Syndicate content
Recent documents in eScholarship@UMMS
Updated: 3 hours 6 min ago

Humanized Mouse Models of Clinical Disease

Tue, 05/16/2017 - 12:44pm

Immunodeficient mice engrafted with functional human cells and tissues, that is, humanized mice, have become increasingly important as small, preclinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (IL2rgnull) in the early 2000s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers. Humanized mice are permitting significant progress in studies of human infectious disease, cancer, regenerative medicine, graft-versus-host disease, allergies, and immunity. Ultimately, use of humanized mice may lead to the implementation of truly personalized medicine in the clinic. This review discusses recent progress in the development and use of humanized mice and highlights their utility for the study of human diseases.

Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension

Tue, 05/16/2017 - 12:44pm

OBJECTIVE: To determine whether a clinically-utilised IL-1 receptor antagonist, anakinra, reduces renal inflammation, structural damage and blood pressure (BP) in mice with established hypertension. METHODS: Hypertension was induced in male mice by uninephrectomy, deoxycorticosterone acetate (2.4mg/d,s.c.) and replacement of drinking water with saline (1K/DOCA/salt). Control mice received uninephrectomy, a placebo pellet and normal drinking water. 10days post-surgery, mice commenced treatment with anakinra (75mg/kg/d, i.p.) or vehicle (0.9% saline, i.p.) for 11 days. Systolic BP was measured by tail cuff while qPCR, immunohistochemistry and flow cytometry were used to measure inflammatory markers, collagen and immune cell infiltration in the kidneys. RESULTS: By 10 days post-surgery, 1K/DOCA/salt-treated mice displayed elevated systolic BP (148.3+/-2.4mmHg) compared to control mice (121.7+/-2.7mmHg; n=18, P<0.0001). The intervention with anakinra reduced BP in 1K/DOCA/salt-treated mice by approximately 20mmHg (n=16, P<0.05), but had no effect in controls. In 1K/DOCA/salt-treated mice, anakinra modestly reduced ( approximately 30%) renal expression of some (CCL5, CCL2; n=7-8; P<0.05) but not all (ICAM-1, IL-6) inflammatory markers, and had no effect on immune cell infiltration (n=7-8, P > 0.05). Anakinra reduced renal collagen content (n=6, P<0.01) but paradoxically appeared to exacerbate the renal and glomerular hypertrophy (n=8-9, P<0.001) that accompanied 1K/DOCA/salt-induced hypertension. CONCLUSION: Despite its anti-hypertensive and renal anti-fibrotic actions, anakinra had minimal effects on inflammation and leukocyte infiltration in mice with 1K/DOCA/salt-induced hypertension. Future studies will assess whether the anti-hypertensive actions of anakinra are mediated by protective actions in other BP-regulating or salt-handling organs such as the arteries, skin and brain.

A common class of transcripts with 5'-intron depletion, distinct early coding sequence features, and N1-methyladenosine modification

Tue, 05/16/2017 - 12:44pm

Introns are found in 5' untranslated regions (5'UTRs) for 35% of all human transcripts. These 5'UTR introns are not randomly distributed: Genes that encode secreted, membrane-bound and mitochondrial proteins are less likely to have them. Curiously, transcripts lacking 5'UTR introns tend to harbor specific RNA sequence elements in their early coding regions. To model and understand the connection between coding-region sequence and 5'UTR intron status, we developed a classifier that can predict 5'UTR intron status with > 80% accuracy using only sequence features in the early coding region. Thus, the classifier identifies transcripts with 5' proximal-intron-minus-like-coding regions ("5IM" transcripts). Unexpectedly, we found that the early coding sequence features defining 5IM transcripts are widespread, appearing in 21% of all human RefSeq transcripts. The 5IM class of transcripts is enriched for non-AUG start codons, more extensive secondary structure both preceding the start codon and near the 5' cap, greater dependence on eIF4E for translation, and association with ER-proximal ribosomes. 5IM transcripts are bound by the exon junction complex (EJC) at noncanonical 5' proximal positions. Finally, N1-methyladenosines are specifically enriched in the early coding regions of 5IM transcripts. Taken together, our analyses point to the existence of a distinct 5IM class comprising approximately 20% of human transcripts. This class is defined by depletion of 5' proximal introns, presence of specific RNA sequence features associated with low translation efficiency, N1-methyladenosines in the early coding region, and enrichment for noncanonical binding by the EJC.

