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1.
J Immigr Minor Health ; 24(5): 1113-1121, 2022 Oct.
Article in English | MEDLINE | ID: mdl-34664155

ABSTRACT

The Mexican state of Tamaulipas serves as a migration waypoint into the US. Here, we determined the contribution of immigrants to TB burden in Tamaulipas. TB surveillance data from Tamaulipas (2006-2013) was used to conduct a cross-sectional characterization of TB immigrants (born outside Tamaulipas) and identify their association with TB treatment outcomes. Immigrants comprised 30.8% of TB patients, with > 99% originating from internal Mexican migration. Most migration was from South to North, with cities adjacent to the US border as destinations. Immigrants had higher odds of risk factors for TB [older age (≥ 65 year old, OR 2.4, 95% CI 2.1, 2.8), low education (OR 1.3, 95% CI 1.2, 1.4), diabetes (OR 1.2, 95% CI 1.1, 1.4)], or abandoning treatment (adjusted OR 1.2, 95% CI 1.0, 1.5). There is a need to identify strategies to prevent TB more effectively in Tamaulipas, a Mexican migration waypoint.


Subject(s)
Emigrants and Immigrants , Tuberculosis , Aged , Cross-Sectional Studies , Humans , Mexico/epidemiology , Risk Factors , Texas/epidemiology , Tuberculosis/diagnosis , Tuberculosis/epidemiology
2.
Front Public Health ; 8: 330, 2020.
Article in English | MEDLINE | ID: mdl-33014952

ABSTRACT

Hispanics/Latinos are expected to constitute 25% of the U.S. population by 2060. Differences in the prevalence of health risk factors, chronic diseases, and access to and utilization of health-care services between Hispanics/Latinos and other populations in the U.S. have been documented. This study aimed to describe and analyze the landscape of Research Program Grants (RPGs) funded by the National Institutes of Health (NIH) between 2008 and 2015 involving Hispanic/Latino health research in six health condition areas-asthma, cancer, dementia, diabetes, liver/gallbladder disease, and obesity-and to identify opportunities for continued research in these areas. Using an NIH internal search engine, we identified new and renewal Hispanic/Latino health RPGs searching for specific Hispanic/Latino identifiers in the Title, Abstract, and Specific Aims. We used descriptive statistics to examine the distribution of funded RPGs by NIH disease-based classification codes for the six health condition areas of interest, and other selected characteristics. The most prominent clusters of research subtopics were identified within each health condition area, and performance sites were mapped at the city level. Within the selected time frame, 3,221 Hispanic/Latino health-related unique RPGs were funded (constituting 4.4% of all funded RPGs), and of those 625 RPGs were eligible for review and coding in the present study. Cancer and obesity were the most commonly studied health condition areas (72%), while studies on mechanisms of disease-biological and non-biological-(72.6%), behavioral research (42.1%) and epidemiological studies (38.1%) were the most common types of research. Most of the primary performance sites were in California, Texas, the northeastern U.S., and Illinois. The predominance of mechanistic, behavioral, and epidemiological studies in our analysis poses opportunities to evaluate knowledge gained and their clinical application, explore new research questions, or to update some methods or instruments. The findings of the present study suggest opportunities to expand research in understudied mechanisms of disease that could explain differences in prevalence of conditions like diabetes and cancer among different heritage groups. In addition, our findings suggest that the impact of interventions or policies designed to reduce health disparities, innovative multi-level interventions, implementation and dissemination studies, the role of health information technology on health outcomes, and the intersectionality of individual, sociocultural, geographic, and other factors on health outcomes, among others, are understudied approaches, which could potentially advance research in Hispanic/Latino health and contribute to the achievement of better health outcomes in this diverse population.


Subject(s)
Hispanic or Latino , National Institutes of Health (U.S.) , Financing, Organized , Humans , Illinois , Texas , United States/epidemiology
3.
Int J Mol Sci ; 21(16)2020 Aug 18.
Article in English | MEDLINE | ID: mdl-32824772

