Correlation of B7-H3 with androgen receptor, immune pathways and poor outcome in prostate cancer: an expression-based analysis.

BACKGROUND: B7-H3 (CD276), part of the B7 superfamily of immune checkpoint molecules, has been shown to have an immunomodulatory role. Its regulation, receptor and mechanism of action remain unclear. B7-H3 protein expression correlates with prostate cancer outcomes, and humanized monoclonal antibodies (that is, enoblituzumab) are currently being investigated for therapeutic use. Here we used genomic expression data to examine the relationship between B7-H3 mRNA expression and prostate cancer. METHODS: Prostatectomy tissue from 2781 patients were profiled using the Affymetrix HuEx 1.0 ST microarray. Pairwise comparisons were used to identify significant associations between B7-H3 expression and clinicopathologic variables, and survival analyses were used to evaluate the prognostic significance of B7-H3. Pearson's correlation analyses were performed to assess the relationship of B7-H3 expression with molecular subtypes and individual transcripts. Androgen receptor (AR) occupancy at the B7-H3 locus was determined using chromatin immunoprecipitation (ChIP), and androgen-dependent expression changes in B7-H3 was evaluated by quantitative reverse transcription PCR in LNCaP cell lines. Oncomine was queried to evaluate B7-H3 expression in metastatic disease. RESULTS: B7-H3 mRNA expression was positively associated with higher Gleason score (P<0.001), tumor stage (P<0.001), and castrate resistant metastatic disease (P<0.0001). High B7-H3 expression correlated with the development of metastasis and prostate cancer specific mortality, but this was not significant on multi-variable analysis. B7-H3 expression correlated with ERG-positive disease (r=0.99) and AR expression (r=0.36). ChIP revealed an AR-binding site upstream of B7-H3, and the presence of androgens decreased B7-H3 expression in LNCaP suggesting potential direct AR regulation. Gene set enrichment analysis demonstrated an association of B7-H3 with androgen signaling as well as immune regulatory pathways. CONCLUSIONS: Higher B7-H3 expression correlates with Gleason grade, prostate cancer stage and poor oncologic outcomes in prostatectomy cohorts. B7-H3 expression appears to be related to androgen signaling as well as the immune reactome.

A dust-obscured massive maximum-starburst galaxy at a redshift of 6.34.

Massive present-day early-type (elliptical and lenticular) galaxies probably gained the bulk of their stellar mass and heavy elements through intense, dust-enshrouded starbursts--that is, increased rates of star formation--in the most massive dark-matter haloes at early epochs. However, it remains unknown how soon after the Big Bang massive starburst progenitors exist. The measured redshift (z) distribution of dusty, massive starbursts has long been suspected to be biased low in z owing to selection effects, as confirmed by recent findings of systems with redshifts as high as ~5 (refs 2-4). Here we report the identification of a massive starburst galaxy at z = 6.34 through a submillimetre colour-selection technique. We unambiguously determined the redshift from a suite of molecular and atomic fine-structure cooling lines. These measurements reveal a hundred billion solar masses of highly excited, chemically evolved interstellar medium in this galaxy, which constitutes at least 40 per cent of the baryonic mass. A 'maximum starburst' converts the gas into stars at a rate more than 2,000 times that of the Milky Way, a rate among the highest observed at any epoch. Despite the overall downturn in cosmic star formation towards the highest redshifts, it seems that environments mature enough to form the most massive, intense starbursts existed at least as early as 880 million years after the Big Bang.

Retroperitoneal hernia following radical cystectomy: case report.

Retroperitoneal hernias are rare. When they occur, they most often occur in naturally occurring fossas, such as with paraduodenal hernias. Due to the anatomy of the ureterovesicular system, patients with prior urological operations may be more likely to develop retroperitoneal hernias. We report the case of a 76-year-old male who had undergone a radical cystectomy with ileal loop conduit for bladder cancer, who presented with recurrent episodes of nausea and vomiting. Upon exploratory laparotomy, he was found to have a retroperitoneal hernia. The patient underwent resection of the strangulated loop of small bowel, and recovered without complications. In our patient, ureteral dissection from his prior procedure had created a defect in the peritoneum posterior to the sigmoid mesocolon, which allowed for herniation and subsequent strangulation of a portion of small bowel. Retroperitoneal hernias may represent an under-diagnosed etiology of intestinal obstruction in post-operative urological patients. Knowledge of anatomy is crucial in patients with previous abdominal operations, and prior operative notes should be reviewed, including non general surgical operations such as urological and gynecological procedures. The surgeon must remain vigilant in such cases of small bowel obstruction, as delayed intervention may lead to bowel compromise.