Large family cohorts of lymphoblastoid cells provide a new cellular model for investigating facioscapulohumeral muscular dystrophy

Tue, 05/16/2017 - 12:44pm

Facioscapulohumeral muscular dystrophy (FSHD) is associated with aberrant epigenetic regulation of the chromosome 4q35 D4Z4 macrosatellite repeat. The resulting DNA hypomethylation and relaxation of epigenetic repression leads to increased expression of the deleterious DUX4-fl mRNA encoded within the distal D4Z4 repeat. With the typical late onset of muscle weakness, prevalence of asymptomatic individuals, and an autosomal dominant mode of inheritance, FSHD is often passed on from one generation to the next and affects multiple individuals within a family. Here we have characterized unique collections of 114 lymphoblastoid cell lines (LCLs) generated from 12 multigenerational FSHD families, including 56 LCLs from large, genetically homogeneous families in Utah. We found robust expression of DUX4-fl in most FSHD LCLs and a good correlation between DNA hypomethylation and repeat length. In addition, DUX4-fl levels can be manipulated using epigenetic drugs as in myocytes, suggesting that some epigenetic pathways regulating DUX4-fl in myocytes are maintained in LCLs. Overall, these FSHD LCLs provide an alternative cellular model in which to study many aspects of D4Z4, DUX4, and FSHD gene regulation in a background of low genetic variation. Significantly, these non-adherent immortal LCLs are amenable for high-throughput screening of potential therapeutics targeting DUX4-fl mRNA or protein expression.

Arteriovenous fistula patency in the 3 years following vonapanitase and placebo treatment

Tue, 05/16/2017 - 12:44pm

OBJECTIVE: This study explored the long-term outcomes of arteriovenous fistulas treated with vonapanitase (recombinant human elastase) at the time of surgical creation.

METHODS: This was a randomized, double-blind, placebo-controlled trial of 151 patients undergoing radiocephalic or brachiocephalic arteriovenous fistula creation who were randomized equally to placebo, vonapanitase 10 mug, or vonapanitase 30 mug. The results after 1 year of follow-up were previously reported. The current analysis occurred when the last patient treated was observed for 3 years. For the current analysis, the primary end point was primary patency; the secondary end points included secondary patency, use of the fistula for hemodialysis, and rate of procedures to restore or to maintain patency.

RESULTS: There was no significant difference in the risk of primary patency loss with vonapanitase 10 mug or 30 mug vs placebo. When seven initial patency loss events related to cephalic arch and central vein balloon angioplasty were excluded, the risk of patency loss was reduced with vonapanitase overall (hazard ratio [HR], 0.63; P = .049) and 30 mug (HR, 0.51; P = .03). In patients with radiocephalic fistulas (n = 67), the risks of primary and secondary patency loss were reduced with 30 mug (HR, 0.37 [P = .02] and 0.24 [P = .046], respectively). The rate of procedures to restore or to maintain fistula patency was reduced with 30 mug vs placebo (0.23 vs 0.72 procedure days/patient/year; P = .03) and also reduced in patients with radiocephalic fistulas with 30 mug vs placebo (0.17 vs 0.85 procedure days/patient/year; P = .048).

CONCLUSIONS: In this study, vonapanitase did not significantly improve primary patency in the primary analysis but did significantly improve primary patency in an analysis that excluded patency loss due to cephalic arch and central vein balloon angioplasty. In patients with radiocephalic fistulas, 30 mug significantly improved primary and secondary patency. Vonapanitase 30 mug decreased the rate of procedures to restore or to maintain patency in the analysis that included all patients and in the subset with radiocephalic fistulas.

