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Abstract Background This is a protocol for a systematic review of the impact of health coaching on changing the health behaviour of offenders. Prisoners are more likely to suffer from health-related issues when compared to the general population. Health coaching has been shown to influence health outcomes of patients with chronic conditions. This review, therefore, aims to assess the effectiveness of health coaching interventions on the health of adolescent and adult offenders in custodial institutions. Methods We plan to conduct a systematic review of the current literature on health coaching interventions delivered in the prison setting. We will include randomised controlled trials and observational studies that compare health coaching to the usual care or other alternative interventions. The ideal interventions will be delivered either by health professionals or peer coaches, and the outcomes extracted in the data collection will be disease-specific, clients’ life and self-management skills, behavioural and psychosocial outcomes. If appropriate, a meta-analysis of the data collected will be carried out on the last stage of the review. Discussion This systematic review will identify and gather evidence on the impact of health coaching interventions delivered in the prison setting and can function as a supporting material for health professionals, prison staff, the healthcare system, and public health departments when considering delivering health coaching. Systematic review registration PROSPERO CRD42016053237 .

Background: A major public health hazard is youth e-cigarette use. Although new, e-cigarette health hazards are becoming well-known in the literature. E-cigarette sale restrictions and laws differ globally. In this cross-sectional study, we studied medical university students' tobacco and e-cigarette use and characteristics in a country where sales and import of e-cigarettes are banned. The primary objective is to determine the prevalence of electronic cigarette use and understand consumption patterns among medical faculty students in this setting., Materials and Methods: The questionnaire was sent using a web-based student information system. Sociodemographic features, tobacco and e-cigarette use, consumption patterns, and e-cigarette risk perceptions were covered in 54 questions., Results: The study comprised 1,054 students (48.7% male) aged 21.5 ± 2.6 years who completed the questionnaire. 37.7%, 20.9% and 23.6% have smoked cigarettes, e-cigarettes, or water pipes. Current cigarette smokers were 17.0%, e-cigarette users 4.0%, and water pipe smokers 4.5%. E-cigarette users were 52.3% dual smokers. The most common symptoms reported by e-cigarette users were cough (58.4%) and dyspnea (54.2%). Multivariable models showed that the male sex, greater monthly income, and a current smoker friend were independent risk factors for e-cigarette ever use, while the male sex, paternal current smoking, and close friends' current smoking status were risk factors for dual use among medical trainees. Many medical students who used electronic cigarettes underestimated nicotine's health hazards and harmful chemicals in e-cigarettes. Despite e-cigarette sales being prohibited in our country, 56.4% and 25.4% of e-cigarette users provided e-cigarettes from tobacco shops and through online sales, respectively., Conclusion: Medical university students use tobacco most often by smoking cigarettes. Despite medical university students being aware of the health hazards of e-cigarettes, the current use of electronic cigarettes is 4.0%. Male sex, greater monthly income, and having current smoker friends are independent risk factors for e-cigarette use, while paternal smoking is a risk factor for dual use among medical trainees. Although in the country, sales of e-cigarettes are banned, ever-use rates for e-cigarettes were remarkably high at 20.9%, and the ease of accessing e-cigarettes was striking., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dilektasli, Guclu, Ozpehlivan, Durak, Gezmis, Ozgur, Cinar, Demirdogen, Ozturk, Ozkaya, Coskun, Ursavas, Uzaslan and Karadag.)

Context Seasonal microclimatic fluctuations can cause changes in sperm quality even in dairy bulls bred under temperate climate. These changes can vary between sires of different age and affect sperm freezability. Aims We aimed to evaluate the modulating effect of bull age and equilibration time before freezing on the seasonal pattern of sperm viability and DNA integrity post-thaw. Methods In the frame of systematic sperm quality control, we assessed the integrity of sperm plasma membrane and acrosome (PMAI) in 15,496 cryopreserved bovine batches, and the percentage of sperm with high DNA fragmentation index (%DFI) after 0h and 3h incubation at 38°C post-thaw (3h) in 3422 batches. Semen was equilibrated for 24h before freezing if collected on Monday or Wednesday and 72h if produced on Friday. We investigated the effect of season, bull age, equilibration, and temperature-humidity index (THI) on the day of semen collection on sperm traits using mixed-effects linear models. Key results PMAI and %DFI (0h and 3h) deteriorated with increasing THI. The effect of THI on %DFI was detected with a 30-day time lag. Seasonal fluctuations of sperm quality were similar between young, mature, and older sires. Prolonged equilibration did not affect PMAI but was linked to elevated %DFI (3h) in summer. Conclusions Extending equilibration from 24 to 72h is compatible with commercial standards of bovine sperm quality post-thaw; however, it could interfere with the seasonal pattern of the latter. Implications Systematic monitoring of bovine sperm quality enables the prompt detection of stress factors related to microclimate and semen processing.

