No abstract

No abstract

No abstract

Explant cultures of adult human trabecular bone fragments give rise to osteoblastic cells, that are known to express osteoblastrelated genes and mineralize extracellular matrix. These osteoblastic cells have also been shown to undergo adipogenesis in vitro and chondrogenesis in vivo. Here we report the in vitro developmental potential of adult human osteoblastic cells (hOB) derived from explant cultures of collagenase-pretreated trabecular bone fragments. In addition to osteogenic and adipogenic differentiation, these cells are capable of chondrogenic differentiation in vitro in a manner similar to adult human bone marrow-derived mesenchymal progenitor cells. High-density pellet cultures of hOB maintained in chemically defined serum-free medium, supplemented with transforming growth factor-P1 , were composed of morphologically distinct, chondrocyte-like cells expressing mRNA transcripts of collagen types 11, IX and X, and aggrecan. The cells within the high-density pellet cultures were surrounded by a sulfated proteoglycan-rich extracellular matrix that immunostained for collagen type I1 and proteoglycan link protein. Osteogenic differentiation of hOB was verified by an increased number of alkaline phosphatase-positive cells, that expressed osteoblast-related transcripts such as alkaline phosphatase, collagen type I, osteopontin and osteocalcin, and formed mineralized matrix in monolayer cultures treated with ascorbate, P-glycerophosphate, and bone morphogenetic protein-2. Adipogenic differentiation of hOB was determined by the appearance of intracellular lipid droplets, and expression of adipocyte-specific genes, such as lipoprotein lipase and peroxisome proliferator-activated receptor y2, in monolayer cultures treated with dexamethasone, indomethacin, insulin and 3-isobutyl-lmethylxanthine. Taken together, these results show that cells derived from collagenase-treated adult human trabecular bone fragments have the potential to differentiate into multiple mesenchymal lineages in vitro, indicating their developmental plasticity and suggesting their mesenchymal progenitor nature.

ABSTRACT-cell population resident within collagenase-treated, culture-processed bone fragments, which upon migration established a homogeneous population of MPCs. Additionally, we have introduced a system of culturing these MPCs that best supports and maintains their optimal differentiation potential during long-term culture expansion. When cultured as described, the trabecular bone-derived cells display stem cell-like capabilities, characterized by a stable undifferentiated phenotype as well as the ability to proliferate extensively while retaining the potential to differentiate along the osteoblastic, adipocytic, and chondrocytic lineages, even when maintained in long-term in vitro culture.

Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies that arise from neuroendocrine cells throughout the body, most commonly originating from the lungs and gastrointestinal tract. Lung NETs can be classified as well differentiated (low-grade typical carcinoids [TCs] and intermediate-grade atypical carcinoids [ACs]) and poorly differentiated (high-grade large cell neuroendocrine carcinoma or SCLC). The incidence of these tumors is increasing, but disease awareness remains low among thoracic specialists, who are often involved in the diagnosis and early treatment for these patients. An accurate and timely diagnosis can ensure the implementation of appropriate treatment and have a substantial impact on prognosis. However, lung NET classification and diagnosis, particularly for TCs/ACs, are complicated by several factors, including a variable natural history and nonspecific symptoms. Surgery remains the only curative option for TCs/ACs, but there is a lack of consensus between lung NET management guidelines regarding optimal treatment approaches in the unresectable/metastatic setting on account of the limited availability of high-level clinical evidence. As a result, a multidisciplinary approach to management of lung NETs is required to ensure a consistent and optimal level of care. RADIANT-4 is the first phase III trial involving a large subpopulation of patients with advanced well-differentiated lung NETs to report reductions in the risk for disease progression and death with everolimus over placebo. This led to the recent U.S. approval of everolimus-the first agent approved for advanced lung TCs/ACs. To further improve evidence-based care, additional randomized controlled trials in patients with lung carcinoids are needed.

