Citations

The Brahma (BRM) and Brahma‐related Gene 1 (BRG1) ATPases are highly conserved homologs that catalyze the chromatin remodeling functions of the multi‐subunit human SWI/SNF chromatin remodeling enzymes in a mutually exclusive manner. SWI/SNF enzyme subunits are mutated or missing in many cancer types, but are overexpressed without apparent mutation in other cancers. Here, we report that both BRG1 and BRM are overexpressed in most primary breast cancers independent of the tumor's receptor status. Knockdown of either ATPase in a triple negative breast cancer cell line reduced tumor formation in vivo and cell proliferation in vitro. Fewer cells in S phase and an extended cell cycle progression time were observed without any indication of apoptosis, senescence, or alterations in migration or attachment properties. Combined knockdown of BRM and BRG1 showed additive effects in the reduction of cell proliferation and time required for completion of cell cycle, suggesting that these enzymes promote cell cycle progression through independent mechanisms. Knockout of BRG1 or BRM using CRISPR/Cas9 technology resulted in the loss of viability, consistent with a requirement for both enzymes in triple negative breast cancer cells. J. Cell. Physiol. 9999: 2683–2694, 2015. © 2015 Wiley Periodicals, Inc.

Background Klippel–Trenaunay syndrome (KTS) is a mixed mesenchymal malformation characterised by varicose veins, venous and capillary malformations, and hypertrophy of soft tissue and bone. The purpose of this study was to evaluate the surgical outcomes in KTS patients to provide standards for comparison with endovenous therapy. Methods The clinical data of consecutive patient with KTS who underwent open venous surgical treatment between January 1987 and December 2008 were reviewed. Demographics, clinical presentation, operative data, and clinical outcomes were recorded. Follow-up information was obtained from the medical records, mailed questionnaires and phone calls. Descriptive statistics, the Kaplan–Meier method and Log-rank statistics were used where appropriate. Results Twenty-seven females and 22 males, (mean age 26.5 years, range 7.7–55.8) were included in this study. All had varicose veins, 36 (73%) had limb hypertrophy, and 33 (67%) had capillary malformations, with two of three clinical features present in all. The most frequent symptom was pain (N = 43, 88%). Forty-nine patients underwent operations on 53 limbs. Stripping of the GSV, small and accessory saphenous and lateral embryonic veins was performed in 17 (32%), 10 (19%), 9 (17%), and 15 (28%) limbs, respectively. Two patients developed deep vein thrombosis, one had pulmonary embolism (PE), and one patient had peroneal nerve palsy. Freedom from disabling pain at 1, 3 and 5 years was 95%, 77% and 59%, respectively, and freedom from secondary procedures was 78% at 3 years, and 74% at 5 years. At the last follow-up visit, the venous clinical severity score had decreased from 9.48 ± 3.27 to 6.07 ± 3.20 (P < 0.001). Conclusions In selected symptomatic patients with KT syndrome, open surgical treatment is safe and durable. Three-fourths of the patients remain free of disabling pain at five years, but secondary procedures are required in one-fourth of the patients. These data can serve as standards for comparison of endovenous therapy for KT syndrome.

Abstract Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation. Clin Cancer Res; 21(12); 2722–9. ©2015 AACR. See related article by Paoletti et al., p. 2771

ABSTRACTIntroductionNeurolymphomatosis (NL) is a rare disorder characterized by invasion of cranial or peripheral nerves, nerve roots, or plexi, usually by aggressive subtypes of non‐Hodgkin lymphoma (NHL). The most common clinical presentation is that of a painful polyneuropathy or polyradiculopathy, followed by cranial neuropathy and, less frequently, by painless polyneuropathy.MethodsClinical and pathologic findings are reported for 2 NL cases.ResultsThe following 2 patients with NL, with disparate clinical presentations, are presented: a patient with subacute onset, painful, multifocal, mixed axonal and demyelinating radiculoplexus neuropathy due to a large B‐cell NHL, who required 2 targeted fascicular nerve biopsies to demonstrate NL; and a patient with a slowly progressive, length‐dependent axonal polyneuropathy due to a low‐grade B‐cell lymphoproliferative disorder, as shown on a diagnostic sural nerve biopsy.ConclusionsThe cases described illustrate the wide clinical spectrum of NL. Muscle Nerve 52:449–454, 2015