Studying behavioural lateralization in animals holds great potential for answering important questions in laterality research and clinical neuroscience. However, comparative research encounters challenges in reliability and validity, requiring new approaches and innovative designs to overcome. Although validated tests exist for some species, there is yet no standard test to compare lateralized manual behaviours between individuals, populations, and animal species. One of the main reasons is that different fine-motor abilities and postures must be considered for each species. Given that pawedness/handedness is a universal marker for behavioural lateralization across species, this article focuses on three commonly investigated species in laterality research: dogs, cats, and rats. We will present six apparatuses (two for dogs, three for cats, and one for rats) that enable an accurate assessment of paw preference. Design requirements and specifications such as zoometric fit for different body sizes and ages, reliability, robustness of the material, maintenance during and after testing, and animal welfare are extremely important when designing a new apparatus. Given that the study of behavioural lateralization yields crucial insights into animal welfare, laterality research, and clinical neuroscience, we aim to provide a solution to these challenges by presenting design requirements and innovations in methodology across species.

The Polycomb group protein SCML2 and the transcriptional cofactor YAP1 regulate diverse cellular biology, including stem cell maintenance, developmental processes, and gene regulation in mammals and flies. However, their molecular and functional interactions are unknown. Here, we show that SCML2 interacts with YAP1, as revealed by immunological assays and mass spectroscopy. We have demonstrated that the steroid hormone androgen regulates the interaction of SCML2 with YAP1 in human tumor cell models. Our proximity ligation assay and GST pulldown showed that SCML2 and YAP1 physically interacted with each other. Silencing SCML2 by RNAi changed the growth behaviors of cells in response to androgen signaling. Mechanistically, this phenomenon is attributed to the interplay between distinct chromatin modifications and transcriptional programs, likely coordinated by the opposing SCML2 and YAP1 activity. These findings suggest that YAP1 and SCML2 cooperate to regulate cell growth, cell survival, and tumor biology downstream of steroid hormones., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)

Amino acid availability is crucial for cancer cells' survivability. Leukemia and colorectal cancer cells have been shown to resist asparagine depletion by utilizing GSK3-dependent proteasomal degradation, termed the Wnt-dependent stabilization of proteins (Wnt/STOP), to replenish their amino acid pool. The inhibition of GSK3α halts the sourcing of amino acids, which subsequently leads to cancer cell vulnerability toward asparaginase therapy. However, resistance toward GSK3α-mediated protein breakdown can occur, whose underlying mechanism is poorly understood. Here, we set out to define the mechanisms driving dependence toward this degradation machinery upon asparagine starvation in cancer cells. We show the independence of known stress response pathways including the integrated stress response mediated with GCN2. Additionally, we demonstrate the independence of changes in cell cycle progression and expression levels of the asparagine-synthesizing enzyme ASNS. Instead, RNA sequencing revealed that GSK3α inhibition and asparagine starvation leads to the temporally dynamic downregulation of distinct ribosomal proteins, which have been shown to display anti-proliferative functions. Using a CRISPR/Cas9 viability screen, we demonstrate that the downregulation of these specific ribosomal proteins can rescue cell death upon GSK3α inhibition and asparagine starvation. Thus, our findings suggest the vital role of the previously unrecognized regulation of ribosomal proteins in bridging GSK3α activity and tolerance of asparagine starvation.

