Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions.

In normal human somatic cells, telomere dysfunction causes cellular senescence, a stable proliferative arrest with tumour suppressing properties. Whether telomere dysfunction-induced senescence (TDIS) suppresses cancer growth in humans, however, is unknown. Here, we demonstrate that multiple and distinct human cancer precursor lesions, but not corresponding malignant cancers, are comprised of cells that display hallmarks of TDIS.

Concomitant inactivation of Rb and E2f8 in hematopoietic stem cells synergizes to induce severe anemia.

The retinoblastoma (Rb) tumor suppressor plays important roles in regulating hematopoiesis, particularly erythropoiesis. In an effort to understand whether Rb function can be mediated by E2F transcription factors in a BM-derived hematopoietic system in mice, we uncovered a functional synergy between Rb and E2F8 to promote erythropoiesis and to prevent anemia. Specifically, whereas Mx1-Cre-mediated inactivation of Rb or E2f8 in hematopoietic stem cells only led to mild erythropoietic defects, concomitant inactivation of both genes resulted in marked ineffective erythropoiesis and mild hemolysis, leading to severe anemia despite the presence of enhanced extramedullary erythropoiesis.

Essential role of ARID2 protein-containing SWI/SNF complex in tissue-specific gene expression.

Unfolding of the gene expression program that converts precursor cells to their terminally differentiated counterparts is critically dependent on the nucleosome-remodeling activity of the mammalian SWI/SNF complex. The complex can be powered by either of two alternative ATPases, BRM or BRG1. BRG1 is critical for development and the activation of tissue specific genes and is found in two major stable configurations.

Interferon regulatory factor 5 activation in monocytes of systemic lupus erythematosus patients is triggered by circulating autoantigens independent of type I interferons.

Objective: Genetic variants of interferon regulatory factor 5 (IRF-5) are associated with susceptibility to systemic lupus erythematosus (SLE). IRF-5 regulates the expression of proinflammatory cytokines and type I interferons (IFNs) believed to be involved in the pathogenesis of SLE. The aim of this study was to determine the activation status of IRF-5 by assessing its nuclear localization in the immune cells of SLE patients and healthy donors, and to identify SLE-associated triggers of IRF-5 activation.

Tissue-specific gene targeting by the multiprotein mammalian DREAM complex.

The mammalian DP, RB-like, E2F, and MuvB-like proteins (DREAM) complex, whose key components include p130 and E2F4, plays a fundamental role in repression of cell cycle-specific genes during growth arrest. Mammalian DREAM is well conserved with Drosophila and Caenorhabditis elegans complexes that repress pivotal developmental genes, but the mammalian complex has been thought to exist only in quiescent cells and not to be linked with development. However, new findings here identify tissue-specific promoters repressed by DREAM in proliferating precursors, revealing a new connection between control of growth arrest and terminal differentiation.

Transcriptional activation by pRB and its coordination with SWI/SNF recruitment.

A central question in cancer biology is why most tumor susceptibility genes are linked with only limited types of cancer. Human germ-line mutation of the retinoblastoma susceptibility gene Rb1 is closely linked with just retinoblastoma and osteosarcoma, although the gene is universally expressed. Functional analysis of pRB and its close relatives, p107 and p130, has largely focused on their roles in repression of proliferation across all tissue types, but genetic evidence indicates an active requirement for pRB in osteoblast differentiation that correlates more directly with osteosarcoma susceptibility.

A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer.

Purpose: We investigated a combination therapy with weekly paclitaxel and all trans-retinoic acid (ATRA) for tolerability, response to treatment, time to progression and survival in previously treated patients with metastatic or recurrent breast cancer. Our rationale was based on preclinical studies demonstrating potentiation of the cytotoxic effects of taxanes and induction of differentiation by ATRA.

Patients And Methods: Seventeen patients with previously treated metastatic or recurrent breast cancer were enrolled to a regimen of all-trans retinoic acid (Vesanoid, tretinoin, Hoffman-La Roche, Inc.

PHF10 is required for cell proliferation in normal and SV40-immortalized human fibroblast cells.

Normal human diploid fibroblasts have limited life span in culture and undergo replicative senescence after 50-60 population doublings. On the contrary, cancer cells typically divide indefinitely and are immortal. Expression of SV40 large T and small t antigens in human fibroblasts transiently extends their life span by 20-30 population doublings and facilitates immortalization.

The rho-specific guanine nucleotide exchange factor Dbs regulates breast cancer cell migration.

Dbs is a Rho-specific guanine nucleotide exchange factor (RhoGEF) that regulates neurotrophin-3-induced cell migration in Schwann cells. Here we report that Dbs regulates cell motility in tumor-derived, human breast epithelial cells through activation of Cdc42 and Rac1. Cdc42 and Rac1 are activated in T47D cells that stably express onco- or proto-Dbs, and activation is dependent upon growth of the cells on collagen I.

Dual FGF-2 and intergrin alpha5beta1 signaling mediate GRAF-induced RhoA inactivation in a model of breast cancer dormancy.

Interactions with the bone marrow stroma regulate dormancy and survival of breast cancer micrometastases. In an in vitro model of dormancy in the bone marrow, we previously demonstrated that estrogen-dependent breast cancer cells are partially re-differentiated by FGF-2, re-express integrin alpha5beta1 lost with malignant transformation and acquire an activated PI3K/Akt pathway. Ligation of integrin alpha5beta1 by fibronectin and activation of the PI3K pathway both contribute to survival of these dormant cells.

Antagonistic roles for BRM and BRG1 SWI/SNF complexes in differentiation.

