The Drosophila Dbf4 ortholog Chiffon forms a complex with Gcn5 that is necessary for histone acetylation and viability.

Metazoans contain two homologs of the Gcn5-binding protein Ada2, Ada2a and Ada2b, which nucleate formation of the ATAC and SAGA complexes, respectively. In Drosophila melanogaster, there are two splice isoforms of Ada2b: Ada2b-PA and Ada2b-PB. Here, we show that only the Ada2b-PB isoform is in SAGA; in contrast, Ada2b-PA associates with Gcn5, Ada3, Sgf29 and Chiffon, forming the Chiffon histone acetyltransferase (CHAT) complex. Chiffon is the Drosophila ortholog of Dbf4, which binds and activates the cell cycle kinase Cdc7 to initiate DNA replication. In flies, Chiffon and Cdc7 are required in ovary follicle cells for gene amplification, a specialized form of DNA re-replication. Although chiffon was previously reported to be dispensable for viability, here, we find that Chiffon is required for both histone acetylation and viability in flies. Surprisingly, we show that chiffon is a dicistronic gene that encodes distinct Cdc7- and CHAT-binding polypeptides. Although the Cdc7-binding domain of Chiffon is not required for viability in flies, the CHAT-binding domain is essential for viability, but is not required for gene amplification, arguing against a role in DNA replication.

Risk factors for symptomatic anastomotic postoperative recurrence following ileo-colic resection in Crohn's disease.

AIM: Crohn's disease is a chronic inflammatory bowel disease characterized by alternating periods of exacerbation and remission. Surgical resection is not curative and postoperative recurrence (POR) remains a challenge in these patients. The aim of this study was to identify clinical variables that influence the risk of symptomatic anastomotic POR in patients with ileo-colonic Crohn's disease. METHOD: A retrospective study of Crohn's disease patients who had undergone ileo-colic resection between January 2014 and December 2018 was performed. For each patient, data including demographic information, Crohn's disease clinical setting, preoperative radiological data, operative and histological data, pre- and postoperative medication history and postoperative clinical course, including recurrence of disease, were extracted. Symptomatic anastomotic POR was defined as symptoms of Crohn's disease in the presence of confirmed anastomotic POR (endoscopic and/or radiological POR). RESULTS: For the study period, 104 patients were eligible and included for analysis. The cumulative probability of symptomatic anastomotic POR was 14%, 30%, 42%, 50% and 50% at 1, 2, 3, 4 and 5 years, respectively. Two clinical variables on multivariate analysis were associated with increased risk of symptomatic anastomotic POR, namely age <17 years at diagnosis [hazard ratio (HR) 2.17, p = 0.019] and gastrointestinal involvement (extent) >30 cm (HR 1.85, p = 0.048). CONCLUSION: This study describes the natural history of POR after ileo-colic resection for Crohn's disease, as defined by endoscopic, radiological and clinical outcomes. Age <17 years at diagnosis and gastrointestinal involvement (extent) >30 cm were independent risk factors for symptomatic anastomotic POR.

Anatomically correct assessment of the orientation of the cardiomyocytes using diffusion tensor imaging.

Diffusion tensor imaging has been used for assessing the orientation of cardiac myocytes for decades. Striking methodological differences exist between studies when quantifying these orientations. This limits the comparability between studies, and impedes collaboration and the drawing of appropriate physiological conclusions. We have sought to elucidate these differences, permitting us to propose a standardised "tool set" that might better establish consensus in future studies. We fixed hearts from seven 25 kg pigs in formalin, and scanned them using diffusion tensor imaging. Using various angle definitions as found in literature, we assessed the orientations of cardiomyocytes, comparing them in terms of helical and intrusion angles, along with the orientation of their aggregations. The difference between assessment of the helical angle with and without relation to the epicardial curvature was 25.2° (SD: 7.9) at the base, 5.8° (1.9) at the equatorial level, and 28.0° (7.0) at the apex, ANOVA P = 0.001. In comparable fashion, the intrusion angle differed by 25.9° (12.9), 7.6° (0.98) and 17.5° (4.7), P = 0.01, and the angle of the aggregates (E3-angle) differed by 25.0° (13.5) at the base, 9.4° (1.7) at the equator, and 23.1° (6.2) apically, P = 0.003. When assessing 14 definitions used in literature to calculate the orientation of aggregates, only 4 rendered identical results. The findings show that any attempt to use projection of eigenvectors introduces considerable bias. The epicardial curvature of the ventricular cone needs to be taken into account when seeking to provide accurate quantification of the orientation of the aggregated cardiomyocytes, especially in the apical and basal regions. This means that projection of eigenvectors should be avoided prior to quantifying myocyte orientation, especially when assessing radial orientation. Based on our results, we suggest appropriate methods for valid assessment of myocyte orientation using diffusion tensor imaging.