The tolerance of amino acid starvation is fundamental to robust cellular fitness. Asparagine depletion is lethal to some cancer cells, a vulnerability that can be exploited clinically. We report that resistance to asparagine starvation is uniquely dependent on an N-terminal low-complexity domain of GSK3α, which its paralog GSK3β lacks. In response to depletion of specific amino acids, including asparagine, leucine, and valine, this domain mediates supramolecular assembly of GSK3α with ubiquitin-proteasome system components in spatially sequestered cytoplasmic bodies. This effect is independent of mTORC1 or GCN2. In normal cells, GSK3α promotes survival during essential amino acid starvation. In human leukemia, GSK3α body formation predicts asparaginase resistance, and sensitivity to asparaginase combined with a GSK3α inhibitor. We propose that GSK3α body formation provides a cellular mechanism to maximize the catalytic efficiency of proteasomal protein degradation in response to amino acid starvation, an adaptive response co-opted by cancer cells for asparaginase resistance., Competing Interests: Declaration of interests Boston Children’s Hospital has filed patents on the subject matter of this manuscript. G.C. is a founder of Samus Therapeutics and a member of its board of directors. A.G. is on a scientific advisory board for Attivare Therapeutics and receives research funding from Astellas Pharma., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The EPHA3 protein tyrosine kinase, a member of the ephrin receptor family, regulates cell fate, cell motility, and cell-cell interaction. These cellular events are critical for tissue development, immunological responses, and the processes of tumorigenesis. Earlier studies revealed that signaling via the STK4-encoded MST1 serine-threonine protein kinase, a core component of the Hippo pathway, attenuated EPHA3 expression. Here, we investigated the mechanism by which MST1 regulates EPHA3. Our findings have revealed that the transcriptional regulators YAP1 and TEAD1 are crucial activators of EPHA3 transcription. Silencing YAP1 and TEAD1 suppressed the EPHA3 protein and mRNA levels. In addition, we identified putative TEAD enhancers in the distal EPHA3 promoter, where YAP1 and TEAD1 bind and promote EPHA3 expression. Furthermore, EPHA3 knockout by CRISPR/Cas9 technology reduced cell-cell interaction and cell motility. These findings demonstrate that EPHA3 is transcriptionally regulated by YAP1/TEAD1 of the Hippo pathway, suggesting that it is sensitive to cell contact-dependent interactions., (© 2022. The Author(s).)

Heterologous hosts are highly important to detect the expression of biosynthetic gene clusters that are cryptic or poorly expressed in their natural hosts. To investigate whether actinorhodin-overproducer Streptomyces coelicolor ∆ppk mutant strain could be a possible prototype as a heterologous expression host, a cosmid containing most of the elm gene cluster of Streptomyces olivaceus Tü2353 was integrated into chromosomes of both S. coelicolor A3(2) and ∆ppk strains. Interestingly, it was found that the production of tetracyclic polyketide 8-demethyl-tetracenomycin (8-DMTC) by recombinant strains caused significant changes in the morphology of cells. All the pellets and clumps were disentangled and mycelia were fragmented in the recombinant strains. Moreover, they produce neither pigmented antibiotics nor agarase and did not sporulate. By eliminating the elm biosynthesis genes from the cosmid, we showed that the morphological properties of recombinants were caused by the production of 8-DMTC. Extracellular application of 8-DMTC on S. coelicolor wild-type cells caused a similar phenotype with the 8-DMTC-producing recombinant strains. The results of this study may contribute to the understanding of the effect of 8-DMTC in Streptomyces since the morphological changes that we have observed have not been reported before. It is also valuable in that it provides useful information about the use of Streptomyces as hosts for the heterologous expression of 8-DMTC., (© 2021. Sociedade Brasileira de Microbiologia.)

The Hippo pathway controls several biological processes, including cell growth, differentiation, motility, stemness, cell contact, immune cell maturation, organ size, and tumorigenesis. The Hippo pathway core kinases MST1/2 and LATS1/2 in mammals phosphorylate and inactivate YAP1 signaling. Increasing evidence indicates that loss of MST1/2 and LATS1/2 function is linked to the biology of many cancer types with poorer outcomes, likely due to the activation of oncogenic YAP1/TEAD signaling. Therefore, there is a renewed interest in blocking the YAP1/TEAD functions to prevent cancer growth. This review introduces the Hippo pathway components and examines their role and therapeutic potentials in prostate, kidney, and bladder cancer., Competing Interests: None., (AJCEU Copyright © 2021.)

