Jet exhaust particles alter human dendritic cell maturation

Objective and design  

Among combustion-derived air pollutants, little is known about jet kerosene characteristics and effects.     

Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity

Autosomal dominant TLR3 deficiency has been identified as a genetic etiology of childhood herpes simplex virus 1 (HSV-1) encephalitis (HSE). This defect is partial, as it results in impaired, but not abolished induction of IFN-β and -λ in fibroblasts in response to TLR3 stimulation. The apparently normal resistance of these patients to other infections, viral illnesses in particular, may thus result from residual TLR3 responses. We report here an autosomal recessive form of complete TLR3 deficiency in a young man who developed HSE in childhood but remained normally resistant to other infections. This patient is compound heterozygous for two loss-of-function TLR3 alleles, resulting in an absence of response to TLR3 activation by polyinosinic-polycytidylic acid (poly(I:C)) and related agonists in his fibroblasts. Moreover, upon infection of the patient's fibroblasts with HSV-1, the impairment of IFN-β and -λ production resulted in high levels of viral replication and cell death. In contrast, the patient's peripheral blood mononuclear cells responded normally to poly(I:C) and to all viruses tested, including HSV-1. Consistently, various TLR3-deficient leukocytes from the patient, including CD14(+) and/or CD16(+) monocytes, plasmacytoid dendritic cells, and in vitro derived monocyte-derived macrophages, responded normally to both poly(I:C) and HSV-1, with the induction of antiviral IFN production. These findings identify a new genetic etiology for childhood HSE, indicating that TLR3-mediated immunity is essential for protective immunity to HSV-1 in the central nervous system (CNS) during primary infection in childhood, in at least some patients. They also indicate that human TLR3 is largely redundant for responses to double-stranded RNA and HSV-1 in various leukocytes, probably accounting for the redundancy of TLR3 for host defense against viruses, including HSV-1, outside the CNS.     

In vitro cytotoxic effects of Brazilian plant extracts on squamous cell carcinoma of the oral cavity

Squamous cell carcinoma (SCC) is the most prevalent cancer of the oral cavity and the fifth most prevalent of all malignancies in males. Many researchers have attempted to develop new treatments that will improve the prognosis of SCC patients. Over 20% of the world's biodiversity is located within the Brazilian forests, but little is known about the chemical and/or pharmacological potential of these plants. Certain extracts obtained from Amazon and Atlantic Forest plants have previously been shown to have cytotoxic activity against various cancers. The aim of this study was to screen these extracts for cytotoxic activity against oral SCC cells. The extracts were analyzed for activity against the KB-ADL#12 cell line at various concentrations up to a maximum dose of 100 μg/mL. Comparisons with a control group were performed using one-way ANOVA. Significant cytotoxicity was induced by the extracts obtained from the aerial parts of Picrolemma sprucei (Simaroubaceae), from the leaves and stems of Laetia suaveolens (Salicaceae), from the aerial parts of Abarema auriculata (Fabaceae-Mimosoideae) and from the stem of A. auriculata.     

Structural insights into a unique cellulase fold and mechanism of cellulose hydrolysis

Clostridium thermocellum is a well-characterized cellulose-degrading microorganism. The genome sequence of C. thermocellum encodes a number of proteins that contain type I dockerin domains, which implies that they are components of the cellulose-degrading apparatus, but display no significant sequence similarity to known plant cell wall–degrading enzymes. Here, we report the biochemical properties and crystal structure of one of these proteins, designated CtCel124. The protein was shown to be an endo-acting cellulase that displays a single displacement mechanism and acts in synergy with Cel48S, the major cellulosomal exo-cellulase. The crystal structure of CtCel124 in complex with two cellotriose molecules, determined to 1.5 Å, displays a superhelical fold in which a constellation of α-helices encircle a central helix that houses the catalytic apparatus. The catalytic acid, Glu96, is located at the C-terminus of the central helix, but there is no candidate catalytic base. The substrate-binding cleft can be divided into two discrete topographical domains in which the bound cellotriose molecules display twisted and linear conformations, respectively, suggesting that the enzyme may target the interface between crystalline and disordered regions of cellulose.     

Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft

PARP-1 is a critical enzyme in the repair of DNA strand breaks. Inhibition of PARP-1 increases the effectiveness of radiation in killing tumor cells. However, although the mechanism(s) are well understood for these radiosensitizing effects in vitro, the underlying mechanism(s) in vivo are less clear. Nicotinamide, a drug structurally related to the first generation PARP-1 inhibitor, 3-aminobenzamide, reduces tumor hypoxia by preventing transient cessations in tumor blood flow, thus improving tumor oxygenation and sensitivity to radiotherapy. Here, we investigate whether olaparib, a potent PARP-1 inhibitor, enhances radiotherapy, not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non-small cell lung carcinoma (NSCLC). In irradiated Calu-6 and A549 cells, olaparib enhanced the cytotoxic effects of radiation (sensitizer enhancement ratio at 10% survival = 1.5 and 1.3) and DNA double-strand breaks persisted for at least 24 hours after treatment. Combination treatment of Calu-6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression (P = 0.007) relative to radiotherapy alone. To determine whether this radiosensitization was solely due to effects on DNA repair, we used a dorsal window chamber model to establish the drug/radiation effects on vessel dynamics. Olaparib alone, when given as single or multiple daily doses, or in combination with fractionated radiotherapy, increased the perfusion of tumor blood vessels. Furthermore, an ex vivo assay in phenylephrine preconstricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide. This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC.     

