Mepolizumab as a Potential Protective Factor of COVID-19 Mortality: A Case Report of Chronic Bronchitis and Asthma in an Elderly Patient.

BACKGROUND Patients with multiple comorbidities who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have a higher risk of mortality. However, treatment with mepolizumab may be a key factor in counteracting the risk of these comorbidities. We present a patient who had an uneventful recovery from coronavirus disease 2019 (COVID-19), despite having 5 independent risk factors for severe disease and increased mortality. CASE REPORT A 75-year-old man with a long-standing history of asthma, chronic bronchitis, coronary artery disease, and hypertension presented to the Emergency Department in November 2020 with a 4-day history of fever, chills, shortness of breath, cough, and fatigue. Six months prior to this presentation, the patient was hospitalized for severe chronic bronchitis and acute exacerbation of asthma. His medications included mepolizumab, aclidinium, ramipril, diltiazem, aspirin, albuterol sulfate, and micronized budesonide/micronized formoterol fumarate dihydrate. Physical examination was unremarkable, except for cardiopulmonary distress. Laboratory tests showed leucocytosis. His chest X-ray revealed infiltrates and interstitial edema in the lower lung fields. A PCR test for SARS-CoV-2 was positive. COVID-19 pneumonia was diagnosed, and the patient was admitted to the hospital, where he was treated with acetaminophen, amoxicillin, dexamethasone, and supplemental oxygen. The patient remained stable and was discharged from the hospital the following day. He was free of all symptoms after 21 days. CONCLUSIONS This case of a 75-year-old man who presented with mild COVID-19 supports the findings from other reports of improvement in clinical outcomes for some patients with asthma who received treatment with mepolizumab.

Endometriosis and COVID-19: A Systematic Review and Meta-Analysis.

Endometriosis is defined as ectopic endometrial tissues dispersed outside the endometrium. This can cause disruption in hormonal and immunological processes, which may increase susceptibility to SARS-CoV-2 infection. Worsening of endometriosis symptoms may occur as a result of this infection. The aim of our review was to estimate the pooled prevalence of SARS-CoV-2 infection and the health impacts of the COVID-19 pandemic in endometriosis patients. We conducted a systematic review and meta-analysis. MEDLINE, Science Direct, Scopus, and Google Scholar databases were searched, using the keywords: (endometriosis) AND (COVID-19 OR SARS-CoV-2). Forest plots and pooled estimates were created using the Open Meta Analyst software. After screening 474 articles, 19 studies met the eligibility criteria for the systematic review, and 15 studies were included in the meta-analyses. A total of 17,799 patients were analyzed. The pooled prevalence of SARS-CoV-2 infection in endometriosis patients was 7.5%. Pooled estimates for the health impacts were 47.2% for decreased access to medical care, 49.3% increase in dysmenorrhea, 75% increase in anxiety, 59.4% increase in depression, and 68.9% increase in fatigue. Endometriosis patients were undeniably impacted by the COVID-19 pandemic, which caused the worsening of symptoms such as dysmenorrhea, pelvic pain, anxiety, depression, and fatigue.

Association between the prevalence of obstructive lung disease and the use of aspirin in a diabetic population.

Background: Many diabetic patients take a daily low-dose of aspirin because they are two to three times more likely to suffer from heart attacks and strokes, but its role in obstructive lung diseases is less clear. Methods: A total of 1,003 subjects in community practice settings were interviewed at home. Patients self-reported their personal and clinical characteristics, including any history of obstructive lung disease (including COPD or asthma). Current medications were obtained by the direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess for a possible association between obstructive lung disease history and the use of aspirin. Results: In a multivariate logistic regression model, a history of obstructive lung disease was significantly associated with the use of aspirin even after correcting for potential confounders, including gender, low income (

The Kidney-Associated Microbiome of Wild-Caught Artibeus spp. in Grenada, West Indies.