The association between hemispheric asymmetries and cognitive ability is one of the key areas of comparative laterality research. In several animal species, individual limb preferences correlate with perceptual, cognitive, or motor abilities, possibly by increasing dexterity of one limb and minimizing response conflicts between hemispheres. Despite this wealth of research, the association between laterality and cognitive abilities in the cat (Felis catus) is not well understood. Therefore, it was the aim of the present study to investigate the relationship between laterality and problem-solving ability in cats. To this end, strength and direction of paw preferences in 41 cats were measured using two novel food reaching tasks in which the animals needed to open a lid in order to reach the food reward. We found that cats that showed a clear preference for one paw were able to open more lids succesfully than ambilateral animals. Moreover, cats that preferred to interact with the test apparatus with their paw from the beginning, opened more lids than cats the first tried to interact with the test apparatus using their heads. Results also suggested a predictive validity of the first paw usage for general paw usage. It was also shown that the cats' individual paw preferences were stable and task-independent. These results yield further support to the idea that lateralization may enhance cognitive abilities., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The transcriptional coactivator YAP1 (yes-associated protein 1) regulates cell proliferation, cell-cell interactions, organ size, and tumorigenesis. Post-transcriptional modifications and nuclear translocation of YAP1 are crucial for its nuclear activity. The objective of this study was to elucidate the mechanism by which the steroid hormone androgen regulates YAP1 nuclear entry and functions in several human prostate cancer cell lines. We demonstrate that androgen exposure suppresses the inactivating post-translational modification phospho-Ser-127 in YAP1, coinciding with increased YAP1 nuclear accumulation and activity. Pharmacological and genetic experiments revealed that intact androgen receptor signaling is necessary for androgen's inactivating effect on phospho-Ser-127 levels and increased YAP1 nuclear entry. We also found that androgen exposure antagonizes Ser/Thr kinase 4 (STK4/MST1) signaling, stimulates the activity of protein phosphatase 2A, and thereby attenuates the phospho-Ser-127 modification and promotes YAP1 nuclear localization. Results from quantitative RT-PCR and CRISPR/Cas9-aided gene knockout experiments indicated that androgen differentially regulates YAP1-dependent gene expression. Furthermore, an unbiased computational analysis of the prostate cancer data from The Cancer Genome Atlas revealed that YAP1 and androgen receptor transcript levels correlate with each other in prostate cancer tissues. These findings indicate that androgen regulates YAP1 nuclear localization and its transcriptional activity through the androgen receptor-STK4/MST1-protein phosphatase 2A axis, which may have important implications for human diseases such as prostate cancer., Competing Interests: Conflict of interest—The authors declare no competing conflicts of interest with the content of this article., (© 2020 Cinar et al.)

Objectives: Isolated iliac artery aneurysms (IAAs) are rare, but nonetheless life-threatening when ruptured. The endovascular approach has taken over open repairs in time. The reported data is constituted of a retrospective series. We reviewed our 10-year-long experience with elective endovascular treatment of iliac aneurysms., Methods: Data regarding 22 patients with 24 IAAs treated with endovascular stent grafting between 2005 and 2015 were reviewed., Results: Twenty-two patients (aged 68.4 ± 9.6 years, range 50-82) with 24 unilateral or bilateral iliac aneurysms were treated. Twenty patients (91%) were male. Two patients with unilateral IAA had prior abdominal aortic aneurysm (AAA) surgical repair. The mean aneurysm diameter was 4.8 ± 2.1 (3.8 to 7.1) mm. Procedural success rate was 100%, only one patient with an iliovenous fistula had periprocedural type II endoleak. Internal iliac artery coil occlusion was applied in 16 of 24 procedures (66%). Thirty-day mortality included one patient (4%)., Conclusion: Endovascular repair is the preferred approach for isolated IAAs. Because of the retrospective nature of data sets, larger cohorts are necessary for better definition of morbidity and mortality rates., (2019 Forum Multimedia Publishing, LLC)

Androgen receptor (AR) signaling is vital to the viability of all forms of prostate cancer (PCa). With the goal of investigating the effect of simultaneous inhibition and depletion of AR on viability of PCa cells, we designed, synthesized and characterized the bioactivities of bifunctional agents which incorporate the independent cancer killing properties of an antiandrogen and genistein, and the AR downregulation effect of genistein within a single molecular template. We observed that a representative conjugate, 9b, is much more cytotoxic to both LNCaP and DU145 cells relative to the antiandrogen and genistein building blocks as single agents or their combination. Moreover, conjugate 9b more effectively down regulates cellular AR protein levels relative to genistein and induces S phase cell cycle arrest. The promising bioactivities of these conjugates warrant further investigation., (Published by Elsevier Ltd.)