ABSTRACT

Infectious diarrhea affects over four billion individuals annually and causes over a million deaths each year. Though not typically prescribed for treatment of uncomplicated diarrheal disease, antimicrobials serve as a critical part of the armamentarium used to treat severe or persistent cases. Due to widespread over- and misuse of antimicrobials, there has been an alarming increase in global resistance, for which a standardized methodology for geographic surveillance would be highly beneficial. To demonstrate that a standardized methodology could be used to provide molecular surveillance of antimicrobial resistance (AMR) genes, we initiated a pilot study to test 130 diarrheal pathogens (Campylobacter spp., Escherichia coli, Salmonella, and Shigella spp.) from the USA, Peru, Egypt, Cambodia, and Kenya for the presence/absence of over 200 AMR determinants. We detected a total of 55 different determinants conferring resistance to ten different categories of antimicrobials: genes detected in ≥ 25 samples included blaTEM, tet(A), tet(B), mac(A), mac(B), aadA1/A2, strA, strB, sul1, sul2, qacEΔ1, cmr, and dfrA1. The number of determinants per strain ranged from none (several Campylobacter spp. strains) to sixteen, with isolates from Egypt harboring a wider variety and greater number of genes per isolate than other sites. Two samples harbored carbapenemase genes, blaOXA-48 or blaNDM. Genes conferring resistance to azithromycin (ere(A), mph(A)/mph(K), erm(B)), a first-line therapeutic for severe diarrhea, were detected in over 10% of all Enterobacteriaceae tested: these included >25% of the Enterobacteriaceae from Egypt and Kenya. Forty-six percent of the Egyptian Enterobacteriaceae harbored genes encoding CTX-M-1 or CTX-M-9 families of extended-spectrum ß-lactamases. Overall, the data provide cross-comparable resistome information to establish regional trends in support of international surveillance activities and potentially guide geospatially informed medical care.


Subject(s)
Campylobacter/genetics , Diarrhea/microbiology , Drug Resistance, Microbial , Enteropathogenic Escherichia coli/genetics , Genes, Bacterial , Salmonella/genetics , Shigella/genetics , Anti-Bacterial Agents/toxicity , Campylobacter/drug effects , Campylobacter/isolation & purification , Campylobacter/pathogenicity , Diarrhea/epidemiology , Enteropathogenic Escherichia coli/drug effects , Enteropathogenic Escherichia coli/isolation & purification , Enteropathogenic Escherichia coli/pathogenicity , Humans , Salmonella/drug effects , Salmonella/isolation & purification , Salmonella/pathogenicity , Shigella/drug effects , Shigella/isolation & purification , Shigella/pathogenicity
4.
Cancer Prev Res (Phila) ; 13(9): 747-760, 2020 09.
Article in English | MEDLINE | ID: mdl-32518084

ABSTRACT

Psychological stressors have been implicated in the progression of various tumor types. We investigated a role for stress in tumor immune cell chemotaxis in the B16F10 mouse model of malignant melanoma. We exposed female mice to 6-hour periods of restraint stress (RST) for 7 days, then implanted B16F10 malignant melanoma tumor cells and continued the RST paradigm for 14 additional days. We determined serum corticosterone and liver catecholamine concentrations in these mice. To evaluate the tumor microenvironment, we performed IHC and examined cytokine expression profiles using ELISA-based analysis of tumor homogenates. We found that tumors in mice subjected to RST grew significantly slower, had reduced tumor C-C motif ligand 2 (CCL2), and contained fewer F4/80-positive macrophages than tumors from unstressed mice. We observed a concomitant increase in norepinephrine among the RST mice. An in vitro assay confirmed that norepinephrine downregulates CCL2 production in both mouse and human macrophages, and that pretreatment with the pan-ß-adrenergic receptor inhibitor nadolol rescues this activity. Furthermore, RST had no effect on tumor growth in transgenic CCL2-deficient mice. This study suggests that stress reduces malignant melanoma by reducing recruitment of tumor-promoting macrophages by CCL2.


Subject(s)
Chemokine CCL2/genetics , Melanoma, Experimental/immunology , Norepinephrine/metabolism , Skin Neoplasms/immunology , Stress, Psychological/immunology , Adrenergic beta-Antagonists/pharmacology , Animals , Cell Line, Tumor/transplantation , Down-Regulation/immunology , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/immunology , Humans , Macrophages/immunology , Macrophages/metabolism , Melanoma, Experimental/genetics , Melanoma, Experimental/metabolism , Melanoma, Experimental/pathology , Mice , Mice, Transgenic , Nadolol/pharmacology , Norepinephrine/antagonists & inhibitors , Restraint, Physical , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Stress, Psychological/metabolism , Tumor Microenvironment/drug effects , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
5.
J Matern Fetal Neonatal Med ; 33(5): 707-711, 2020 Mar.
Article in English | MEDLINE | ID: mdl-29996681