Subperiosteal abscess of the orbit: duration of intravenous antibiotic therapy in nonsurgical cases.

PURPOSE: To report the duration of intravenous (IV) antibiotic administration and outcomes in a cohort of patients with subperiosteal abscess (SPA) of the orbit triaged to nonsurgical management. METHODS: A retrospective cohort study based on records of patients younger than 9 years admitted to a regional pediatric hospital with a diagnosis of orbital cellulitis from 1999 through 2008. Patients with computed tomography (CT)-confirmed SPA and associated sinusitis were included. Patients who underwent surgical drainage of sinuses and/or orbits during that admission were excluded. Patients discharged with a peripherally inserted central catheter for a predetermined treatment interval were excluded. Dates and times of first and last doses of inpatient IV antibiotics were recorded. Records were reviewed for evidence of hospital readmission for relevant diagnoses. Outcome measures included duration of IV antibiotic administration and hospital readmission. RESULTS: Forty-two patients met study criteria. Duration of IV treatment ranged from 2 to 8 days (mean and median, each 4 days). Forty-one patients were not readmitted with a relevant diagnosis from the time of hospital discharge to completion of data acquisition in April 2011. One patient was readmitted for recurrent acute infection 10 weeks after discharge and underwent urgent SPA and sinus drainage; review of the initial CT revealed an ethmoidal mucocoele. CONCLUSIONS: The duration of IV therapy associated with successful nonsurgical management of appropriately selected children with SPA is considerably shorter than that recommended in current pediatric infectious disease literature. The findings suggest that clinical judgment, based on each patient's initial CT findings and evolving signs, symptoms, and laboratory profile, should be a major determinant of IV intervals.

Aged monkeys as a partial model for Parkinson's disease.

Parkinson's Disease (PD) and the natural aging process share a number of biochemical mechanisms, including reduced function of dopaminergic systems. The present study aims to determine the extent that motor and behavioral changes in aged monkeys resemble parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The behavioral and physiological changes in PD are believed to result largely from selective depletion of dopamine in the nigrostriatal system. In the present study, ten aged female monkeys were compared with three groups: 9 untreated young adult female monkeys, 10 young adult male monkeys and 13 older male monkeys that had been exposed to MPTP. Trained observers, blind as to age and drug condition and without knowledge of the hypotheses, scored the monkeys using the Parkinson's factor score (Parkscore), which has been validated by a high correlation with post mortem striatal dopamine (DA) concentrations. The aged animals had higher scores on the Parkscore compared with the young adults, with most of its component behavioral items showing significance (tremor, Eating Problems, Delayed initiation of movement, and Poverty of Movement). L-Dopa and DA-agonists did not clearly reverse the principal measure of parkinsonism. DA concentrations post mortem were 63% lower in 3 aged monkeys in the ventral putamen compared with 4 young adults, with greater reductions in putamen than in caudate (45%). We conclude that aged monkeys, unexposed to MPTP, show a similar profile of parkinsonism to that seen after the neurotoxin exposure to MPTP in young adult monkeys. The pattern of greater DA depletion in putamen than in caudate in aged monkeys is the same as in human Parkinson's disease and contrasts with the greater depletion in caudate seen after MPTP. Aged monkeys of this species reflect many facets of Parkinson's disease, but like older humans do not improve with standard dopamine replacement pharmacotherapies.

Visual improvement after optic nerve sheath decompression in a case of congenital hydrocephalus and persistent visual loss despite intracranial pressure correction via shunting.

Among the sequelae of persistent raised intracranial pressure (ICP) are ophthalmologic signs and symptoms, including cranial nerve palsies, visual field deficits, papilledema, and vision loss. Elevated pressure within the optic nerve sheath may not be relieved by shunt procedures, which can decrease generalized ICP. The authors present a case of acute visual loss in the setting of chronic hydrocephalus and multiple shunt revisions. Despite shunt correction resolving systemic symptoms of raised ICP, this child had persistent visual loss. Bilateral optic nerve sheath decompression was performed, and the visual acuity improved over the next 3 days. This case highlights the importance of routine ophthalmologic examination in patients with hydrocephalus and shunts and demonstrates the utility of optic nerve sheath decompression as a surgical intervention when shunting alone does not resolve visual loss.

Out-of-school time activity participation profiles of children with physical disabilities: a cluster analysis.