Mechanisms of castration-resistant prostate cancer (CRPC) are not well understood, thus hindering rational-based drug design. Activation of STAT3/5A, key components of the JAK/STAT pathway, is implicated in aggressive PC, yet their clinical relevance in CRPC remains elusive. Here, we evaluated the possible role of STAT3/5A in CRPC using immunological, quantitative mRNA expression profiling, and pharmacological methods. We observed a strong nuclear immunoreactivity for STAT3 and STAT5A in 93% (n=14/15) and 80% (n=12/15) of CRPC cases, respectively, compared with benign prostatic hyperplasia (BPH). We demonstrated that PC cells express varying levels of STAT3 and STAT5A transcripts. In addition, we demonstrate that pimozide, a psychotropic drug and an indirect inhibitor of STAT5, attenuated PC cells growth, and induced apoptosis in a dose-dependent manner. Furthermore, our analysis of the PC public data revealed that the STAT3/5A genes were frequently amplified in metastatic CRPC. These findings suggest that STAT3/5A potentially serves as a predictive biomarker to evaluate the therapeutic efficacy of a cancer drug targeting the JAK/STAT pathway. Since the JAK/STAT and AR pathways are suggested to be functionally synergistic, inhibition of the JAK/STAT signaling alone or together with AR may lead to a novel treatment modality for patients with advanced PC., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing conflicts of interest.

Dysregulation of MST1/STK4, a key kinase component of the Hippo-YAP pathway, is linked to the etiology of many cancers with poor prognosis. However, how STK4 restricts the emergence of aggressive cancer remains elusive. Here, we investigated the effects of STK4, primarily localized in the cytoplasm, lipid raft, and nucleus, on cell growth and gene expression in aggressive prostate cancer. We demonstrated that lipid raft and nuclear STK4 had superior suppressive effects on cell growth in vitro and in vivo compared with cytoplasmic STK4. Using RNA sequencing and bioinformatics analysis, we identified several differentially expressed (DE) genes that responded to ectopic STK4 in all three subcellular compartments. We noted that the number of DE genes observed in lipid raft and nuclear STK4 cells were much greater than cytoplasmic STK4. Our functional annotation clustering showed that these DE genes were commonly associated with oncogenic pathways such as AR, PI3K/AKT, BMP/SMAD, GPCR, WNT, and RAS as well as unique pathways such as JAK/STAT, which emerged only in nuclear STK4 cells. These findings indicate that MST1/STK4/Hippo signaling restricts aggressive tumor cell growth by intersecting with multiple molecular pathways, suggesting that targeting of the STK4/Hippo pathway may have important therapeutic implications for cancer.

Genetic variations in chromosome Y are enabling researchers to identify paternal lineages, which are informative for introgressions and migrations. In this study, the male-specific region markers, sex-determining region-Y (SRY), amelogenin (AMELY) and zinc finger (ZFY) were analysed in seven Turkish native goat breeds, Angora, Kilis, Hair, Honamlı, Norduz, Gürcü and Abaza. A SNP in the ZFY gene defined a new haplotype Y2C. All domestic haplogroups originate from Capra aegagrus, while the finding of Y1A, Y1B, Y2A and Y2C in 32, 4, 126 and 2 Turkish domestic goats, respectively, appears to indicate a predomestic origin of the major haplotypes. The occurrence of four haplotypes in the Hair goat and, in contrast, a frequency of 96% of Y1A in the Kilis breed illustrate that Y-chromosomal variants have a more breed-dependent distribution than mitochondrial or autosomal DNA. This probably reflects male founder effects, but a role in adaptation cannot be excluded., (© 2015 Blackwell Verlag GmbH.)

The transcriptional co-activator Yes-associated protein 1 (YAP1), a key nuclear effector of the Hippo pathway, is a potent oncogene, and yet, the interaction between YAP1 and androgen receptor (AR) remains unexplored. Here we identify YAP1 as a physiological binding partner and positive regulator of AR in prostate cancer. YAP1 and AR co-localize and interact with each other predominantly within cell nuclei by an androgen-dependent mechanism in a hormone naive and an androgen-independent mechanism in castration-resistant prostate cancer cells. The growth suppressor MST1 kinase modulates androgen-dependent and -independent nuclear YAP1-AR interactions through directly regulating YAP1 nuclear accumulation. Disruption of YAP1 signalling by genetic (RNAi) and pharmacological (Verteporfin) approaches suppresses AR-dependent gene expression and prostate cancer cell growth. These findings indicate that the YAP1-AR axis may have a critical role in prostate cancer progression and serves as a viable drug target.