The mammalian SWI/SNF chromatin-remodeling complex is essential for the multiple changes in gene expression that occur during differentiation. However, the basis within the complex for specificity in effecting positive versus negative changes in gene expression has only begun to be elucidated. The catalytic core of the complex can be either of two closely related ATPases, BRM or BRG1, with the potential that the choice of alternative subunits is a key determinant of specificity.

Regulation of apoptosis by type III interferons.

Objective: Two types of interferons (IFNs), type I (IFN-alpha/beta) and type III (IFN-lambdas), utilize distinct receptor complexes to induce similar signalling and biological activities, including recently demonstrated for IFN-lambdas antitumour activity. However, ability of type III IFNs to regulate cell population growth remains largely uncharacterized.

Materials And Methods: Intact and modified human colorectal adenocarcinoma HT29 cells were used to study regulation of apoptosis by IFN-lambdas.

IRF-5 is a mediator of the death receptor-induced apoptotic signaling pathway.

The efficient and regulated response to cellular stress is coordinated by a genetic regulatory network in which a given transcription factor controls the expression of diverse target genes depending on the cell type and/or nature of the stimuli. The tumor suppressor p53 is thought to preferentially regulate the balance between cell survival and death. The interferon regulatory factor 5 (IRF-5), known to be involved in the innate immune response to pathogens, is also a critical regulator of DNA damage-induced apoptosis.

Foreign-body reaction to the Artelon CMC joint spacer: case report.

The Artelon CMC spacer (Small Bone Innovations, Inc., Morrisville, PA) is a relatively new device that was developed for the treatment of basal joint arthritis. It is composed of a biodegradable polycaprolactone-based polyurethane urea that acts to resurface the distal part of the trapezium and stabilize the trapeziometacarpal joint by augmenting the joint capsule.

Primary alveolar soft part sarcoma of fibula demonstrating ASPL-TFE3 fusion: a case report and review of the literature.

Alveolar soft part sarcoma is a rare soft tissue tumor typically affecting young adults. These tumors are most often seen in the deep soft tissues of the extremities and patients generally present with advanced disease. Primary bone involvement is extremely rare and has only been reported in seven cases.

Hemicondylar hamate replacement arthroplasty for proximal interphalangeal joint fracture dislocations: an assessment of graft suitability.

Purpose: Proximal interphalangeal (PIP) joint fracture-dislocations are complex injuries, and successful surgical treatment can be challenging. The hamate appears to be an appropriate graft based on its general shape and dimensions. The purpose of this study was to evaluate the rationale and suitability of the hamate as an autograft for proximal interphalangeal joint fracture-dislocations and to determine the inherent stability of the donor site after graft harvesting.

Influence of prescription benefits on reported pain in cancer patients.

Objective: To identify associations between prescription coverage and cancer pain and its sequelae in indigent patients.

Design And Setting: A retrospective chart review at UMDNJ-University Hospital.

Patients And Outcome Measures: Charts from 20 patients with Medicaid and 20 patients categorized as Self-pay/Charity Care were analyzed for the influence of insurance coverage on reported pain at the time of a hospital discharge and at three subsequent clinic visits.

Image-based study of interferongenic interactions between plasmacytoid dendritic cells and HSV-infected monocyte-derived dendritic cells.

Plasmacytoid dendritic cells (pDC) are well-known for their ability to produce large quantities of interferon-alpha (IFN-alpha) in response to viruses. In addition, pDC produce IFN-alpha in response to HSV-infected cells. We demonstrate that both tonsil and PBMC contain pDC that respond to stimulation with HSV either in suspension or in tonsil tissue-fragment culture.

The RhoGEF domain of p210 Bcr-Abl activates RhoA and is required for transformation.

The BCR-ABL oncogene encodes an in-frame fusion protein containing N-terminal sequences derived from Bcr and C-terminal sequences derived from Abl. Bcr contains a centrally located Rho-specific guanine nucleotide exchange factor (RhoGEF) domain that is retained within p210 Bcr-Abl. Although this domain is subject to autoinhibition in the context of Bcr, here we show that it is constitutively activated in p210 Bcr-Abl.

Extramedullary hematopoiesis presenting as a focal splenic mass: a case report.

We report the ultrasound, computed tomographic, and magnetic resonance imaging findings in a case of extramedullary hematopoiesis presenting as a focal splenic mass in a patient with myelodysplastic syndrome. Ultrasound demonstrated a well-circumscribed hyperechoic mass, whereas computed tomography showed a heterogeneous mass better visualized after administration of intravenous contrast. On magnetic resonance imaging, the lesion was hypointense to the spleen on T1-weighted images, with increased signal on T2-weighted images, and demonstrated enhancement after intravenous contrast administration.

Effect of sirolimus on infection incidence in liver transplant recipients.

Sirolimus is a new immunosuppressive agent that lacks the nephrotoxicity and neurotoxicity associated with calcineurin inhibitors. The addition of sirolimus to immunosuppressive protocols may thus allow sparing of calcineurin inhibitors and reduction or elimination of associated toxicities. Between January 2000 and July 2001, sirolimus was administered to 55 of 116 consecutive liver recipients.

Nonhemophilic hemosiderotic synovitis of the shoulder. A case report.

In a nonhemophilic 72-year-old man, a persistent degenerative hemarthrosis of the shoulder joint was associated with a complete tear of the rotator cuff. Extensive, rusty synovial pigmentation and hyperplasia (hemosiderotic synovitis) mimicking pigmented villonodular synovitis (PVS) were noted at surgery. Spontaneous hemarthrosis of the shoulder includes rapid onset of severe pain, limitation of movement, subsequent appearance of a bruise on the affected shoulder and arm, and radiological evidence of joint degeneration.