Publications by authors named "Russell S Taichman"

124 Publications

Retraction notice to <"Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis"> <[Cellular Signaling 17/12 (2005) 1578-1592]>.

Cell Signal 2021 Apr 13;80:109909. Epub 2021 Jan 13.

Department of Periodontics, Prevention and Geriatrics, University of Michigan School of Dentistry, 1011 North University Avenue, Ann Arbor, MI 48109-1078, United States.

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http://dx.doi.org/10.1016/j.cellsig.2020.109909DOI Listing
April 2021

Abscisic acid regulates dormancy of prostate cancer disseminated tumor cells in the bone marrow.

Neoplasia 2021 01 6;23(1):102-111. Epub 2020 Dec 6.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA; Department of Periodontics, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Prostate cancer (PCa) commonly metastasizes to the bone where the cells frequently undergo dormancy. The escape of disseminated tumor cells from cellular dormancy is a major cause of recurrence in marrow. Abscisic acid (ABA), a phytohormone, is known to regulate dormancy of plant seeds and to regulate other stress responses in plants. Recently, ABA was found to be synthesized by mammals cells and has been linked to human disease. Yet the role of ABA in regulating tumor dormancy or reactivation is unknown. We found that ABA is produced by human marrow cells, and exogenous ABA inhibits PCa cell proliferation while increasing the expression of p27, p21, and p16 and decreasing the expression of the proliferation marker, Ki67. Further, ABA significantly increased the percentage of PCa cells in the G phase of the cell cycle as well as the duration the cells were arrested in G. We found that ABA regulates an increase of PPARγ receptor expression and suppressed phosphorylation of mTOR/p70S6K signaling and resulting in the induction of the cellular dormancy. We then confirmed that ABA regulates G cell cycle arrest through PPARγ receptor signaling in vitro and under co-culture conditions with osteoblasts. Finally, we demonstrate that ABA regulates PCa dormancy in vivo following intratibial injection in an animal model. Together these data suggest that the ABA and PPARγ signaling pathways contribute to the establishment of PCa cellular dormancy in the bone marrow microenvironment. These findings may suggest critical pathways for targeting metastatic disease.
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http://dx.doi.org/10.1016/j.neo.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721692PMC
January 2021

CXCL12γ induces human prostate and mammary gland development.

Prostate 2020 09 13;80(13):1145-1156. Epub 2020 Jul 13.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.

Background: Epithelial stem cells (ESCs) demonstrate a capacity to maintain normal tissues homeostasis and ESCs with a deregulated behavior can contribute to cancer development. The ability to reprogram normal tissue epithelial cells into prostate or mammary stem-like cells holds great promise to help understand cell of origin and lineage plasticity in prostate and breast cancers in addition to understanding normal gland development. We previously showed that an intracellular chemokine, CXCL12γ induced cancer stem cells and neuroendocrine characteristics in both prostate and breast adenocarcinoma cell lines. However, its role in normal prostate or mammary epithelial cell fate and development remains unknown. Therefore, we sought to elucidate the functional role of CXCL12γ in the regulation of ESCs and tissue development.

Methods: Prostate epithelial cells (PNT2) or mammary epithelial cells (MCF10A) with overexpressed CXCL12γ was characterized by quantitative real-time polymerase chain reaction, Western blots, and immunofluorescence for lineage marker expression, and fluorescence activated cell sorting analyses and sphere formation assays to examine stem cell surface phenotype and function. Xenotransplantation animal models were used to evaluate gland or acini formation in vivo.

Results: Overexpression of CXCL12γ promotes the reprogramming of cells with a differentiated luminal phenotype to a nonluminal phenotype in both prostate (PNT2) and mammary (MCF10A) epithelial cells. The CXCL12γ-mediated nonluminal type cells results in an increase of epithelial stem-like phenotype including the subpopulation of EPCAM /CD49f /CD24 /CD44 cells capable of sphere formation. Critically, overexpression of CXCL12γ promotes the generation of robust gland-like structures from both prostate and mammary epithelial cells in in vivo xenograft animal models.

Conclusions: CXCL12γ supports the reprogramming of epithelial cells into nonluminal cell-derived stem cells, which facilitates gland development.
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http://dx.doi.org/10.1002/pros.24043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491592PMC
September 2020

Adrenergic Blockade Promotes Maintenance of Dormancy in Prostate Cancer Through Upregulation of GAS6.

Transl Oncol 2020 Jul 28;13(7):100781. Epub 2020 Apr 28.

Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI; School of Dentistry, University of Alabama-Birmingham, Birmingham, AL. Electronic address:

Men diagnosed with localized prostate cancer can develop metastases many years after initial treatment, resulting in a poor prognosis. The purpose of this study was to investigate the mechanisms by which signaling through norepinephrine (NE) may incite relapse of quiescent prostate cancer. We used an unbiased bioinformatics pipeline to examine mechanisms for recurrence related to sympathetic signaling in the bone marrow. A transcription factor cell array identified ATF1, RAR, and E2F as key nodes in prostate cancer cells exiting quiescence through adrenergic signaling. Subsequent secretome analysis identified GAS6 as affecting activity of these three factors, leading to cell cycle reentry. GAS6 expression was downregulated in osteoblasts through activation of the cAMP pathway and was targeted in vitro and in vivo using pharmacological agents (propranolol and phentolamine). Propranolol increased expression of GAS6 by osteoblasts, and phentolamine significantly inhibited expression. Propranolol treatment was sufficient to both increase GAS6 expression in marrow osteoblasts as well as eliminate the effects of NE signaling on GAS6 expression. These results demonstrate a strong correlation between adrenergic signaling, GAS6 expression, and recurrence in prostate cancer, suggesting a novel therapeutic direction for patients at high risk of metastasis.
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http://dx.doi.org/10.1016/j.tranon.2020.100781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191848PMC
July 2020

Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion.

Transl Oncol 2020 Apr 25;13(4):100747. Epub 2020 Mar 25.

Department of Urology, University of Michigan, Ann Arbor, MI 48109; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109. Electronic address:

Wnt signaling has been implicated as a driver of prostate cancer-related osteoblast differentiation, and previous studies have linked modifications in Wnt function with the induction of tumor metastasis. A unique aspect of prostate cancer bone metastases in mouse models is their relative predilection to the hindlimb (femur) compared to the forelimb (humerus). Comparative gene expression profiling was performed within the humerus and femur from non-tumor-bearing mice to evaluate differences in the microenvironments of these locations. This revealed the relative overexpression of the Wnt signaling inhibitors WIF1 and SOST in the humerus compared to the femur, with increased WNT5A expression in femur bone marrow, suggesting a coordinated upregulation of Wnt signals within the femur compared to the humerus. Conditioned medium (CM) from bone marrow stromal cells (HS-5 cells) was used to mimic the bone marrow microenvironment, which strongly promoted prostate cancer cell invasion (3.3-fold increase in PC3 cells, P < .05; 7-fold increase in LNCaP cells, P < .05). WNT5A shRNA knockdown within the CM-producing HS-5 cells significantly decreased PC3 (56%, P < .05) and LNCaP (60%, P < .05) cell invasion. Similarly, preincubation of CM with WIF1 significantly blocked LNCaP cell invasion (40%, P < .05). shRNA-mediated knockdown of the Wnt receptors FZD4 and FZD8 also strongly inhibited tumor cell invasion (60% inhibition shFZD4, P < .05; 63% shFZD8, P < .05). Furthermore, small molecule inhibition of JNK, which is an important component of the noncanonical Wnt signaling pathway, significantly inhibited CM-mediated tumor invasion. Overall, this study reveals a role for Wnt signaling as a driver of prostate cancer bone metastatic tropism and invasion.
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http://dx.doi.org/10.1016/j.tranon.2020.100747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109463PMC
April 2020

Author Correction: Anticancer polymers designed for killing dormant prostate cancer cells.

Sci Rep 2019 Nov 25;9(1):17455. Epub 2019 Nov 25.

Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, 48109, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-019-53859-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877596PMC
November 2019

Primary prostate cancer educates bone stroma through exosomal pyruvate kinase M2 to promote bone metastasis.

J Exp Med 2019 12 23;216(12):2883-2899. Epub 2019 Sep 23.

Department of Urology, Medical School, University of Michigan, Ann Arbor, MI

Prostate cancer (PCa) metastasizes selectively to bone through unknown mechanisms. In the current study, we identified exosome-mediated transfer of pyruvate kinase M2 (PKM2) from PCa cells into bone marrow stromal cells (BMSCs) as a novel mechanism through which primary tumor-derived exosomes promote premetastatic niche formation. We found that PKM2 up-regulates BMSC CXCL12 production in a HIF-1α-dependent fashion, which subsequently enhances PCa seeding and growth in the bone marrow. Furthermore, serum-derived exosomes from patients with either primary PCa or PCa metastasis, as opposed to healthy men, reveal that increased exosome PKM2 expression is associated with metastasis, suggesting clinical relevance of exosome PKM2 in PCa. Targeting the exosome-induced CXCL12 axis diminished exosome-mediated bone metastasis. In summary, primary PCa cells educate the bone marrow to create a premetastatic niche through primary PCa exosome-mediated transfer of PKM2 into BMSCs and subsequent up-regulation of CXCL12. This novel mechanism indicates the potential for exosome PKM2 as a biomarker and suggests therapeutic targets for PCa bone metastasis.
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http://dx.doi.org/10.1084/jem.20190158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888980PMC
December 2019

Detection and isolation of disseminated tumor cells in bone marrow of patients with clinically localized prostate cancer.

Prostate 2019 10 26;79(14):1715-1727. Epub 2019 Aug 26.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.

Background: Disseminated tumor cells (DTCs) have been reported in the bone marrow (BM) of patients with localized prostate cancer (PCa). However, the existence of these cells continues to be questioned, and few methods exist for viable DTC isolation. Therefore, we sought to develop novel approaches to identify and, if detected, analyze localized PCa patient DTCs.

