Prognostic Value of Proliferation Index and Expression of the RNA Component of Human Telomerase (hTR) in Papillary Meningiomas

Papillary meningioma is a rare subtype of meningioma that often behaves aggressively. In order to characterize factors that may influence this behavior, we chose to compare MIB-1 labeling index (LI) and telomerase RNA localization (hTR) in papillary meningiomas, meningiomas, and atypical meningiomas. LI is now often used to supplement histologic grade in the evaluation of these lesions. More recent studies indicate that increased expression of hTR is detected in many neoplastic cells, and may play an essential role in cell immortalization. The study group consisted of five papillary meningiomas (and a recurrence in one case), 11 conventional meningiomas, and eight atypical meningiomas. Conventional meningiomas showed either negative or 1+ hTR. Atypical meningiomas showed 1+ hTR. Papillary meningiomas showed the highest hTR (five of six, including recurrence, 2–3+ and one 1+). Generally, the LI was very low for conventional meningiomas (<2%). The LI of atypical meningiomas ranged from 3–19%, mean 12%, and from 5.5–17.5%, mean 11.75% for papillary meningiomas. LI differentiated between meningiomas, and papillary or atypical meningiomas. hTR further delineated papillary (moderate to high) from atypical meningiomas (low). The combined variable of LI and hTR expression could be a useful independent prognostic indicator in patients with papillary meningioma.     

The role of lean body mass and physical activity in bone health in children

In the context of physical education curricula, markers of physical fitness (e.g., aerobic capacity, muscular strength, flexibility, and body mass index or body fat) are usually evaluated in reference to health standards. Despite their possible mediating role in the relationship between weight-bearing or muscle forces and features of bone tissue, these attributes of fitness may not be the most relevant to predict skeletal health. It is therefore important to analyze the relative contribution of these factors to the variability in bone tissue of different parts of the skeleton, and to analyze it by gender, as sensitivity to mechanical loading can diverge for boys and girls. We compared the effects of habitual physical activity (PA) and lean mass, as surrogates of weight-bearing and muscle forces, and of physical fitness (aerobic and muscle capacity of lower and upper limbs) on bone mineral content (BMC) and size of total body, lumbar spine, femoral neck, and 1/3 radius in 53 girls and 64 boys from 7.9 to 9.7 years of age. After controlling for bone age, body mass, body height, and calcium intake, lean mass was the most important predictor of bone size and/or mineral in both genders (p < 0.05), while habitual weight-bearing PA positively influenced BMC in boys (p < 0.05). The effect of muscle in bone was not determined by PA and fitness score did not explain bone variability. Femoral neck was the bone site more closely associated with mechanical loading factors; boys with a PA > 608 counts/min/day (~105 min/day of moderate and vigorous intensity) showed 13–20% more BMC than those with less physical activity, and girls with a lean mass >19 kg showed 12–19% more BMC than those with less lean mass. These findings suggest that lean mass was the most important predictor of bone size and/or mineralization in both genders, while habitual weight-bearing PA appears to positively impact on bone mineral in prepubertal boys and that both lean mass and PA need to be considered in physical education curricula and other health-enhancing programs.     

Melatonin enhances pro-inflammatory cytokine levels and protects against Chagas disease

Abstract:  Pro-inflammatory and modulatory cytokines have an essential role in host defense against human and murine Trypanosoma cruzi infection. Control of T. cruzi parasitism during the acute phase of infection is considered to be critically dependent on direct macrophage activation by cytokines. Melatonin has been proposed to regulate the immune system by affecting cytokine production in immunocompetent cells, enhancing the production of several T helper (Th)1 cytokines. The aims of this work were to evaluate in rats, the influences of exogenous melatonin treatment on T. cruzi- infected host's immune responses. With this in mind, several immunological parameters were analyzed, including tumor necrosis factor-α, γ-interferon, interleukin-12, nitric oxide (NO) and macrophage count. The melatonin therapy was provided in one of two different treatment regimens, that is, either beginning 7 days prior to infection or concomitant with the infection. Both treatments triggered an up-regulation of the immune response, with the concomitant treatment being more effective; in this case all cytokines studied, with exception of NO, displayed enhanced concentrations and there was a higher number of peritoneal macrophages, which displayed reduced concentrations under melatonin therapy. We conclude that melatonin plays a pivotal role in up-regulating the Th1 immune response thus controlling parasite replication.     

The multigenic structure of the MHC locus contributes to positive selection efficiency: a role for MHC class II gene-specific restriction

The study of T cell positive selection in the thymus has long been focused on the specificity of the MHC-TCR interactions, making use of genetically manipulated mice that display TCR specificities or selecting peptides of limited diversity. However, little is known on the role of the MHC molecules irrespective of the peptide specificity and the implications of MHC multigenic structure in thymic positive selection have not been addressed. Here, we investigated the effect of MHC class II genetic configuration on the positive selection efficiency of naturally generated pre-selection repertoires in the mouse thymus. Analysis of positively selected thymocyte populations in MHC-congenic and -transgenic mice revealed that expression of I-E molecule in the thymic cortex increases positive selection efficiency of CD4 cells by approximately 50%. We show that increments in positive selection attributable to either the I-A and I-E genes are not due to increased MHC class II expression in the thymic cortex and are not affected by the number of MHC alleles. Collectively, our findings imply that MHC class II gene-restricted TCR specificities significantly contribute to positive selection efficiency, introducing the notion that multigenic structure of the MHC locus serves to increase selection of non-overlapping TCR repertoires.     