Bats are capable of asymptomatically carrying a diverse number of microorganisms, including human pathogens, due to their unique immune system. Because of the close contact between bats and humans, there is a possibility for interspecies transmission and consequential disease outbreaks. Herein, high-throughput sequencing was used to determine the kidney-associated microbiome of a bat species abundant in Grenada, West Indies, Artibeus spp. Results indicate that the kidney of these bats can carry potential human pathogens. An endogenous retrovirus, Desmodus rotundus endogenous retrovirus isolate 824, phylogenetically related to betaretroviruses from rodents and New World primates, was also identified.

Association between prevalence of obstructive lung disease and obesity: results from The Vermont Diabetes Information System.

BACKGROUND: The association of obesity with the development of obstructive lung disease, namely asthma and/or chronic obstructive pulmonary disease, has been found to be significant in general population studies, and weight loss in the obese has proven beneficial in disease control. Obese patients seem to present with a specific obstructive lung disease phenotype including a reduced response to corticosteroids. Obesity is increasingly recognized as an important factor to document in obstructive lung disease patients and a critical comorbidity to report in diabetic patients, as it may influence disease management. This report presents data that contributes to establishing the relationship between obstructive lung disease in a diabetic cohort, a population highly susceptible to obesity. METHODS: A total of 1003 subjects in community practice settings were interviewed at home at the time of enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any history of obstructive lung disease. Laboratory data were obtained directly from the clinical laboratory, and current medications were obtained by direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between obstructive lung disease history and obesity. RESULTS: In a multivariate logistic regression model, a history of obstructive lung disease was significantly associated with obesity (body mass index ≥30) even after correcting for potential confounders including gender, low income (<$30,000/year), number of comorbidities, number of prescription medications, cigarette smoking, and alcohol problems (adjusted odds ratio (OR) = 1.58, P = 0.03, 95% confidence interval (CI) = 1.05, 2.37). This association was particularly strong and significant among female patients (OR = 2.18, P = < 0.01, CI = 1.27, 3.72) but not in male patients (OR = 0.97, P = 0.93, CI = 0.51, 1.83). CONCLUSION: These data suggest an association between obesity and obstructive lung disease prevalence in patients with diabetes, with women exhibiting a stronger association. Future studies are needed to identify the mechanism by which women disproportionately develop obstructive lung disease in this population.

Potential enhanced association between obstructive lung disease and history of depression in patients with diabetes.

BACKGROUND: Depression is one of the most common comorbidities of chronic diseases including diabetes and obstructive lung diseases (emphysema, chronic bronchitis, and asthma). Obstructive lung diseases and depression have few symptoms in common. However, they are both common in adults and associated with chronic inflammation. It is not clear if their coappearance in diabetic patients is coincidental or associated beyond that expected by chance. METHODS: A total of 1,003 adults with diabetes in community practice settings were interviewed at home at the time of their enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any obstructive lung disease. Laboratory data were obtained directly from the clinical laboratory, and current medications were obtained by direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between the prevalence of obstructive lung disease and depression. RESULTS: In a multivariate logistic regression model, obstructive lung disease was significantly associated with depression even after correcting for gender, obesity (≥30 kg/m2), high comorbidities (>2), low annual income (<$30,000/ year), cigarette smoking, alcohol problems, and education level (odds ratio=1.83; 95% confidence interval 1.27, 2.62; P <0.01). CONCLUSION: These data suggest a potential enhanced association between obstructive lung disease and depression in patients with diabetes. Future studies are needed to identify if inflammation is implicated in this association as a common denominator.

Metagenomic analysis of Aedes aegypti and Culex quinquefasciatus mosquitoes from Grenada, West Indies.

The mosquitoes Aedes aegypti (Linnaeus, 1762) (Diptera: Culicidae) and Culex quinquefasciatus Say, 1823 (Diptera: Culicidae) are two major vectors of arthropod-borne pathogens in Grenada, West Indies. As conventional vector control methods present many challenges, alternatives are urgently needed. Manipulation of mosquito microbiota is emerging as a field for the development of vector control strategies. Critical to this vector control approach is knowledge of the microbiota of these mosquitoes and finding candidate microorganisms that are common to the vectors with properties that could be used in microbiota modification studies. Results showed that bacteria genera including Asaia, Escherichia, Pantoea, Pseudomonas, and Serratia are common to both major arboviral vectors in Grenada and have previously been shown to be good candidates for transgenetic studies. Also, for the first time, the presence of Grenada mosquito rhabdovirus 1 is reported in C. quinquefasciatus.

