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Abstract Background Predictive molecular biomarkers to select optimal treatment for patients with glioblastoma and other cancers are lacking. New strategies are needed when large randomized trials with correlative molecular data are not feasible. Methods Gene signatures (GS) were developed from 31 orthotopic glioblastoma patient-derived xenografts (PDXs), treated with standard therapies, to predict benefit from radiotherapy (RT-GS), temozolomide (Chemo-GS), or the combination (ChemoRT-GS). Independent validation was performed in a heterogeneously treated clinical cohort of 502 glioblastoma patients with overall survival as the primary endpoint. Multivariate Cox analysis was used to adjust for confounding variables and evaluate interactions between signatures and treatment. Results PDX models recapitulated the clinical heterogeneity of glioblastoma patients. RT-GS, Chemo-GS, and ChemoRT-GS were correlated with benefit from treatment in the PDX models. In independent clinical validation, higher RT-GS scores were associated with increased survival only in patients receiving RT (P = 0.0031, hazard ratio [HR] = 0.78 [0.66–0.92]), higher Chemo-GS scores were associated with increased survival only in patients receiving chemotherapy (P < 0.0001, HR = 0.66 [0.55–0.8]), and higher ChemoRT-GS scores were associated with increased survival only in patients receiving ChemoRT (P = 0.0001, HR = 0.54 [0.4–0.74]). RT-GS and ChemoRT-GS had significant interactions with treatment on multivariate analysis (P = 0.0009 and 0.02, respectively), indicating that they are bona fide predictive biomarkers. Conclusions Using a novel PDX-driven methodology, we developed and validated 3 platform-independent molecular signatures that predict benefit from standard of care therapies for glioblastoma. These signatures may be useful to personalize glioblastoma treatment in the clinic and this approach may be a generalizable method to identify predictive biomarkers without resource-intensive randomized trials.

Apolipoprotein E (apoE) is linked to the risk for Alzheimer’s disease (AD) and thus has been suggested to be an important therapeutic target. In our drug screening effort, we identified Ondansetron (OS), an FDA-approved 5-HT3 antagonist, as an apoE-modulating drug. OS at low micromolar concentrations significantly increased apoE secretion from immortalized astrocytes and primary astrocytes derived from apoE3 and apoE4-targeted replacement mice without generating cellular toxicity. Other 5-HT3 antagonists also had similar effects as OS, though their effects were milder and required higher concentrations. Antagonists for other 5-HT receptors did not increase apoE secretion. OS also increased mRNA and protein levels of the ATB-binding cassette protein A1 (ABCA1), which is involved in lipidation and secretion of apoE. Accordingly, OS increased high molecular weight apoE. Moreover, the liver X receptor (LXR) and ABCA1 antagonists blocked the OS-induced increase of apoE secretion, indicating that the LXR-ABCA1 pathway is involved in the OS-mediated facilitation of apoE secretion from astrocytes. The effects of OS on apoE and ABCA1 were also observed in human astrocytes derived from induced pluripotent stem cells (iPSC) carrying the APOE ε3/ε3 and APOE ε4/ε4 genotypes. Oral administration of OS at clinically-relevant doses affected apoE levels in the liver, though the effects in the brain were not observed. Collectively, though further studies are needed to probe its effects in vivo, OS could be a potential therapeutic drug for AD by modulating poE metabolism through the LXR-ABCA1 pathway.

Pulmonary hypertension (PH) is highly heterogeneous and despite treatment advances it remains a life‐shortening condition. There have been significant advances in imaging technologies, but despite evidence of their potential clinical utility, practice remains variable, dependent in part on imaging availability and expertise. This statement summarizes current and emerging imaging modalities and their potential role in the diagnosis and assessment of suspected PH. It also includes a review of commonly encountered clinical and radiological scenarios, and imaging and modeling‐based biomarkers. An expert panel was formed including clinicians, radiologists, imaging scientists, and computational modelers. Section editors generated a series of summary statements based on a review of the literature and professional experience and, following consensus review, a diagnostic algorithm and 55 statements were agreed. The diagnostic algorithm and summary statements emphasize the key role and added value of imaging in the diagnosis and assessment of PH and highlight areas requiring further research.

