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1.  Detection of myeloma in skeleton of mice by whole-body optical fluorescence imaging 
Molecular cancer therapeutics  2007;6(6):1701-1708.
Development of new therapies for myeloma has been hindered by the lack of suitable preclinical animal models of the disease in which widespread tumor foci in the skeleton can be detected reliably. Traditional means of detecting skeletal tumor infiltration such as histopathology are cumbersome and labor-intensive and do not allow temporal monitoring of tumor progression or regression in response to therapy. To resolve this problem, we modified the Radl 5TGM1 model of myeloma bone disease such that fluorescent myeloma tumors can be optically imaged in situ. Here, we show that murine myeloma 5TGM1 tumor cells, engineered to express enhanced green fluorescent protein (eGFP; 5TGM1-eGFP cells), can be imaged in a temporal fashion using a fluorescence illuminator and a charge-coupled device camera in skeletons of live C57BL/KaLwRij mice. High-resolution, whole-body images of tumor-bearing mice revealed that myeloma cells homed almost exclusively to the skeleton, with multiple focal tumor foci in the axial skeleton, consistent with myeloma tumor distribution in humans. Finally, the tested antitumor treatment effect of Velcade (bortezomib), a proteasome inhibitor used clinically in myeloma, was readily detected by GFP imaging, suggesting the power of the technique in combination with the Radl 5TGM1-eGFP model for rapid preclinical assessment and sensitive monitoring of novel and potential therapeutics. Whole-body GFP imaging is practical, convenient, inexpensive, and rapid, and these advantages should enable a high throughput when evaluating in vivo efficacy of new potential antimyeloma therapeutics and assessing response to treatment.
PMCID: PMC4482358  PMID: 17541032
2.  TGF-β promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling 
Cancer research  2010;71(3):822-831.
Breast cancer frequently metastasizes to bone, where tumor cells receive signals from the bone marrow microenvironment. One relevant factor is TGF-β, which up regulates expression of the Hedgehog (Hh) signaling molecule Gli2 which in turn increases secretion of important osteolytic factors such as parathyroid hormone-related protein (PTHrP). PTHrP inhibition can prevent tumor-induced bone destruction, whereas Gli2 over expression in tumor cells can promote osteolysis. In this study, we tested the hypothesis that Hh inhibition in bone metastatic breast cancer would decrease PTHrP expression and therefore osteolytic bone destruction. However, when mice engrafted with human MDA-231 breast cancer cells were treated with the Hh receptor antagonist cyclopamine, we observed no effect on tumor burden or bone destruction. In vitro analyses revealed that osteolytic tumor cells lack expression of the Hh receptor, Smoothened, suggesting an Hh-independent mechanism of Gli2 regulation. Blocking Gli signaling in metastatic breast cancer cells with a Gli2-Repressor gene (Gli2-Rep) reduced endogenous and TGF-β-stimulated PTHrP mRNA expression, but did not alter tumor cell proliferation. Furthermore, mice inoculated with Gli2-Rep-expressing cells exhibited a decrease in osteolysis, suggesting that Gli2 inhibition may block TGF-β propagation of a vicious osteolytic cycle in this MDA-231 model of bone metastasis. Accordingly, in the absence of TGF-β signaling, Gli2 expression was down regulated in cells, whereas enforced over expression ofGli2 restored PTHrP activity. Taken together, our findings suggest that Gli2 is required for TGF-β to stimulate PTHrP expression, and that blocking Hh-independent Gli2 activity will inhibit tumor-induced bone destruction.
PMCID: PMC3077118  PMID: 21189326
Gli; PTHrP; Osteolysis; Breast cancer; Hedgehog; Cyclopamine; Bone Metastasis
3.  Seroprevalence of 13 common pathogens in a rapidly growing U.S. minority population: Mexican Americans from San Antonio, TX 
BMC Research Notes  2011;4:433.
Infection risks vary among individuals and between populations. Here we present information on the seroprevalence of 13 common infectious agents in a San Antonio-based sample of Mexican Americans. Mexican Americans represent the largest and most rapidly growing minority population in the U.S., and they are also considered a health disparities population.
We analyzed 1227 individuals for antibody titer to Chlamydophila pneumoniae, Helicobacter pylori, Toxoplasma gondii, cytomegalovirus, Epstein-Barr virus, herpes simplex virus-1, herpes simplex virus-2 (HSV-2), human herpesvirus-6 (HHV-6), varicella zoster virus (VZV), adenovirus-36, hepatitis A virus, and influenza A and B. Seroprevalence was examined as a function of sex, age, household income, and education.
