Citations

Treatment options for refractory hepatic encephalopathy (HE) are limited. Patients who fail medical management may harbor large portosystemic shunts (PSSs) which are possible therapeutic targets. This study aims to describe patient selection, effectiveness, and safety of percutaneous PSS embolization in those with medically refractory HE. A retrospective evaluation of consecutive adult patients with medically refractory HE referred for PSS embolization at a tertiary center was performed (2003‐2015). Patient data collected included the type of HE, medications, Model for End‐Stage Liver Disease (MELD) score, shunt type, embolization approach, and materials used. Outcomes of interest were immediate (7 days), intermediate (1‐4 months), and longer‐term (6‐12 months) effectiveness and periprocedural safety. Effectiveness was determined based on changes in hospitalization frequency, HE medications, and symptoms. Twenty‐five patients with large PSS were evaluated for shunt embolization. Five were excluded due to high MELD scores (n = 1), comorbid conditions (n = 1), or technical considerations (n = 3). Of 20 patients who underwent embolization, 13 had persistent and 7 had recurrent HE; 100% (20/20) achieved immediate improvement. Durable benefit was achieved in 100% (18/18) and 92% (11/12) at 1‐4 and 6‐12 months, respectively. The majority (67%; 8/12) were free from HE‐related hospitalizations over 1 year; 10% developed procedural complications, and all resolved. Six developed new or worsening ascites. In conclusion, PSS embolization is a safe and effective treatment strategy that should be considered for select patients with medically refractory HE. Liver Transplantation 22 723–731 2016 AASLD.

ABSTRACT Mengovirus, a member of the Picornaviridae family, has a broad cell tropism and can cause encephalitis and myocarditis in multiple mammalian species. Attenuation has been achieved by shortening the polycytidine tract in the 5′ noncoding region (NCR). A poly(C)-truncated strain of mengovirus, vMC 24 , resulted in significant tumor regression in immunocompetent BALB/c mice bearing syngeneic MPC-11 plasmacytomas, but the associated toxicities were unacceptable. To enhance its safety profile, microRNA target sequences complementary to miR-124 or miR-125 (enriched in nervous tissue), miR-133 and miR-208 (enriched in cardiac tissue), or miR-142 (control; enriched in hematopoietic tissues) were inserted into the vMC 24 NCRs. The microRNA-detargeted viruses showed reduced replication and cell killing specifically in cells expressing the cognate microRNAs, but certain insertions additionally were associated with nonspecific suppression of viral fitness in vivo. In vivo toxicity testing confirmed that miR-124 targets within the 5′ NCR suppressed virus replication in the central nervous system while miR-133 and miR-208 targets in the 3′ NCR suppressed viral replication in cardiac tissue. A dual-detargeted virus named vMC 24 -NC, with miR-124 targets in the 5′ NCR and miR-133 plus miR-208 targets in the 3′ NCR, showed the suppression of replication in both nervous and cardiac tissues but retained full oncolytic potency when administered by intratumoral (10 6 50% tissue culture infectious doses [TCID 50 ]) or intravenous (10 7 to 10 8 TCID 50 ) injection into BALB/c mice bearing MPC-11 plasmacytomas. Overall survival of vMC 24 -NC-treated tumor-bearing mice was significantly improved compared to that of nontreated mice. MicroRNA-detargeted mengoviruses offer a promising oncolytic virotherapy platform that merits further development for clinical translation. IMPORTANCE The clinical potential of oncolytic virotherapy for cancer treatment has been well demonstrated, justifying the continued development of novel oncolytic viruses with enhanced potency. Here, we introduce mengovirus as a novel oncolytic agent. Mengovirus is appealing as an oncolytic virotherapy platform because of its small size, simple genome structure, rapid replication cycle, and broad cell/species tropism. However, mengovirus can cause encephalomyelitis and myocarditis. It can be partially attenuated by shortening the poly(C) tract in the 5′ NCR but remains capable of damaging cardiac and nervous tissue. Here, we further enhanced the safety profile of a poly(C)-truncated mengovirus by incorporating muscle- and neuron-specific microRNA target sequences into the viral genome. This dual-detargeted virus has reduced pathogenesis but retained potent oncolytic activity. Our data show that microRNA targeting can be used to further increase the safety of an attenuated mengovirus, providing a basis for its development as an oncolytic platform.