Double hit lymphoma or triple hit lymphoma (DHL/THL) is a rare form of aggressive B-Cell Lymphoma. Overexpression of MYC, BCL2 or/and BCL6 due to genomic rearrangements are the key molecular features of DHL/THL. Patients with DHL/THL show very aggressive disease course and poor survival due to the lack of effective treatment modalities. Here, we established new THL cell model and assessed its in vitro growth characteristics along with the DHL cell line in response to potent MYC inhibitors, 10058-F4 and JQ-1, and a BCL2 inhibitor, ABT-199, with or without chemotherapeutic agent vincristine or doxorubicin. We found that 10058-F4, JQ-1 or ABT-199 exposure as a single agent inhibited the growth of DHL/THL cells in a dose-dependent manner. Combined exposure of 10058-F4 or JQ-1 and ABT-199 as well as vincristine or doxorubicin markedly suppressed the growth of DHL/THL cells compared with the single treatment. As assessed by multiple approaches, apoptosis induced by ABT-199, 10058-F4 or JQ-1 was underlying cause of the observed growth suppression. These findings suggest that co-inhibition of MYC and BCL2 signaling is a promising therapeutic strategy for patients with DHL/THL lymphomas., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Previous studies have demonstrated structural changes in the heart and cardiac dysfunction in foetuses with intrauterine growth restriction. There are no available data that evaluated left ventricular dimensions and mass in neonates with symmetric and asymmetric intrauterine growth restriction. Therefore, we aimed to evaluate left ventricular dimensions, systolic functions, and mass in neonates with symmetric and asymmetric intrauterine growth restriction. We also assessed associated maternal risk factors, and compared results with healthy appropriate for gestational age neonates., Methods: In all, 62 asymmetric intrauterine growth restriction neonates, 39 symmetric intrauterine growth restriction neonates, and 50 healthy appropriate for gestational age neonates were evaluated by transthoracic echocardiography., Results: The asymmetric intrauterine growth restriction group had significantly lower left ventricular end-systolic and end-diastolic diameters and posterior wall diameter in systole and diastole than the control group. The symmetric intrauterine growth restriction group had significantly lower left ventricular end-diastolic diameter than the control group. All left ventricular dimensions were lower in the asymmetric intrauterine growth restriction neonates compared with symmetric intrauterine growth restriction neonates (p>0.05), but not statistically significant except left ventricular posterior wall diameter in diastole (3.08±0.83 mm versus 3.54 ±0.72 mm) (p<0.05). Both symmetric and asymmetric intrauterine growth restriction groups had significantly lower relative posterior wall thickness (0.54±0.19 versus 0.48±0.13 versus 0.8±0.12), left ventricular mass (9.8±4.3 g versus 8.9±3.4 g versus 22.2±5.7 g), and left ventricular mass index (63.6±29.1 g/m2 versus 54.5±24.4 g/m2 versus 109±28.8 g/m2) when compared with the control group., Conclusions: Our study has demonstrated that although neonates with both symmetric and asymmetric intrauterine growth restriction had lower left ventricular dimensions, relative posterior wall thickness, left ventricular mass, and mass index when compared with appropriate for gestational age neonates, left ventricular systolic functions were found to be preserved. In our study, low socio-economic level, short maternal stature, and low maternal weight were found to be risk factors to develop intrauterine growth restriction. To our knowledge, our study is the first to evaluate left ventricular dimensions, wall thicknesses, mass, and systolic functions in neonates with intrauterine growth restriction and compare results with respect to asymmetric or symmetric subgroups.