High prevalence of Phasi Charoen-like virus from wild-caught Aedes aegypti in Grenada, W.I. as revealed by metagenomic analysis.

Arboviruses cause diseases of significant global health concerns. Interactions between mosquitoes and their microbiota as well as the important role of this interaction in the mosquito's capacity to harbor and transmit pathogens have emerged as important fields of research. Aedes aegypti is one of the most abundant mosquitoes in many geographic locations, a vector capable of transmitting a number of arboviruses such as dengue and Zika. Currently, there are few studies on the metavirome of this mosquito particularly in the Americas. This study analyzes the metavirome of A. aegypti from Grenada, a Caribbean nation with tropical weather, abundant A. aegypti, and both endemic and arboviral pathogens transmitted by this mosquito. Between January and December 2018, 1152 mosquitoes were collected from six semi-rural locations near houses in St. George Parish, Grenada, by weekly trapping using BG-Sentinel traps. From these, 300 A. aegypti were selected for analysis. The metavirome was analyzed using the Illumina HiSeq 1500 for deep sequencing. The generation sequencing library construction protocol used was NuGEN Universal RNA with an average read length of 125 bp. Reads were mapped to the A. aegypti assembly. Non-mosquito reads were analyzed using the tools FastViromeExplorer. The NCBI total virus, RNA virus, and eukaryotic virus databases were used as references. The metagenomic comparison analysis showed that the most abundant virus-related reads among all databases and assemblies was Phasi Charoen-like virus. The Phasi Charoen-like virus results are in agreement to other studies in America, Asia and Australia. Further studies using wild-caught mosquitoes is needed to assess the impact of this insect-specific virus on the A. aegypti lifecycle and vector capacity.

PCR-Based Bloodmeal Analysis of Aedes aegypti and Culex quinquefasciatus (Diptera: Culicidae) in St. George Parish, Grenada.

Blood-feeding patterns of mosquitoes affect the transmission and maintenance of arboviral diseases. In the Caribbean, Aedes aegypti (L.) and Culex quinquefasciatus Say mosquitoes are the dominant mosquito species in developed areas. However, no information is available on the bloodmeal hosts of these invasive vectors in Grenada, where arboviral pathogens such as dengue, chikungunya, and Zika viruses cause significant human suffering. To this end, Ae. aegypti and Cx. quinquefasciatus mosquitoes were investigated from five semirural locations near houses in St. George's Parish, from 2017 to 2018. Polymerase chain reaction was conducted on DNA extracted from individual blood-fed mosquitoes using vertebrate-specific cytochrome b primers. The 32 Ae. aegypti bloodmeals included humans (70%), mongooses (18%), domestic dogs (6%), a domestic cat (3%), and an unidentified bird (3%). Thirty-seven Cx. quinquefasciatus mosquitoes took bloodmeals from seven species of birds (51%), humans (27%), domestic cats (8%), iguanas (5%), a domestic dog (3%), a rat (3%), and a common opossum (3%). The high percentage of human bloodmeal hosts in our study, especially by the normally anthropophilic Ae. aegypti, is expected. The bloodmeal sources and the percentage of nonhuman bloodmeals (30%) taken by Ae. aegypti are comparable to other studies. The large range of hosts may be explained in part by the semirural nature of most local housing. Accordingly, this may contribute to an exchange of pathogens between domestic, peridomestic, and sylvatic transmission cycles.

The role of chronic inflammation in obesity-associated cancers.

There is a strong relationship between metabolism and immunity, which can become deleterious under conditions of metabolic stress. Obesity, considered a chronic inflammatory disease, is one example of this link. Chronic inflammation is increasingly being recognized as an etiology in several cancers, particularly those of epithelial origin, and therefore a potential link between obesity and cancer. In this review, the connection between the different factors that can lead to the chronic inflammatory state in the obese individual, as well as their effect in tumorigenesis, is addressed. Furthermore, the association between obesity, inflammation, and esophageal, liver, colon, postmenopausal breast, and endometrial cancers is discussed.