A single monoclonal protein typically characterizes monoclonal gammopathies, but a small proportion may have more than one M protein identifiable. In the setting of symptomatic multiple myeloma (MM), the development of a new monoclonal protein following therapy is associated with better outcomes. As for the precursor conditions, monoclonal gammopathy undetermined significance (MGUS) and smoldering multiple myeloma (SMM), there is limited information on the impact of a second monoclonal protein on the disease course, including progression and response to treatment. The outcomes of patients with MGUS and SMM with more than one monoclonal protein, after identifying 539 patients with biclonal proteins on electrophoresis and/or immunofixation, were reported. About 22 of 393 patients with MGUS/biclonal gammopathy of undetermined significance (BGUS) progressed to SMM (6), MM (11), AL (3), or WM (2), and 5 of 16 patients with biclonal SMM progressed to MM. The rate of progression for BGUS was approximately 1% per year, which is similar to MGUS with one monoclonal protein. The median estimated time of progression of biclonal SMM was 2.6 years; similar to monoclonal SMM. For patients with biclonal MM, both M spikes responded to treatment and, upon relapse, the original dominant M protein remained dominant as the disease progressed. In conclusion, the presence of a second monoclonal protein does not appear to affect the progression of precursor states and suggests multiple monoclonal proteins do not clinically impact one another in the course of the disease. Am. J. Hematol. 91:473–475, 2016. © 2016 Wiley Periodicals, Inc.

AbstractDisorders affecting smooth muscle structure/function may require technologies that can generate large scale, differentiated and contractile smooth muscle cells (SMC) suitable for cell therapy. To date no clonal precursor population that provides large numbers of differentiated SMC in culture has been identified in a rodent. Identification of such cells may also enhance insight into progenitor cell fate decisions and the relationship between smooth muscle precursors and disease states that implicate differentiated SMC. In this study, we used classic clonal expansion techniques to identify novel self-renewing Islet 1 (Isl-1) positive primitive progenitor cells (PPC) within rat bone marrow that exhibited canonical stem cell markers and preferential differentiation towards a smooth muscle-like fate. We subsequently used molecular tagging to select Isl-1 positive clonal populations from expanded and de novo marrow cell populations. We refer to these previously undescribed cells as the PPC given its stem cell marker profile, and robust self-renewal capacity. PPC could be directly converted into induced smooth muscle cells (iSMC) using single transcription factor (Kruppel-like factor 4) knockdown or transactivator (myocardin) overexpression in contrast to three control cells (HEK 293, endothelial cells and mesenchymal stem cells) where such induction was not possible. iSMC exhibited immuno- and cytoskeletal-phenotype, calcium signaling profile and contractile responses similar to bona fide SMC. Passaged iSMC could be expanded to a scale sufficient for large scale tissue replacement. PPC and reprogramed iSMC so derived may offer future opportunities to investigate molecular, structure/function and cell-based replacement therapy approaches to diverse cardiovascular, respiratory, gastrointestinal, and genitourinary diseases that have as their basis smooth muscle cell functional aberrancy or numerical loss.

AbstractBACKGROUNDFor many years, basic and clinical researchers have taken advantage of the analytical sensitivity and specificity afforded by mass spectrometry in the measurement of proteins. Clinical laboratories are now beginning to deploy these work flows as well. For assays that use proteolysis to generate peptides for protein quantification and characterization, synthetic stable isotope–labeled internal standard peptides are of central importance. No general recommendations are currently available surrounding the use of peptides in protein mass spectrometric assays.CONTENTThe Clinical Proteomic Tumor Analysis Consortium of the National Cancer Institute has collaborated with clinical laboratorians, peptide manufacturers, metrologists, representatives of the pharmaceutical industry, and other professionals to develop a consensus set of recommendations for peptide procurement, characterization, storage, and handling, as well as approaches to the interpretation of the data generated by mass spectrometric protein assays. Additionally, the importance of carefully characterized reference materials—in particular, peptide standards for the improved concordance of amino acid analysis methods across the industry—is highlighted. The alignment of practices around the use of peptides and the transparency of sample preparation protocols should allow for the harmonization of peptide and protein quantification in research and clinical care.

