Randomized, Placebo-Controlled Analysis of the Knee Synovial Environment Following Platelet-Rich Plasma Treatment for Knee Osteoarthritis.

Background: Platelet-rich-plasma (PRP) is used to treat knee osteoarthritis; however, mechanistic evidence of PRP effectiveness for pain relief is limited.

Objective: To assess molecular biomarkers and mesenchymal stem cells (MSCs) in synovial fluid during PRP treatment of the osteoarthritic knee joint.

Design: Single blinded, randomized, placebo controlled pilot study.

Blueprint for cancer research: Critical gaps and opportunities.

We are experiencing a revolution in cancer. Advances in screening, targeted and immune therapies, big data, computational methodologies, and significant new knowledge of cancer biology are transforming the ways in which we prevent, detect, diagnose, treat, and survive cancer. These advances are enabling durable progress in the goal to achieve personalized cancer care.

Telomere lengths in women treated for breast cancer show associations with chemotherapy, pain symptoms, and cognitive domain measures: a longitudinal study.

Background: Survival rates for breast cancer (BC) have improved, but quality of life post-diagnosis/treatment can be adversely affected, with survivors reporting a constellation of psychoneurological symptoms (PNS) including stress, anxiety, depression, pain, fatigue, sleep disturbance, and cognitive dysfunction.

Methods: To assess a potential relationship between telomere length (TL) and the development/persistence of PNS, we longitudinally studied 70 women (ages 23-71) with early stage BC (I-IIIA) at 5 time-points: prior to treatment (baseline), the mid-point of their chemotherapy cycle, 6 months, 1 year, and 2 years following the initiation of chemotherapy. Measures quantified included assessments of each of the PNS noted above and TL [using both a multiplex qPCR assay and a chromosome-specific fluorescence in situ hybridization (FISH) assay].

Tumor cell escape from therapy-induced senescence.

H460 non-small cell lung, HCT116 colon and 4T1 breast tumor cell lines induced into senescence by exposure to either etoposide or doxorubicin were able to recover proliferative capacity both in mass culture and when enriched for the senescence-like phenotype by flow cytometry (based on β-galactosidase staining and cell size, and a senescence-associated reporter, BTG1-RFP). Recovery was further established using both real-time microscopy and High-Speed Live-Cell Interferometry (HSLCI) and was shown to be accompanied by the attenuation of the Senescence-Associated Secretory Phenotype (SASP). Cells enriched for the senescence-like phenotype were also capable of forming tumors when implanted in both immunodeficient and immunocompetent mice.

Fibronectin fibrils regulate TGF-β1-induced Epithelial-Mesenchymal Transition.

Epithelial-Mesenchymal Transition (EMT) is a dynamic process through which epithelial cells transdifferentiate from an epithelial phenotype into a mesenchymal phenotype. Previous studies have demonstrated that both mechanical signaling and soluble growth factor signaling facilitate this process. One possible point of integration for mechanical and growth factor signaling is the extracellular matrix.

Is Senescence Reversible?

Senescence was originally identified by the finite lifespan of normal cells that is a consequence of telomere shortening with each cycle of DNA replication. Cells undergoing replicative senescence display pronounced morphological and biochemical changes such as flattening and/or enlargement, increases in p21(WAF1) and/or p16(INK4A), a senescence-associated secretory phenotype, and often senescence-associated heterochromatic foci. Senescence also occurs in tumor cells in response to various forms of chemotherapy or radiation (therapy-induced senescence), which could be the basis for prolonged or (ideally) permanent growth arrest.

Restoring SIRT6 Expression in Hutchinson-Gilford Progeria Syndrome Cells Impedes Premature Senescence and Formation of Dysmorphic Nuclei.

Objectives: Mice overexpressing SIRT6 live longer than wild-type mice while SIRT6 knockout mice exhibit similar degenerative phenotypes as individuals with Hutchinson-Gilford progeria syndrome (HGPS). Thus, we sought to test whether levels of SIRT6 are reduced in cells from individuals with HGPS and whether restored SIRT6 expression may impede premature aging phenotypes.

Methods: Levels of endogenous SIRT6 and progerin in HGPS and normal fibroblasts were assessed by Western blotting and immunofluorescence.

Telomere length: a review of methods for measurement.

Background: The exciting discovery that telomere shortening is associated with many health conditions and that telomere lengths can be altered in response to social and environmental exposures has underscored the need for methods to accurately and consistently quantify telomere length.

Objectives: The purpose of this article is to provide a comprehensive summary that compares and contrasts the current technologies used to assess telomere length.