Peer Reviewed: Differences in Patterns of Alcohol Consumption Among Hispanics in the United States,by Survey Language Preference,Behavioral Risk Factor Surveillance System, 2005

Introduction

Alcohol consumption is pervasive in the United States, and extent of alcohol consumption for the growing US Hispanic population needs further study. We examined the association between language chosen for a national health survey and alcohol use among Hispanic adults.

Methods

Hispanic participants aged 18 years and older (N = 20,234) from the 2005 Behavioral Risk Factor Surveillance System were stratified by choice of language (English, n = 13,035; Spanish, n = 7,199) for completing the survey. Differences for these 2 groups in current alcohol use, heavy alcohol use, and binge drinking were determined by using χ² analyses and logistic regression models.

Results

In bivariate associations, current drinking (P < .001), heavy drinking (P < .001), and binge drinking (P = .002) were significantly higher among participants who chose to complete the survey in English than among those who elected to complete the survey in Spanish. After controlling for demographic characteristics, associations between language choice and drinking behaviors were found to be greatest among women. Compared with women who chose to complete the survey in Spanish, women who chose to complete the survey in English were more than twice as likely to report current drinking (odds ratio [OR] = 2.42, 95% confidence interval [CI] = 2.02-2.91), heavy drinking (OR = 3.82, 95% CI = 1.44-10.10), and binge drinking (OR = 2.51, 95% CI = 1.64-3.84).

Conclusion

This study suggests that language choice when completing a health survey is a predictor of high levels of alcohol use among Hispanic adults in the United States and that differences in drinking behaviors based on language choice for a survey are more profound among women.     

Drinking patterns and alcohol problems among Hispanics in the U.S.: a review

The literature on drinking patterns and alcohol problems among Hispanic Americans is critically reviewed. The picture provided by studies which have been examined indirect indicators of alcohol problems is contradictory. Some results suggest that Hispanics in the U.S.A. are over-represented among alcohol-related deaths and among those arrested for drunk driving and in treatment in alcoholism programs. Other studies do not provide evidence of over-representation. Studies in the general population indicate that there is more heavy drinking and alcohol-related problems among Hispanics than among other ethnic groups in the U.S.A. general population. However, very few of these studies were specifically designed to evaluate alcohol use and problems among this ethnic group, and these results are based on the analysis of a small number of Hispanic respondents. In the conclusions this and other methodological limitations are discussed and new areas for study are proposed.     

Intrinsic expression of Nod2 in CD4+ T lymphocytes is not necessary for the development of cell-mediated immunity and host resistance to Toxoplasma gondii

Nod2 belongs to the nucleotide-binding domain leucine-rich repeat family of proteins and senses bacterial cell wall components to initiate innate immune responses against various pathogens. Recently, it has been reported that T-cell-intrinsic expression of Nod2 promotes host defense against Toxoplasma gondii infection by inducing type 1 immunity. Here, we present results that demonstrate that Nod2 does not play a role in the defense against T. gondii infection. Nod2-deficient mice were fully capable of inducing Th1 immune responses and did not show enhanced susceptibility to infection. Upon TCR stimulation in vitro, Nod2-deficient CD4(+) T cells showed normal activation, IL-2 production, proliferation, and Th1/2 differentiation. Nod2 mRNA and protein were expressed in CD4(+) T and CD8(+) T cells at substantial levels. Therefore, Nod2, although expressed in CD4(+) T cells, does not have an intrinsic function in T-cell activation and differentiation.     

Poly(ADPR)polymerase inhibition and apoptosis induction in cDDP-treated human carcinoma cell lines

Poly(ADPR)polymerases' (PARPs) inhibitors potentiate the cytotoxic effects of chemotherapeutic agents like alkylating compounds and TOPO I poisons, while their action in combination with cisplatin still needs investigation. In fact, one of the earliest responses to DNA single- or double-strand breaks is the synthesis of poly(ADP-ribose) (PAR) by PARPs; these enzymes are components of DNA repair machineries and substrates of caspases. Cisplatin (cDDP) yields intra- and inter-strand DNA cross-links and several proteins that recognise cDDP-induced DNA damage, such as p53, are also targets of poly(ADP-ribosyl)ation. We compared the effects of treatments with cDDP and the PARPs inhibitor PJ34 in p53 mutated carcinoma cell lines (HeLa, KB, HT29) that exhibited differential sensitivities to the drugs, in terms of cell growth inhibition and onset of apoptosis. In cDDP-resistant HT29 cells we determined: (i) PJ34 potentiation of cDDP-induced cell growth inhibition; (ii) an increment of PARP-1 automodification following cDDP treatment. In cDDP-sensitive HeLa cells, we found that the drug induced apoptotic cell death associated with caspase-dependent PARP-1 proteolysis.     