Urban Commuter Campus Students' Perspectives on Sexual Violence: Implications for Response and Prevention.

Sexual violence victimization is unacceptably common in the US, with nearly half of women and one in five men reporting lifetime sexual coercion and/or unwanted sexual contact; much violence occurs in campus settings. The majority of sexual violence prevention programs designed to date were not developed around the needs of urban commuter campus students. The present study explored qualitatively how these students conceptualize sexual violence and prevention. Face-to-face in-depth interviews were conducted with students on how they recognized sexual violence and understood prevention. Interviews were audiotaped, transcribed, and analyzed. Commuter students used "gut feelings" to identify sexual violence, reporting minimal direct consent communication. Intersecting social identities and multiple, concurrent roles limit the potential impact of existing prevention programs. Further research to design and evaluate tailored sexual violence prevention programming for urban commuter campus students is needed.

Describing the Spectrum of Patient Reported Outcomes after Radical Prostatectomy: Providing Information to Improve Patient Counseling and Shared Decision Making.

PURPOSE: Preoperative counseling incorporating the best case, the worst case and the most likely outcome scenarios aid patient decision making. This information is not readily available for prostate cancer counseling because most patient reported outcomes are presented as averages, which minimize individual patient experiences. Using the EPIC (Expanded Prostate Index Composite) we present data to characterize the best case and the worst case after prostatectomy. MATERIALS AND METHODS: The EPIC bowel, urinary irritation, continence and sexual function scores were measured in 1,418 men stratified by baseline function who underwent prostatectomy. Patient level functional trajectories were modeled using a Bayesian hierarchical model. The 5-year best and worst case outcomes were defined as the upper 95th and the lower 5th percentiles, respectively. RESULTS: Five years after surgery in patients with good baseline urinary continence the best case was a score of 100.0 (95% credible interval 100.0-100.0) and the worst case was 54.4 (95% credible interval 42.2-63.7). Among men with good baseline sexual function who underwent nerve sparing surgery the best case was 83.9 points (95% credible interval 74.1-93.1) and the worst case was 17.6 (95% credible interval 7.5-26.1). The differences between best and worst case for bowel and urinary irritation were relatively small (11.4 and 13.6 points, respectively). CONCLUSIONS: Prostatectomy exerted a minimal negative impact on urinary irritation and bowel function with minimal variability. There was a larger range in patient experience for urinary continence and sexual function with most patients experiencing a significant functional decline. Future studies of best and worst case outcomes of multiple treatment modalities may provide valuable information for shared decision making in prostate cancer treatment.

How are the cardiomyocytes aggregated together within the walls of the left ventricular cone?

The manner of packing together of the cardiomyocytes within the walls of the cardiac ventricles has now been investigated for over half a millennium. In 1669, Lower dissected the ventricular mass, likening the arrangement to skeletal musculature, in the form of a myocardial band extending between the right and left atrioventricular junctions. Pettigrew subsequently showed obvious helical arrangements to be evident within the ventricular walls, but emphasised that the cardiomyocytes were attached to each other, and could not justifiably be compared with skeletal cardiomyocytes. Torrent-Guasp then reactivated the notion that the ventricular mass was formed of a solitary band. Unlike Lower, he dissected the band as extending between the pulmonary to the aortic roots. Multiple investigations conducted using gross dissection and histology, and more recently diffusion tensor magnetic resonance imaging and computed tomographic analysis, have shown an absence of any anatomical boundaries within the walls that might permit the mass uniformly to be dissected so as to reveal the band. A response to a recent letter to the Journal, nonetheless, claimed that the dissections had been validated by clinicians interpreting the findings so as to provide an explanation for ventricular cardiodynamics, arguing that the findings provided a suitable anatomical model for this purpose. Anatomical models, however, are of no value unless they are anatomically correct. In this review, therefore, we summarise the evidence showing that the cardiomyocytes making up the ventricular walls, rather than forming a ventricular myocardial band, are instead aggregated together to form a three-dimensional myocardial mesh.