The UMCCTS: A Decade of Advancing Health Through Translation

Tue, 05/16/2017 - 11:40am

Katherine Luzuriaga, MD, is PI and Director, UMass Center for Clinical and Translational Science and Vice Provost, Clinical and Translational Research at UMass Medical School. Dr. Luzuriaga is also the UMass Memorial Health Care Chair in Biomedical Research and Professor, Program in Molecular Medicine, Pediatrics and Medicine. In her presentation, she reviews the history, goals, programs and achievements of the UMass Center for Clinical and Translational Science.

UMass & The Life Sciences: A Collaborative Gene Fully Expressed

Tue, 05/16/2017 - 11:20am

Michael F. Collins, MD, is Senior Vice President for the Health Sciences for the University of Massachusetts and Chancellor, UMass Medical School. In his presentation he describes UMass’s system-wide strategic planning, coordination, and collaboration to position the UMass System for sustained and impactful external engagement in the life sciences.

Agenda: 2017 UMass Center for Clinical and Translational Science Research Retreat

Tue, 05/16/2017 - 10:30am

Agenda for the 7th annual UMass Center for Clinical and Translational Science Research Retreat, held Tuesday, May 16, 2017 at the University of Massachusetts Medical School, Worcester, MA.

ACR Appropriateness Criteria Imaging After Shoulder Arthroplasty

Mon, 05/15/2017 - 2:06pm

There has been a rapid increase in the number of shoulder arthroplasties, including partial or complete humeral head resurfacing, hemiarthroplasty, total shoulder arthroplasty, and reverse total shoulder arthroplasty, performed in the United States over the past two decades. Imaging can play an important role in diagnosing the complications that can occur in the setting of these shoulder arthroplasties. This review is divided into two parts. The first part provides a general discussion of various imaging modalities, comprising radiography, CT, MRI, ultrasound, and nuclear medicine, and their role in providing useful, treatment-guiding information. The second part focuses on the most appropriate imaging algorithms for shoulder arthroplasty complications such as aseptic loosening, infection, fracture, rotator cuff tendon tear, and nerve injury. The evidence-based ACR Appropriateness Criteria guidelines offered in this report were reached via an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (the RAND/UCLA Appropriateness Method and the Grading of Recommendations Assessment, Development, and Evaluation) for rating the appropriateness of imaging and treatment procedures for specific clinical scenarios. Further analysis and review of the guidelines were performed by a multidisciplinary expert panel. In those instances in which there was insufficient or equivocal data for recommending the appropriate imaging algorithm, expert opinion may have supplemented the available evidence.

Imaging for Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis (SAPHO) Syndrome

Mon, 05/15/2017 - 2:06pm

Multifocal osteomyelitis and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome constitute a spectrum of disease that includes inflammatory bone lesions and dermatologic findings. Radiographic features resemble those of the spondyloarthropathies with anterior chest wall involvement. Early radiographic findings are osteodestructive with lytic lesions. Bone scintigraphy of the sternoclavicular region classically yields a 'bull's head' pattern of radionuclide uptake. Magnetic resonance imaging (MRI) can demonstrate corner lesions of vertebral bodies. Ultrasound often reveals peripheral enthesitis. Late radiographic features are usually osteoproliferative. PET/CT can identify chronic lesions. Differential diagnostic considerations include osteomyelitis and malignancy, which often prompt bone biopsy.

CAD-RADS: Coronary Artery Disease - Reporting and Data System: An Expert Consensus Document of the Society of Cardiovascular Computed Tomography (SCCT), the American College of Radiology (ACR) and the North American Society for Cardiovascular Imaging (NAS

Mon, 05/15/2017 - 2:06pm

The intent of CAD-RADS - Coronary Artery Disease Reporting and Data System is to create a standardized method to communicate findings of coronary CT angiography (coronary CTA) in order to facilitate decision-making regarding further patient management. The suggested CAD-RADS classification is applied on a per-patient basis and represents the highest-grade coronary artery lesion documented by coronary CTA. It ranges from CAD-RADS 0 (Zero) for the complete absence of stenosis and plaque to CAD-RADS 5 for the presence of at least one totally occluded coronary artery and should always be interpreted in conjunction with the impression found in the report. Specific recommendations are provided for further management of patients with stable or acute chest pain based on the CAD-RADS classification. The main goal of CAD-RADS is to standardize reporting of coronary CTA results and to facilitate communication of test results to referring physicians along with suggestions for subsequent patient management. In addition, CAD-RADS will provide a framework of standardization that may benefit education, research, peer-review and quality assurance with the potential to ultimately result in improved quality of care.

