West Scarborough, MAINE, United States
West Scarborough, MAINE, United States

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Maine Medical Center Research Institute | Date: 2016-06-01

The present invention provides antagonists and methods of use thereof in the treatment of cancer and abnormal immune suppression diseases.

Prudovsky I.,Maine Medical Center Research Institute
Nucleus (Austin, Tex.) | Year: 2012

Cycling eukaryotic cells rapidly re-establish the nuclear envelope and internal architecture following mitosis. Studies with a specific anti-nucleosome antibody recently demonstrated that the surface ("epichromatin") of interphase and mitotic chromatin possesses a unique and conserved conformation, suggesting a role in postmitotic nuclear reformation. Here we present evidence showing that the anionic glycerophospholipid phosphatidylserine is specifically located in epichromatin throughout the cell cycle and is associated with nucleosome core histones. This suggests that chromatin bound phosphatidylserine may function as a nucleation site for the binding of ER and re-establishment of the nuclear envelope.

Brown A.C.,Maine Medical Center Research Institute | Muthukrishnan S.D.,Maine Medical Center Research Institute | Oxburgh L.,Maine Medical Center Research Institute
Developmental Cell | Year: 2015

FGF, BMP, and WNT balance embryonic nephron progenitor cell (NPC) renewal and differentiation. By modulating these pathways, we have created an in vitro niche in which NPCs from embryonic kidneys or derived from human embryonic stem cells can be propagated. NPC cultures expanded up to one billion-fold in this environment can be induced to form tubules expressing nephron differentiation markers. Single-cell culture reveals phenotypic variability within the early CITED1-expressing NPC compartment, indicating that it is a mixture of cells with varying progenitor potential. Furthermore, we find that the developmental age of NPCs does not correlate with propagation capacity, indicating that cessation of nephrogenesis is related to factors other than an intrinsic clock. This in vitro nephron progenitor niche will have important applications for expansion of cells for engraftment and will facilitate investigation of mechanisms that determine the balance between renewal and differentiation in these cells. The embryonic mammalian kidney maintains nephron progenitor cells (NPCs) within a specific niche. Niche signals have been recapitulated in culture, allowing many million-fold expansion of NPCs. NPC propagation facilitates investigation of mechanisms governing their proliferation and differentiation and provides sufficient cell numbers to generate kidney tissue in vitro. © 2015 Elsevier Inc..

Yoon J.K.,Maine Medical Center Research Institute | Lee J.-S.,Maine Medical Center Research Institute
Cellular Signalling | Year: 2012

R-spondins (RSPOs) are a family of cysteine-rich secreted proteins containing a single thrombospondin type I repeat (TSR) domain. A vast amount of information regarding cellular signaling and biological functions of RSPOs has emerged over the last several years, especially with respect to their roles in the activation of the WNT signaling pathway. The identification of several classes of RSPO receptors may indicate that this family of proteins can affect several signaling cascades. Herein, we summarize the current understanding of RSPO signaling and its biological functions, and discuss its potential therapeutic implications to human diseases. © 2011 Elsevier Inc..

Motyl K.J.,Maine Medical Center Research Institute
Discovery medicine | Year: 2011

Caloric restriction is associated with a reduction in body weight and temperature, as well as a reduction in trabecular bone volume and paradoxically an increase in adipocytes within the bone marrow. The nature of these adipocytes is uncertain, although there is emerging evidence of a direct relationship between bone remodeling and brown adipocytes. For example, in heterotrophic ossification, brown adipocytes set up a hypoxic gradient that leads to vascular invasion, chondrocyte differentiation, and subsequent bone formation. Additionally, deletion of retinoblastoma protein in an osteosarcoma model leads to increased hibernoma (brown fat tumor). Brown adipose tissue (BAT) becomes senescent with age at a time when thermoregulation is altered, bone loss becomes apparent, and sympathetic activity increases. Interestingly, heart rate is an unexpected but good predictor of fracture risk in elderly individuals, pointing to a key role for the sympathetic nervous system in senile osteoporosis. Hence the possibility exists that BAT could play an indirect role in age-related bone loss. However, evidence of an indirect effect from thermogenic dysfunction on bone loss is currently limited. Here, we present current evidence for a relationship between brown adipose tissue and bone as well as provide novel insights into the effects of thermoregulation on bone mineral density.

