Clinical relevance of serum angiogenic activity in patients with transitional cell carcinoma of the bladder

Angiogenesis is essential for tumor growth and progression and is mediated by positive and negative regulators of vessel growth. Since angiogenic mediators found in patient serum have been postulated to reflect the angiogenic potential of a malignant tumor, we investigated the angiogenic activity in the serum of patients with transitional cell carcinoma (TCC). The data were correlated to tumor characteristics and the clinical course of the patients. Eighty-one patients with transitional cell carcinoma and 53 control persons were included in the study. Preoperative serum samples were collected and both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were quantified by ELISA. Additionally, the serum evoked proliferative activity on human umbilical vein endothelial cells (HUVEC) was evaluated. Data were compared to the clinical course of the patients. Serum of tumor patients significantly enhanced the proliferative capacity of HUVEC, compared to cells grown in standard culture medium (p = 0.0032), but not when compared to serum from control persons. Serum from patients with superficial TCC and well differentiated tumors induced a significantly higher angiogenic response (ANG(hi)) than serum from patients with poorly differentiated and invasive carcinomas (ANG(lo); p = 0.037). VEGF level of ANG(hi) serum was 384.22 +/- 247.76 pg/ml (n = 37) which significantly differed from mean VEGF level detected in ANG(lo) serum (247.72 +/- 211.93 pg/ml, n = 42; p = 0.019). Similarly, mean bFGF levels were 9.58 +/- 5.91 pg/ml in ANG(hi) serum versus 5.74 +/- 3.52 pg/ml) in ANG(lo) serum (p = 0.0043). A negative correlation was established between VEGF/bFGF serum concentration and patient prognosis. The experiments demonstrate a positive correlation between VEGF and bFGF serum level and endothelial proliferation in vitro. The inverse relationship between angiogenic activity and tumor stage might disclose information about angiogenesis and tumor progression in TCC.     

Ligand binding to symmetrical FeZn hybrids of variants of human HbA with modifications in the alpha1-beta2 interface

The equilibria of oxygen binding to and kinetics of CO combination with the symmetrical iron-zinc hybrids of a series of variants of human adult hemoglobin A have been measured at pH 7 in the presence of inositol hexaphosphate (IHP). In addition, the kinetics of CO combination have also been measured in the absence of IHP. The hybrids have the heme groups of either the alpha or the beta subunits replaced by zinc protoporphyrin IX, which is unable to bind a ligand and is a good model for permanently deoxygenated heme. The variants examined involve residues located in the alpha1beta2 interface of the hemoglobin tetramer. Alterations of residues located in the hinge region of the interface are found to affect the properties of both the alpha and the beta subunits of the protein. In contrast, alterations of residues in the switch region of the interface have substantial effects only on the mutant subunit and are poorly communicated to the normal partner subunit. When the logarithms of the rate constants for the combination of the first CO molecule with a single subunit in the presence of IHP are analyzed as functions of the logarithms of the dissociation equilibrium constants for the binding of the first oxygen under the same conditions, a linear relationship is found. The relationship is somewhat different for the alpha and beta subunits, consistent with the well-known differences in the geometries of their ligand binding sites.     

Ionizing radiation‐induced long‐term expression of senescence markers in mice is independent of p53 and immune status

Exposure to IR has been shown to induce the formation of senescence markers, a phenotype that coincides with lifelong delayed repair and regeneration of irradiated tissues. We hypothesized that IR‐induced senescence markers could persist long‐term in vivo, possibly contributing to the permanent reduction in tissue functionality. Here, we show that mouse tissues exposed to a sublethal dose of IR display persistent (up to 45 weeks, the maximum time analyzed) DNA damage foci and increased p16^INK4a expression, two hallmarks of cellular senescence and aging. BrdU‐labeling experiments revealed that IR‐induced damaged cells are preferentially eliminated, at least partially, in a tissue‐dependent manner. Unexpectedly, the accumulation of damaged cells was found to occur independent from the DNA damage response modulator p53, and from an intact immune system, as their levels were similar in wild‐type and Rag2^?/? γC^?/? mice, the latter being deficient in T, B, and NK cells. Together, our results provide compelling evidence that exposure to IR induces long‐term expression of senescence markers in vivo, an effect that may contribute to the reduced tissue functionality observed in cancer survivors.     

Whole genome sequencing of a natural recombinant Toxoplasma gondii strain reveals chromosome sorting and local allelic variants

Background  

Toxoplasma gondii is a zoonotic parasite of global importance. In common with many protozoan parasites it has the capacity for sexual recombination, but current evidence suggests this is rarely employed. The global population structure is dominated by a small number of clonal genotypes, which exhibit biallelic variation and limited intralineage divergence. Little is known of the genotypes present in Africa despite the importance of AIDS-associated toxoplasmosis.     

