Effects of Obesity on the Regulation of Macrophage Population in the Prostate Tumor Microenvironment.

Obesity is associated with a greater risk of prostate cancer mortality. However, the mechanisms connecting obesity to the progression of prostate cancer remain unknown. This study determined the impact of obesity on macrophage recruitment and tumor-associated macrophage (TAM) polarization in the prostate tumor microenvironment, since a high concentration of TAMs in tumors has been linked to progression in prostate cancer. We utilized an in vitro model in which pre-adipocytes, prostate cancer cells, and macrophages were exposed to sera from obese or nonobese men, or conditioned media generated under obese or nonobese conditions. Matrigel invasion chambers were used to assess macrophage recruitment in vitro, and immunohistochemical analysis evaluated recruitment in a PTEN knockout mouse model. qPCR was used to measure mRNA levels of CCL2, COX-2, IL-10, TGF-beta, VEGF-A, arginase-1, and MMP-9. PGE2 production was measured by ELISA. Obesity increased macrophage and TAM recruitment, and increased mRNA levels of TAM markers in macrophages. Similarly, obese conditions increased CCL2 and COX-2 expression, as well as PGE2 levels in prostate cancer cells. COX-2 inhibition resulted in lower expression of obesity-induced TAM markers. Our data suggest that obesity promotes macrophage infiltration into the prostate tumor microenvironment, and induces TAM polarization through the COX-2/PGE2 pathway.

A diagnosis of prostate cancer and pursuit of active surveillance is not followed by weight loss: potential for a teachable moment.

BACKGROUND: Obesity is a risk factor for incident prostate cancer (PC) as well as risk of disease progression and mortality. We hypothesized that men diagnosed with lower-risk PC and who elected active surveillance (AS) for their cancer management would likely initiate lifestyle changes that lead to weight loss. METHODS: Patients were enrolled in the Prostate Active Surveillance Study (PASS), a multicenter prospective biomarker discovery and validation study of men who have chosen AS for their PC. Data from 442 men diagnosed with PC within 1 year of study entry who completed a standard of care 12-month follow-up visit were analyzed. We examined the change in weight and body mass index (BMI) over the first year of study participation. RESULTS: After 1 year on AS, 7.5% (33/442) of patients had lost 5% or more of their on-study weight. The proportion of men who lost 5% or more weight was similar across categories of baseline BMI: normal/underweight (8%), overweight (6%) and obese (10%, χ2 test P=0.44). The results were similar for patients enrolled in the study 1 year or 6 months after diagnosis. By contrast, after 1 year, 7.7% (34/442) of patients had gained >5% of their weight. CONCLUSIONS: Only 7.5% of men with low-risk PC enrolled in AS lost a modest (⩾5%) amount of weight after diagnosis. Given that obesity is related to PC progression and mortality, targeted lifestyle interventions may be effective at this 'teachable moment', as men begin AS for low-risk PC.

In vivo prostate cancer detection and grading using restriction spectrum imaging-MRI.

BACKGROUND: Magnetic resonance imaging (MRI) is emerging as a robust, noninvasive method for detecting and characterizing prostate cancer (PCa), but limitations remain in its ability to distinguish cancerous from non-cancerous tissue. We evaluated the performance of a novel MRI technique, restriction spectrum imaging (RSI-MRI), to quantitatively detect and grade PCa compared with current standard-of-care MRI. METHODS: In a retrospective evaluation of 33 patients with biopsy-proven PCa who underwent RSI-MRI and standard MRI before radical prostatectomy, receiver-operating characteristic (ROC) curves were performed for RSI-MRI and each quantitative MRI term, with area under the ROC curve (AUC) used to compare each term's ability to differentiate between PCa and normal prostate. Spearman rank-order correlations were performed to assess each term's ability to predict PCa grade in the radical prostatectomy specimens. RESULTS: RSI-MRI demonstrated superior differentiation of PCa from normal tissue, with AUC of 0.94 and 0.85 for RSI-MRI and conventional diffusion MRI, respectively (P=0.04). RSI-MRI also demonstrated superior performance in predicting PCa aggressiveness, with Spearman rank-order correlation coefficients of 0.53 (P=0.002) and -0.42 (P=0.01) for RSI-MRI and conventional diffusion MRI, respectively, with tumor grade. CONCLUSIONS: RSI-MRI significantly improves upon current noninvasive PCa imaging and may potentially enhance its diagnosis and characterization.

Novel technique for characterizing prostate cancer utilizing MRI restriction spectrum imaging: proof of principle and initial clinical experience with extraprostatic extension.