Osteopontin modulates inflammation, mucin production, and gene expression signatures after inhalation of asbestos in a murine model of fibrosis.

Inflammation and lung remodeling are hallmarks of asbestos-induced fibrosis, but the molecular mechanisms that control these events are unclear. Using laser capture microdissection (LCM) of distal bronchioles in a murine asbestos inhalation model, we show that osteopontin (OPN) is up-regulated by bronchiolar epithelial cells after chrysotile asbestos exposures. In contrast to OPN wild-type mice (OPN(+/+)) inhaling asbestos, OPN null mice (OPN(-/-)) exposed to asbestos showed less eosinophilia in bronchoalveolar lavage fluids, diminished lung inflammation, and decreased mucin production. Bronchoalveolar lavage fluid concentrations of inflammatory cytokines (IL-1ß, IL-4, IL-6, IL-12 subunit p40, MIP1α, MIP1ß, and eotaxin) also were significantly less in asbestos-exposed OPN(-/-) mice. Microarrays performed on lung tissues from asbestos-exposed OPN(+/+) and OPN(-/-) mice showed that OPN modulated the expression of a number of genes (Col1a2, Timp1, Tnc, Eln, and Col3a1) linked to fibrosis via initiation and cross talk between IL-1ß and epidermal growth factor receptor-related signaling pathways. Novel targets of OPN identified include genes involved in cell signaling, immune system/defense, extracellular matrix remodeling, and cell cycle regulation. Although it is unclear whether the present findings are specific to chrysotile asbestos or would be observed after inhalation of other fibers in general, these results highlight new potential mechanisms and therapeutic targets for asbestosis and other diseases (asthma, smoking-related interstitial lung diseases) linked to OPN overexpression.

Increased efficacy of doxorubicin delivered in multifunctional microparticles for mesothelioma therapy.

New and effective treatment strategies are desperately needed for malignant mesothelioma (MM), an aggressive cancer with a poor prognosis. We have shown previously that acid-prepared mesoporous microspheres (APMS) are nontoxic after intrapleural or intraperitoneal (IP) administration to rodents. The purpose here was to evaluate the utility of APMS in delivering chemotherapeutic drugs to human MM cells in vitro and in two mouse xenograft models of MM. Uptake and release of doxorubicin (DOX) alone or loaded in APMS (APMS-DOX) were evaluated in MM cells. MM cell death and gene expression linked to DNA damage/repair were also measured in vitro. In two severe combined immunodeficient mouse xenograft models, mice received saline, APMS, DOX or APMS-DOX injected directly into subcutaneous (SC) MM tumors or injected IP after development of human MMs peritoneally. Other mice received DOX intravenously (IV) via tail vein injections. In comparison to DOX alone, APMS-DOX enhanced intracellular uptake of DOX, MM death and expression of GADD34 and TP73. In the SC MM model, 3× weekly SC injections of APMS-DOX or DOX alone significantly inhibited tumor volumes, and systemic DOX administration was lethal. In mice developing IP MMs, significant (p < 0.05) inhibition of mesenteric tumor numbers, weight and volume was achieved using IP administration of APMS-DOX at one-third the DOX concentration required after IP injections of DOX alone. These results suggest APMS are efficacious for the localized delivery of lower effective DOX concentrations in MM and represent a novel means of treating intracavitary tumors.

An association between anti-platelet drug use and reduced cancer prevalence in diabetic patients: results from the Vermont Diabetes Information System Study.