T helper 17 cells play a critical pathogenic role in lung cancer

Lung cancer development is associated with extensive pulmonary inflammation. In addition, the linkage between chronic obstructive pulmonary disease (COPD) and lung cancer has been demonstrated in population-based studies. IL-17–producing CD4 helper T cells (Th17 cells) play a critical role in promoting chronic tissue inflammation. Although Th17 cells are found in human COPD and lung cancer, their role is not understood. We have thus used a mouse model of lung cancer, in which an oncogenic form of K-ras (K-ras^G12D), frequently found in human lung cancer, is restrictedly expressed in lung epithelial cells [via Clara cell secretory protein (CCSP^cre)]. In this model, Th17 and Treg but not Th1 cells were found enriched at the tumor tissues. When CCSP^cre/K-ras^G12D mice were weekly challenged with a lysate of nontypeable Haemophilus influenza (NTHi), which induces COPD-type inflammation and accelerates the tumor growth, they showed greatly enhanced Th17 cell infiltration in the lung tissues. Lack of IL-17, but not IL-17F, resulted in a significant reduction in lung tumor numbers in CCSP^cre/K-ras^G12D mice and also those treated with NTHi. Absence of IL-17 not only resulted in reduction of tumor cell proliferation and angiogenesis, but also decreased the expression of proinflammatory mediators and reduced recruitment of myeloid cells. Depletion of Gr-1⁺CD11b⁺ myeloid cells in CCSP^cre/K-ras^G12D mice suppressed tumor growth in lung, indicating Gr-1⁺CD11b⁺ myeloid cells recruited by IL-17 play a protumor role. Taken together, our data demonstrate a critical role for Th17 cell-mediated inflammation in lung tumorigenesis and suggest a novel way for prevention and treatment of this disease.Inflammation plays an important role in tumor development (1, 2). Although targeting inflammation and tumor microenvironment has been considered as a new direction of cancer therapy, the mechanisms underlying cancer-associated inflammation have not been well understood. Lung cancer is a leading cause of death in the world. Accumulating evidence has shown that inflammation is associated with pathogenesis of lung cancer, especially those induced by cigarette smoke (3). The primary risk factor among smokers to develop lung cancer is the presence of chronic obstructive pulmonary disease (COPD) (4), which is characterized by chronic pulmonary inflammation, airway remodeling and destruction of lung parenchyma. Human lung cancers are inflicted with alterations in various subsets of lymphocytes and myeloid cells (5, 6), reminiscent of immune activation during chronic inflammation. Several studies have shown NFκB signaling as a mechanistic link between inflammation and lung cancer using a mouse model of lung adenocarcinoma (7, 8). However, the specific inflammatory cell types or molecules potentiating lung cancer are not understood clearly.We and others have identified a novel subset of CD4 helper T cells that produce IL-17 and are referred as Th17 cells (9, 10). Th17 cells have been associated with inflammatory diseases such as rheumatoid arthritis, asthma, lupus, and allograft rejection. An important function of IL-17 is to promote tissue inflammation through the up-regulation of proinflammatory cytokines and chemokines (11). Consistently, we have shown that transgenic overexpression of IL-17 in the lungs resulted in chemokine up-regulation and tissue infiltration by leukocytes, although mice treated with neutralizing IL-17–specific antibody were also found to be resistant to the induction of experimental autoimmune encephalomyelitis (9). These and other studies collectively demonstrated that IL-17 and Th17 cells play nonredundant function in promoting inflammation.Increased frequencies of IL-17 and Th17 cells have been reported in patients with different types of tumors (12), including lung adenocarcinoma (13). The density of intratumoral IL-17–positive cells in primary human nonsmall cell lung cancer was inversely correlated with patient outcome and correlated with smoking status of the patients (14). Th17 cells specific for a common tumor antigen were found in lung cancer patients as part of their spontaneous immune response to the autologous tumor (15). However, the function of Th17 cells and IL-17 in the development of lung cancer remains to be shown. Animal model studies have revealed contrasting roles of IL-17 in various tumors (16). Tumor-promoting effect of IL-17 was shown in some models such as colon cancer (17–20), whereas in others, IL-17 supported anti-tumor immunity, including in B16 melanoma model (21–24). Thus, the role of IL-17 could be complex and tumor-specific.To properly evaluate the role of IL-17 in inflammation-associated lung cancer, we used a model of oncogenic K-ras mutation expressed only in the lung. Mice expressing K-ras mutation in Clara cells (CCSP^cre/K-ras^G12D mice) spontaneously develop lung adenocarcinoma (25). In addition, we induced COPD-type lung inflammation by challenging mice with lysates of nontypeable Haemophilus influenza (NTHi). Inflammation driven by NTHi can promote tumor growth in CCSP^cre/K-ras^G12D mice (25). These experiments collectively indicate a tumorigenic role of IL-17–mediated inflammation in the development of lung cancer.