BACKGROUND: Standard magnetic resonance imaging (MRI) of the prostate lacks sensitivity in the diagnosis and staging of prostate cancer (PCa). To improve the operating characteristics of prostate MRI in the detection and characterization of PCa, we developed a novel, enhanced MRI diffusion technique using restriction spectrum imaging (RSI-MRI). METHODS: We compared the efficacy of our novel RSI-MRI technique with standard MRI for detecting extraprostatic extension (EPE) among 28 PCa patients who underwent MRI and RSI-MRI prior to radical prostatectomy, 10 with histologically proven pT3 disease. RSI cellularity maps isolating the restricted isotropic water fraction were reconstructed based on all b-values and then standardized across the sample with z-score maps. Distortion correction of the RSI maps was performed using the alternating phase-encode technique. RESULTS: 27 patients were evaluated, excluding one patient where distortion could not be performed. Preoperative standard MRI correctly identified extraprostatic the extension in two of the nine pT3 (22%) patients, whereas RSI-MRI identified EPE in eight of nine (89%) patients. RSI-MRI correctly identified pT2 disease in the remaining 18 patients. CONCLUSIONS: In this proof of principle study, we conclude that our novel RSI-MRI technology is feasible and shows promise for substantially improving PCa imaging. Further translational studies of prostate RSI-MRI in the diagnosis and staging of PCa are indicated.

Assessment of genetic variability and relatedness among atypical Aeromonas salmonicida from marine fishes, using AFLP-fingerprinting.

Atypical strains of Aeromonas salmonicida are the causal agent of atypical furunculosis or ulcer disease in various fish species, including spotted wolffish Anarhichas minor, which is a promising species in the Norwegian fish-farming industry. Isolates of atypical A. salmonicida comprise a very heterogenous group showing large variety in biochemical, molecular and virulence characteristics. The genetic variability among atypical isolates from wolffish was characterised using amplified fragment length polymorphism analysis: AFLP-fingerprinting. Additional isolates from halibut Hippoglossus hippoglossus, turbot Scophthalmus maximus, cod Gadus morhua and several salmonid fishes were included for assessment of variability and relatedness among a total of 56 atypical isolates of A. salmonicida. They were compared to reference strains of A. salmonicida subspecies and to other Aeromonas species pathogenic in fishes. AFLP-fingerprints subjected to similarity analysis yielded a grouping of the isolates into several clusters, revealing genetic heterogeneity among the isolates. There seems to be a correlation between genetic similarity among isolates and the fish host. The Icelandic isolates, mainly from cod, formed a very homogeneous subcluster, which was closely related to the wolffish isolates. All atypical isolates from spotted and common wolffish grouped together in a large cluster and appear to be very homogeneous, even though they had been isolated over a period of 8 yr at different locations in Norway. On the other hand, most of the isolates from turbot and halibut grouped together into 2 different clusters, while the 9 atypical isolates from salmonids appeared in 4 different clusters. Thus, the atypical isolates of A. salmonicida from halibut, turbot and salmonid fishes seem to be more genetically diverse than those from wolffish and cod.

Heterogeneous nuclear ribonucleoprotein E1B-AP5 is methylated in its Arg-Gly-Gly (RGG) box and interacts with human arginine methyltransferase HRMT1L1.

The heterogeneous nuclear ribonucleoprotein (hnRNP) family includes predominantly nuclear proteins acting at different stages of mRNA metabolism. A characteristic feature of hnRNPs is to undergo post-translational asymmetric arginine methylation catalysed by different type 1 protein arginine methyltransferases (PRMTs). A novel mammalian hnRNP, E1B-AP5, recently identified by its interaction with adenovirus early protein E1B-55 kDa, has been proposed to have a regulatory role in adenoviral and host-cell mRNA processing/nuclear export [Gabler, Schutt, Groitl, Wolf, Shenk and Dobner (1998) J. Virol. 72, 7960-7971]. Here we report that E1B-AP5 is methylated in vivo in its Arg-Gly-Gly (RGG)-box domain, known to mediate protein-RNA interactions. The activity responsible for E1B-AP5 methylation forms a complex with E1B-AP5 in vivo. The predominant mammalian arginine methyltransferase HRMT1L2 (hPRMT1) did not detectably methylate endogenous E1B-AP5 despite efficiently methylating a recombinant RGG-box domain of E1B-AP5. Using yeast two-hybrid screening we identified HRMT1L1 (PRMT2) as one of the proteins interacting with E1B-AP5. By in situ immunofluorescence we demonstrated that E1B-AP5 co-localizes with the nuclear fraction of HRMT1L1. The Src homology 3 (SH3) domain of HRMT1L1 was essential for its interaction with E1B-AP5 in vivo. We suggest that HRMT1L1 is responsible for specific E1B-AP5 methylation in vivo.