Resolving the natural myocardial remodelling brought upon by cardiac contraction; a porcine ex-vivo cardiovascular magnetic resonance study of the left and right ventricle.

BACKGROUND: The three-dimensional rearrangement of the right ventricular (RV) myocardium during cardiac deformation is unknown. Previous in-vivo studies have shown that myocardial left ventricular (LV) deformation is driven by rearrangement of aggregations of cardiomyocytes that can be characterised by changes in the so-called E3-angle. Ex-vivo imaging offers superior spatial resolution compared with in-vivo measurements, and can thus provide novel insight into the deformation of the myocardial microstructure in both ventricles. This study sought to describe the dynamic changes of the orientations of the cardiomyocytes in both ventricles brought upon by cardiac contraction, with particular interest in the thin-walled RV, which has not previously been described in terms of its micro-architecture. METHODS: The hearts of 14 healthy 20 kg swine were excised and preserved in either a relaxed state or a contracted state. Myocardial architecture was assessed and compared between the two contractional states by quantification of the helical, transmural and E3-angles of the cardiomyocytes using high-resolution diffusion tensor imaging. RESULTS: The differences between the two states of contraction were most pronounced in the endocardium where the E3-angle decreased from 78.6° to 24.8° in the LV and from 82.6° to 68.6° in the RV. No significant change in neither the helical nor the transmural angle was found in the cardiomyocytes of the RV. In the endocardium of the LV, however, the helical angle increased from 35.4° to 47.8° and the transmural angle increased from 3.1° to 10.4°. CONCLUSION: The entire myocardium rearranges through the cardiac cycle with the change in the orientation of the aggregations of cardiomyocytes being the predominant mediator of myocardial wall thickening. Interestingly, differences also exist between the RV and LV, which helps in the explanation of the different physiological capabilities of the ventricles.

Variation in egg mass within two Atlantic herring Clupea harengus stocks.

The main objective of this study was to investigate if egg size (mass) at spawning is invariant for Scotia-Fundy summer and autumn (SFSH) and Icelandic summer (ISSH) spawning herring Clupea harengus. Oocyte dry mass measurements for SFSH females collected in 2001 and ISSH females collected in 1999 and 2000 showed a large variation. Difference in egg dry mass among fish was found to vary by as much as twofold in each stock. For ISSH, variation in egg mass was also apparent from oocyte volume measurements made jointly with a histological examination of the ovaries. Approximately 20% of the variation in egg mass could be explained by maternal whole-body mass or total length, indicating that length or age composition in the stocks can potentially influence the recruitment success. This implies that fisheries management strategies should aim to maintain a broad range in age composition.

Modulation of Premetastatic Niche by the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Pazopanib in Localized High-Risk Prostate Cancer Followed by Radical Prostatectomy: A Phase II Randomized Trial.

LESSONS LEARNED: Pazopanib was not effective in altering the premetastatic niche in the neoadjuvant setting.Pazopanib was safe and well tolerated without any new safety signals. BACKGROUND: Vascular endothelial growth factor receptor 1 (VEGFR1) expressing myeloid-derived suppressor cells (VEGFR1+ MDSCs) potentially foster metastases by establishing a premetastatic niche. In a preclinical study, VEGFR1+ clustering in lymph nodes (LNs) independently predicted time to biochemical recurrence (TTBR) in localized prostate cancer [1]. The hypothesis was that neoadjuvant pazopanib therapy will decrease VEGFR1+ clusters in pelvic lymph nodes and improve outcomes. METHODS: This is a phase II trial (NCT01832259) of neoadjuvant pazopanib 800 mg versus placebo daily for 4 weeks in high-risk localized prostate cancer. The primary endpoint was a decrease in VEGFR1+ MDSC clustering assessed by immunohistochemistry (IHC) analysis. Secondary endpoints were safety, feasibility, and TTBR. RESULTS: Thirty patients were randomized to pazopanib versus placebo, with 15 patients randomized to each arm. Demographic and disease characteristics were similar in both arms. There was no difference in the VEGFR1+ clustering between the treatment arms (p = .345). Neoadjuvant therapy with pazopanib was well tolerated, and surgical complications were similar in both arms. CONCLUSION: Neoadjuvant pazopanib therapy did not alter the premetastatic niche; however, treatment targeting vascular endothelial growth factor (VEGF) in the preoperative period was safe and feasible, which may open up the avenue to investigate novel combinatorial regimens, including a VEGF inhibitor in combination with immune checkpoint inhibitor in this setting.