BACKGROUND: Diabetes is associated with an increased risk of several malignancies. Both diabetic patients and patients with cancer have an increase in platelet reactivity and platelet activation has recently emerged as a potential mediator of cancer progression. Drug therapies, such as aspirin, that reduce platelet reactivity reduce both cardiovascular and cancer risk. METHODS: We performed a cross-sectional analysis to assess the association between history of cancer and current anti-platelet drug use in a primary care population of adults with diabetes enrolled in the Vermont Diabetes Information System. RESULTS: Self-reported characteristics, medical history, and a complete medication list were recorded on 1007 diabetic adults. Fifty percent of diabetic patients used an anti-platelet drug. In unadjusted analysis, no association was seen between anti-platelet drug use and cancer history (OR = 0.93; P = .70). Platelet inhibitor use was associated with a decreased patient-reported history of malignancy in a multivariate logistic regression adjusted for age, sex, body mass index, comorbidity, and number of medications (OR = 0.66; CI 0.44-0.99; P = .045). Similar odds of association were seen in both males and females, and for aspirin and non-aspirin platelet inhibitor therapy. CONCLUSIONS: Our data suggest an association between anti-platelet drug use and reduced cancer prevalence in patients with diabetes. Given the potentially large implications of our observations in the diabetic population, further studies are required to determine if this association is causal.

Alterations in gene expression in human mesothelial cells correlate with mineral pathogenicity.

Human mesothelial cells (LP9/TERT-1) were exposed to low and high (15 and 75 microm(2)/cm(2) dish) equal surface area concentrations of crocidolite asbestos, nonfibrous talc, fine titanium dioxide (TiO2), or glass beads for 8 or 24 hours. RNA was then isolated for Affymetrix microarrays, GeneSifter analysis and QRT-PCR. Gene changes by asbestos were concentration- and time-dependent. At low nontoxic concentrations, asbestos caused significant changes in mRNA expression of 29 genes at 8 hours and of 205 genes at 24 hours, whereas changes in mRNA levels of 236 genes occurred in cells exposed to high concentrations of asbestos for 8 hours. Human primary pleural mesothelial cells also showed the same patterns of increased gene expression by asbestos. Nonfibrous talc at low concentrations in LP9/TERT-1 mesothelial cells caused increased expression of 1 gene Activating Transcription Factor 3 (ATF3) at 8 hours and no changes at 24 hours, whereas expression levels of 30 genes were elevated at 8 hours at high talc concentrations. Fine TiO2 or glass beads caused no changes in gene expression. In human ovarian epithelial (IOSE) cells, asbestos at high concentrations elevated expression of two genes (NR4A2, MIP2) at 8 hours and 16 genes at 24 hours that were distinct from those elevated in mesothelial cells. Since ATF3 was the most highly expressed gene by asbestos, its functional importance in cytokine production by LP9/TERT-1 cells was assessed using siRNA approaches. Results reveal that ATF3 modulates production of inflammatory cytokines (IL-1 beta, IL-13, G-CSF) and growth factors (VEGF and PDGF-BB) in human mesothelial cells.

Association of angiotensin-converting enzyme inhibitor therapy and comorbidity in diabetes: results from the Vermont diabetes information system.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACE inhibitors) reduce peripheral vascular resistance via blockage of angiotensin converting enzyme (ACE). ACE inhibitors are commonly used to treat congestive heart failure and high blood pressure, but other effects have been reported. In this study, we explored the association between ACE inhibitor therapy and the prevalence of comorbid conditions in adults with diabetes METHODS: We surveyed 1003 adults with diabetes randomly selected from community practices. Patients were interviewed at home and self-reported their personal and clinical characteristics including comorbidity. Current medications were obtained by direct observation of medication containers. We built logistic regression models with the history of comorbidities as the outcome variable and the current use of ACE inhibitors as the primary predictor variable. We adjusted for possible confounding by social (age, sex, alcohol drinking, cigarette smoking) and clinical factors (systolic blood pressure, body mass index (BMI), glycosolated hemoglobin (A1C), number of comorbid conditions, and number of prescription medications). RESULTS: ACE users reported a history of any cancer (except the non-life-threatening skin cancers) less frequently than non-users (10% vs. 15%; odd ratio = 0.59; 95% confidence interval [0.39, 0.89]; P = 0.01); and a history of stomach ulcers or peptic ulcer disease less frequently than non-users (12% vs. 16%, odd ratio = 0.70, [0.49, 1.01], P = 0.06). After correcting for potential confounders, ACE inhibitors remained significantly inversely associated with a personal history of cancer (odds ratio = 0.59, [0.39, 0.89]; P = 0.01) and peptic ulcer disease (odd ratio = 0.68, [0.46, 1.00], P = 0.05). CONCLUSION: ACE inhibitor use is associated with a lower likelihood of a history of cancer and peptic ulcers in patients with diabetes. These findings are limited by the cross sectional study design, self-report of comorbid diagnoses, and lack of information on the timing and duration of ACE inhibitor use. Further research is needed to confirm these associations and understand their mechanisms.