ABSTRACT

Objective: To determine if an elevated fetal umbilical artery Doppler pulsatility index is associated with abnormal respiratory function and atopy in children aged 12 years.Methods: This prospective case-control study compared children that had an elevated fetal umbilical artery Doppler pulsatility index (>90th centile) to those with a normal pulsatility index (<90th centile). All subjects were delivered at full-term and with appropriate growth for gestational age. Outcome measures included; (i) presence of asthma and/or atopy; (ii) spirometry measurements and (iii) serum C-reactive protein and leptin. Multiple regression was used to account for parental smoking, childhood age, gender and socioeconomic status.Results: 174 children with an average age of 12.1 (±0.6 SD), 48% of who were male were included in the analysis. Of the 174, 99 (57%) were in the normal umbilical artery Doppler pulsatility index group and 75 (43%) elevated umbilical artery Doppler pulsatility index groups. The overall proportion of subjects with asthma was 28% (48/174) and atopy 56% (98/174). No association was found between elevated fetal umbilical artery Doppler pulsatility index and asthma (p = .47) or atopy (p = .75) at age 12 years. Similarly there was no association between FEV1(%) (p = .96), forced vital capacity (FVC)(%) (p = .98), elevated serum C-reactive protein (p = .69) or leptin (p = .20) and an elevated fetal umbilical artery Doppler pulsatility index.Conclusions: An elevated umbilical artery Doppler at 28-weeks gestation in the absence of prematurity or fetal growth restriction is not associated with altered respiratory function or the presence of atopy in children aged 12 years. These findings support the theory that such disease has a multifactorial pathophysiology.


Subject(s)
Asthma/etiology , C-Reactive Protein/metabolism , Leptin/blood , Pulsatile Flow , Umbilical Arteries/diagnostic imaging , Adolescent , Case-Control Studies , Child , Female , Humans , Male , Prospective Studies , Respiratory Function Tests , Ultrasonography, Doppler , Ultrasonography, Prenatal
6.
PLoS One ; 14(11): e0224309, 2019.
Article in English | MEDLINE | ID: mdl-31693710

ABSTRACT

In recent years, vaccines against tumor antigens have shown potential for combating invasive cancers, including primary tumors and metastatic lesions. This is particularly pertinent for breast cancer, which is the second-leading cause of cancer-related death in women. MUC1 is a glycoprotein that is normally expressed on glandular epithelium, but is overexpressed and under-glycosylated in most human cancers, including the majority of breast cancers. This under-glycosylation exposes the MUC1 protein core on the tumor-associated form of the protein. We have previously shown that a vaccine consisting of MUC1 core peptides stimulates a tumor-specific immune response. However, this immune response is dampened by the immunosuppressive microenvironment within breast tumors. Thus, in the present study, we investigated the effectiveness of MUC1 vaccination in combination with four different drugs that inhibit different components of the COX pathway: indomethacin (COX-1 and COX-2 inhibitor), celecoxib (COX-2 inhibitor), 1-methyl tryptophan (indoleamine 2,3 dioxygenase inhibitor), and AH6809 (prostaglandin E2 receptor antagonist). These treatment regimens were explored for the treatment of orthotopic MUC1-expressing breast tumors in mice transgenic for human MUC1. We found that the combination of vaccine and indomethacin resulted in a significant reduction in tumor burden. Indomethacin did not increase tumor-specific immune responses over vaccine alone, but rather appeared to reduce the proliferation and increase apoptosis of tumor cells, thus rendering them susceptible to immune cell killing.


Subject(s)
Breast Neoplasms/therapy , Cancer Vaccines/administration & dosage , Cyclooxygenase Inhibitors/administration & dosage , Indomethacin/administration & dosage , Mammary Neoplasms, Experimental/therapy , Mucin-1/immunology , Animals , Breast Neoplasms/immunology , Cancer Vaccines/immunology , Combined Modality Therapy/methods , Female , Humans , Immunogenicity, Vaccine/drug effects , Immunogenicity, Vaccine/immunology , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/immunology , Mice , Mice, Transgenic , Mucin-1/genetics , Tumor Burden/drug effects , Tumor Burden/immunology , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/immunology
7.
Glob Heart ; 14(2): 191-194, 2019 06.
Article in English | MEDLINE | ID: mdl-31324374