Relative Risks for Lethal Prostate Cancer Based on Complete Family History of Prostate Cancer Death.

BACKGROUND: There are few published familial relative risks (RR) for lethal prostate cancer. This study estimates RRs for lethal prostate cancer based on comprehensive family history data, with the goal of improving identification of those men at highest risk of dying from prostate cancer. METHODS: We used a population-based genealogical resource linked to a statewide electronic SEER cancer registry and death certificates to estimate relative risks (RR) for death from prostate cancer based upon family history. Over 600,000 male probands were analyzed, representing a variety of family history constellations of lethal prostate cancer. RR estimates were based on the ratio of the observed to the expected number of lethal prostate cancer cases using internal rates. RESULTS: RRs for lethal prostate cancer based on the number of affected first-degree relatives (FDR) ranged from 2.49 (95% CI: 2.27, 2.73) for exactly 1 FDR to 5.30 (2.13, 10.93) for ≥3 affected FDRs. In an absence of affected FDRs, increased risk was also significant for increasing numbers of affected second-degree or third degree relatives. Equivalent risks were observed for similar maternal and paternal family history. CONCLUSIONS: This study provides population-based estimates of lethal prostate cancer risk based on lethal prostate cancer family history. Many family history constellations associated with two to greater than five times increased risk for lethal prostate cancer were identified. These lethal prostate cancer risk estimates hold potential for use in identification, screening, early diagnosis, and treatment of men at high risk for death from prostate cancer. Prostate77:41-48, 2017. © 2016 Wiley Periodicals, Inc.

Characterization of a Drosophila ortholog of the Cdc7 kinase: a role for Cdc7 in endoreplication independent of Chiffon.

Cdc7 is a serine-threonine kinase that phosphorylates components of the pre-replication complex during DNA replication initiation. Cdc7 is highly conserved, and Cdc7 orthologs have been characterized in organisms ranging from yeast to humans. Cdc7 is activated specifically during late G1/S phase by binding to its regulatory subunit, Dbf4. Drosophila melanogaster contains a Dbf4 ortholog, Chiffon, which is essential for chorion amplification in Drosophila egg chambers. However, no Drosophila ortholog of Cdc7 has yet been characterized. Here, we report the functional and biochemical characterization of a Drosophila ortholog of Cdc7. Co-expression of Drosophila Cdc7 and Chiffon is able to complement a growth defect in yeast containing a temperature-sensitive Cdc7 mutant. Cdc7 and Chiffon physically interact and can be co-purified from insect cells. Cdc7 phosphorylates the known Cdc7 substrates Mcm2 and histone H3 in vitro, and Cdc7 kinase activity is stimulated by Chiffon and inhibited by the Cdc7-specific inhibitor XL413. Drosophila egg chamber follicle cells deficient for Cdc7 have a defect in two types of DNA replication, endoreplication and chorion gene amplification. However, follicle cells deficient for Chiffon have a defect in chorion gene amplification but still undergo endocycling. Our results show that Cdc7 interacts with Chiffon to form a functional Dbf4-dependent kinase complex and that Cdc7 is necessary for DNA replication in Drosophila egg chamber follicle cells. Additionally, we show that Chiffon is a member of an expanding subset of DNA replication initiation factors that are not strictly required for endoreplication in Drosophila.

A High-Affinity Native Human Antibody Disrupts Biofilm from Staphylococcus aureus Bacteria and Potentiates Antibiotic Efficacy in a Mouse Implant Infection Model.

