The Johns Hopkins Medical Institutes

Baltimore, MD, United States

The Johns Hopkins Medical Institutes

Baltimore, MD, United States
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Pendleton C.,The Johns Hopkins Medical Institutes | Li Q.,The Johns Hopkins Medical Institutes | Chesler D.A.,The Johns Hopkins Medical Institutes | Yuan K.,The Johns Hopkins Medical Institutes | And 2 more authors.
PLoS ONE | Year: 2013

Introduction: Glioblastoma is the most common primary malignant brain tumor, and is refractory to surgical resection, radiation, and chemotherapy. Human mesenchymal stem cells (hMSC) may be harvested from bone marrow (BMSC) and adipose (AMSC) tissue. These cells are a promising avenue of investigation for the delivery of adjuvant therapies. Despite extensive research into putative mechanisms for the tumor tropism of MSCs, there remains no direct comparison of the efficacy and specificity of AMSC and BMSC tropism towards glioma. Methods: Under an IRB-approved protocol, intraoperative human Adipose MSCs (hAMSCs) were established and characterized for cell surface markers of mesenchymal stem cell origin in conjunction with the potential for tri-lineage differentiation (adipogenic, chondrogenic, and osteogenic). Validated experimental hAMSCs were compared to commercially derived hBMSCs (Lonza) and hAMSCs (Invitrogen) for growth responsiveness and glioma tropism in response to glioma conditioned media obtained from primary glioma neurosphere cultures. Results: Commercial and primary culture AMSCs and commercial BMSCs demonstrated no statistically significant difference in their migration towards glioma conditioned media in vitro. There was statistically significant difference in the proliferation rate of both commercial AMSCs and BMSCs as compared to primary culture AMSCs, suggesting primary cultures have a slower growth rate than commercially available cell lines. Conclusions: Adipose- and bone marrow-derived mesenchymal stem cells have similar in vitro glioma tropism. Given the well-documented ability to harvest larger numbers of AMSCs under local anesthesia, adipose tissue may provide a more efficient source of MSCs for research and clinical applications, while minimizing patient morbidity during cell harvesting. © 2013 Pendleton et al.

Ryoo S.,Kangwon National University | Berkowitz D.E.,The Johns Hopkins Medical Institutes | Lim H.K.,Yonsei University
Korean Journal of Anesthesiology | Year: 2011

Atherosclerotic vascular disease is the leading cause of morbidity and mortality in developed countries. While it is a complex condition resulting from numerous genetic and environmental factors, it is well recognized that oxidized low-density lipoprotein produces pro-atherogenic effects in endothelial cells (ECs) by inducing the expression of adhesion molecules, stimulating EC apoptosis, inducing superoxide anion formation and impairing protective endothelial nitric oxide (NO) formation. Emerging evidence suggests that the enzyme arginase reciprocally regulates NO synthase and NO production by competing for the common substrate L-arginine. As oxidized LDL (OxLDL) results in arginase activation/upregulation, it appears to be an important contributor to endothelial dysfunction by a mechanism that involves substrate limitation for endothelial NO synthase (eNOS) and NO synthesis. Additionally, arginase enhances production of reactive oxygen species by eNOS. Arginase inhibition in hypercholesterolemic (ApoE-/-) mice or arginase II deletion (ArgII-/-) mice restores endothelial vasorelaxant function, reduces vascular stiffness and markedly reduces atherosclerotic plaque burden. Furthermore, arginase activation contributes to vascular changes including polyamine-dependent vascular smooth muscle cell proliferation and collagen synthesis. Collectively, arginase may play a key role in the prevention and treatment of atherosclerotic vascular disease. © the Korean Society of Anesthesiologists, 2011.

Cicchiello L.A.,Yale University | Hamper U.M.,The Johns Hopkins Medical Institutes | Scoutt L.M.,Yale University
Obstetrics and Gynecology Clinics of North America | Year: 2011

Ultrasound should be considered the first-line imaging modality of choice in women presenting with acute or chronic pelvic pain of suspected gynecologic or obstetric origin because many, if not most, gynecologic/obstetric causes of pelvic pain are easily diagnosed on ultrasound examination. Since the clinical presentation of gynecologic causes of pelvic pain overlaps with gastrointestinal and genitourinary pathology, referral to CT or MRI, especially in pregnant patients, should be considered if the US examination is nondiagnostic. © 2011 Elsevier Inc.