Methods: We used fluorescence-activated cell sorting (FACS) to isolate a putative DTC population, which was negative for CD45, CD235a, alkaline phosphatase, and CD34, and strongly expressed EPCAM. We examined tumor cell content by bulk cell RNA sequencing (RNA-Seq) and whole-exome sequencing after whole genome amplification. We also enriched for BM DTCs with α-EPCAM immunomagnetic beads and performed quantitative reverse trancriptase polymerase chain reaction (qRT-PCR) for PCa markers.

Results: At a threshold of 4 cells per million BM cells, the putative DTC population was present in 10 of 58 patients (17%) with localized PCa, 4 of 8 patients with metastatic PCa of varying disease control, and 1 of 8 patients with no known cancer, and was positively correlated with patients' plasma PSA values. RNA-Seq analysis of the putative DTC population collected from samples above (3 patients) and below (5 patients) the threshold of 4 putative DTCs per million showed increased expression of PCa marker genes in 4 of 8 patients with localized PCa, but not the one normal donor who had the putative DTC population present. Whole-exome sequencing also showed the presence of single nucleotide polymorphisms and structural variants in the gene characteristics of PCa in 2 of 3 localized PCa patients. To examine the likely contaminating cell types, we used a myeloid colony formation assay, differential counts of cell smears, and analysis of the RNA-Seq data using the CIBERSORT algorithm, which most strongly suggested the presence of B-cell lineages as a contaminant. Finally, we used EPCAM enrichment and qRT-PCR for PCa markers to estimate DTC prevalence and found evidence of DTCs in 21 of 44 samples (47%).

Conclusion: These data support the presence of DTCs in the BM of a subset of patients with localized PCa and describe a novel FACS method for isolation and analysis of viable DTCs.
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http://dx.doi.org/10.1002/pros.23896DOI Listing
October 2019

Circulating Tumor Cell-Based Molecular Classifier for Predicting Resistance to Abiraterone and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer.

Neoplasia 2019 08 2;21(8):802-809. Epub 2019 Jul 2.

Department of Urology, University of Michigan, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. Electronic address:

While circulating tumor cell (CTC)-based detection of AR-V7 has been demonstrated to predict patient response to second-generation androgen receptor therapies, the rarity of AR-V7 expression in metastatic castrate-resistant prostate cancer (mCRPC) suggests that other drivers of resistance exist. We sought to use a multiplex gene expression platform to interrogate CTCs and identify potential markers of resistance to abiraterone and enzalutamide. 37 patients with mCRPC initiating treatment with enzalutamide (n = 16) or abiraterone (n = 21) were prospectively enrolled for CTC collection and gene expression analysis using a panel of 89 prostate cancer-related genes. Gene expression from CTCs was correlated with PSA response and radioclinical progression-free survival (PFS) using Kaplan-Meier and Cox regression analyses. Twenty patients (54%) had detectable CTCs. At a median follow-up of 11.3 months, increased expression of the following genes was significantly associated with shorter PSA PFS and radioclinical PFS: AR, AR-V7, PSA, PSCA, TSPAN8, NKX3.1, and WNT5B. Additionally, high SPINK1 expression was associated with increased PFS. A predictive model including all eight genes gave an area under the curve (AUC) of 0.84 for PSA PFS and 0.86 for radioclinical PFS. In comparison, the AR-V7 only model resulted in AUC values of 0.65 and 0.64.These data demonstrate that clinically relevant information regarding gene expression can be obtained from whole blood using a CTC-based approach. Multigene classifiers in this setting may allow for the development of noninvasive predictive biomarkers to guide clinical management.
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http://dx.doi.org/10.1016/j.neo.2019.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612010PMC
August 2019

Bone microenvironment signaling of cancer stem cells as a therapeutic target in metastatic prostate cancer.

Cell Biol Toxicol 2020 04 27;36(2):115-130. Epub 2019 Jun 27.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, 48109, USA.

Prostate cancer (PCa) is one of the most prevalent cancers and the second leading cause of cancer death among US males. When diagnosed in an early disease stage, primary tumors of PCa may be treated with surgical resection or radiation, sometimes combined with androgen deprivation therapy, with favorable outcomes. Unfortunately, the treatment efficacy of each approach decreases significantly in later stages of PCa that involve metastasis to soft tissues and bone. Metastatic PCa is a heterogeneous disease containing host cells, mature cancer cells, and subpopulation of cancer stem cells (CSC). CSCs are highly tumorigenic due to their self-renewing and differentiating potential, clinically resulting in recurrence and resistance to standard therapies. Therefore, there is a large unmet clinical need to develop therapies, which target CSC activity. In this review, we summarize the main signaling pathways that are implicated in the current pre-clinical and clinical studies of recurrent metastatic PCa within the bone microenvironment targeting CSCs and discuss the trajectory of therapeutics moving forward.
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http://dx.doi.org/10.1007/s10565-019-09483-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933113PMC
April 2020

Anticancer polymers designed for killing dormant prostate cancer cells.

Sci Rep 2019 01 31;9(1):1096. Epub 2019 Jan 31.

Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, 48109, USA.