Many serious bacterial infections are difficult to treat due to biofilm formation, which provides physical protection and induces a sessile phenotype refractory to antibiotic treatment compared to the planktonic state. A key structural component of biofilm is extracellular DNA, which is held in place by secreted bacterial proteins from the DNABII family: integration host factor (IHF) and histone-like (HU) proteins. A native human monoclonal antibody, TRL1068, has been discovered using single B-lymphocyte screening technology. It has low-picomolar affinity against DNABII homologs from important Gram-positive and Gram-negative bacterial pathogens. The disruption of established biofilm was observedin vitroat an antibody concentration of 1.2 µg/ml over 12 h. The effect of TRL1068in vivowas evaluated in a murine tissue cage infection model in which a biofilm is formed by infection with methicillin-resistantStaphylococcus aureus(MRSA; ATCC 43300). Treatment of the established biofilm by combination therapy of TRL1068 (15 mg/kg of body weight, intraperitoneal [i.p.] administration) with daptomycin (50 mg/kg, i.p.) significantly reduced adherent bacterial count compared to that after daptomycin treatment alone, accompanied by significant reduction in planktonic bacterial numbers. The quantification of TRL1068 in sample matrices showed substantial penetration of TRL1068 from serum into the cage interior. TRL1068 is a clinical candidate for combination treatment with standard-of-care antibiotics to overcome the drug-refractory state associated with biofilm formation, with potential utility for a broad spectrum of difficult-to-treat bacterial infections.

Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21.

Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus.

Inherited Variants in SULT1E1 and Response to Abiraterone Acetate by Men with Metastatic Castration Refractory Prostate Cancer.

PURPOSE: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict the response to abiraterone acetate in men with metastatic, castration refractory prostate cancer. The variations may serve as prognostic and predictive biomarkers to allow for more individualized therapy. MATERIALS AND METHODS: We evaluated 832 single nucleotide polymorphisms from the OmniExpress genotyping platform (Illumina®) in the boundaries of 61 candidate genes reported to be involved in the androgen metabolic pathway. The purpose was to investigate them for an association with time to treatment failure in 68 white men with metastatic, castration refractory prostate cancer undergoing treatment with abiraterone acetate. Cox proportional hazard analysis was used with Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation as covariates. Each single nucleotide polymorphism was assessed using an allele carriage genetic model in which carriage of 1 or more minor alleles contributes to increased risk. Subset analyses were done to determine whether metastasis site, or prior treatment with ketoconazole or docetaxel would interact with the single nucleotide polymorphisms investigated. RESULTS: Six single nucleotide polymorphisms in the estrogen sulfotransferase gene SULT1E1 were associated with time to treatment failure on abiraterone acetate therapy after false discovery rate (q value) correction for multiple testing while controlling for Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation (q <0.05). CONCLUSIONS: Single nucleotide polymorphisms in SULT1E1 were significantly associated with time to treatment failure in men on abiraterone acetate therapy. The single nucleotide polymorphisms may serve as predictive markers for treatment with abiraterone acetate.

The Comparative Harms of Open and Robotic Prostatectomy in Population Based Samples.

PURPOSE: Robotic assisted radical prostatectomy has largely replaced open radical prostatectomy for the surgical management of prostate cancer despite conflicting evidence of superiority with respect to disease control or functional sequelae. Using population cohort data, in this study we examined sexual and urinary function in men undergoing open radical prostatectomy vs those undergoing robotic assisted radical prostatectomy. MATERIALS AND METHODS: Subjects surgically treated for prostate cancer were selected from 2 large population based prospective cohort studies, the Prostate Cancer Outcomes Study (enrolled 1994 to 1995) and the Comparative Effectiveness Analysis of Surgery and Radiation (enrolled 2011 to 2012). Subjects completed baseline, 6-month and 12-month standardized patient reported outcome measures. Main outcomes were between-group differences in functional outcome scores at 6 and 12 months using linear regression, and adjusting for baseline function, sociodemographic and clinical characteristics. Sensitivity analyses were used to evaluate outcomes between patients undergoing open radical prostatectomy and robotic assisted radical prostatectomy within and across CEASAR and PCOS. RESULTS: The combined cohort consisted of 2,438 men, 1,505 of whom underwent open radical prostatectomy and 933 of whom underwent robotic assisted radical prostatectomy. Men treated with robotic assisted radical prostatectomy reported better urinary function at 6 months (mean difference 3.77 points, 95% CI 1.09-6.44) but not at 12 months (1.19, -1.32-3.71). Subjects treated with robotic assisted radical prostatectomy also reported superior sexual function at 6 months (8.31, 6.02-10.56) and at 12 months (7.64, 5.25-10.03). Sensitivity analyses largely supported the sexual function findings with inconsistent support for urinary function results. CONCLUSIONS: This population based study reveals that men undergoing robotic assisted radical prostatectomy likely experience less decline in early urinary continence and sexual function than those undergoing open radical prostatectomy. The clinical meaning of these differences is uncertain and longer followup will be required to establish whether these benefits are durable.

