Citations

BackgroundPostmenopausal hormone therapy (HT) increases the risk of venous thrombosis and ischemic stroke.ObjectivesWe postulated that HT might increase the risk of ischemic stroke by promoting venous clots that travel to the brain through a right to left shunt (RLS).MethodsA total of 2,389 records were studied. After eliminating the premenopausal patients, and those with TIAs and non‐ischemic strokes, the medical records of 1846 postmenopausal women hospitalized at four institutions for ischemic stroke were reviewed to identify those who had undergone an adequate study to assess for RLS. The proportion of women with a shunt in users and non‐users of HT was compared in stroke patients and in a reference population consisting of postmenopausal women undergoing elective cardiac catheterization.ResultsThere were 363 (20%) records that had complete data and were included in the analysis. A shunt was more prevalent in patients with a cryptogenic stroke than in patients with a stroke of known cause (55/88 (63%) vs. 53/275 (19%), P < 0.001). In patients with a stroke of known cause, the frequency of a shunt was similar to that in reference women 31/136 (23%), and the proportion of women with a shunt was similar in non‐users and current users of HT (14% vs. 20%, P = 0.40). However, among patients with a cryptogenic stroke, the prevalence of a shunt was 1.5 times higher in current users than non‐users of HT (82% vs. 56%, P = 0.04).ConclusionsApproximately 23% of older women have a RLS. HT in these women may increase the risk of ischemic stroke by promoting paradoxical embolism. © 2014 Wiley Periodicals, Inc.

Abstract Matrix metalloproteinase 10 (Mmp10; stromelysin 2) is a member of a large family of structurally related matrix metalloproteinases, many members of which have been implicated in tumor progression, invasion and metastasis. However, emerging evidence suggests a possible role for Mmps in tumor initiation. Here we reveal an unexpected role for Mmp10 in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC). Mouse lung cancer cell cultures enriched in stem-like cells grow as undifferentiated tumor “oncospheres” that express elevated levels of the cancer stem cell markers Aldh1, CD133, Nanog, Notch3, Notch 4, Hey 1 and Hey 2. These cells also express elevated levels of Mmp10 mRNA and secrete elevated levels of Mmp10 protein. Functionally, these lung CSCs exhibit self-renewal, the ability to clonally expand, enhanced transforming potential in vitro, and enhanced tumorigenic properties when injected orthotopically into the lungs of syngeneic mice. RNAi-mediated knockdown of Mmp10 in these cells leads to a loss of stem cell marker gene expression and a dramatic inhibition of oncosphere growth, clonal expansion, transformed growth in vitro, and lung tumor formation and metastasis in vivo. In contrast, oncospheres implanted into syngeneic non-transgenic or Mmp10−/− mice show no significant difference in tumor initiation, growth or metastasis, demonstrating the importance of Mmp10 produced by cancer cells rather than the tumor microenvironment in lung tumor initiation and maintenance. Analysis of gene expression data from human tumors demonstrates that Mmp10 is elevated in many human tumor types including lung, head and neck, esophageal, colon, breast, melanoma, bladder, cervical, ovarian, prostate and brain. Furthermore, gene set enhancement analysis (GSEA) demonstrates that elevated Mmp10 expression correlates with tumor metastasis and with cancer stem-like genomic signatures in human lung tumors. Thus, Mmp10 is required for maintenance of a highly tumorigenic, cancer-initiating, metastatic stem-like cell population in lung cancer. Our data demonstrate for the first time that Mmp10 is a critical lung cancer stem cell gene and novel therapeutic target for lung cancer stem cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-204. doi:1538-7445.AM2012-LB-204

Brown fat is specialized for energy expenditure and has therefore been proposed to function as a defense against obesity. Despite recent advances in delineating the transcriptional regulation of brown adipocyte differentiation, cellular lineage specification and developmental cues specifying brown-fat cell fate remain poorly understood. In this study, we identify and isolate a subpopulation of adipogenic progenitors (Sca-1 + /CD45 − /Mac1 − ; referred to as Sca-1 + progenitor cells, ScaPCs) residing in murine brown fat, white fat, and skeletal muscle. ScaPCs derived from different tissues possess unique molecular expression signatures and adipogenic capacities. Importantly, although the ScaPCs from interscapular brown adipose tissue (BAT) are constitutively committed brown-fat progenitors, Sca-1 + cells from skeletal muscle and subcutaneous white fat are highly inducible to differentiate into brown-like adipocytes upon stimulation with bone morphogenetic protein 7 (BMP7). Consistent with these findings, human preadipocytes isolated from subcutaneous white fat also exhibit the greatest inducible capacity to become brown adipocytes compared with cells isolated from mesenteric or omental white fat. When muscle-resident ScaPCs are re-engrafted into skeletal muscle of syngeneic mice, BMP7-treated ScaPCs efficiently develop into adipose tissue with brown fat-specific characteristics. Importantly, ScaPCs from obesity-resistant mice exhibit markedly higher thermogenic capacity compared with cells isolated from obesity-prone mice. These data establish the molecular characteristics of tissue-resident adipose progenitors and demonstrate a dynamic interplay between these progenitors and inductive signals that act in concert to specify brown adipocyte development.

Background Hepatitis B virus (HBV) genotype B and C seem not to affect the therapeutic response to lamivudine (3TC). Whether a given genotype has an earlier emergence of 3TC resistance remains unclear. We thus conducted this study to elucidate the association of HBV genotype with the emergence of 3TC-resistant strains in Taiwanese patients. Methods Forty chronic hepatitis B patients who developed resistance after 3TC therapy were retrospectively enrolled. HBV genotype, serum alanine aminotransferase (ALT) and HBV DNA levels were determined at baseline. The presence of 3TC-resistant mutations was confirmed by direct sequencing whenever biochemical breakthrough developed. Results The distribution of HBV genotype B and C in 40 patients receiving 3TC therapy were 60% and 40%, respectively. The mean interval to detect 3TC- resistant strain was 19.6 ±1.7 months. By using multivariate analysis, HBV genotype B and higher pre-treatment HBV DNA level were independently associated with earlier detection of 3TC-resistant strains. In addition, genotype B was significantly associated with development of 3TC resistance within the first 12 months of 3TC therapy compared with genotype C (odds ratio 8.27; P=0.004). Conclusions Compared with HBV genotype C, genotype B appears to have an earlier biochemical resistance to 3TC than genotype C. Therefore, more frequent monitoring of viral load or genotypical resistance might be needed for patients with HBV genotype B infection receiving 3TC therapy, especially during the first year.