The discovery of anticancer therapeutics effective in eliminating dormant cells is a significant challenge in cancer biology. Here, we describe new synthetic polymer-based anticancer agents that mimic the mode of action of anticancer peptides. These anticancer polymers developed here are designed to capture the cationic, amphiphilic traits of anticancer peptides. The anticancer polymers are designed to target anionic lipids exposed on the cancer cell surfaces and act by disrupting the cancer cell membranes. Because the polymer mechanism is not dependent on cell proliferation, we hypothesized that the polymers were active against dormant cancer cells. The polymers exhibited cytotoxicity to proliferating prostate cancer. Importantly, the polymer killed dormant prostate cancer cells that were resistant to docetaxel. This study demonstrates a new approach to discover novel anticancer therapeutics.
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http://dx.doi.org/10.1038/s41598-018-36608-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355926PMC
January 2019

Minimal Residual Disease in Prostate Cancer.

Adv Exp Med Biol 2018;1100:47-53

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.

Detection of minimal residual disease (MRD) in prostate cancer over several decades has greatly informed our understanding of dissemination and recurrence, but has not yet been routinely used in clinical care. Investigators have detected MRD by identification of prostate cancer cells in the bone marrow; termed disseminated tumor cells (DTCs) and blood; termed circulating tumor cells (CTCs). Various techniques including PSA-RT PCR, PSA immunocytochemistry, cytokeratin immunocytochemistry, and immune-magnetic depletion of hematopoietic cells followed by EPCAM based positive selection, have been used. Importantly, detection of DTCs correlates with recurrence. Research into prostate cancer CTCs has intensified recently, but their use in MRD evaluation has been more limited. Investigators are using semi-automated platforms to detect and begin to study prostate cancer CTCs in patients with no evidence of disease. PSA immunocytochemistry also detects CTCs and correlates with recurrence. Emerging technologies have the potential to greatly aid research in this exciting field.
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http://dx.doi.org/10.1007/978-3-319-97746-1_3DOI Listing
July 2019

Determining Competitive Potential of Bone Metastatic Cancer Cells in the Murine Hematopoietic Stem Cell Niche.

Methods Mol Biol 2019 ;2002:141-150

Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.

The ability of cancer cells to compete with hematopoietic stem cells (HSCs) to target the bone marrow microenvironment, or the HSC niche, during the dissemination process is critical for the development of bone metastasis. Here, we describe the methods for testing the relative potential of cancer cells to compete with HSCs for occupancy of the HSC niche by measuring the peripheral blood level of engrafted HSCs by flow cytometry in mice after bone marrow transplantation and tandem cancer cell inoculation. This method is useful for determining the molecular mechanisms for the roles of HSCs in the regulation of bone metastases.
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http://dx.doi.org/10.1007/7651_2018_178DOI Listing
March 2020

Parallels between hematopoietic stem cell and prostate cancer disseminated tumor cell regulation.

Bone 2019 02 26;119:82-86. Epub 2018 Feb 26.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA. Electronic address:

The bone marrow is the primary site of hematopoiesis and the home for hematopoietic stem cells (HSCs) in adult mammals. Prostate cancer commonly metastasizes to the bone and forms bone metastases in almost all patients who die of the disease. Prostate cancer bone metastases are thought to develop after rare bone marrow disseminated tumor cells (DTCs) escape a dormant state and reactivate. Prostate cancer DTCs and normal HSCs have been shown to compete for residence in the bone marrow and share many of same regulatory mechanisms for survival, proliferation and homing. In this review, we highlight these parallels in order to help our readers use the literature in HSC and DTC biology to inform their research and generate hypotheses in both fields.
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http://dx.doi.org/10.1016/j.bone.2018.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109615PMC
February 2019

Dural Cells Release Factors Which Promote Cancer Cell Malignancy and Induce Immunosuppressive Markers in Bone Marrow Myeloid Cells.

Neurosurgery 2018 12;83(6):1306-1316

Veterans Affairs Medical Center, Ann Arbor, Michigan.

Background: Thirty per cent of cancer patients develop spine metastases with a substantial number leading to spinal cord compression and neurological deficits. Many demonstrate a propensity toward metastasis to the posterior third of the vertebral body. The dura, the outer layer of the meninges, lies in intimate contact with the posterior border of the vertebral body and has been shown to influence adjacent bone. The effects of the dura on bone marrow and cancer cells have not been examined. Understanding the biology of spinal metastasis will provide insights into mechanisms of cancer growth and allow for new treatment strategies.

Objective: To examine the extent to which dura influences bone marrow/tumor cell metastatic characteristics.

Methods: Dura conditioned media (DCM) from primary dura was examined for the ability to stimulate tumor cell proliferation/invasion and to alter bone marrow cell populations. RNA sequencing of dural fibroblasts was performed to examine expression of cytokines and growth factors.

Results: DCM induced a significant increase in invasion and proliferation of multiple tumor cell lines, and of patient-derived primary spinal metastatic cells. DCM also increased the proliferation of bone marrow myeloid cells, inducing expression of immunosuppressive markers. RNA sequencing of dural fibroblasts demonstrated abundant expression of cytokines and growth factors involved in cancer/immune pathways.