Key Points IV therapy with oncolytic VSV-IFNβ-NIS virus extends survival of immunocompetent mice with AML. The therapeutic outcome of VSV-IFNβ-NIS–treated mice with AML is augmented by anti-PD-L1 immunotherapy.

Background: There is a paucity of data on the results of reverse (anteverting) periacetabular osteotomy (RPAO) for treatment of femoroacetabular impingement (FAI) secondary to acetabular retroversion. Purpose: To evaluate the midterm outcomes of RPAO for FAI secondary to acetabular retroversion in those with and without hip dysplasia. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review identified RPAOs performed on patients with acetabular retroversion in isolation or in the setting of dysplasia (lateral center-edge angle [LCEA] ≤19°). Acetabular retroversion with FAI was diagnosed clinically and radiographically, with a positive crossover and posterior wall signs on pelvic radiographs. Twenty-three patients (30 hips) met the inclusion criteria; 20 hips with isolated retroversion and 10 hips with retroversion and hip dysplasia. The average age at the time of the procedure was 26 years (range, 13-45 years). The average length of follow-up was 5 years (range, 2-19 years). Harris Hip Score (HHS) and radiographs were evaluated preoperatively and at last follow-up. Results: The mean preoperative LCEA was 31° (range, 22°-49°) in the isolated retroversion group and 9° (range, –4° to 17°) in the dysplastic group. Postoperatively, the LCEA in the dysplastic group increased to 35° (range, 15°-46°) ( P = .0001). The crossover sign corrected in 55% (11/20) of the isolated retroversion group and 80% (8/10) of the dysplastic group. The acetabular index (mean ± SD) improved from 1.3 ± 0.3 to 1.7 ± 0.6 ( P = .0001), indicating improved anteversion. At the latest follow-up, the average HHS in the isolated retroversion group increased from 58 preoperatively (range, 23-77) to 93 (range, 68-100) ( P = .0001); the HHS in the dysplastic group improved from 49 (range, 20-74) to 92 (range, 77-100) ( P < .0001). Complication rates were similar in both groups. Excluding hardware removal, additional surgeries were performed in 13% (4/30). Conclusion: RPAO performed for FAI in the young patient with isolated acetabular retroversion or retroversion in the setting of dysplasia successfully improved clinical and radiographic results at mid- to long-term follow-up.

Purpose Patients with low literacy, low numeracy, and/or linguistic needs can experience challenges understanding diabetes information and applying concepts to their self-management. The authors designed a toolkit of education materials that are sensitive to patients’ literacy and numeracy levels, language preferences, and cultural norms and that encourage shared goal setting to improve diabetes self-management and health outcomes. The Partnership to Improve Diabetes Education (PRIDE) toolkit was developed to facilitate diabetes self-management education and support. Methods The PRIDE toolkit includes a comprehensive set of 30 interactive education modules in English and Spanish to support diabetes self-management activities. The toolkit builds upon the authors’ previously validated Diabetes Literacy and Numeracy Education Toolkit (DLNET) by adding a focus on shared goal setting, addressing the needs of Spanish-speaking patients, and including a broader range of diabetes management topics. Each PRIDE module was evaluated using the Suitability Assessment of Materials (SAM) instrument to determine the material’s cultural appropriateness and its sensitivity to the needs of patients with low literacy and low numeracy. Reading grade level was also assessed using the Automated Readability Index (ARI), Coleman-Liau, Flesch-Kincaid, Fry, and SMOG formulas. Conclusions The average reading grade level of the materials was 5.3 (SD 1.0), with a mean SAM of 91.2 (SD 5.4). All of the 30 modules received a “superior” score (SAM >70%) when evaluated by 2 independent raters. The PRIDE toolkit modules can be used by all members of a multidisciplinary team to assist patients with low literacy and low numeracy in managing their diabetes.