Advantages of day-before lymphoscintigraphy and undiluted methylene blue dye injections for sentinel lymph node biopsies for melanoma

Mon, 05/15/2017 - 2:06pm

BACKGROUND AND OBJECTIVES: Lymphatic mapping (LM) and blue dye injections are essential to identification of sentinel lymph nodes (SLN) for melanoma. LM is performed the day before (DB) or the same day (SD) of surgery, but the optimal timing is unknown. Similarly, methylene blue (MB), used during SLN biopsy (SLNB), is administered diluted (dMB) or undiluted (uMB), but the relative efficacies are unknown.

METHODS: Patients who underwent SLNB for melanoma from 2009 to 2013 at our institution were evaluated. Outcomes included operative correlation with LM, SLN identification, and postoperative complications.

RESULTS: One hundred seventy-one patients underwent SLNB. Sixty-seven (39%) had DB LM. Sixty-seven (39%) received uMB. Operative findings correlated with both LM groups, though the DB patients had lower background count (P = 0.018) and lower highest SLN radioactive signal count (P = 0.046). More uMB patients had blue SLNs (90% vs. 68%, P = 0.001). There was no difference in the total number of SLNs or complication rates in the LM and MB groups.

CONCLUSIONS: This is the first study to compare the use of DB LM with SD LM and the efficacy of uMB versus dMB. DB LM and uMB offer advantageous alternatives for patients and their surgeons without loss of accuracy or increased morbidity.

Facial Drooping, Aphasia, and an Incidental Lung Mass in a Nonsmoker

Mon, 05/15/2017 - 2:06pm

BACKGROUND: Atrial fibrillation and atrial flutter are atrial tachycardias associated with embolic strokes. To date, there have only been a few reports highlighting the incidence of these atrial tachycardias due to mechanical compression of myocardial structures and the pulmonary vasculature in certain mediastinal masses and cysts.

CASE: We present a case of a 75-year-old gentleman who is a nonsmoker with a history of hypertension who presents with an acute embolic stroke due to atrial flutter likely from mechanical compression from an underlying squamous cell carcinoma of the lung.

CONCLUSION: This case represents, to the best of our knowledge, a rare case of squamous cell carcinoma of the lung in a nonsmoker likely leading to mechanical compression and a resultant atrial tachycardia with an embolic stroke.

Use of Morpholino Oligomers for Pretargeting

Mon, 05/15/2017 - 2:06pm

Differing from the conventional direct-targeting strategy in which a probe or payload is directly loaded onto a targeting molecule that binds to the native target, pretargeting is an improved targeting strategy. It converts the native target to an artificial target specific for a secondary targeting molecule loaded with the probe or payload (effector). The effector is small and does not accumulate in normal tissues, which accelerates the targeting process and generates high target to nontarget ratios. DNA/cDNA analogs can serve as the recognition pair, i.e., the artificial target and the secondary targeting effector. Morpholino oligomers are so far the most investigated and the most successful DNA/cDNA analog recognition pairs for pretargeting. Herein, we describe the pretargeting principles, the pretargeting strategy using Morpholino oligomers, and the preclinical success so far achieved.

Molecular Imaging of Stems Cells: In Vivo Tracking and Clinical Translation

Mon, 05/15/2017 - 2:06pm

After further evaluation of different possibilities of tracking stem cells, we do expect that many clinical questions, raised from applications of stem cells-based therapies, will find an answer in molecular imaging. Therefore, we do believe that stem cell-based therapies and molecular imaging will live together happily ever after.