32 APC = adenomatous polyposis coli; bHLH = basic helix-loop-helix; BMP = bone morphogenetic protein; Cbfa1 = core binding factor alpha 1; ECM = extracellular matrix; ERK = extracellular signal-regulated kinase; ES = embryonic stem; GDF = growth/differentiation factor; IBMX = 3-isobutyl-1-methylxanthine; IL = interleukin; JNK = c-Jun N-terminal kinase; LRP = low-density lipoprotein receptor-related peptide; MAPK = mitogen-activated protein kinase; MSC = mesenchymal stem cell; PLA = poly-L-lactide; PLGA = poly-L-lactide-co-glycolide; PPAR-γ = peroxisome proliferator-activated receptor-γ; SMAD = vertebrate homologue of Drosophila Mothers Against Decapentaplegic (MAD); TGF-β = transforming growth factor beta; WISP = Wnt-1-inducible protein. Arthritis Research and Therapy Vol 5 No 1 Tuan et al. IntroductionDespite the pluripotency of embryonic stem (ES) cells, legal and moral controversies concerning their use for therapeutic and clinical application have prompted active examination of the reservoirs of progenitor cells harbored within the adult organism. In principle, such unspecialized cells are considered to be quiescent, but capable of selfrenewing; their asymmetric division produces one identical daughter stem cell and a second progenitor cell that becomes committed to a lineage-specific differentiation program [1]. These cells remain in their 'undifferentiated' state from suppression by some intrinsic or extrinsic factor, until stimulated. Such adult stem cells have been discovered and characterized in a multitude of tissues, suggesting the potential for therapeutic application in their host tissue [2][3][4]. As these cells are capable of differentiation along specific lineages and of being recruited to tissues in need, the promise for autologous clinical implantation or genetically engineered stem cells for protein or drug delivery without the risk of immunorejection looms on the horizon. However, the success of future clinical applications depends critically upon a thorough understanding of the biology of these cells, and new findings are continuously being reported. For example, there is recent evidence suggesting that the pluripotent stem cell, once thought to be restricted to the fates of a lineage hierarchy, is capable of transdifferentiation. Some recent examples include the observations that the hematopoietic stem cells of bone marrow have been shown to become hepatic oval cells [5][6][7]; that muscle satellite cells exhibit hematopoietic potential [8]; that neural stem cells have been shown to produce lineage-committed hematopoietic progenitors [9]; and that mesenchymal stem cells from bone marrow have traveled to skeletal muscle [10], differentiated into neuronal tissue [11,12], supplied mesangial cells during repair processes [13], and given rise to cardiomyocytes in vitro [14,15]. These observations strongly imply a critical influence of microenvironmental cues on cell fate. Sources of mesenchymal stem cellsThis review focuses on the adult mesenchymal stem cell (MSC), which has the potential to dif...

Background Duodenal adenocarcinoma is a rare cancer usually studied as a group with periampullary or small bowel adenocarcinoma; therefore, its natural history is poorly understood. Methods Patients with duodenal adenocarcinoma were identified from a single-institution pancreaticoduodenectomy database. Patients with adenocarcinoma arising from the ampulla of Vater were excluded. Univariate and multivariate analyses were performed to identify clinicopathologic variables associated with survival and recurrence after resection. Results From 1984 to 2006, a total of 122 patients with duodenal adenocarcinoma underwent pancreaticoduodenectomy. Overall survival after resection was 48% at 5 years and 41% at 10 years. Five-year survival decreased as the number of lymph nodes involved by metastasis increased from 0 to 1–3 to ≥4 (68%, 58%, 17%, respectively, P < 0.01) and as the lymph node ratio increased from 0 to >0–0.2 to >0.2–0.4 to >0.4 (68%, 57%, 14%, 14%, respectively, P < 0.01). Lymph node metastasis was the only independent predictor of decreased survival in multivariate analysis. Recurrence after resection was predominantly distant (81%). Adjuvant chemoradiation did not decrease local recurrence or prolong overall survival; however, patients who received chemoradiation more commonly had nodal metastasis (P = 0.03). Conclusions The prognostic significance of both the absolute number and ratio of involved lymph nodes emphasizes the need for adequate lymphadenectomy to accurately stage duodenal adenocarcinoma. The mostly distant pattern of recurrence underscores the need for the development of effective systemic therapies.