A novel combination: ranpirnase and rosiglitazone induce a synergistic apoptotic effect by down-regulating Fra-1 and Survivin in cancer cells.

Accumulating evidence supports the idea that two known phosphatidylinositol 3'-kinase (PI3K) downstream proteins, Fra-1 and Survivin, are potential targets for cancer therapy. Increased expression of Fra-1, a Fos family member of the transcription factor activator protein-1, has been implicated in both the maintenance and the progression of the transformed state of several cancer cells. In addition, high Survivin expression in tumors correlates with more aggressive behavior, lower response to chemotherapeutic drugs, and shortened survival time. Previously, we reported that, in malignant mesothelioma cells with increased PI3K activity, small-molecule inhibitors of the PI3K/AKT pathway acted cooperatively with the amphibian RNase chemotherapeutic drug ranpirnase to inhibit cell growth. Because the thiazolidinedione antidiabetic drug rosiglitazone targets the PI3K/AKT pathway, we investigated the effect of the combination of these two drugs in cell survival in several cancer cell lines. We show here that the combination of ranpirnase and rosiglitazone synergistically decreases cell viability and increases cell apoptosis in several cancer cell lines. Cell killing is associated with decreased Fra-1 and Survivin expression and knockdown of Fra-1 increases cell killing by ranpirnase in a dose-dependent manner but not by rosiglitazone. The drug combination does not have a synergistic effect on killing in Fra-1 knockdown cells, showing that Fra-1 modulation accounts in part for the synergism. The novel drug combination of ranpirnase and rosiglitazone is a promising combination to treat cancers with increased PI3K-dependent Fra-1 expression or Survivin.

HGF mediates cell proliferation of human mesothelioma cells through a PI3K/MEK5/Fra-1 pathway.

The ligand hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase, c-Met, are highly expressed in most human malignant mesotheliomas (MMs) and may contribute to their increased growth and viability. Based upon our observation that RNA silencing of fos-related antigen 1 (Fra-1) inhibited c-met expression in rat mesotheliomas (1), we hypothesized that Fra-1 was a key player in HGF-induced proliferation in human MMs. In three of seven human MM lines evaluated, HGF increased Fra-1 levels and phosphorylation of both extracellular signal-regulated kinase 5 (ERK5) and AKT that were inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY290042. HGF-dependent phosphorylation and Fra-1 expression were decreased after knockdown of Fra-1, whereas overexpression of Fra-1 blocked the expression of mitogen/extracellular signal-regulated kinase kinases (MEK)5 at the mRNA and protein levels. Stable MM cell lines using a dnMEK5 showed that basal Fra-1 levels were increased in comparison to empty vector control lines. HGF also caused increased MM cell viability and proliferating cell nuclear antigen (PCNA) expression that were abolished by knockdown of MEK5 or Fra-1. Data suggest that HGF-induced effects in some MM cells are mediated via activation of a novel PI3K/ERK5/Fra-1 feedback pathway that might explain tumor-specific effects of c-Met inhibitors on MM and other tumors.

Fra-1 governs cell migration via modulation of CD44 expression in human mesotheliomas.