ABSTRACT

Stakeholder engagement is crucial for turning discovery into health. Although it is a highly effective approach for research in general, it is an essential component in late-stage translation research and implementation science in which the central objective is to accelerate the sustained uptake and integration of proven-effective interventions into routine clinical and public health practice. Where the stakeholder is an entire community, the term community engagement has often been used and has traditionally been defined as "the process of working collaboratively with groups of people who are affiliated by geographic proximity, special interests, or similar situations with respect to issues affecting their well-being." More recently, this definition has been expanded to specifically incorporate pre-study needs assessment, shared decision making about study themes and specific aims, data collection and analysis, interpretation and dissemination of research findings, and plans for scale-up and spread of research findings. In this article, the authors explore the scientific foundations of stakeholder engagement in biomedical research and public health practice. They highlight the strategic vision goals and objectives of the National Heart, Lung, and Blood Institute and the commitment to advance dissemination and implementation research and community-engaged participatory research. The authors conclude with comments on the stakeholder engagement efforts in the National Heart, Lung, and Blood Institute-funded TREIN/Hy-TREC consortium's work published in this issue of Global Heart and their perspectives on the challenges and opportunities as we chart the future together.


Subject(s)
Implementation Science , National Heart, Lung, and Blood Institute (U.S.)/organization & administration , Stakeholder Participation , Translational Research, Biomedical/methods , Humans , United States
9.
Ethn Dis ; 29(Suppl 1): 77-82, 2019.
Article in English | MEDLINE | ID: mdl-30906153

ABSTRACT

Rapid advancements in translational research have produced innovative clinical discoveries and evidence-based interventions that are ready for uptake in real-world settings, creating vast opportunities and challenges for implementation science. However, there is an inadequate research workforce to study effective strategies and delivery of implementation to advance the field. Novel career development initiatives will build scholars for the next generation of implementation science to bridge research to practice for diverse populations to advance health equity, specifically with a strategic focus on heart, lung, blood and sleep diseases and conditions. Along with traditional mentoring and curricula, research training includes state-of-the-art approaches using complex methods and multi-disciplinary collaborations between researchers, practice settings, and diverse communities. Implementation science scholars strive not only to decrease the lag time between the discovery of evidence-based interventions and successful implementation but also how to advance health equity and to reduce disparities for underserved populations that suffer disproportionally.


Subject(s)
Employment , Health Equity , Implementation Science , Curriculum , Humans , Medically Underserved Area , Mentoring , Research Personnel/education , Vulnerable Populations
10.
Mil Med Res ; 6(1): 3, 2019 01 29.
Article in English | MEDLINE | ID: mdl-30691524

ABSTRACT

BACKGROUND: Pharyngeal and anorectal reservoirs of gonorrhea (GC) and chlamydia (CT) are increasingly recognized among heterosexual women. While a number of studies performed at sexually transmitted disease (STD) clinics have found a high prevalence of extragenital GC/CT infection, such screening is typically not offered during routine primary care visits for women. We sought to define the prevalence of and factors associated with extragenital GC/CT among women in the U.S. Navy. METHODS: We recruited servicewomen stationed in San Diego, California, between the ages of 18 and 25 who presented for an annual physical exam between January and September, 2017. Nucleic acid amplification testing was performed on swabs collected at endocervical, oropharyngeal and anorectal sites to assess the presence of GC/CT. An anonymous behavioral questionnaire was also administered to characterize sexual risk. Descriptive statistics were used to compare women with and without a prior history of any sexually transmitted infection (STI) (self-report) along with a current GC/CT diagnosis. This study was approved by the Institutional Review Board of the Uniformed Services University of Health Sciences. RESULTS: Of the 75 patients who were approached, 60 subjects were enrolled in the study, including white 20 (33.3%), black/African American 18 (31.0%), Hispanic/Latina 13 (21.7%) and Asian/Pacific Islander 9 (15.5%) women. Among all the women, six (10.0%) were diagnosed with CT infection, all via endocervical exam. Of these, five (8.3%) had concurrent anorectal infection, including two cases (3.3%) accompanied by pharyngeal infection. Of the subjects, 15 (25.0%) reported anal intercourse in their most recent sexual encounter, most of which was condomless (13/15, 86.7%). A high number of women who reported sex with a casual male partner (19/45, 42.2%) reported rarely or never using condoms; last, 41.7% consuming at least 3 drinks on a typical drinking day, and one-third of the reported drinking more than once per week. CONCLUSIONS: We found a high prevalence of anorectal CT infection, although no infections were detected without concurrent endocervical involvement. Nonetheless, the high prevalence of condomless anal intercourse reported by participants argues for further study and ongoing consideration of extragenital screening among high-risk patients. Behavioral interventions are also warranted given the high prevalence of sexual and related risk factors.


