 ± 27.0 vs 79.5 ± 21.4; P = .02). The overall success rate was 67% for all patients with subchondral edema/cystic change compared with 85% in the control group ( P = .04). Conclusion: The presence of a subchondral edema with an acetabular cyst on MRI is indicative of a full-thickness cartilage lesion at the time of arthroscopy. These patients have inferior outcomes for arthroscopic treatment of FAI compared with patients with similar age and activity level without MRI subchondral cystic changes.

Abstract Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles. Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

Notch family members are transmembrane receptors that mediate essential developmental programs. Upon ligand binding, a proteolytic event releases the intracellular domain of Notch, which translocates to the nucleus to regulate gene transcription. In addition, Notch trafficking across the endolysosomal system is critical in its regulation. In this study we report that Notch recycling to the cell surface is dependent on the COMMD–CCDC22–CCDC93 (CCC) complex, a recently identified regulator of endosomal trafficking. Disruption in this system leads to intracellular accumulation of Notch2 and concomitant reduction in Notch signaling. Interestingly, among the 10 copper metabolism MURR1 domain containing (COMMD) family members that can associate with the CCC complex, only COMMD9 and its binding partner, COMMD5, have substantial effects on Notch. Furthermore, Commd9 deletion in mice leads to embryonic lethality and complex cardiovascular alterations that bear hallmarks of Notch deficiency. Altogether, these studies highlight that the CCC complex controls Notch activation by modulating its intracellular trafficking and demonstrate cargo-specific effects for members of the COMMD protein family.

Objectives/HypothesisExternal beam radiation to the neck is widely considered a contraindication for thyroplasty due to concern for infection and implant extrusion. We present a case series of our experience regarding thyroplasty performed in a previously radiated field.Study DesignRetrospective case study at a tertiary academic referral center.MethodsUsing the institution's clinical notes search tool, records from 1999 through 2014 documenting thyroplasty and radiation were identified and reviewed. Patients who received external beam radiation to the operative field prior to thyroplasty were included. Data including duration of radiation, timing and specifics of thyroplasty, postoperative complications, risk factors, clinical voice outcomes, and length of follow‐up were collected.ResultsFourteen patients met criteria for the study. Of all thyroplasty performed, 11 were Silastic implants, two were Gore‐Tex implants, six had concurrent arytenoid adduction, and one was a midline type II thyroplasty. In terms of risk factors for postoperative complications, two were diabetic, none were active smokers, and one had a splenectomy. All patients were given postoperative antibiotics. The median duration of follow‐up after surgery was 14.2 months. No patients were found to have postoperative complications. Pre‐ and postoperative voice data were assessed. Overall, there was improvement in voice outcomes.ConclusionsThyroplasty may be an option for patients who have previously undergone external beam radiation. Short‐term and intermediate outcomes in our patients showed no postoperative complications, and generally voice or dysphagia improved. Careful selection is still warranted when considering thyroplasty in a previously irradiated neck, and long‐term outcomes need further study.Level of Evidence4 Laryngoscope, 126:1849–1853, 2016

Abstract Purpose: Prostate cancers incite tremendous morbidity upon metastatic growth. We previously identified Asporin (ASPN) as a potential mediator of metastatic progression found within the tumor microenvironment. ASPN contains an aspartic acid (D)-repeat domain and germline polymorphisms in D-repeat-length have been associated with degenerative diseases. Associations of germline ASPN D polymorphisms with risk of prostate cancer progression to metastatic disease have not been assessed. Experimental Design: Germline ASPN D-repeat-length was retrospectively analyzed in 1,600 men who underwent radical prostatectomy for clinically localized prostate cancer and in 548 noncancer controls. Multivariable Cox proportional hazards models were used to test the associations of ASPN variations with risk of subsequent oncologic outcomes, including metastasis. Orthotopic xenografts were used to establish allele- and stroma-specific roles for ASPN D variants in metastatic prostate cancer. Results: Variation at the ASPN D locus was differentially associated with poorer oncologic outcomes. ASPN D14 [HR, 1.72; 95% confidence interval (CI), 1.05–2.81, P = 0.032] and heterozygosity for ASPN D13/14 (HR, 1.86; 95% CI, 1.03–3.35, P = 0.040) were significantly associated with metastatic recurrence, while homozygosity for the ASPN D13 variant was significantly associated with a reduced risk of metastatic recurrence (HR, 0.44; 95% CI, 0.21–0.94, P = 0.035) in multivariable analyses. Orthotopic xenografts established biologic roles for ASPN D14 and ASPN D13 variants in metastatic prostate cancer progression that were consistent with patient-based data. Conclusions: We observed associations between ASPN D variants and oncologic outcomes, including metastasis. Our data suggest that ASPN expressed in the tumor microenvironment is a heritable modulator of metastatic progression. Clin Cancer Res; 22(2); 448–58. ©2015 AACR.