Emergent Endovascular Management of Long-Segment and Flow-Limiting Carotid Artery Dissections in Acute Ischemic Stroke Intervention with Multiple Tandem Stents

Mon, 05/15/2017 - 2:06pm

BACKGROUND AND PURPOSE: Although most cervical dissections are managed medically, emergent endovascular treatment may become necessary in the presence of intracranial large-vessel occlusions, flow-limiting and long-segment dissections with impending occlusion, and/or hypoperfusion-related ischemia at risk of infarction. We investigated the role of emergent endovascular stenting of long-segment carotid dissections in the acute ischemic stroke setting. MATERIALS AND METHODS: We retrospectively studied long-segment carotid dissections requiring stent reconstruction with multiple tandem stents (>/=3 stents) and presenting with acute (<12>hours) ischemic stroke symptoms (NIHSS score, >/=4). We analyzed patient demographics, vascular risk factors, clinical presentations, imaging/angiographic findings, technical procedures/complications, and clinical outcomes. RESULTS: Fifteen patients (mean age, 51.5 years) with acute ischemic stroke (mean NIHSS score, 15) underwent endovascular stent reconstruction for vessel and/or ischemic tissue salvage. All carotid dissections presented with >70% flow limiting stenosis and involved the distal cervical ICA with a minimum length of 3.5 cm. Carotid stent reconstruction was successful in all patients with no residual stenosis or flow limitation. Nine patients (60%) harbored intracranial occlusions, and 6 patients (40%) required intra-arterial thrombolysis/thrombectomy, achieving 100% TICI 2b-3 reperfusion. Two procedural complications were limited to thromboembolic infarcts from in-stent thrombus and asymptomatic hemorrhagic infarct transformation (7% morbidity, 0% mortality). Angiographic and ultrasound follow-up confirmed normal carotid caliber and stent patency, with 2 cases of <20% in-stent stenosis. Early clinical improvement resulted in a mean discharge NIHSS score of 6, and 9/15 (60%) patients achieved a 90-day mRS of

Radiologic-Pathologic Discordance and Outcome After MRI-Guided Vacuum-Assisted Biopsy

Mon, 05/15/2017 - 2:06pm

OBJECTIVE: The purpose of this study was to determine the rate, characteristics, and outcomes of discordant MRI-guided vacuum-assisted biopsy (VAB) in women with suspected breast cancer.

MATERIALS AND METHODS: This retrospective study reviewed 1314 MRI-guided VABs performed in 1211 women between 2007 and 2013 and yielded 25 discordant results in 24 women. MRI characteristics; BI-RADS assessments; whether the lesion was missed, partially sampled, or excised at biopsy; and biopsy and surgical pathology results were reviewed. Statistical analyses were performed using Fisher exact and Mann-Whitney U tests.

RESULTS: Among 1314 lesions that underwent MRI-guided VAB, 25 results were discordant (1.9%; 95% CI, 1.2-2.8%), and nine lesions with discordant results (36.0%, 95% CI, 18.5-56.9%) were malignant at surgical excision (three invasive ductal carcinoma and six ductal carcinoma in situ). There was no significant association between malignancy and lesion type, size, enhancement pattern, BI-RADS assessment, or clinical indication. Forty-four percent (11/25) of discordant lesions were missed, 48.0% (12/25) were partially sampled, and 8.0% (2/25) appeared to have been excised. Of the nine malignant lesions, 44.4% (4/9) discordant malignant lesions were missed, 44.4% (4/9) were partially sampled, and 11.1% (1/9) appeared to have been excised. Lesion sizes and types were similar in the missed and partially excised groups.

CONCLUSION: The potential for false-negative results at MRI-guided VAB underscores the importance of radiologic-histologic correlation and imaging review after biopsy. Rebiopsy or excision in discordant cases is therefore recommended.