OBJECTIVE: To determine out-of-school activity participation profiles of school-aged children with physical disabilities. METHODS: Activity participation profiles were determined by cluster analysing 427 children's responses on multiple dimensions of participation (intensity, location, companionship, enjoyment, preference) in five activity types (recreational, active physical, social, skill-based, self-improvement). Socio-demographic, child, parent, family and environmental predictors of group membership were determined, along with child functioning, socio-demographic, self-concept and social support variables significantly associated with group membership. RESULTS: The cluster analysis revealed four groups, labelled Social Participators (a highly social and neighbourhood-focused group), Broad Participators (a group of high participators who enjoy participation), Low Participators (a group with low enjoyment and weak preferences) and Recreational Participators (a group of younger children who participate in recreational activities with family members). The groups showed meaningful differences across a range of socio-demographic, child, parent, family and environmental variables. CONCLUSIONS: The findings support an affective and contextual view of participation, indicating the importance of motivational theory and a person-environment approach in understanding the complexity of children's out-of-school activity participation.

Late onset optic neuropathy in methylmalonic and propionic acidemia.

PURPOSE: To describe 3 cases of late-onset bilateral optic neuropathy with visual dysfunction in patients with organic acidemia. DESIGN: Retrospective case series. METHODS: A total of 3 subjects, a 16-year-old male with methylmalonic acidemia (MMA), a 21-year-old male with MMA, and a 20-year-old female with propionic acidemia (PA), are included in this series. Comparison of the patients' clinical course, ophthalmologic exam, and testing are discussed. The outcome measures include visual acuity (VA), fundus appearance, visual fields, brain imaging, and genetic testing. RESULTS: All 3 subjects had late-onset severe bilateral VA loss with bilateral optic nerve pallor, central or cecocentral scotomas on visual field testing, and negative diagnostic workups for other causes of bilateral optic neuropathy. CONCLUSIONS: Patients with organic acidemia may develop late-onset bilateral optic neuropathy with visual dysfunction despite lifelong propiogenic amino acid restriction and dietary supplementation.

Existing technologies to reduce specific toxicant emissions in cigarette smoke.

BACKGROUND: The World Health Organization Tobacco Product Regulation (TobReg) study group has proposed emissions level performance standards for nine toxicants (NNN, NNK, acetaldehyde, acrolein, 1,3-butadiene, CO, BaP, benzene and formaldehyde, all expressed as micrograms per milligram nicotine as measured under the Canadian intensive method) in cigarette smoke for parties to the FCTC in conjunction with regular monitoring of emissions of nine other toxicants of interest, nicotine and nicotine-free dry particulate matter (NFDPM, or "tar"). METHODS: We examined the published literature and publicly available tobacco industry documents to determine the extent to which existing available technologies can be applied to reduce the emissions of the specified toxicants in cigarette smoke. RESULTS: Agricultural practices (for example, fertilisers, curing), plant characteristics (for example, protein content, nicotine content), tobacco blending (for example, American blend vs Virginia blend) and cigarette design (for example, additives, filters, paper) issues all have roles in the generation and reduction of specific smoke toxicants. The tobacco industry has explored a number of technologies, including selective filtration, changes to curing practices and rod additives to reduce specific toxicants. CONCLUSIONS: Technologies exist to reduce the toxicants identified by TobReg. The extent to which the industry is able to simultaneously reduce toxicants, however, is unknown.

Human cancer cells require ATR for cell cycle progression following exposure to ionizing radiation.

The vast majority of cancer cells have defective checkpoints that permit the cell cycle to progress in the presence of double-strand DNA breaks (DSBs) caused by ionizing radiation (IR) and radiomimetic drugs. ATR (ataxia telangiectasia-mutated and Rad3-related) has recently been shown to be activated by DSBs, although the consequences of this activity are largely unknown. In this report, we use advanced gene targeting methods to generate biallelic hypomorphic ATR mutations in human colorectal cancer cells and demonstrate that progression of the cancer cell cycle after IR treatment requires ATR. Cells with mutant ATR accumulated at a defined point at the beginning of the S phase after IR treatment and were unable to progress beyond that point, whereas cells at later stages of the S phase during the time of irradiation progressed and completed DNA replication. The prolonged arrest of ATR mutant cancer cells did not involve the ataxia telangiectasia mutated-dependent S-phase checkpoint, but rather closely resembled a previously characterized form of cell cycle arrest termed S-phase stasis. As ATR strongly contributed to clonogenic survival after IR treatment, these data suggest that blocking ATR activity might be a useful strategy for inducing S-phase stasis and promoting the radiosensitization of checkpoint-deficient cancer cells.