Conclusion: Factors released by primary dural cells induce proliferation of tumor cells and alter bone marrow to create a fertile environment for tumor growth. The dura therefore may play an important role in the increased incidence of metastases to adjacent bone.
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http://dx.doi.org/10.1093/neuros/nyx626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191887PMC
December 2018

Multigene Profiling of CTCs in mCRPC Identifies a Clinically Relevant Prognostic Signature.

Mol Cancer Res 2018 04 16;16(4):643-654. Epub 2018 Feb 16.

Department of Urology, University of Michigan, Ann Arbor, Michigan.

The trend toward precision-based therapeutic approaches dictated by molecular alterations offers substantial promise for men with metastatic castration-resistant prostate cancer (mCRPC). However, current approaches for molecular characterization are primarily tissue based, necessitating serial biopsies to understand changes over time and are limited by the challenges inherent to extracting genomic material from predominantly bone metastases. Therefore, a circulating tumor cell (CTC)-based assay was developed to determine gene expression across a panel of clinically relevant and potentially actionable prostate cancer-related genes. CTCs were isolated from the whole blood of mCRPC patients ( = 41) and multiplex qPCR was performed to evaluate expression of prostate cancer-related target genes ( = 78). A large fraction of patients (27/41, 66%) had detectable CTCs. Increased androgen receptor () expression (70% of samples) and evidence of Wnt signaling (67% of samples) were observed. The fusion was expressed in 41% of samples, and the aggressive prostate cancer-associated long noncoding RNA was upregulated in 70%. [HR 3.62, 95% confidence interval (CI), 1.63-8.05, = 0.002], (HR 5.56, 95% CI, 1.79-17.20, = 0.003), and (HR 3.86, 95% CI, 1.60-9.32, = 0.003) were independently predictive of overall survival (FDR < 10%) after adjusting for a panel of previously established prognostic variables in mCRPC (Halabi nomogram). A model including Halabi, , and expression, termed the miCTC score, outperformed the Halabi nomogram alone (AUC = 0.89 vs. AUC = 0.70). Understanding the molecular landscape of CTCs has utility in predicting clinical outcomes in patients with aggressive prostate cancer and provides an additional tool in the arsenal of precision-based therapeutic approaches in oncology. Analysis of CTC gene expression reveals a clinically prognostic "liquid biopsy" signature in patients with metastatic castrate-resistance prostate cancer. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882567PMC
April 2018

CXCL12γ Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes.

Cancer Res 2018 04 5;78(8):2026-2039. Epub 2018 Feb 5.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.

There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact the development of m-CRPC. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12γ expression was detected in small-cell carcinoma of metastatic tissues and circulating tumor cells from m-CRPC patients and in prostate cancer cells displaying an neuroendocrine phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12γ induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCα/NFκB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance Together, our results establish a significant function for CXCL12γ in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease. Expression of CXCL12γ induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324566PMC
April 2018

Integrin alpha V beta 3 targeted dendrimer-rapamycin conjugate reduces fibroblast-mediated prostate tumor progression and metastasis.

J Cell Biochem 2018 11 22;119(10):8074-8083. Epub 2018 Jun 22.

Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan.

Therapeutic strategies targeting both cancer cells and associated cells in the tumor microenvironment offer significant promise in cancer therapy. We previously reported that generation 5 (G5) dendrimers conjugated with cyclic-RGD peptides target cells expressing integrin alpha V beta 3. In this study, we report a novel dendrimer conjugate modified to deliver the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. In vitro analyses demonstrated that this drug conjugate, G5-FI-RGD-rapamycin, binds to prostate cancer (PCa) cells and fibroblasts to inhibit mTOR signaling and VEGF expression. In addition, G5-FI-RGD-rapamycin inhibits mTOR signaling in cancer cells more efficiently under proinflammatory conditions compared to free rapamycin. In vivo studies established that G5-FI-RGD-rapamycin significantly inhibits fibroblast-mediated PCa progression and metastasis. Thus, our results suggest the potential of new rapamycin-conjugated multifunctional nanoparticles for PCa therapy.
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http://dx.doi.org/10.1002/jcb.26727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066451PMC
November 2018

Reduction of two histone marks, H3k9me3 and H3k27me3 by epidrug induces neuroendocrine differentiation in prostate cancer.

J Cell Biochem 2018 04 9;119(4):3697-3705. Epub 2018 Jan 9.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor,, Michigan.

Neuroendocrine prostate cancer (NE PCa) is an aggressive malignancy, often presenting with advanced metastasis. We previously reported that reduction of histone marks regulated by DNMT1 following epidrug (5-Azacitidine, 5-Aza) treatment controls induction of epithelial to mesenchymal (EMT) and a cancer stem cell (CSC) phenotype, which facilitates tumorigenesis in PCa cells. Here, we use the epidrug 5-Aza as a model for how histone marks may regulate the reprogramming of prostate adenocarcinoma into NE phenotypic cells. First, we observed that 5-Aza treatment of PCa cells in vitro induces a neuron-like phenotype. In addition, significant increases in the expression of the NE markers N-Myc downstream regulated gene 1 (NDRG1), enolase-2 (ENO2), and synaptophysin were observed. Critically, a high density of NE cells with synaptophysin expression was found in tumors generated by 5-Aza pretreatment of PCa cells. Importantly, induction of NE differentiation of PCa cells was associated with an enhancement of NDRG1 expression by reduction of two histone marks, H3K9me3 and H3K27me3. Further, more NDRG1 expression was detected in the subset of PCa cells with reduced expression of H3K9me3 or H3K27me3 in the tumors generated by 5-Aza pretreated PCa cells and critically, these biological differences are also observed in small cell carcinoma in advanced stage of human primary PCa tumors. Our results suggest that reduction of histone marks regulated by the epidrug 5-Aza may control induction of a NE phenotype, which facilitates PCa progression. These studies suggest a strong rationale for developing therapeutics, which target epigenetic regulation.
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http://dx.doi.org/10.1002/jcb.26586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826874PMC
April 2018