Seroprevalence estimates ranged from 9% for T. gondii to 92% for VZV, and were similar in both sexes except for HSV-2, which was more prevalent in women. Many pathogens exhibited a significant seroprevalence change over the examined age range (15-94 years), with 7 pathogens increasing and HHV-6 decreasing with age. Socioeconomic status significantly correlated with serostatus for some pathogens.
Our findings demonstrate substantial seroprevalence rates of these common infections in this sample of Mexican Americans from San Antonio, Texas that suffers from high rates of chronic diseases including obesity and type-2 diabetes.
PMCID: PMC3214184  PMID: 22018212
4.  Caspase-2 Deficiency Enhances Aging-Related Traits in Mice 
Alteration of apoptotic activity has been observed in a number of tissues in aging mammals, but it remains unclear whether and/or how apoptosis may affect aging. Caspase-2 is a member of the cysteine protease family that plays a critical role in apoptosis. To understand the impact of compromised apoptosis function on mammalian aging, we conducted a comparative study on caspase-2 deficient mice and their wild-type littermates with a specific focus on the aging-related traits at advanced ages. We found that caspase-2 deficiency enhanced a number of traits commonly seen in premature aging animals. Loss of caspase-2 was associated with shortened maximum lifespan, impaired hair growth, increased bone loss, and reduced body fat content. In addition, we found that the livers of caspase-2 deficient mice had higher levels of oxidized proteins than those of age-matched wild-type mice, suggesting that caspase-2 deficiency compromised the animal's ability to clear oxidatively damaged cells. Collectively, these results suggest that caspase-2 deficiency affects aging in the mice. This study thus demonstrates for the first time that disruption of a key apoptotic gene has a significant impact on aging.
PMCID: PMC1828128  PMID: 17188333
caspase-2; maximum lifespan; bone; hair growth; fat
5.  TGF-β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development 
Journal of Clinical Investigation  1999;103(2):197-206.
Breast cancer frequently metastasizes to the skeleton, and the associated bone destruction is mediated by the osteoclast. Growth factors, including transforming growth factor-β (TGF-β), released from bone matrix by the action of osteoclasts, may foster metastatic growth. Because TGF-β inhibits growth of epithelial cells, and carcinoma cells are often defective in TGF-β responses, any role of TGF-β in metastasis is likely to be mediated by effects on the surrounding normal tissue. However, we present evidence that TGF-β promotes breast cancer metastasis by acting directly on the tumor cells. Expression of a dominant–negative mutant (TβRIIΔcyt) of the TGF-β type II receptor rendered the human breast cancer cell line MDA-MB-231 unresponsive to TGF-β. In a murine model of bone metastases, expression of TβRIIΔcyt by MDA-MB-231 resulted in less bone destruction, less tumor with fewer associated osteoclasts, and prolonged survival compared with controls. Reversal of the dominant–negative signaling blockade by expression of a constitutively active TGF-β type I receptor in the breast cancer cells increased tumor production of parathyroid hormone–related protein (PTHrP), enhanced osteolytic bone metastasis, and decreased survival. Transfection of MDA-MB-231 cells that expressed the dominant–negative TβRIIΔcyt with the cDNA for PTHrP resulted in constitutive tumor PTHrP production and accelerated bone metastases. These data demonstrate an important role for TGF-β in the development of breast cancer metastasis to bone, via the TGF-β receptor–mediated signaling pathway in tumor cells, and suggest that the bone destruction is mediated by PTHrP.
PMCID: PMC407876  PMID: 9916131
6.  A Role for Interleukin-6 in Host Defense against Murine Chlamydia trachomatis Infection 
Infection and Immunity  1998;66(9):4564-4567.
Interleukin-6-deficient (IL-6−/−) knockout mice had significantly increased Chlamydia trachomatis levels in lung tissue and increased mortality compared to B6129F2/J controls early after intranasal infection. Gamma interferon production and chlamydia-specific antibody levels were consistent with a decreased but reversible Th1-like response in IL-6−/− mice. IL-6 is needed for an optimal early host response to this infection.
PMCID: PMC108560  PMID: 9712822

Results 1-6 (6)