Staedtke V.,Ludwig Center for Cancer Genetics and Therapeutics | Staedtke V.,The Johns Hopkins Medical Institutes | Roberts N.J.,Ludwig Center for Cancer Genetics and Therapeutics | Roberts N.J.,Johns Hopkins Medical Institutions | And 2 more authors.
Genes and Diseases | Year: 2016

The attenuated anaerobic bacterium Clostridium novyi-NT (C. novyi-NT) is known for its ability to precisely germinate in and eradicate treatment-resistant hypoxic tumors in various experimental animal models and spontaneously occurring canine sarcomas. In this article, we review the therapeutic and toxicologic aspects of C. novyi-NT therapy, key challenges and limitations, and promising strategies to optimize its performance via recombinant DNA technology and immunotherapeutic approaches, to establish C. novyi-NT as an essential tool in cancer therapy. © 2016 Chongqing Medical University.

PubMed | Howard Hughes Medical Institute, The Johns Hopkins Medical Institutes and Gothenburg University
Type: | Journal: eLife | Year: 2016

We determined whether the mutations found in ovarian cancers could be identified in the patients ovarian cyst fluids. Tumor-specific mutations were detectable in the cyst fluids of 19 of 23 (83%) borderline tumors, 10 of 13 (77%) type I cancers, and 18 of 18 (100%) type II cancers. In contrast, no mutations were found in the cyst fluids of 18 patients with benign tumors or non-neoplastic cysts. Though large, prospective studies are needed to demonstrate the safety and clinical utility of this approach, our results suggest that the genetic evaluation of cyst fluids might be able to inform the management of the large number of women with these lesions.

PubMed | Howard Hughes Medical Institute, Interventional Imaging, BluePearl Veterinary Partners, University of Houston and 10 more.
Type: Journal Article | Journal: Science translational medicine | Year: 2014

Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted.

PubMed | Dartmouth Hitchcock Medical Center, University of California at Davis and The Johns Hopkins Medical Institutes
Type: Journal Article | Journal: JAMA surgery | Year: 2015

Arteriovenous fistula (AVF) access improves survival in patients with end-stage renal disease (ESRD) compared with other modalities when used at first hemodialysis. Use varies between locations, but, to our knowledge, no study has related this finding to mortality on a national scale.To quantify regional variation in AVF access at first hemodialysis, as well as the associated effect on mortality in the US Renal Data System.The US Renal Data System tracks all patients with ESRD in the United States. A retrospective analysis of the population from January 1, 2006, to December 31, 2010, was performed. Univariate analyses ( test; 2-tailed, unpaired t test; and analysis of variance) as well as multivariable logistic regressions were carried out to compare patient characteristics, incident AVF frequencies, and corrected mortality hazards between ESRD Network Programs, which comprise 18 states, commonwealths, and protectorates in which residents receive hemodialysis. Of the patients receiving hemodialysis in these networks, the data on 464,547 individuals who were beginning renal replacement therapy were analyzed. Analysis was started April 1, 2013, and ended August 3, 2014.Mortality hazard variation between ESRD Network Programs in the United States and incident AVF frequency.Of the 464,547 patients beginning hemodialysis in this cohort, first hemodialysis with an AVF ranged from 11.1% to 22.2% depending on the ESRD Network in which they maintained residency (P<.001). Similarly, corrected mortality hazard varied by 28% (hazard ratios from 0.99 [95% CI, 0.96-1.03] to 1.27 [95% CI, 1.22-1.31]; P<.001). Logistic regression determined nephrology care to increase the odds of a patient beginning hemodialysis using an AVF by 11-fold (odds ratio, 11.42 [95% CI, 10.93-11.93]; P<.001); congestive heart failure was a negative correlatefold (odds ratio, 0.65 [95% CI, 0.64-0.67]; P<.001). No region achieved the 50% Fistula First Breakthrough Initiative (now known as Fistula First Catheter Last) target for incident AVF access.Marked regional variation in functional incident AVF frequency and risk-adjusted ESRD mortality exists across the United States. Differences in access to preoperative nephrology care and patient comorbidities may explain some of these variations, but an opportunity to implement best-practice guidelines exists.