Clinical Assessment of Urinary Tract Damage during Sustained-Release Estrogen Supplementation in Mice.

Comp Med 2017 02;67(1):11-21

Unit for Laboratory Animal Medicine (ULAM), University of Michigan, Ann Arbor, Michigan;, Email:

Estrogen supplementation is a key component of numerous mouse research models but can adversely affect the urinary system. The goal of this study was to develop a clinical scoring system and identify biomarkers of occult urinary tract lesions prior to the development of systemic illness in mice. Ovariectomized or sham-surgery SCID mice were implanted subcutaneously with a placebo pellet or one containing sustained-release estradiol (0.18 mg 60-d release 17β-estradiol). Mice were assessed twice weekly for 4 to 6 wk by using a clinical scoring system that included body condition, general activity, posture, hair coat, hydration, abdominal distension, urine staining of coat and skin, and ability to urinate. Samples were collected weekly for urinalysis, BUN, creatinine, and serum estradiol levels. Terminal samples were analyzed for histopathologic lesions. Compared with placebo controls, estradiolsupplemented mice had higher serum estradiol levels at weeks 2 and 3; significant differences in total clinical scores by the 3-wk time point; and in body condition, general activity, posture, hair coat, and urine staining scores by the 6-wk terminal time point. Urinary tract lesions included hydronephrosis, pyelonephritis, cystitis, and urolithiasis. All mice with urolithiasis had crystalluria, and 5 of the 6 mice with pyelonephritis or hydroureter had dilute urine (that is, specific gravity less than 1.030). However, these findings were not specific to mice with lesions. A total clinical score of 3.5 (maximum, 24) identified estradiol-supplemented mice with 83% specificity and 50% sensitivity, but no single clinical parameter, biomarker, or the total clinical score accurately predicted occult urinary tract lesions. Considering the lesions we observed, prudence is warranted when using pelleted sustained-release estradiol in mice, and important parameters to monitor for animal health include urine staining, body condition score, urine sediment, and urine specific gravity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310620PMC
February 2017

Dental Students', Alumni, and Dentists' Perspectives on Leadership: Impact of the Scholars Program in Dental Leadership.

J Dent Educ 2017 Jan;81(1):44-53

Ms. Niemchick is a dental student, School of Dentistry, University of Michigan; Dr. Delgado is a resident, Orthodontic Graduate Program, Dental School, University of Detroit Mercy; Dr. Taichman is Major M. Ash Collegiate Professor, Associate Dean for Research, and Professor of Dentistry, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan; and Dr. Inglehart is Professor of Dentistry, Department of Periodontology and Oral Medicine, School of Dentistry, and Adjunct Professor, Department of Psychology, College of Literature, Science of Arts, University of Michigan.

In 2006, the Scholars Program in Dental Leadership (SPDL) was created at the University of Michigan School of Dentistry with the aim of preparing dental students to take on leadership roles in their profession and communities. The aims of this quantitative study were to investigate how SPDL alumni and current participants evaluated this program; to assess whether SPDL alumni evaluated their leadership-related educational experiences, leadership perceptions, and attitudes towards leadership activities in dentistry more positively than did non-SPDL dental students and general dentists; and to explore if leadership-related educational/clinical experiences were correlated with these constructs. Participants were 218 of 431 dental students across all four years (response rate 51%), 32 of whom were participants in the SPDL; 32 of 53 SPDL alumni (response rate 60%); and 595 of 3,000 general dentists invited to participate (response rate 20%). Both current and past SPDL participants evaluated the program on average positively (3.75 and 3.92, respectively, on a five-point scale). Non-SPDL students and alumni evaluated leadership-related educational experiences more positively than did the dentists (3.65/3.61 vs. 2.49; p<0.001). Their evaluations of different indicators of dental leadership differed as well. Students and alumni evaluated being recognized (4.40/4.60 vs. 4.20; p<0.001), making a contribution to the community (4.04/4.40 vs. 3.81; p<0.001), and views on practice efficiency (4.61/4.53 vs. 4.36; p<0.001) more positively than did the general dentists. The SPDL alumni had more positive evaluations of organized dentistry (4.17 vs. 3.77/3.71; p=0.045) and academia (3.97 vs. 3.48/3.45; p=0.01) than did the students and general dentists. Educational/clinical experiences were positively correlated with most leadership-related constructs. These results showed that the SPDL positively affected alumni perceptions of leadership indicators and attitudes.
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January 2017

Axl is required for TGF-β2-induced dormancy of prostate cancer cells in the bone marrow.