Early Affective Processing in Patients with Acute Posttraumatic Stress Disorder: Magnetoencephalographic Correlates

Background

In chronic PTSD, a preattentive neural alarm system responds rapidly to emotional information, leading to increased prefrontal cortex (PFC) activation at early processing stages (<100 ms). Enhanced PFC responses are followed by a reduction in occipito-temporal activity during later processing stages. However, it remains unknown if this neuronal pattern is a result of a long lasting mental disorder or if it represents changes in brain function as direct consequences of severe trauma.

Methodology

The present study investigates early fear network activity in acutely traumatized patients with PTSD. It focuses on the question whether dysfunctions previously observed in chronic PTSD patients are already present shortly after trauma exposure. We recorded neuromagnetic activity towards emotional pictures in seven acutely traumatized PTSD patients between one and seven weeks after trauma exposure and compared brain responses to a balanced healthy control sample. Inverse modelling served for mapping sources of differential activation in the brain.

Principal Findings

Compared to the control group, acutely traumatized PTSD patients showed an enhanced PFC response to high-arousing pictures between 60 to 80 ms. This rapid prefrontal hypervigilance towards arousing pictorial stimuli was sustained during 120–300 ms, where it was accompanied by a reduced affective modulation of occipito-temporal neural processing.

Conclusions

Our findings indicate that the hypervigilance-avoidance pattern seen in chronic PTSD is not necessarily a product of an endured mental disorder, but arises as an almost immediate result of severe traumatisation. Thus, traumatic experiences can influence emotion processing strongly, leading to long-lasting changes in trauma network activation and expediting a chronic manifestation of maladaptive cognitive and behavioral symptoms.     

Angiotensin receptor type 1 and endothelin receptor type A on immune cells mediate migration and the expression of IL-8 and CCL18 when stimulated by autoantibodies from systemic sclerosis patients

Introduction

Agonistic autoantibodies (Aabs) against the angiotensin II receptor type 1 (AT1R) and the endothelin receptor type A (ETAR) have been identified in patients with systemic sclerosis (SSc). In our present study, we examined the expression of the AT1R and the ETAR in human immune cells and the pathological effects mediated through these receptors by their corresponding Aabs.

Methods

Protein expression of AT1R and ETAR on peripheral blood mononuclear cells (PBMCs) from healthy individuals and SSc patients was analyzed using flow cytometry, and mRNA expression of both receptors in PBMCs from healthy donors was examined by real-time PCR. In addition, PBMCs from healthy donors were stimulated in vitro with affinity-purified immunoglobulin G (IgG) fractions from SSc patients positive for AT1R and ETAR Aabs, as well as with IgG from healthy donors serving as controls. Alterations in cell surface marker expression, cytokine secretion and chemotactic motility were analyzed using flow cytometry, enzyme-linked immunosorbent assays and chemotaxis assays, respectively. The results were correlated with the characteristics and clinical findings of the IgG donors.

Results

Both AT1R and ETAR were expressed on PBMCs in humans. Protein expression of both receptors was decreased in SSc patients compared with that of healthy donors and declined during the course of disease. IgG fractions of SSc patients positive for AT1R and ETAR Aabs induced T-cell migration in an Aab level–dependent manner. Moreover, IgG of SSc patients stimulated PBMCs to produce more interleukin 8 (IL-8) and chemokine (C-C motif) ligand 18 (CCL18) than did the IgG of healthy donors. All effects were significantly reduced by selective AT1R and ETAR antagonists. Statistical analysis revealed an association of SSc-IgG induced high IL-8 concentrations with an early disease stage and of high CCL18 concentrations with lung fibrosis onset and vascular complications in the respective IgG donors.

Conclusion

In our present study, we could demonstrate the expression of both AT1R and ETAR on human peripheral T cells, B cells and monocytes. The decreased receptor expression in SSc patients, the inflammatory and profibrotic effects upon Aab stimulation of PBMCs in vitro and the associations with clinical findings suggest a role for Aab-induced activation of immune cells mediated by the AT1R and the ETAR in the pathogenesis or even the onset of the disease.     

Lifetime Victimization and Physical Health Outcomes among Lesbian and Heterosexual Women

Background

Lifetime victimization experiences, including child sexual abuse (CSA), child physical abuse (CPA), adult sexual assault (ASA), and adult physical assault (APA), are associated with health problems.

Purpose

To examine relationships between cumulative victimization and physical health among heterosexual and lesbian women and determine whether these relationships differ by sexual identity.

Methods

Large samples of heterosexual (n = 482) and lesbian women (n = 394) were interviewed. Questions included lifetime victimization experiences and physical health problems.

Results

Compared to women who reported no childhood victimization, those who reported experiencing both CSA and CPA were 44% more likely to report health problems and women who experienced all four types of victimization (CSA, CPA, APA, ASA) were nearly 240% as likely to report physical health problems. Interaction analyses revealed the association between victimization and physical health did not differ by sexual identity.

Conclusions

Although lesbians were more likely to report all types of victimization, results suggest that victimization conferred increased physical health risks regardless of sexual identity.