AbstractClinical research ethics consultation services have been established across academic health centers over the past decade. This paper presents the results of collaboration within the CTSA consortium to develop a standard approach to the collection of research ethics consultation information to serve as a foundation for quality improvement, education, and research efforts. This approach includes categorizing and documenting descriptive information about the requestor, research project, the ethical question, the consult process, and describing the basic structure for a consult note. This paper also explores challenges in determining how to share some of this information between collaborating institutions related to concerns about confidentially, data quality, and informatics. While there is much still to be learned to improve the process of clinical research ethics consultation, these tools can advance these efforts, which, in turn, can facilitate the ethical conduct of research.

Objectives The objective of this study was to evaluate the problem of multiple chronic conditions and polypharmacy in patients with fibromyalgia. Design Retrospective medical record review. Setting Olmsted County, Minnesota. Participants 1111 adults with fibromyalgia. Primary and secondary outcome measures Number and type of chronic medical and psychiatric conditions, medication use. Results Medical record review demonstrated that greater than 50% of the sample had seven or more chronic conditions. Chronic joint pain/degenerative arthritis was the most frequent comorbidity (88.7%), followed by depression (75.1%), migraines/chronic headaches (62.4%) and anxiety (56.5%). Approximately, 40% of patients were taking three or more medications for symptoms of fibromyalgia. Sleep aids were the most commonly prescribed medications in our sample (33.3%) followed by selective serotonin reuptake inhibitors (28.7%), opioids (22.4%) and serotonin norepinephrine reuptake inhibitors (21.0%). Conclusions The results of our study highlight the problem of multiple chronic conditions and high prevalence of polypharmacy in fibromyalgia. Clinicians who care for patients with fibromyalgia should take into consideration the presence of multiple chronic conditions when recommending medications.

Findings suggest that more intensive efforts than audit and feedback will be required to improve the quality of psychosocial care, and that greater recognition of problems with emotional well-being may tax the ability of practices to link patients with appropriate services.

Treatment with an all‐oral interferon‐free antiviral regimen using simeprevir and sofosbuvir with or without ribavirin (RBV) for 12 weeks resulted in high sustained virologic response (SVR) rates along with minimal adverse events in non–liver transplant (LT) patients with hepatitis C virus (HCV) genotype 1 infection. This is the first multicenter report on the efficacy, safety, and tolerability of this regimen in LT recipients. A total of 123 patients (76% male, 74% white, 60% genotype 1a, 30% METAVIR F3‐F4, 4% decompensation, 11% cholestatic recurrence, 7% had kidney transplant, and 82% previously failed pegylated interferon/RBV‐based regimens) received treatment and were followed for a median of 30 weeks (range 12‐53 weeks). The median time from LT to treatment was 32 months (range 2‐317 months). Tacrolimus was the primary immunosuppression in 91% of patients. Minimal immunosuppression dose adjustments were required. An SVR 12 weeks after treatment completion (SVR12) was achieved in 90% of patients (95% confidence interval 84%‐96%). In patients with genotype 1a infection, the SVR12 rate was significantly lower in those with METAVIR F3‐F4 (71%) compared to those with F0‐F2 (91%). Half of the patients achieved undetected HCV RNA at treatment week 4, and their SVR12 rate was significantly higher (96%) compared to those with detectable HCV RNA (83%). Treatment was very well tolerated with mild degrees of adverse events, except for one death possibly due to drug‐induced lung injury. In the 25 patients who received RBV, 72% developed anemia requiring intervention. Conclusion : An all‐oral interferon‐free antiviral regimen using simeprevir and sofosbuvir with or without RBV for 12 weeks was very well tolerated and resulted in excellent SVR12 rates in LT recipients with HCV genotype 1 infection. (H epatology 2015;61:1880–1886)