Insights from echocardiography, magnetic resonance imaging, and microcomputed tomography relative to the mid-myocardial left ventricular echogenic zone.

BACKGROUND: The anatomical substrate for the mid-mural ventricular hyperechogenic zone remains uncertain, but it may represent no more than ultrasound reflected from cardiomyocytes orientated orthogonally to the ultrasonic beam. We sought to ascertain the relationship between the echogenic zone and the orientation of the cardiomyocytes. METHODS: We used 3D echocardiography, diffusion tensor imaging, and microcomputed tomography to analyze the location and orientation of cardiomyocytes within the echogenic zone. RESULTS: We demonstrated that visualization of the echogenic zone is dependent on the position of the transducer and is most clearly seen from the apical window. Diffusion tensor imaging and microcomputed tomography show that the echogenic zone seen from the apical window corresponds to the position of the circumferentially orientated cardiomyocytes. An oblique band seen in the parasternal view relates to cardiomyocytes orientated orthogonally to the ultrasonic beam. CONCLUSIONS: The mid-mural ventricular hyperechogenic zone represents reflected ultrasound from cardiomyocytes aligned orthogonal to the ultrasonic beam. The echogenic zone does not represent a space, a connective tissue sheet, a boundary between ascending and descending limbs of a hypothetical helical ventricular myocardial band, nor an abrupt change in cardiomyocyte orientation.

The functional architecture of skeletal compared to cardiac musculature: Myocyte orientation, lamellar unit morphology, and the helical ventricular myocardial band.

How the cardiomyocytes are aggregated within the heart walls remains contentious. We still do not fully understand how the end-to-end longitudinal myocytic chains are arranged, nor the true extent and shape of the lamellar units they aggregate to form. In this article, we show that an understanding of the complex arrangement of cardiac musculature requires knowledge of three-dimensional myocyte orientation (helical and intrusion angle), and appreciation of myocyte packing within the connective tissue matrix. We show how visualization and segmentation of high-resolution three-dimensional image data can accurately identify the morphology and orientation of the myocytic chains, and the lamellar units. Some maintain that the ventricles can be unwrapped in the form of a "helical ventricular myocardial band," that is, as a compartmentalized band with selective regional innervation and deformation, and a defined origin and insertion like most skeletal muscles. In contrast to the simpler interpretation of the helical ventricular myocardial band, we provide insight as to how the complex myocytic chains, the heterogeneous lamellar units, and connective tissue matrix form an interconnected meshwork, which facilitates the complex internal deformations of the ventricular wall. We highlight the dangers of disregarding the intruding cardiomyocytes. Preparation of the band destroys intruding myocytic chains, and thus disregards the functional implications of the antagonistic auxotonic forces they produce. We conclude that the ventricular myocardium is not analogous to skeletal muscle, but is a complex three-dimensional meshwork, with a heterogeneous branching lamellar architecture.

Prostate cancer risk prediction based on complete prostate cancer family history.