Background: Low-intensity pulsed ultrasound (LIPUS), as a safe biophysiotherapy, can enhance bone-tendon (B-T) healing in vivo and induce osteogenic or chondrogenic differentiation of mesenchymal stromal cells in vitro. This study aimed to determine whether LIPUS can improve the efficacy of transplanted mesenchymal stromal cells on B-T healing. Hypothesis: LIPUS can induce lineage-specific differentiation of transplanted adipose-derived stromal cells (ASCs) at the B-T healing site, thus resulting in superior healing quality when compared with LIPUS or ASCs alone. Study Design: Controlled laboratory study. Methods: A total of 112 mature rabbits with partial patellectomy in the hindlimb were randomly assigned into mock sonication without ASCs (control), ultrasonication without ASCs (LIPUS), mock sonication with ASCs (ASCs), and ultrasonication with ASCs (LIPUS + ASCs). The treatment time of the mock sonication or ultrasonication was 20 minutes per day. Autologous ASCs were transplanted to the healing site by fibrin glue during the operation, and LIPUS was delivered daily starting at postoperative day 3 until euthanasia. The patella–patellar tendon junctions were postoperatively harvested at 8 and 16 weeks for radiological, histological, and mechanical evaluations. Additionally, 9 animals were used for ASC tracking with mCherry protein. Results: Radiologically, there was more new bone formation and remodeling in the LIPUS + ASCs group as compared with the other groups. Synchrotron radiation micro–computed tomography showed that the LIPUS + ASCs group significantly increased bone volume fraction, trabecular thickness, and trabecular number at the healing site as compared with the other groups at postoperative 8 weeks ( P < .05 for all). Histologically, immunohistochemical staining confirmed that the transplanted mCherry-ASCs can differentiate into osteoblasts and fibrochondrocytic-like cells. Meanwhile, as compared with the other groups, the LIPUS + ASCs group showed more formation and maturity of the fibrocartilage layer and new bone at postoperative weeks 8 and 16 ( P < .05 for all). Biomechanically, the LIPUS + ASCs group showed significantly higher failure load and stiffness versus the other groups at postoperative weeks 8 and 16 ( P < .05 for all). Conclusion: Autologous ASC transplantation stimulated with LIPUS can result in superior B-T healing quality when compared with LIPUS or ASCs alone. Clinical Relevance: This study demonstrates the effectiveness of using ASC transplantation stimulated with LIPUS for B-T healing and provides a foundation for future clinical studies.

Introduction . Primary cardiac sarcoma (PCS) has a poor prognosis compared to other sarcomas due to late presentation, challenging resection, incidence of metastases, and limited efficacy of systemic therapies. Methods . A medical record search engine was queried to identify patients diagnosed with PCS from 1992 to 2017 at the University of Michigan. Results . Thirty-nine patients with PCS had a median age of 41 years (range 2–77). Common histologies were angiosarcoma (AS, 14), high-grade undifferentiated pleomorphic sarcoma (UPS, 10), and leiomyosarcoma (LMS, 5). Sites of origin were left atrium (18), right atrium (16), and pericardium (5). AS was the most common right-sided tumor; UPS was more common on the left. Eighteen patients presented with metastases involving lung (10), bone (7), liver (5), and brain (4). Twenty-five patients underwent resection, achieving 3 R 0 resections. Patients received a median of 2 (1–6) systemic therapies. Median overall survival (OS) was 12.1 months (range 0–79). Median OS was 14.0 months and 8.2 months in patients who did or did not undergo resection, respectively ( p = 0.018 ). Brain metastases occurred in 12 (31%) patients, 9 (75%) of whom had left heart tumors, at a median of 8.5 months (range 0–75) from diagnosis. Median OS was 5.6 months (range 0–30) after the diagnosis of brain metastases. Conclusions . PCS portends a poor prognosis, because of difficulty in obtaining complete resection of sarcoma, advanced stage at diagnosis, and high risk of brain metastases. Providers should be aware of the increased risk of brain metastases and consider brain imaging at diagnosis and follow-up.