Subject(s)
Chlamydia Infections/transmission , Military Personnel/statistics & numerical data , Adolescent , Adult , California , Chi-Square Distribution , Chlamydia Infections/epidemiology , Chlamydia trachomatis/pathogenicity , Female , Humans , Male , Mass Screening/methods , Nucleic Acid Amplification Techniques/methods , Pharynx/microbiology , Prevalence , Rectum/microbiology , Sexual Behavior/psychology , Surveys and Questionnaires
11.
Transl Oncol ; 9(4): 295-305, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27567952

ABSTRACT

BACKGROUND: Earlier detection of transformed cells using target-specific imaging techniques holds great promise. We have developed TAB 004, a monoclonal antibody highly specific to a protein sequence accessible in the tumor form of MUC1 (tMUC1). We present data assessing both the specificity and sensitivity of TAB 004 in vitro and in genetically engineered mice in vivo. METHODS: Polyoma Middle T Antigen mice were crossed to the human MUC1.Tg mice to generate MMT mice. In MMT mice, mammary gland hyperplasia is observed between 6 and 10 weeks of age that progresses to ductal carcinoma in situ by 12 to 14 weeks and adenocarcinoma by 18 to 24 weeks. Approximately 40% of these mice develop metastasis to the lung and other organs with a tumor evolution that closely mimics human breast cancer progression. Tumor progression was monitored in MMT mice (from ages 8 to 22 weeks) by in vivo imaging following retro-orbital injections of the TAB 004 conjugated to indocyanine green (TAB-ICG). At euthanasia, mammary gland tumors and normal epithelial tissues were collected for further analyses. RESULTS: In vivo imaging following TAB-ICG injection permitted significantly earlier detection of tumors compared with physical examination. Furthermore, TAB-ICG administration in MMT mice enabled the detection of lung metastases while sparing recognition of normal epithelia. CONCLUSIONS: The data highlight the specificity and the sensitivity of the TAB 004 antibody in differentiating normal versus tumor form of MUC1 and its utility as a targeted imaging agent for early detection, tumor monitoring response, as well as potential clinical use for targeted drug delivery.

13.
Mil Med ; 181(6): 524-9, 2016 06.
Article in English | MEDLINE | ID: mdl-27244061

ABSTRACT

Staphylococcal skin and soft tissue infections (SSTIs), especially those due to methicillin-resistant Staphylococcus aureus (MRSA) are an important public health issue for the military. Limited data exist regarding the prevalence of S. aureus colonization in the shipboard setting. We conducted a cross-sectional, observational study to determine the point prevalence of S. aureus colonization among military personnel onboard a naval vessel. Asymptomatic active duty personnel completed a survey for risk factors associated with colonization and SSTIs. Culture specimens were obtained from the anterior nares, pharynx, groin, and perirectal regions. MRSA isolates underwent testing for antimicrobial resistance, virulence factors, and pulsed-field type. 400 individuals were enrolled, 198 (49.5%) of whom were colonized with S. aureus, with MRSA identified in 14 participants (3.5%). No significant risk factors were associated with MRSA colonization. USA800 was the most common colonizing MRSA strain in the cohort and was detected in 10 participants (71%). Two participants (14%) were colonized with USA300 MRSA. In this first report of S. aureus epidemiology in a shipboard setting, we observed high rates of S. aureus and MRSA colonization. Longitudinal studies are needed to document the incident rates of S. aureus colonization during shipboard deployment and its impact on SSTI risk.