Sci Rep 2016 11 7;6:36520. Epub 2016 Nov 7.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.

Disseminated prostate cancer (PCa) cells in the marrow survive for years without evidence of proliferation, while maintaining the capacity to develop into metastatic lesions. These dormant disseminated tumor cells (DTCs) may reside in close proximity to osteoblasts, while expressing high levels of Axl, one of the tyrosine kinase receptors for growth arrest specific 6 (Gas6). Yet how Axl regulates DTC proliferation in marrow remains undefined. Here, we explored the impact of the loss of Axl in PCa cells (PC3 and DU145) on the induction of their dormancy when they are co-cultured with a pre-osteoblastic cell line, MC3T3-E1. MC3T3-E1 cells dramatically decrease the proliferation of PCa cells, however this suppressive effect of osteoblasts is significantly reduced by the reduction of Axl expression in PCa cells. Interestingly, expression of both TGF-β and its receptors were regulated by Axl expression in PCa cells, while specific blockade of TGF-β signaling limited the ability of the osteoblasts to induce dormancy of PCa cells. Finally, we found that both Gas6 and Axl are required for TGF-β2-mediated cell growth suppression. Taken together, these data suggest that a loop between the Gas6/Axl axis and TGF-β2 signaling plays a significant role in the induction of PCa cell dormancy.
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http://dx.doi.org/10.1038/srep36520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098246PMC
November 2016

Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy.

J Cell Biochem 2017 04 10;118(4):891-902. Epub 2016 Nov 10.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.

Many prostate cancer (PCa) recurrences are thought to be due to reactivation of disseminated tumor cells (DTCs). We previously found a role of the TAM family of receptor tyrosine kinases TYRO3, AXL, and MERTK in PCa dormancy regulation. However, the mechanism and contributions of the individual TAM receptors is largely unknown. Knockdown of MERTK, but not AXL or TYRO3 by shRNA in PCa cells induced a decreased ratio of P-Erk1/2 to P-p38, increased expression of p27, NR2F1, SOX2, and NANOG, induced higher levels of histone H3K9me3 and H3K27me3, and induced a G1/G0 arrest, all of which are associated with dormancy. Similar effects were also observed with siRNA. Most importantly, knockdown of MERTK in PCa cells increased metastasis free survival in an intra-cardiac injection mouse xenograft model. MERTK knockdown also failed to inhibit PCa growth in vitro and subcutaneous growth in vivo, which suggests that MERTK has specificity for dormancy regulation or requires a signal from the PCa microenvironment. The effects of MERTK on the cell cycle and histone methylation were reversed by p38 inhibitor SB203580, which indicates the importance of MAP kinases for MERTK dormancy regulation. Overall, this study shows that MERTK stimulates PCa dormancy escape through a MAP kinase dependent mechanism, also involving p27, pluripotency transcription factors, and histone methylation. J. Cell. Biochem. 118: 891-902, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.25768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296338PMC
April 2017

DNMT1 Regulates Epithelial-Mesenchymal Transition and Cancer Stem Cells, Which Promotes Prostate Cancer Metastasis.

Neoplasia 2016 09;18(9):553-66

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA. Electronic address:

Cancer metastasis is a multistep process associated with the induction of an epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs). Although significant progress has been made in understanding the molecular mechanisms regulating EMT and the CSC phenotype, little is known of how these processes are regulated by epigenetics. Here we demonstrate that reduced expression of DNA methyltransferase 1 (DNMT1) plays an important role in the induction of EMT and the CSC phenotype by prostate cancer (PCa) cells, with enhanced tumorigenesis and metastasis. First, we observed that reduction of DNMT1 by 5-azacitidine (5-Aza) promotes EMT induction as well as CSCs and sphere formation in vitro. Reduced expression of DNMT1 significantly increased PCa migratory potential. We showed that the increase of EMT and CSC activities by reduction of DNMT1 is associated with the increase of protein kinase C. Furthermore, we confirmed that silencing DNMT1 is correlated with enhancement of the induction of EMT and the CSC phenotype in PCa cells. Additionally, chromatin immunoprecipitation assay reveals that reduction of DNMT1 promotes the suppression of H3K9me3 and H3K27me3 on the Zeb2 and KLF4 promoter region in PCa cells. Critically, we found in an animal model that significant tumor growth and more disseminated tumor cells in most osseous tissues were observed following injection of 5-Aza pretreated-PCa cells compared with vehicle-pretreated PCa cells. Our results suggest that epigenetic alteration of histone demethylation regulated by reduction of DNMT1 may control induction of EMT and the CSC phenotype, which facilitates tumorigenesis in PCa cells and has important therapeutic implications in targeting epigenetic regulation.
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http://dx.doi.org/10.1016/j.neo.2016.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031902PMC
September 2016

The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer.

Oncotarget 2016 Jul;7(27):41217-41232

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.