Proceedings of the third international molecular pathological epidemiology (MPE) meeting

Mon, 05/15/2017 - 2:06pm

Molecular pathological epidemiology (MPE) is a transdisciplinary and relatively new scientific discipline that integrates theory, methods, and resources from epidemiology, pathology, biostatistics, bioinformatics, and computational biology. The underlying objective of MPE research is to better understand the etiology and progression of complex and heterogeneous human diseases with the goal of informing prevention and treatment efforts in population health and clinical medicine. Although MPE research has been commonly applied to investigating breast, lung, and colorectal cancers, its methodology can be used to study most diseases. Recent successes in MPE studies include: (1) the development of new statistical methods to address etiologic heterogeneity; (2) the enhancement of causal inference; (3) the identification of previously unknown exposure-subtype disease associations; and (4) better understanding of the role of lifestyle/behavioral factors on modifying prognosis according to disease subtype. Central challenges to MPE include the relative lack of transdisciplinary experts, educational programs, and forums to discuss issues related to the advancement of the field. To address these challenges, highlight recent successes in the field, and identify new opportunities, a series of MPE meetings have been held at the Dana-Farber Cancer Institute in Boston, MA. Herein, we share the proceedings of the Third International MPE Meeting, held in May 2016 and attended by 150 scientists from 17 countries. Special topics included integration of MPE with immunology and health disparity research. This meeting series will continue to provide an impetus to foster further transdisciplinary integration of divergent scientific fields.

Treatment of complex anterior cerebral artery aneurysms with Pipeline flow diversion: mid-term results

Mon, 05/15/2017 - 2:06pm

BACKGROUND: The off-label use of flow diverters in the treatment of distal aneurysms continues to be debated.

OBJECTIVE: To report our multicenter experience in the treatment of complex anterior cerebral artery aneurysms with the Pipeline embolization device (PED).

METHODS: The neurointerventional databases of the four participating institutions were retrospectively reviewed for aneurysms treated with PED between October 2011 and January of 2016. All patients treated for anterior cerebral artery aneurysms were included in the analysis. Clinical presentation, location, type, vessel size, procedural complications, clinical and imaging follow-up were included in the analysis.

RESULTS: Twenty patients (13 female) with 20 aneurysms met the inclusion criteria in our study. Fifteen aneurysms were classified as saccular and five as fusiform (mean size 7.3 mm). Thirteen aneurysms were located in the anterior communicating region (ACOM or A1/2 junction), six were A2-pericallosal, and one was located in the A1 segment. Six patients had presented previously with subarachnoid hemorrhage and had their aneurysms initially clipped or coiled. There was one minor event (a small caudate infarct) and one major event (intraparenchymal hemorrhage). Sixteen of the 20 patients had angiographic follow-up (mean 10 months). Eleven aneurysms were completely occluded, one had residual neck, and four had residual aneurysm filling.

CONCLUSIONS: The treatment of complex anterior cerebral artery aneurysms with the PED as an alternative for patients who are not good candidates for conventional methods is technically feasible and safe. Mid-term results are promising but larger series with long-term follow-up are required to assess its effectiveness.

An in vitro evaluation of distal emboli following Lazarus Cover-assisted stent retriever thrombectomy

Mon, 05/15/2017 - 2:06pm

BACKGROUND: Formation of clot fragments during mechanical thrombectomy for acute ischemic stroke can occlude the distal vasculature, which may reduce the rate of good clinical outcome.

OBJECTIVE: To examine the hypothesis that distal embolization can be reduced using stent retriever thrombectomy in combination with Lazarus Cover technology.

METHODS: Hard, fragment-prone clots were used to create middle cerebral artery occlusions in a vascular phantom. Three different treatment strategies using Solitaire FR included: group 1-proximal flow control with an 8F balloon guide catheter (BGC), group 2-thrombectomy through a 6F conventional guide catheter (CGC), and group 3-a similar thrombectomy procedure to group 2 but including the Lazarus Cover device. The primary endpoint was distal emboli quantified by the number and size of the clot debris.

RESULTS: The Cover-assisted stent retriever thrombectomy significantly reduced the generation of clot fragments >200 mum as compared with thrombectomy with a CGC, and was similar to the BGC group. Particle size distribution recanalization, with only one failed recanalization with partial clot retention after three passes in one experiment of stent retriever thrombectomy through a CGC. Use of the adjunctive Cover device did not prolong the procedure as compared with control groups.

CONCLUSIONS: For a fragment-prone clot, Solitaire thrombectomy in conjunction with the Cover device may lower the risk of distal embolization and is comparable to BGC-protected embolectomy.