Measuring children's participation in recreation and leisure activities: construct validation of the CAPE and PAC.

There is a need for psychometrically sound measures of children's participation in recreation and leisure activities, for both clinical and research purposes. This paper provides information about the construct validity of the Children's Assessment of Participation and Enjoyment (CAPE) and its companion measure, Preferences for Activities of Children (PAC). These measures are appropriate for children and youth with and without disabilities between the ages of 6 and 21 years. They provide information about six dimensions of participation (i.e. diversity, intensity, where, with whom, enjoyment and preference) and two categories of recreation and leisure activities: (i) formal and informal activities; and (ii) five types of activities (recreational, active physical, social, skill-based and self-improvement). This paper presents information about the performance of the CAPE and PAC activity type scores using data from a study involving 427 children with physical disabilities between the ages of 6 and 15 years. Intensity, enjoyment and preference scores were significantly correlated with environmental, family and child variables, in expected ways. Predictions also were supported with respect to differences in mean scores for boys vs. girls, and children in various age groups. The information substantiates the construct validity of the measures. The clinical and research utility of the measures are discussed.

A study of recrystallization in single-phase aluminium using in-situ annealing in the scanning electron microscope.

In-situ annealing experiments were performed in the scanning electron microscope on a single-phase Al-0.13Mg alloy cold rolled to different strain levels. Once the validity of the technique had been verified by comparison of the recrystallization kinetics and final grain size with bulk annealed samples, the method was used in combination with electron back-scattered diffraction (EBSD) to study the potential mechanisms for recrystallization in this alloy. During annealing of material rolled to moderate strains (epsilont < 0.7), the primary mechanism was strain-induced boundary migration (SIBM). In material rolled to higher true strains (epsilont > 1.4), recrystallization occurred extensively along pre-existing cube bands and EBSD measurements showed that the mean size of cells within the cube bands was larger than for all other orientations measured, suggesting a size advantage was responsible for the strengthening of cube texture during recrystallization. SIBM was shown to occur concurrently with the nucleation along cube bands but this contributed a lower proportion of nucleation sites during recrystallization.

Factors affecting family-centred service delivery for children with disabilities.

BACKGROUND: The provision of family-centred services (FCS) emphasizes a partnership between parents and service providers so that families are involved in every aspect of services for their child. There is evidence that providing FCS is associated with improvements in parents' satisfaction with services, decreased parental stress, and positive child outcomes. METHODS: The purpose of this study was to examine factors that are most important in determining parent perceptions of the family centredness of care and parent satisfaction with service. A cross-sectional survey was completed by 494 parents, 324 service providers, and 15 CEOs from 16 organizations delivering children's rehabilitation services. Analyses were completed using a structural equation modelling approach. RESULTS: Survey return rates ranged from 77 to 94%. Findings indicate that the principal determinants of parent satisfaction with services are the family-centred culture at the organization and parent perceptions of FCS. Parent satisfaction with services was also influenced by the number of places where services were received and the number of health and development problems experienced by their child. CONCLUSION: Parent satisfaction with services is strongly influenced by the perception that services are more family centred, fewer places where services were received and fewer health and development problems for their child. Ways in which organizations can improve satisfaction through carrying out family-centred behaviours are discussed.

Characterizing the deformed state in Al-0.1 Mg alloy using high-resolution electron backscattered diffraction.

The application of high resolution electron backscatter diffraction (EBSD) in a field emission gun scanning electron microscope to the characterization of a deformed aluminium alloy is discussed and the results are compared with those obtained by transmission electron microscopy. It is shown that the adequate spatial resolution, accompanied by the improvement in angular resolution to approximately 0.5 degrees that can be achieved by data processing, together with the extensive quantitative data obtainable, make EBSD a suitable method for characterizing the cell or subgrain structures in deformed aluminium. The various methods of analysing EBSD data to obtain subgrain sizes are discussed and it is concluded that absolute subgrain reconstruction is the most accurate.

Expression of a sodium bicarbonate cotransporter in human parotid salivary glands.