Dissemination of cancer stem cells (CSCs) serves as the basis of metastasis. Recently, we demonstrated that circulating prostate cancer targets the hematopoietic stem cell (HSCs) 'niche' in marrow during dissemination. Once in the niche, disseminated tumor cells (DTCs) may remain dormant for extended periods. As the major function of the HSC niche is to maintain stem cell functions, we hypothesized that the niche regulates CSC activities of DTCs. Here we show that DTCs recovered from marrow were significantly enriched for a CSC phenotype. Critically, the conversion of DTCs to CSCs is regulated by niche-derived GAS6 through the Mer/mTOR; molecules previously shown to regulate dormancy. The data demonstrate that the niche plays a significant role in maintaining tumor-initiating prostate cancer in marrow and suggests a functional relationship between CSCs and dormancy. Understanding how the marrow niche regulates the conversion of DTCs to CSCs is critical for the development of therapeutics specifically targeting skeletal bone metastasis and dormancy.
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http://dx.doi.org/10.18632/oncotarget.9251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173053PMC
July 2016

Growth Arrest-Specific 6 (GAS6) Promotes Prostate Cancer Survival by G Arrest/S Phase Delay and Inhibition of Apoptosis During Chemotherapy in Bone Marrow.

J Cell Biochem 2016 12 26;117(12):2815-2824. Epub 2016 Sep 26.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, 48109, Michigan.

Prostate cancer (PCa) is known to develop resistance to chemotherapy. Growth arrest-specific 6 (GAS6), plays a role in tumor progression by regulating growth in many cancers. Here, we explored how GAS6 regulates the cell cycle and apoptosis of PCa cells in response to chemotherapy. We found that GAS6 is sufficient to significantly increase the fraction of cells in G and the duration of phase in PCa cells. Importantly, the effect of GAS6 on G is potentiated during docetaxel chemotherapy. GAS6 altered the levels of several key cell cycle regulators, including the downregulation of Cyclin B1 (G /M phase), CDC25A, Cyclin E1, and CDK2 (S phase entry), while the upregulation of cell cycle inhibitors p27 and p21, Cyclin D1, and CDK4. Importantly, these changes became further accentuated during docetaxel treatment in the presence of GAS6. Moreover, GAS6 alters the apoptotic response of PCa cells during docetaxel chemotherapy. Docetaxel induced PCa cell apoptosis is efficiently suppressed in PCa cell culture in the presence of GAS6 or GAS6 secreted from co-cultured osteoblasts. Similarly, the GAS6-expressing bone environment protects PCa cells from apoptosis within primary tumors in vivo studies. Docetaxel induced significant levels of Caspase-3 and PARP cleavage in PCa cells, while GAS6 protected PCa cells from docetaxel-induced apoptotic signaling. Together, these data suggest that GAS6, expressed by osteoblasts in the bone marrow, plays a significant role in the regulation of PCa cell survival during chemotherapy, which will have important implications for targeting metastatic disease. J. Cell. Biochem. 117: 2815-2824, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.25582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223280PMC
December 2016

Endogenous GAS6 and Mer receptor signaling regulate prostate cancer stem cells in bone marrow.

Oncotarget 2016 May;7(18):25698-711

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.

Unlabelled: GAS6 and its receptors (Tryo 3, Axl, Mer or "TAM") are known to play a role in regulating tumor progression in a number of settings. Previously we have demonstrated that GAS6 signaling regulates invasion, proliferation, chemotherapy-induced apoptosis of prostate cancer (PCa) cells. We have also demonstrated that GAS6 secreted from osteoblasts in the bone marrow environment plays a critical role in establishing prostate tumor cell dormancy. Here we investigated the role that endogenous GAS6 and Mer receptor signaling plays in establishing prostate cancer stem cells in the bone marrow microenvironment.We first observed that high levels of endogenous GAS6 are expressed by disseminated tumor cells (DTCs) in the bone marrow, whereas relatively low levels of endogenous GAS6 are expressed in PCa tumors grown in a s.c.

Setting: Interestingly, elevated levels of endogenous GAS6 were identified in putative cancer stem cells (CSCs, CD133+/CD44+) compared to non-CSCs (CD133-/CD44-) isolated from PCa/osteoblast cocultures in vitro and in DTCs isolated from the bone marrow 24 hours after intracardiac injection. Moreover, we found that endogenous GAS6 expression is associated with Mer receptor expression in growth arrested (G1) PCa cells, which correlates with the increase of the CSC populations. Importantly, we found that overexpression of GAS6 activates phosphorylation of Mer receptor signaling and subsequent induction of the CSC phenotype in vitro and in vivo.Together these data suggest that endogenous GAS6 and Mer receptor signaling contribute to the establishment of PCa CSCs in the bone marrow microenvironment, which may have important implications for targeting metastatic disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041937PMC
http://dx.doi.org/10.18632/oncotarget.8365DOI Listing
May 2016

Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer.

Neoplasia 2016 Jan;18(1):1-9

Michigan Center for Translational Pathology; Department of Urology; Comprehensive Cancer Center.

A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status ((+) or (-)), which identified MET expression as markedly increased in AR(-) samples. In vitro, AR signaling inhibition in AR(+) CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR(+) CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR(-) disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR(-) prostate cancer.
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http://dx.doi.org/10.1016/j.neo.2015.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735600PMC
January 2016