Predictors and correlates of adaptive functioning in children with developmental disorders.

Autism is a developmental disorder marked by impairments in socialization, communication, and perseverative behavior and is associated with cognitive impairment and deficits in adaptive functioning. Research has consistently demonstrated that children with autism have deficits in adaptive functioning more severe than their cognitive deficits. This study investigates the correlates and predictors of adaptive functioning as measured by the Vineland Adaptive Behavior Scales in high- and low-functioning children with autism and their age and nonverbal IQ matched controls. Thirty-five 9-year-old children with high-functioning autism (HAD) were compared with 31 age-matched children with developmental language disorder (DLD), and 40 9-year-old children with low-functioning autism (LAD) were compared with 17 age-matched children with low IQ on adaptive functioning, IQ, autistic symptomology, and tests of language and verbal memory. Results indicate that both groups with autism were significantly impaired compared to their matched controls on Socialization and Daily Living, but not Communication and that these impairments were more pronounced in the HAD group than in the LAD group. Adaptive behavior was strongly correlated with autistic symptomology only in the HAD group. Regression analyses indicated that IQ was strongly predictive of adaptive behavior in both low-functioning groups, but tests of language and verbal memory predicted adaptive behavior in the higher functioning groups. Results suggest that IQ may act as a limiting factor for lower functioning children but higher functioning children are impaired by specific deficits, including autistic symptomology and impaired language and verbal memory.

Executive functioning in high-functioning children with autism.

Executive functioning was investigated in 34 children (24 boys and 10 girls) with developmental language disorder (DLD) and 21 children (18 boys and 3 girls) with high-functioning autistic disorder (HAD) matched on Full Scale IQ, Nonverbal IQ, age (mean age 9 year, 1 month), and SES. The DLD group had a Verbal IQ that was 10 points higher than the HAD group. These children were given the Wisconsin Card Sorting Test (WCST), the Mazes subtest from the WISC-R, the Underlining test, and the Rapid Automatized Naming test. In addition, these children were given the Vineland Scales of Adaptive Functioning and the Wing Diagnostic Symptom Checklist in order to assess severity of autistic symptomatology. Results indicated that the only significant difference between the two groups on the cognitive tasks was perseverative errors on the WCST; there was no significant difference on total number of categories achieved or total number of errors on the WCST or on the other executive function measures. There was also significant overlap in the scores between the two groups and the difference in perseverative errors was no longer significant when Verbal IQ was partialled out. Executive functioning was strongly related to all IQ variables in the DLD group and particularly related to Verbal IQ in the HAD group. Although there was a relationship in the HAD group between executive functioning and adaptive functioning, as well as between executive functioning and autistic symptomatology, these relationships were generally no longer significant in the HAD group after the variance due to Verbal IQ was accounted for. The results are interpreted to indicate that although impaired executive functioning is a commonly associated feature of autism, it is not universal in autism and is unlikely to cause autistic behaviors or deficits in adaptive function.

Intron sequences provide a tool for high-resolution phylogenetic analysis of volvocine algae.

Three nuclear spliceosomal introns in conserved locations were amplified and sequenced from 28 strains representing 14 species and 4 genera of volvocalean green algae. Data derived from the three different introns yielded congruent results in nearly all cases. In pairwise comparisons, a spectrum of taxon-specific sequence differences ranging from complete identity to no significant similarity was observed, with the most distantly related organisms lacking any conserved elements apart from exon-intron boundaries and a pyrimidine-rich stretch near the 3' splice site. A metric (SI50), providing a measure of the degree of similarity of any pair of intron sequences, was defined and used to calculate phylogenetic distances between organisms whose introns displayed statistically significant similarities. The rate of sequences divergence in the introns was great enough to provide useful information about relationships among different geographical isolates of a single species, but in most cases was too great to provide reliable guides to relationships above the species level. A substitution rate of approximately 3 x 10(-8) per intron position per year was estimated, which is about 150-fold higher than in nuclear genes encoding rRNA and about 10-fold higher than the synonymous substitution rate in protein-coding regions. Thus, these homologous introns not only provide useful information about intraspecific phylogenetic relationships, but also illustrate the concept that different parts of a gene may be subject to extremely different intensities of selection. The intron data generated here (1) reliably resolve for the first time the relationships among the five most extensively studied strains of Volvox, (2) reveal that two other Volvox species may be more closely related than had previously been suspected, (3) confirm prior evidence that particular isolates of Eudorina elegans and Pleodorina illinoisensis appear to be sibling taxa, and (4) contribute to the resolution of several hitherto unsettled issues in Chlamydomonas taxonomy.