Rosen C.J.,Maine Medical Center Research Institute | Taylor C.L.,U.S. National Institutes of Health
Nature Reviews Endocrinology | Year: 2013

Misconceptions about vitamin D continue to grow despite publications in the past few years that have attempted to clarify risk. We present our perspective, and offer several conclusions. Calcium and vitamin D supplementation can reduce fracture risk by ∼10%. On the other hand, little evidence exists to support a threshold measure for vitamin D status (serum levels of 25-hydroxyvitamin D) above which fractures are reduced. The association of serum concentrations of 25-hydroxyvitamin D with other chronic diseases is confounded by multiple factors and conflicting outcomes that cannot be used to support a causal association. High doses of vitamin D supplements might not be completely harmless and should be avoided until additional data becomes available. Similarly, scant rationale exists for aggressive vitamin D supplementation for pregnant or lactating women. Dispelling misconceptions about vitamin D will ultimately benefit health-care providers and patients alike. © 2013 Macmillan Publishers Limited. All rights reserved.

Motyl K.J.,Maine Medical Center Research Institute | Rosen C.J.,Maine Medical Center Research Institute
Biochimie | Year: 2012

Despite growing evidence for adipose tissue regulation of bone mass, the role of the adipokine leptin in bone remodeling remains controversial. The majority of in vitro studies suggest leptin enhances osteoblastic proliferation and differentiation while inhibiting adipogenic differentiation from marrow stromal cells. Alternatively, some evidence demonstrates either no effect or a pro-apoptotic action of leptin on stromal cells. Similarly, in vivo work has demonstrated both positive and negative effects of leptin on bone mass. Most of the literature supports the idea that leptin suppresses bone mass by acting in the brainstem to reduce serotonin-dependent sympathetic signaling from the ventromedial hypothalamus to bone. However, other studies have found partly or entirely contrasting actions of leptin. Recently one study found a significant effect of surgery alone with intracerebroventricular administration of leptin, a technique crucial for understanding centrally-mediated leptin regulation of bone. Thus, two mainstream hypotheses for the role of leptin on bone emerge: 1) direct regulation through increased osteoblast proliferation and differentiation and 2) indirect suppression of bone formation through a hypothalamic relay. At the present time, it remains unclear whether these effects are relevant in only extreme circumstances (i.e. models with complete deficiency) or play an important homeostatic role in the regulation of peak bone acquisition and skeletal remodeling. Ultimately, determining the actions of leptin on the skeleton will be critical for understanding how the obesity epidemic may be impacting the prevalence of osteoporosis. © 2012 Elsevier Masson SAS. All rights reserved.

Rosen C.J.,Maine Medical Center Research Institute
New England Journal of Medicine | Year: 2011

A healthy 61-year-old white woman is concerned about a low vitamin D level detected during an assessment of her skeletal health. Her menopause began at 54 years of age. She has no history of falls, and there is no family history of hip fracture. She takes no medications or supplements. Her height is 157.5 cm (5 ft 2 in.), and her weight 59.1 kg (130 lb). The results of a physical examination are unremarkable, and the findings on laboratory studies are normal. The T score for bone mineral density at the hip is -1.5, and the serum level of 25-hydroxyvitamin D is 21 ng per milliliter (53 nmol per liter). What do you advise? Copyright © 2011 Massachusetts Medical Society.

Scheller E.L.,University of Michigan | Rosen C.J.,Maine Medical Center Research Institute
Annals of the New York Academy of Sciences | Year: 2014

Marrow adipose tissue (MAT) is functionally distinct from both white and brown adipose tissue and can contribute to systemic and skeletal metabolism. MAT formation is a spatially and temporally defined developmental event, suggesting that MAT is an organ that serves important functions and, like other organs, can undergo pathologic change. The well-documented inverse relationship between MAT and bone mineral density has been interpreted to mean that MAT removal is a possible therapeutic target for osteoporosis. However, the bone and metabolic phenotypes of patients with lipodystrophy argues that retention of MAT may actually be beneficial in some circumstances. Furthermore, MAT may exist in two forms, regulated and constitutive, with divergent responses to hematopoietic and nutritional demands. In this review, we discuss the role of MAT in lipodystrophy, bone loss, and metabolism, and highlight our current understanding of this unique adipose tissue depot. © 2014 New York Academy of Sciences.

Maine Medical Center Research Institute | Date: 2015-02-26

The present invention relates to compositions and methods associated with cocktails of growth factors and small molecules that target specific cell signaling pathways, the cocktails having been formulated to allow/promote the expansion of progenitor cells (e.g., nephron progenitor cells) within a defined culture system.

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