Subject(s)
Military Personnel/statistics & numerical data , Prevalence , Staphylococcal Infections/epidemiology , Adult , Cross-Sectional Studies , Female , Hair Removal/adverse effects , Humans , Male , Methicillin-Resistant Staphylococcus aureus/pathogenicity , Risk Factors , Ships , Soft Tissue Infections/epidemiology , Soft Tissue Infections/etiology , Staphylococcal Infections/etiology , Staphylococcus aureus/pathogenicity , Surveys and Questionnaires , United States/epidemiology , Workforce
14.
Front Immunol ; 5: 67, 2014.
Article in English | MEDLINE | ID: mdl-24605110

ABSTRACT

Mucin 1 (MUC1) is a transmembrane mucin glycoprotein that is over-expressed and aberrantly glycosylated in >80% of human pancreatic ductal adenocarcinoma (PDA) and is associated with poor prognosis. To understand the role of MUC1 in PDA, we have recently developed two mouse models of spontaneous PDA, one that expresses full-length human MUC1 transgene (KCM mice) and one that is null for MUC1 (KCKO mice). We have previously reported that KCM mice express high levels of myeloid derived suppressor cells (MDSCs) in their tumors and develop highly aggressive PDA. To further understand the underlying mechanism for high MDSC levels in KCM-tumors, we generated primary cell lines from KCM and KCKO-tumors. In this study, we report that MDSCs derived using KCM cells express significantly higher levels of arginase 1 and inducible nitric oxide synthase (markers associated with immune suppression) and lower levels of CD115 (a marker associated with maturation of myeloid cells) as compared to KCKO-derived MDSCs. Functionally, KCM-derived MDSCs secrete significantly higher levels of urea and nitric oxide (NO) when co-cultured with normal splenic cells as compared to KCKO-derived MDSCs. Data indicates that KCM-derived MDSCs remain immature and are more suppressive as compared to KCKO-derived MDSCs. This was further corroborated in vivo where MDSCs isolated from KCM-tumor-bearing mice retained their immature state and were highly suppressive as compared to MDSCs derived from KCKO-tumor-bearing mice. Finally, we show that KCM cells secrete significantly higher levels of prostaglandin E2 (PGE2), a COX-2 metabolite and a known driver of suppressive MDSCs as compared to KCKO cells. Thus, inhibiting PGE2 with a specific COX-2 inhibitor reverses the immunosuppressive and immature phenotype of KCM-derived MDSCs. This is the first report that clearly suggests a functional role of pancreatic tumor-associated MUC1 in the development of functional MDSCs.

15.
J Virol ; 87(18): 10283-94, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23864625

ABSTRACT

Vesicular stomatitis virus (VSV) is a promising oncolytic agent against various malignancies. Here, for the first time, we tested VSV in vitro and in vivo in a clinically relevant, immunocompetent mouse model of pancreatic ductal adenocarcinoma (PDA). Our system allows the study of virotherapy against PDA in the context of overexpression (80% of PDA patients) or no expression of human mucin 1 (MUC1), a major marker for poor prognosis in patients. In vitro, we tested three VSV recombinants, wild-type VSV, VSV-green fluorescent protein (VSV-GFP), and a safe oncolytic VSV-ΔM51-GFP, against five mouse PDA cell lines that either expressed human MUC1 or were MUC1 null. All viruses demonstrated significant oncolytic abilities independent of MUC1 expression, although VSV-ΔM51-GFP was somewhat less effective in two PDA cell lines. In vivo administration of VSV-ΔM51-GFP resulted in significant reduction of tumor growth for tested mouse PDA xenografts (+MUC1 or MUC1 null), and antitumor efficacy was further improved when the virus was combined with the chemotherapeutic drug gemcitabine. The antitumor effect was transient in all tested groups. The developed system can be used to study therapies involving various oncolytic viruses and chemotherapeutics, with the goal of inducing tumor-specific immunity while preventing premature virus clearance.


Subject(s)
Adenocarcinoma/therapy , Biological Therapy/methods , Carcinoma, Pancreatic Ductal/therapy , Mucin-1/biosynthesis , Oncolytic Viruses/growth & development , Vesiculovirus/growth & development , Adenocarcinoma/pathology , Animals , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Disease Models, Animal , Humans , Male , Mice , Treatment Outcome
16.
Breast Cancer Res ; 15(2): R32, 2013 Apr 11.
Article in English | MEDLINE | ID: mdl-23577751