The human parotid gland secretes much of the bicarbonate that enters the mouth. Prompted by studies of animal models, this study sought evidence for the expression of a functional Na(+)-HCO(3)(-) cotransporter (NBC) in human parotid acinar cells. Microfluorometric measurements of intracellular pH in isolated acini showed that the recovery from an acid load was achieved in part by HCO(3)(-) uptake via a Na(+)-dependent, DIDS-sensitive mechanism. By reverse transcriptase-polymerase chain reaction, a full-length NBC1 clone was obtained showing more than 99% homology with the human pancreatic isoform hpNBC1. Expressed in Xenopus oocytes, the electrogenicity of the transporter was detected as an inwardly directed, Na(+)- and HCO(3)(-)-dependent flux of negative charge. Immunohistochemistry using antibodies raised to NBC1 showed strong staining of the basolateral membrane of the acinar cells. Therefore, it was concluded that a functional electrogenic Na(+)-HCO(3)(-) cotransporter is expressed in the human parotid gland, and that it contributes to pH regulation in the acinar cells and could play a significant part in salivary secretion.

Immunomodulation of glioma cells after gene therapy: induction of major histocompatibility complex class I but not class II antigen in vitro.

OBJECTIVE: Acquired immunity has been demonstrated in Fischer rats bearing syngeneic 9L tumors after herpes simplex virus (HSV) thymidine kinase (TK) gene transfection and ganciclovir treatment. The nature of this immunity in rats and its relevance to the HSV TK/ganciclovir protocol for human subjects remain to be determined. In this study, levels of major histocompatibility complex (MHC) Class I and II antigen expression were measured before and after HSV TK transfection, in an effort to document immunomodulatory changes caused by gene therapy. METHODS: Tumor cells from the 9L gliosarcoma cell line, three primary human glioma cultures, and the human glioma cell line U87 MG were transduced with HSV TK vector-containing supernatant from fibroblast-producing cells (titer of 5 x 10(6) colony-forming units/ml) and selected in G418 medium for neomycin resistance. Clones were pooled or individually selected for cell-killing assays with ganciclovir, to confirm TK expression (10(3) cells/well in a 96-well dish). Northern analyses using MHC Class I and Class II complementary deoxyribonucleic acid probes were performed on blots containing total ribonucleic acid from wild-type tumor cells and HSV TK transfectants. A beta-actin complementary deoxyribonucleic acid probe served as an internal control. Cell surface expression was confirmed with flow cytometry. The induction of MHC Class I was tested for cycloheximide and genistein sensitivity. RESULTS: All cell cultures exhibited increases in MHC Class I but not MHC Class II expression, as determined by Northern analysis densitometry and flow cytometry. Cycloheximide treatment did not diminish the up-regulation of MHC Class I after retroviral transfection, implicating a signal transduction pathway that does not require ongoing protein synthesis. Genistein pretreatment of cell cultures did diminish the up-regulation of MHC Class I, implicating a tyrosine kinase in the signaling cascade. CONCLUSION: Induction of MHC Class I in rat and human glioma cells after HSV TK retroviral gene therapy is a primary effect that is dependent on tyrosine kinase activity. Specific immune responses generated after transfection may represent an important general side effect of gene therapy protocols. Elucidation of the mechanism of immunomodulation after gene therapy will likely yield safer and more effective clinical protocols.

Identification and localization of aquaporin water channels in human salivary glands.

Aquaporin (AQP) water channels are expressed in a variety of fluid-transporting epithelia and are likely to play a significant role in salivary secretion. Our aim was to identify and localize the aquaporins expressed in human salivary glands. Total RNA was extracted from human parotid, submandibular, sublingual, and labial glands and from human brain. Expression of aquaporin mRNA was assessed by RT-PCR using specific primers for human AQP1, AQP3, AQP4, and AQP5. All four aquaporins were detected by RT-PCR in all of the glands, and the sequences were confirmed after further amplification with nested primers. Cleaned PCR products were then used as (32)P-labeled cDNA probes in a semiquantitative Northern blot analysis using glyceraldehyde-3-phosphate dehydrogenase as reference. Only AQP1, AQP3, and AQP5 mRNAs were present at significant levels. AQP localization was determined by immunohistochemistry on paraffin sections using affinity-purified primary antibodies and peroxidase-linked secondary antibodies. Each salivary gland type showed a broadly similar staining pattern: AQP1 was localized to the capillary endothelium and myoepithelial cells; AQP3 was present in the basolateral membranes of both mucous and serous acinar cells; AQP4 was not detected; and AQP5 was expressed in the luminal and canalicular membranes of both types of acinar cell. We conclude that AQP3 and AQP5 together may provide a pathway for transcellular osmotic water flow in the formation of the primary saliva.