Discussion: Multiple methods have been developed for the study of telomeres.

Breast epithelial cell infiltration in enhanced electrospun silk scaffolds.

In the present study, the effects of air-flow impedance electrospinning and air-flow rates on silk-based scaffolds for biological tissues were investigated. First, the properties of scaffolds obtained from 7% and 12% silk concentrations were defined. In addition, cell infiltration and viability of MCF-10A breast epithelial cells cultured onto these scaffolds were used to determine the biological suitability of these nanostructures.

Potential epigenetic mechanism(s) associated with the persistence of psychoneurological symptoms in women receiving chemotherapy for breast cancer: a hypothesis.

Due to recent treatment advances, there have been improvements in the proportion of women surviving a diagnosis of breast cancer (BC). However, many of these survivors report persistent adverse side effects following treatment, such as cognitive dysfunction, depressive symptoms, anxiety, fatigue, sleep disturbances, and pain. Investigators have examined circulating levels of inflammatory markers, particularly serum cytokines, for a potential causal relationship to the development/persistence of these psychoneurological symptoms (PNS).

Mesenchymal stem cells in mammary adipose tissue stimulate progression of breast cancer resembling the basal-type.

Data are accumulating to support a role for adipose-derived mesenchymal stem cells (MSCs) in breast cancer progression; however, to date most studies have relied on adipose MSCs from non-breast sources. There is a particular need to investigate the role of adipose MSCs in the pathogenesis of basal-like breast cancer, which develops at a disproportionate rate in pre-menopausal African-American women with a gain in adiposity. The aim of this study was to better understand how breast adipose MSCs (bMSCs) contribute to the progression of basal-like breast cancers by relying on isogenic HMT-3255 S3 (pre-invasive) and T4-2 (invasive) human cells that upon transplantation into nude mice resemble this tumor subtype.

Defining essential stem cell characteristics in adipose-derived stromal cells extracted from distinct anatomical sites.

The discovery of adipose-derived stromal cells (ASCs) has created many opportunities for the development of patient-specific cell-based replacement therapies. We have isolated multiple cell strains of ASCs from various anatomical sites (abdomen, arms/legs, breast, buttocks), indicating widespread distribution of ASCs throughout the body. Unfortunately, there exists a general lack of agreement in the literature as to their "stem cell" characteristics.

Electrospinning adipose tissue-derived extracellular matrix for adipose stem cell culture.

Basement membrane-rich extracellular matrices, particularly murine sarcoma-derived Matrigel, play important roles in regenerative medicine research, exhibiting marked cellular responses in vitro and in vivo, although with limited clinical applications. We find that a human-derived matrix from lipoaspirate fat, a tissue rich in basement membrane components, can be fabricated by electrospinning and used to support cell culture. We describe practical applications and purification of extracellular matrix (ECM) from adipose tissue (At-ECM) and its use in electrospinning scaffolds and adipose stem cell (ASC) culture.

Multipotent adipose stromal cells and breast cancer development: Think globally, act locally.

It has long been appreciated that stromal cells within the breast tumor microenvironment contribute to mammary carcinogenesis. However, to date, very little is known regarding the role of local adipose-derived stromal cells (ASCs) in the development of breast cancer. Based on pathological, epidemiological and experimental data, we postulate that breast-derived ASCs are unique mesenchymal stem-like cells that play a critical role in the development of breast cancer and discuss the global implications of this working model in terms of breast cancer prevention, early detection, and new targeted therapies.

Elevated TRF2 in advanced breast cancers with short telomeres.

Telomere repeat binding factor 2 (TRF2) binds directly to telomeres and preserves the structural integrity of chromosome ends. In vitro models suggest that expression of TRF2 protein increases during mammary cancer progression. However, a recent study has reported that TRF2 mRNA levels tend to be lower in clinical specimens of malignant breast tissue.

Isolating adipose-derived mesenchymal stem cells from lipoaspirate blood and saline fraction.

Isolation of adipose-derived stem cells (ASCs) typically involves 8+ hours of intense effort, requiring specialized equipment and reagents. Here, we present an improved technique for isolating viable populations of mesenchymal stem cells from lipoaspirate saline fractions within 30 minutes. Importantly, the cells exhibit remarkable similarities to those obtained using the traditional isolation protocols, in terms of their multipotent differentiation potential and immunophenotype.

Mechanism of dominant-negative telomerase function.