The contribution of hysterectomy to the occurrence of urge and stress urinary incontinence symptoms

Objective To study the contribution of hysterectomy to the occurrence of urge-or stress urinary incontinence symptoms
Design A population-based, cross-sectional cohort study conducted in 1999
Setting A university medical centre in The Netherlands
Population Random sample of 2322 women, between 35 and 70 years of age, from a suburban area in the central part of The Netherlands
Methods Self-report questionnaire with questions from the Urogenital Distress Inventory, sociodemographic variables and data on obstetric and gynaecological history
Main outcome measures Multivariate logistic regression analysis was used to obtain odds ratios with 95% confidence interval of the type and bothersomeness of urinary incontinence for hysterectomy
Results One thousand, six hundred and twenty-six women (70%) responded. The adjusted odds of urge (1.9, 1.4;2.6) and bothersome urge (2.6, 1.4;4.4) urinary incontinence were increased for women who had a hysterectomy. This association was not limited to the elderly but also occurred in women under 60 years of age. No increased odds of stress or bothersome stress incontinence were found
Conclusions Meta-analysis has shown that hysterectomy increases the odds of urinary incontinence by 30%. However, a distinction between the different types of urinary incontinence symptoms has not been made. Such a distinction is of importance since urge incontinence gives a significantly greater reduction in health-related quality of life as compared with stress incontinence. Therefore, our finding that women scheduled for hysterectomy have an increased risk of developing urge incontinence symptoms indicates that these women should be counselled about this particular consequence     

Cerebral cavernous malformations: Typical and atypical imaging characteristics

Cavernous malformations (CMs) are benign vascular malformations that maybe seen anywhere in the central nervous system. They are dynamic lesions, growing or shrinking over time and only rarely remaining stable. Size varies from a few millimeters to a few centimeters. CMs can be sporadic or familial, and while most of them are congenital, de novo and acquired lesions may also be seen. Etiology is still unknown. A genetic molecular mechanism has been proposed since a cerebral cavernous malformation gene loss of function was found in both familial and sporadic lesions. Additionally, recent studies suggest that formation of CMs in humans may be associated with a distinctive bacterial gut composition (microbioma). Imaging is fairly typical but may vary according to age, location, and etiology. Follow-up is not well established because CMs patients have a highly unpredictable clinical course. Angiogenic and inflammatory mechanisms have been implicated in disease activity, as well as lesional hyperpermeability and iron deposition. Imaging and serum biomarkers of these mechanisms are under current investigation. Treatment options, including surgery or radiosurgery, are not well defined and are dependent upon multiple factors, including clinical presentation, lesion location, number of hemorrhagic events, and medical comorbidities. Our purpose is to review the imaging features of CMs based on their size, location, and etiology, as well as their differential diagnosis and best imaging approach. New insights in etiology will be briefly considered. Follow-up strategies, including serum and imaging biomarkers, and treatment options will also be discussed.     

HIF-1α-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion

PTK6/Brk is a non-receptor tyrosine kinase overexpressed in cancer. Here we demonstrate that cytosolic PTK6 is rapidly and robustly induced in response to hypoxic conditions in a HIF-1-independent manner. Furthermore, a proportion of hypoxic PTK6 subsequently re-localized to the cell membrane. We observed that the rapid stabilization of PTK6 is associated with a decrease in PTK6 ubiquitylation and we have identified c-Cbl as a putative PTK6 E3 ligase in normoxia. The consequences of hypoxia-induced PTK6 stabilization and subcellular re-localization to the plasma membrane include increased cell motility and invasion, suggesting PTK6 targeting as a therapeutic approach to reduce hypoxia-regulated metastatic potential. This could have particular significance for breast cancer patients with triple negative disease.     

NP1 regulates neuronal activity-dependent accumulation of BAX in mitochondria and mitochondrial dynamics

In cultured cerebellar granule neurons, low neuronal activity triggers the intrinsic program of apoptosis, which requires protein synthesis-dependent BAX translocation to mitochondria, a process that may underlie neuronal damage in neurodegeneration. However, the mechanisms that link neuronal activity with the induction of the mitochondrial program of apoptosis remain unclear. Neuronal pentraxin 1 (NP1) is a pro-apoptotic protein induced by low neuronal activity that is increased in damaged neurites in Alzheimer's disease-affected brains. Here we report that NP1 facilitates the accumulation of BAX in mitochondria and regulates mitochondrial dynamics during apoptosis in rat and mouse cerebellar granule neurons in culture. Reduction of neuronal activity increases NP1 protein levels in mitochondria and contributes to mitochondrial fragmentation in a Bax-dependent manner. In addition, NP1 is involved in mitochondrial transport in healthy neurons. These results show that NP1 is targeted to mitochondria acting upstream of BAX and uncover a novel function for NP1 in the regulation of mitochondrial dynamics and trafficking during apoptotic neurodegeneration.