Background: Accurate identification of stroke cases from electronic health record (EHR) is needed for efficient and valid clinical and epidemiology research. A number of studies have evaluated the validity of using ICD-9 and ICD-10 codes for stroke identification. Previous research results show that sensitivity and positive predictive value (PPV) for stroke identification is the lowest among all other cerebrovascular diseases, with notable differences observed by stroke pathological subtypes. While most prevalent cerebrovascular disease cases can be detected using 430-438/I60-I69 collectively, more accurate and comprehensive stroke phenotyping algorithm is needed to identify incident stroke cases from EHR. In our work, we compared case identification results using ICD-codes exclusively with ICD plus a natural language processing (NLP) algorithm. Methods: We developed the NLP part of our stroke algorithm using a list of expert provided stroke-related keywords, which covers transient ischemic attack (TIA), ischemic stroke, and hemorrhagic stroke. We validated the hybrid (ICD+NLP) algorithm and compared it with ICD-exclusive algorithm in a previously established atrial fibrillation cohort (n=5,062). Clinical notes and ICD codes of all patients after the incident AF event were reviewed by two nurse abstracters to confirm new stroke incidences. All past clinical notes and ICD codes of a subset of patients (n=402) were reviewed to confirm lifetime (prior and current) stroke cases. Manual abstraction results were considered the gold standard for evaluation of ICD only and ICD+NLP automatic extraction. Sensitivity and positive predictive values (PPV) of both algorithms were calculated. Results: Among 5,062 patients, 593 patients were confirmed to have suffered a stroke after atrial fibrillation while 4,469 patients were confirmed with no EHR evidence of stroke after AF. The ICD-exclusive algorithm had a sensitivity of 47.2% and a PPV of 47.8% for detecting new stroke incidences. The hybrid stroke algorithm achieved a sensitivity of 92.4% and a PPV of 60.6% for extraction of incident stroke. For extraction of lifetime stroke cases, the hybrid approach achieved a sensitivity of 93.9% and a PPV of 88.7%. Performance of new stroke incidence extraction is limited because past/current stroke mentions in clinical notes are difficult to distinguish by our NLP algorithm (may be a future direction). Conclusions: We developed and validated a stroke algorithm that performed well for identifying incident and lifetime stroke cases. The addition of NLP into the stroke algorithm improved the sensitivity and PPV of compared to an ICD-exclusive algorithm.

Hypertrophic cardiomyopathy (HCM) is triggered mainly by mutations in genes encoding sarcomeric proteins, but a significant proportion of patients lack a genetic diagnosis. We identified a potentially novel mutation in ryanodine receptor 2, RyR2-P1124L, in a patient from a genotype-negative HCM cohort. The aim of this study was to determine whether RyR2-P1124L triggers functional and structural alterations in isolated RyR2 channels and whole hearts. We found that P1124L induces significant conformational changes in the SPRY2 domain of RyR2. Recombinant RyR2-P1124L channels displayed a cytosolic loss-of-function phenotype, which contrasted with a higher sensitivity to luminal [Ca 2+ ], indicating a luminal gain of function. Homozygous mice for RyR2-P1124L showed mild cardiac hypertrophy, similar to the human patient. This phenotype, evident at 1 year of age, was accompanied by an increase in the expression of calmodulin (CaM). P1124L mice also showed higher susceptibility to arrhythmia at 8 months of age, before the onset of hypertrophy. RyR2-P1124L has a distinct cytosolic loss-of-function and a luminal gain-of-function phenotype. This bifunctionally divergent behavior triggers arrhythmias and structural cardiac remodeling, and it involves overexpression of CaM as a potential hypertrophic mediator. This study is relevant to continue elucidating the possible causes of genotype-negative HCM and the role of RyR2 in cardiac hypertrophy.

ABSTRACTTissue‐engineering approaches have great potential to improve the treatment of tendon injuries which are major musculoskeletal disorders. The purpose of this study was to assess the tissue engineering potential of a novel multilayered decellularized tendon “book” scaffold with bone marrow mesenchymal stem cells (BMSCs) sheets for repair of an Achilles tendon defect in a rabbit model. In this study, we developed a novel book‐shaped decellularized scaffold derived from the extracellular matrix of tendon tissues from New Zealand white rabbits. Hematoxylin and eosin (H&E) staining, 4′, 6‐diamidino‐2‐phenylindole (DAPI) staining, DNA quantitation, and scanning electron microscopy (SEM) confirmed the efficiency of decellularization. After culturing BMSCs on decellularized scaffolds, 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide (MTT) assay, SEM, quantitative real time polymerase chain reaction (qRT‐PCR), and immunofluorescence analysis demonstrated that decellularized scaffolds have the capacity to yield homogeneous distribution and alignment of BMSCs, as well as support their differentiation into tendon. Tenomodulin and Alpha‐1 collagen type I are important indicators for evaluating tenogenic differentiation of BMSCs. When decellularized “book” scaffolds with BMSCs sheets were used to repair a 1 mm Achilles tendon defect, histomorphological analysis, immunohistochemical assessment, and biomechanical testing showed that the book‐shaped decellularized tendon matrix scaffold and BMSCs sheets could promote the regeneration of type I collagen at the wound site during healing, and improve the mechanical properties of the repaired tendon. Therefore, the results of this study suggest that the novel decellularized “book” tendon scaffolds combined with BMSCs sheets have therapeutic effects on improving the healing quality of the Achilles tendon. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1–11, 2019.