Human telomerase uses its integral core components, hTR and hTERT, to maintain telomeres in many cell types. Expression of a dominant-negative mutant of the catalytic subunit of telomerase, DN-hTERT, has been shown to cause telomere shortening and ultimately cell death in a number of tumor-derived cell lines. However, the mechanism of dominant-negative hTERT function and its fate inside the cell are still unknown.

Elevated expression of nuclear Hsp90 in invasive breast tumors.

With the current trend for early breast cancer detection, there is also a growing demand for discovering markers to assist in the patient risk stratification. Molecular chaperones play essential roles in the post-translational maturation of oncogenic client proteins and are strongly associated with carcinogenesis. To better define the role of chaperones in breast cancer, tissue arrays were immunostained for the chaperones Hsp90 and p23 and assessed in terms of reactivity, intensity and cellular localization.

Genetic inhibition of telomerase results in sensitization and recovery of breast tumor cells.

Telomerase, a ribonucleoprotein enzyme minimally composed of an RNA template (human telomerase RNA) and a catalytically active protein subunit (human telomerase reverse transcriptase), synthesizes telomeric repeats onto chromosome ends and is obligatory for continuous tumor cell proliferation. Telomerase is an attractive anticancer therapeutic target because its activity is present in >90% of human cancers, including >95% of breast carcinomas. Traditional chemotherapies lack the ability to effectively control and cure breast cancer, in part because residual cells are often resistant to DNA-damaging modalities.

Japanese medaka: a new vertebrate model for studying telomere and telomerase biology.

A good understanding of telomeres and telomerase biology is crucial for unraveling mechanisms related to aging and cancer. However, in vivo vertebrate studies of telomere biogenesis and telomerase function have been limited by the development of appropriate animal model systems. The present study aims to demonstrate evolutionary conservation of telomerase in vertebrate species, supporting the potential application of fish as vertebrate model for studying telomeres and telomerase function.

Overexpression of telomerase-associated chaperone proteins in prostatic intraepithelial neoplasia and carcinomas.

Over 90% of prostate cancers express telomerase activity. In an experimental model, hsp90 and p23, which are necessary for telomerase assembly and function, dramatically increase during tumorigenic conversion. We immunohistochemically analyzed 60 prostate carcinomas, 50 prostatic intraepithelial neoplasias (PIN) and 25 benign prostatic tissues to determine whether hsp90/p23 expression correlates with advancing stage and whether chaperone distribution overlaps with hTERT, the catalytic component of telomerase.

Accelerated senescence: an emerging role in tumor cell response to chemotherapy and radiation.

Treatment of malignancies with chemotherapeutic drugs and/or radiotherapy is designed to eliminate the disease by depriving the tumor cell of its reproductive potential. Frequently, the desired effect of cell killing is achieved through the promotion of apoptosis; however, accumulating evidence suggests that apoptosis may not be the exclusive or even primary mechanism whereby tumor cells lose their self-renewal capacity after radiation or drug treatment, particularly in the case of solid tumors. While failure to undergo apoptosis in response to chemotherapeutic drugs or radiation may represent a mechanism of drug and radiation resistance, particularly in the case of leukemias and lymphomas, it is gradually being recognized that in the case of solid tumors, loss of reproductive capacity can occur through alternative pathways including reproductive cell death or mitotic catastrophe, through autophagic cell death, and as described below, through a terminally arrested state similar to replicative senescence.

Recovery from stress is a function of age and telomere length.

Cells are constantly exposed to a wide variety of stimuli and must be able to mount appropriate physiological responses in order to maintain proper form and function. Cells from every organism have evolved highly conserved mechanisms to cope with environmental changes, including the widely studied heat shock response (HSR), which is induced by a variety of cellular stresses such as heavy metal ion exposure. It has long been known that as organisms and individual cells age, their ability to appropriately cope with environmental stress is attenuated.

Upregulation of telomerase function during tissue regeneration.

Telomerase plays a primary role in the maintenance of telomeres in immortal, germ, and tumor cells in humans but is lacking in most somatic cells and tissues. However, many species, including fish and inbred mice, express telomerase in most cells and tissues. Little is known about the expression of telomerase in aquatic species, although the importance of telomerase for longevity has been suggested.

A chemotherapy-associated senescence bystander effect in breast cancer cells.

A bystander effect typically refers to the death, altered growth or damage of cells that have not directly received chemotherapy or irradiation. Cancer cells derived from solid tumors readily undergo senescence in response to chemotherapeutic agents, prompting us to test for the existence of a senescence bystander effect. MCF-7 breast cancer cells were acutely exposed to Adriamycin to trigger senescence.