ABSTRACT

INTRODUCTION: Breast cancer remains the second leading cause of cancer-related deaths for women in the United States. Metastasis is regulated not only by intrinsic genetic changes in malignant cells, but also by the microenvironment, especially those associated with chronic inflammation. We recently reported that mice with autoimmune arthritis have significantly increased incidence of bone and lung metastasis and decreased survival associated with breast cancer. In this study, we evaluated the mechanism underlying the increased metastasis. METHODS: We used two mouse models; one that develops spontaneous autoimmune arthritis (SKG mice) injected with metastatic breast cancer cells (4T1), and another that develops spontaneous breast cancer (MMTV-PyV MT mice) injected with type II collagen to induce autoimmune arthritis. Mast cell levels and metastasis were monitored. RESULTS: First, we confirmed that breast tumor-bearing arthritic mice have a significantly higher incidence of bone and lung metastasis than do their nonarthritic counterparts. Next, we showed increased recruitment of mast cells within the primary tumor of arthritic mice, which facilitates metastasis. Next, we report that arthritic mice without any tumors have higher numbers of mast cells in the bones and lungs, which may be the underlying cause for the enhanced lung and bone metastases observed in the arthritic mice. Next, we showed that once the tumor cells populate the metastatic niches (bones and lungs), they further increase the mast cell population within the niche and assist in enhancing metastasis. This may primarily be due to the interaction of c-Kit receptor present on mast cells and stem cell factor (SCF, the ligand for ckit) expressed on tumor cells. Finally, we showed that targeting the SCF/cKit interaction with an anti-ckit antibody reduces the differentiation of mast cells and consequently reduces metastasis. CONCLUSION: This is the first report to show that mast cells may play a critical role in remodeling not only the tumor microenvironment but also the metastatic niche to facilitate efficient metastasis through SCF/cKit interaction in breast cancer with arthritis.


Subject(s)
Arthritis, Experimental/physiopathology , Bone Neoplasms/secondary , Breast Neoplasms/pathology , Lung Neoplasms/secondary , Mast Cells/pathology , Proto-Oncogene Proteins c-kit/metabolism , Stem Cell Factor/metabolism , Animals , Apoptosis , Arthritis, Experimental/complications , Blotting, Western , Bone Neoplasms/etiology , Bone Neoplasms/metabolism , Breast Neoplasms/etiology , Breast Neoplasms/metabolism , Cell Movement , Cell Proliferation , Female , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunoenzyme Techniques , Lung Neoplasms/etiology , Lung Neoplasms/metabolism , Mast Cells/metabolism , Mice , Mice, Inbred BALB C , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Tumor Cells, Cultured , Tumor Microenvironment
17.
J Surg Oncol ; 107(7): 713-22, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23335066

ABSTRACT

BACKGROUND AND OBJECTIVES: MUC1 is over-expressed and aberrantly glycosylated in >60% of human pancreatic cancer (PC). Development of novel approaches for detection and/or targeting of MUC1 are critically needed and should be able to detect MUC1 on PC cells (including cancer stem cells) and in serum. METHODS: The sensitivity and specificity of the anti-MUC1 antibody, TAB 004, was determined. CSCs were assessed for MUC1 expression using TAB 004-FITC on in vitro PC cell lines, and on lineage(-) cells from in vivo tumors and human samples. Serum was assessed for shed MUC1 via the TAB 004 EIA. RESULTS: In vitro and in vivo, TAB 004 detected MUC1 on >95% of CSCs. Approximately, 80% of CSCs in patients displayed MUC1 expression as detected by TAB 004. Shed MUC1 was detected serum in mice with HPAF-II (MUC1(high) ) but not BxPC3 tumors (MUC1(low)). The TAB 004 EIA was able to accurately detect stage progression in PC patients. CONCLUSIONS: The TAB 004 antibody may be explored as a therapeutic targeting agent for CSCs in PC. The TAB 004 EIA detected circulating MUC1 in a stage-dependent manner in patients with PC and thus may be explored as a PC stage diagnostic biomarker.


Subject(s)
Adenocarcinoma/metabolism , Mucin-1/immunology , Mucin-1/isolation & purification , Neoplastic Stem Cells/immunology , Pancreatic Neoplasms/metabolism , AC133 Antigen , Adenocarcinoma/immunology , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Animals , Antibodies, Monoclonal/pharmacology , Antigens, CD/immunology , Blotting, Western , Enzyme-Linked Immunosorbent Assay , Female , Fluorescent Antibody Technique , Gene Expression Regulation, Neoplastic , Glycoproteins/immunology , Glycosylation , Humans , Immunoenzyme Techniques , Immunohistochemistry , Male , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, Nude , Mice, Transgenic , Middle Aged , Neoplasm Staging , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Peptides/immunology , Sensitivity and Specificity , Up-Regulation
18.
J Exp Biol ; 215(Pt 22): 3997-4005, 2012 Nov 15.
Article in English | MEDLINE | ID: mdl-22899533