Problems and coping strategies of individuals with traumatic brain injury and their spouses.

A pilot investigation is reported on the problems and coping strategies of 20 married men and 11 married women with traumatic brain injury (TBI) and their able-bodied spouses. All injured subjects experienced severe head injury at least one and a half years earlier. A structured, small-group discussion process was used to elicit a prioritized list of problems and a similar list of coping strategies. Individuals with TBI and their spouses identified problems in living as most important; loss of employment and restrictions on autonomy were reported as the most problematic. Men with TBI placed priority on controlling their anger, whereas, women with TBI were concerned with their mood disorders, particularly depression. Women with TBI and able-bodied wives of men with TBI placed high priority on the use of support groups as a coping strategy. Men placed higher priority on individualistic approaches to adjustment, such as suppression of feelings. A number of testable hypotheses resulted from the pilot study.

Traumatic brain injury and marital relationships: a literature review.

This is a review of the research regarding the effects of traumatic brain injury (TBI) on the marital relationship. Individuals who have withstood a severe traumatic brain injury usually exhibit a range of cognitive and behavioural disabilities. Typical problems outlined in the research include: attention and concentration deficits, memory and information-processing deficits, judgement and perception difficulties. While these impediments pose problems for community re-integration, they may become sources of difficulty for the spouse. The following report critically examines the literature on the effects of head injury on marital relationships. This research has demonstrated that spouses' reactions to TBI include feelings of anxiety, isolation, and loss. In addition, this literature review shows that there is a dearth of research that has regarded the individual with TBI to be a valid source of information, or has considered women with TBI in a marital situation.

Radiation therapy and clinical physics practices in the midwest (1982-1986).

As a part of an on-site physics review procedure, the Midwest Center for Radiological Physics (MWCRP) interviewed midwest clinical radiotherapy physicists and radiation therapists in institutions that participated in federally funded Cancer Control Programs. Information from 77 institutions was compiled regarding types of megavoltage units, daily patient load, radiotherapy personnel, treatment planning responsibilities, dosimetric practices, and treatment planning computers. Even though some practices, such as frequency of patient charge checks, were consistent throughout the midwest, other practices varied considerably such as patient load with the number of megavoltage units. This information may be useful either for planning a new facility, considering the needs for staff, or for comparing existing practices and responsibilities.

Calibration and use of the Wisconsin kVp test cassette.

The Ardran-Crooks kVp test cassette is widely used in diagnostic radiology to provide a rapid, simple, noninvasive measurement of x-ray tube potential. A modified version of this cassette called the Wisconsin kVp Test Cassette was introduced commercially in the U. S. in 1972. Since then, the method of calibration of these cassettes has changed significantly. Wisconsin kVp Test Cassettes calibrated by the manufacturer prior to August 1982 may yield underestimates of kVp measurements, particularly when using the 90-110 and 110-130 kVp regions with single-phase units. In August 1982 significant improvements in the calibration methods were implemented. The resultant change in calibration is demonstrated by data from the Centers for Radiological Physics. Present calibration methods are believed to be accurate within the greater of +/- 2 kVp or 2% of actual peak tube potential. Proper use of the cassette is necessary to achieve this level of accuracy.

The use of Teflon-embedded calcium sulphate: dysprosium thermoluminescent dosimeters for chest radiography.

As part of a U.S. multi-regional pilot study conducted by the six Centers for Radiological Physics, 12-mm-diameter by 0.4-mm-thick CaSO4:Dy Teflon-embedded discs were evaluated and used to measure patient entrance exposure on 60 "average" patients at 12 clinical centers. The discs were found to have adequate sensitivity, reproducibility and linearity up to 69.7 microC kg-1 (270 mR). The minimum measurable exposure was estimated as 0.4 microC kg-1 (1.5 mR). All responses were corrected for energy dependence, which varied +/- 20% from 1.7 to 6.5 mm Al half-value layer. Patient entrance exposure values ranged from 1.3 to 28 microC kg-1 (5 to 110 mR), with a median value of 5.2 microC kg-1 (20 mR). This value agreed with exposure measurements made on the chest radiography equipment using an ionization chamber and a phantom which simulated an "average" patient, and with published Nationwide Evaluation of X-Ray Trends (NEXT) data for the same period.