Silencing of Fra-1, a component of the dimeric transcription factor, activator protein-1 (AP-1), inhibits mRNA expression of c-met and cd44 in rat mesothelioma cells and is causally linked to maintenance of the transformed phenotype. However, the mechanisms of Fra-1 regulation and Fra-1 regulated gene expression in human malignant mesothelioma (MM) are unclear. We first show in a panel of human MM cells that Fra-1 mRNA expression in MM is complex and regulated by extracellular signal-regulated kinase (ERK1, ERK2), Src, and phosphatidyl-inositol-3-kinase (PI3K) pathways in a tumor-specific fashion. Cell lines with PI3K-dependent Fra-1 expression were SV40 positive and expressed the lowest basal Fra-1 levels. Levels of Fra-1 expression correlated with amounts of CD44 expression that were greater in simian virus 40 negative (SV40-) MM cells. Using dominant negative (dn), short hairpin (sh) and small interference (si) RNA constructs, we next demonstrate that expression of CD44, the principal hyaluronic receptor in MMs, correlates with Fra-expression in both simian virus 40 positive (SV40+) and SV40- MMs. Moreover, both Fra-1 and CD44 expression are linked to cell migration in SV40- MM cells. Lastly, in contrast to normal lung tissue, tissue microarrays revealed that Fra-1 was expressed in 33 of 34 human MMs, and that all CD44+ tumors were SV40-. These results suggest that Fra-1 is associated with cell migration in human MMs and that Fra-1 modulation of CD44 may govern migration of selected MMs.

Association between cancer prevalence and use of thiazolidinediones: results from the Vermont Diabetes Information System.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) have emerged as important drug targets for diabetes. Drugs that activate PPARgamma, such as the thiazolidinediones (TZDs), are widely used for treatment of Type 2 diabetes mellitus. PPARgamma signaling could also play an anti-neoplastic role in several in vitro models, although conflicting results are reported from in vivo models. The effects of TZDs on cancer risk in humans needs to be resolved as these drugs are prescribed for long periods of time in patients with diabetes. METHODS: A total of 1003 subjects in community practice settings were interviewed at home at the time of enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any history of malignancy. Laboratory data were obtained directly from the clinical laboratory and current medications were obtained by direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between cancer diagnosis and the use of TZDs. RESULTS: In a multivariate logistic regression model, a diagnosis of cancer was significantly associated with TZD use, even after correcting for potential confounders including other oral anti-diabetic agents (sulfonylureas and biguanides), age, glycosylated hemoglobin A1C, body mass index, cigarette smoking, high comorbidity, and number of prescription medications (odds ratio = 1.59, P = 0.04). This association was particularly strong among patients using rosiglitazone (OR = 1.89, P = 0.02), and among women (OR = 2.07, P = 0.01). CONCLUSION: These data suggest an association between TZD use and cancer in patients with diabetes. Further studies are required to determine if this association is causal.

Unique uptake of acid-prepared mesoporous spheres by lung epithelial and mesothelioma cells.

Lung cancers, malignant mesotheliomas (MM), and fibrosis are devastating diseases with limited treatment strategies, in part due to poorly-effective drug delivery to affected areas of lung. We hypothesized that acid-prepared mesoporous spheres (APMS) (1-2 microm diameter, 40 A pore size) might be effective vehicles for pulmonary chemotherapeutic drug delivery. To assess this, APMS, chemically modified with different surface molecules (lipid, a linker having a terminal amine group, a thiol group, or tetraethylene glycol [TEG]), were evaluated for uptake and possible cytotoxic effects after in vitro administration to murine alveolar epithelial Type II (C10) and human mesothelioma (MM) cells and after intrapleural or intranasal administration to C57Bl/6 mice. APMS coated with TEG (APMS-TEG) were most efficiently taken up by C10 and MM cells. The mechanism of cell uptake was rapid, actin-dependent, and did not involve clathrin- or caveolae-mediated mechanisms nor fusion of membrane-bound APMS with lysosomes. When injected intrapleurally in mice, APMS-TEG were taken up by both CD45-positive and -negative cells of the diaphragm, lung, and spleen, whereas APMS administered by the intranasal route were predominantly in lung epithelial cells and alveolar macrophages. After intrapleural or intranasal administration, APMS were nonimmunogenic and nontoxic as evaluated by differential cell counts and lactate dehydrogenase levels in bronchoalveolar and pleural lavage fluids. In the treatment of lung and pleural diseases, APMS-TEG may be useful tools to deliver chemotherapeutic drugs or molecular constructs.