ABSTRACT

Some wild antelopes are fast sprinters and more resistant to fatigue than others. This study therefore investigated two wild antelope species to better understand their reported performance capability. Muscle samples collected post mortem from the vastus lateralis and longissimus lumborum of fallow deer (Dama dama) and springbok (Antidorcas marsupialis) were analysed for myosin heavy chain isoform content, citrate synthase, 3-hydroxyacyl CoA dehydrogenase, phosphofructokinase, lactate dehydrogenase and creatine kinase activities. Cross-sectional areas, fibre type and oxidative capacities of each fibre type were determined in the vastus lateralis only. The predominant fibre type in both muscle groups and species were type IIX (>50%), with springbok having more type IIX fibres than fallow deer (P<0.05). Overall cross-sectional area was not different between the two species. The metabolic pathway analyses showed high glycolytic and oxidative capacities for both species, but springbok had significantly higher CS activities than fallow deer. Large variation and overlap in oxidative capacities existed within and between the fibre types. Some type IIX fibres presented with oxidative capacities similar to those from type I and IIA fibres. The data suggest that springbok and fallow deer are able sprint at >90 and 46 km h(-1), respectively, partly from having large type IIX fibre contents and high glycolytic capacities. The high oxidative capacities also suggest that these animals may be able to withstand fatigue for long periods of time.


Subject(s)
Antelopes/metabolism , Deer/metabolism , Muscle Fatigue/physiology , Muscle Fibers, Skeletal/metabolism , Running/physiology , Animals , Female , Humans , Male , Muscle Fibers, Skeletal/cytology , Muscle Fibers, Skeletal/enzymology , Myosin Heavy Chains/metabolism , NAD/metabolism , Oxidation-Reduction , Protein Isoforms/metabolism , Staining and Labeling , Time Factors
19.
Emerg Infect Dis ; 18(3): 502-6, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22377220

ABSTRACT

To determine whether hepatitis E virus (HEV) is a cause of hepatitis among HIV-infected persons, we evaluated 1985-2009 data for US military beneficiaries. Evidence of acute or prior HEV infection was detected for 7 (4%) and 5 (3%) of 194 HIV-infected persons, respectively. HEV might be a cause of acute hepatitis among HIV-infected persons.


Subject(s)
Coinfection/epidemiology , HIV Infections/complications , Hepatitis E/complications , Hepatitis E/epidemiology , Adult , CD4 Lymphocyte Count , Female , HIV Infections/diagnosis , Hepatitis E/diagnosis , Humans , Male , Retrospective Studies , Seroepidemiologic Studies , Viral Load
20.
J Exp Biol ; 214(Pt 23): 4041-7, 2011 Dec 01.
Article in English | MEDLINE | ID: mdl-22071196

ABSTRACT

The aim of the study was to investigate the skeletal muscle characteristics of black wildebeest (Connochaetes gnou) in terms of fibre type and metabolism. Samples were obtained post mortem from the vastus lateralis and longissimus lumborum muscles and analysed for myosin heavy chain (MHC) content. Citrate synthase (CS), 3-hydroxyacyl co A dehydrogenase (3HAD), phosphofructokinase (PFK), lactate dehydrogenase (LDH) and creatine kinase (CK) activities were measured spectrophotometrically to represent the major metabolic pathways in these muscles. Both muscles had less than 20% MHC I, whereas MHC IIa and MHC IIx were expressed in excess of 50% in the vastus lateralis and longissimus lumborum muscles, respectively. Overall fibre size was 2675±1034 µm(2), which is small compared with other species. Oxidative capacity (CS and 3HAD) in both muscles was high and did not differ from one another, but the longissimus lumborum had significantly (P<0.05) higher PFK, LDH and CK activities. No relationships were observed between fibre type and the oxidative and oxygen-independent metabolic capacity as measured by specific enzyme activities. This study confirms the presence of both fast-twitch fibres and high oxidative capacity in black wildebeest, indicating an animal that can run very fast but is also fatigue resistant.


Subject(s)
Artiodactyla/metabolism , Muscle Fibers, Skeletal/metabolism , Animals , Female , Humans , Immunohistochemistry , Male , Muscle Fibers, Skeletal/cytology , Muscle Fibers, Skeletal/enzymology , Myosin Heavy Chains/metabolism , Oxidation-Reduction , Protein Isoforms/metabolism
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