BACKGROUND: Prostate cancer (PC) relative risks (RRs) are typically estimated based on status of close relatives or presence of any affected relatives. This study provides RR estimates using extensive and specific PC family history. METHODS: A retrospective population-based study was undertaken to estimate RRs for PC based on complete family history of PC. A total of 635,443 males, all with ancestral genealogy data, were analyzed. RRs for PC were determined based upon PC rates estimated from males with no PC family history (without PC in first, second, or third degree relatives). RRs were determined for a variety of constellations, for example, number of first through third degree relatives; named (grandfather, father, uncle, cousins, brothers); maternal, paternal relationships, and age of onset. RESULTS: In the 635,443 males analyzed, 18,105 had PC. First-degree RRs ranged from 2.46 (=1 first-degree relative affected, CI = 2.39-2.53) to 7.65 (=4 first-degree relatives affected, CI = 6.28-9.23). Second-degree RRs for probands with 0 affected first-degree relatives ranged from 1.51 (≥1 second-degree relative affected, CI = 1.47-1.56) to 3.09 (≥5 second-degree relatives affected, CI = 2.32-4.03). Third-degree RRs with 0 affected first- and 0 affected second-degree relatives ranged from 1.15 (≥1 affected third-degree relative, CI = 1.12-1.19) to 1.50 (≥5 affected third-degree relatives, CI = 1.35-1.66). RRs based on age at diagnosis were higher for earlier age at diagnoses; for example, RR = 5.54 for ≥1 first-degree relative diagnosed before age 50 years (CI = 1.12-1.19) and RR = 1.78 for >1 second-degree relative diagnosed before age 50 years, CI = 1.33, 2.33. RRs for equivalent maternal versus paternal family history were not significantly different. CONCLUSIONS: A more complete PC family history using close and distant relatives and age at diagnosis results in a wider range of estimates of individual RR that are potentially more accurate than RRs estimated from summary family history. The presence of PC in second- and even third-degree relatives contributes significantly to risk. Maternal family history is just as significant as paternal family history. PC RRs based on a proband's complete constellation of affected relatives will allow patients and care providers to make more informed screening, monitoring, and treatment decisions.

A high-affinity native human antibody neutralizes human cytomegalovirus infection of diverse cell types.

Human cytomegalovirus (HCMV) is the most common infection causing poor outcomes among transplant recipients. Maternal infection and transplacental transmission are major causes of permanent birth defects. Although no active vaccines to prevent HCMV infection have been approved, passive immunization with HCMV-specific immunoglobulin has shown promise in the treatment of both transplant and congenital indications. Antibodies targeting the viral glycoprotein B (gB) surface protein are known to neutralize HCMV infectivity, with high-affinity binding being a desirable trait, both to compete with low-affinity antibodies that promote the transmission of virus across the placenta and to displace nonneutralizing antibodies binding nearby epitopes. Using a miniaturized screening technology to characterize secreted IgG from single human B lymphocytes, 30 antibodies directed against gB were previously cloned. The most potent clone, TRL345, is described here. Its measured affinity was 1 pM for the highly conserved site I of the AD-2 epitope of gB. Strain-independent neutralization was confirmed for 15 primary HCMV clinical isolates. TRL345 prevented HCMV infection of placental fibroblasts, smooth muscle cells, endothelial cells, and epithelial cells, and it inhibited postinfection HCMV spread in epithelial cells. The potential utility for preventing congenital transmission is supported by the blockage of HCMV infection of placental cell types central to virus transmission to the fetus, including differentiating cytotrophoblasts, trophoblast progenitor cells, and placental fibroblasts. Further, TRL345 was effective at controlling an ex vivo infection of human placental anchoring villi. TRL345 has been utilized on a commercial scale and is a candidate for clinical evaluation.

Identification of specific Y chromosomes associated with increased prostate cancer risk.

BACKGROUND: Evidence supports the possibility of a role of the Y chromosome in prostate cancer, but controversy exists. METHODS: A novel analysis of a computerized population-based resource linking genealogy and cancer data was used to test the hypothesis of a role of the Y chromosome in prostate cancer predisposition. Using a statewide cancer registry from 1966 linked to a computerized genealogy representing over 1.2 million descendants of the Utah pioneers, 1,000 independent sets of males, each set hypothesized to share the same Y chromosome as represented in genealogy data, were tested for a significant excess of prostate cancer. RESULTS: Multiple Y chromosomes representing thousands of potentially at-risk males were identified to have a significant excess risk for prostate cancer. CONCLUSIONS: This powerful and efficient in silico test of an uncommon mode of inheritance has confirmed evidence for Y chromosome involvement in prostate cancer.