PubMed | ICON Medical Imaging, University of Washington, Covance, The Johns Hopkins Medical Institutes and 8 more.
Type: Journal Article | Journal: Nuclear medicine and biology | Year: 2016

Fialuridine (FIAU) is a nucleoside analog that is a substrate for bacterial thymidine kinase (TK). Once phosphorylated by TK, [(124)I]FIAU becomes trapped within bacteria and can be detected with positron emission tomography/computed tomography (PET/CT). [(124)I]FIAU PET/CT has been shown to detect bacteria in patients with musculoskeletal bacterial infections. Accurate diagnosis of prosthetic joint infections (PJIs) has proven challenging because of the lack of a well-validated reference. In the current study, we assessed biodistribution and dosimetry of [(124)I]FIAU, and investigated whether [(124)I]FIAU PET/CT can diagnose PJIs with acceptable accuracy.To assess biodistribution and dosimetry, six subjects with suspected hip or knee PJI and six healthy subjects underwent serial PET/CT after being dosed with 74MBq (2mCi) [(124)I]FIAU intravenously (IV). Estimated radiation doses were calculated with the OLINDA/EXM software. To determine accuracy of [(124)I]FIAU, 22 subjects with suspected hip or knee PJI were scanned at 2-6 and 24-30h post IV injection of 185MBq (5mCi) [(124)I]FIAU. Images were interpreted by a single reader blinded to clinical information. Representative cases were reviewed by 3 additional readers. The utility of [(124)I]FIAU to detect PJIs was assessed based on the correlation of the patients infection status with imaging results as determined by an independent adjudication board (IAB).The kidney, liver, spleen, and urinary bladder received the highest radiation doses of [(124)I]FIAU. The effective dose was 0.16 to 0.20mSv/MBq and doses to most organs ranged from 0.11 to 0.76mGy/MBq. PET image quality obtained from PJI patients was confounded by metal artifacts from the prostheses and pronounced FIAU uptake in muscle. Consequently, a correlation with infection status and imaging results could not be established.[(124)I]FIAU was well-tolerated in healthy volunteers and subjects with suspected PJI, and had acceptable dosimetry. However, the utility of [(124)I]FIAU for the clinical detection of PJIs is limited by poor image quality and low specificity.

PubMed | The Johns Hopkins Medical Institutes
Type: Journal Article | Journal: Translational respiratory medicine | Year: 2016

SALL4 and OCT4 are transcription factors and play essential roles in stem cell development and oncogenesis. However, the expression of these transcription factors has not been well studied in lung cancers. In this study, we evaluated the expression of SALL4 and OCT4 in non-small cell lung carcinomas (NSCLC) by immunochemistry. NSCLC tissue microarrays (TMAs) were constructed with a total of 77 primary lung adenocarcinomas (ADCs) and 90 primary lung squamous cell carcinomas (SqCCs). A mouse monoclonal anti-human SALL4 (1:400 dilution) and a polyclonal anti-human OCT4 (1:200 dilution) antibodies were used. Nuclear staining of SALL4 and OCT4 was scored semi-quantitatively using a three tiered scale. The expressions of SALL4 and OCT4 were correlated with the tumor differentiation, pathological stage, and patients clinical information.In primary ADCs, the stronger expression of SALL4 and OCT4 was 7.8% and 9.1%, respectively. The stronger expression of SALL4 was inversely correlated with tumor differentiations. In primary SqCCs, the stronger expressions of SALL4 and OCT4 were 16.7% and 0%, respectively. The expression of SALL4 is correlated with the expression of OCT4, but inversely correlated with the tumor stage in SqCCs.We found that both SALL4 and OCT4 were differentially expressed in a subset of primary ADC and SqCC. Our finding suggest that different stem cell markers may be expressed and/or play differential role in different subtypes of NSCLC. The potential role of SALL4 and OCT4 needs to be further investigated in NSCLC.

PubMed | Dartmouth Hitchcock Medical Center and The Johns Hopkins Medical Institutes
Type: Journal Article | Journal: The Urologic clinics of North America | Year: 2015

Bladder cancer is a heterogeneous disease characterized by complex networks of molecular alterations and gene expression. This review summarizes some of the recent genomic studies that have further advanced the understanding of the pathways driving bladder cancer, highlighting several important biomarkers and potential targeted therapeutic strategies that are now in clinical trials. In addition, noninvasive techniques to evaluate biomarkers in patients urine and serum for early detection and surveillance are discussed.

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