Keutel syndrome (KS) is an autosomal recessive disease characterised by abnormal cartilage calcification, brachytelephalangism, peripheral pulmonary artery stenosis, hearing loss and midface retrusion. KS is caused by homozygous mutations in MGP, a gene encoding Matrix Gla protein which acts as a calcification inhibitor in extracellular matrix. We present two Turkish sisters (22 and 13 years old) who had abnormal cartilage calcification, brachytelephalangism, congenital heart defect and chronic asthmatic bronchitis. The patients were homozygous for c.62-2A>G (IVS1-2 A>G) mutation in MGP gene. Abnormal cartilage calcification, brachytelephalangism and midfacial retrusion are the hallmarks of KS. It was observed that the younger sister had striking cartilaginous calcifications, midfacial retrusion and severe brachytelephalangism while her older sister had mild costal cartilaginous calcifications and brachytelephalangism without any midfacial retrusion. Intrafamiliar clinical variability for KS has not been described previously.

The Ly-6 superfamily of proteins, which affects diverse processes in the immune system, has attracted renewed attention due to the ability of some Ly-6 proteins to bind to and modulate the function of neuronal nicotinic acetylcholine receptors (nAChRs). However, there is a scarcity of knowledge regarding the distribution and developmental regulation of these proteins in the brain. We use protein cross-linking and synaptosomal fractions to demonstrate that the Ly-6 proteins Lynx1 and Ly6H are membrane-bound proteins in the brain, which are present on the cell surface and localize to synaptic compartments. We further estimate the amount of Lynx1 in the rat cortex using known amounts of a heterologously expressed soluble Lynx1 variant (ws-Lynx1) to be approximately 8.6 ng/μg total protein, which is in line with the concentrations of ws-Lynx1 required to affect nAChR function. In addition, we demonstrate that Lynx1 and Ly6H are expressed in cultured neurons, but not cultured micro- or astroglial cultures. In addition, Lynx1, but not Ly6H was detected in the CSF. Finally, we show that the Ly-6 proteins Lynx1, Lynx2, Ly6H, and PSCA, display distinct expression patterns during postnatal development in the rat frontal cortex and hippocampus at the mRNA and protein level, and that this is paralleled to some degree by the expression of the nAChR subunits α2, α4, α7 and β2. Our results demonstrate a developmental pattern, localization, and concentration of Ly-6 proteins in the brain, which support a role for these proteins in the modulation of signaling at synaptic membranes.

Background: Conventional surgical repair of thoracic aortic dissections is a challenge due to mortality and morbidity risks., Objectives: We analyzed our experience in hybrid aortic arch repair for complex dissections of the aortic arch., Methods: Between 2009 and 2013, 18 patients (the mean age of 67 ± 8 years-old) underwent hybrid aortic arch repair. The procedural strategy was determined on the individual patient., Results: Thirteen patients had type I repair using trifurcation and another patient with bifurcation graft. Two patients had type II repair with replacement of the ascending aorta. Two patients received extra-anatomic bypass grafting to left carotid artery allowing covering of zone 1. Stent graft deployment rate was 100%. No patients experienced stroke. One patient with total debranching of the aortic arch following an acute dissection of the proximal arch expired 3 months after TEVAR due to heart failure. There were no early to midterm endoleaks. The median follow-up was 20 ± 8 months with patency rate of 100%., Conclusion: Various debranching solutions for different complex scenarios of the aortic arch serve as less invasive procedures than conventional open surgery enabling safe and effective treatment of this highly selected subgroup of patients with complex aortic pathologies.

The androgen receptor (AR) is a transcription factor that employs many diverse interactions with coregulatory proteins in normal physiology and in prostate cancer (PCa). The AR mediates cellular responses in association with chromatin complexes and kinase cascades. Here we report that the nuclear matrix protein, scaffold attachment factor B1 (SAFB1), regulates AR activity and AR levels in a manner that suggests its involvement in PCa. SAFB1 mRNA expression was lower in PCa in comparison with normal prostate tissue in a majority of publicly available RNA expression data sets. SAFB1 protein levels were also reduced with disease progression in a cohort of human PCa that included metastatic tumors. SAFB1 bound to AR and was phosphorylated by the MST1 (Hippo homolog) serine-threonine kinase, previously shown to be an AR repressor, and MST1 localization to AR-dependent promoters was inhibited by SAFB1 depletion. Knockdown of SAFB1 in androgen-dependent LNCaP PCa cells increased AR and prostate-specific antigen (PSA) levels, stimulated growth of cultured cells and subcutaneous xenografts and promoted a more aggressive phenotype, consistent with a repressive AR regulatory function. SAFB1 formed a complex with the histone methyltransferase EZH2 at AR-interacting chromatin sites in association with other polycomb repressive complex 2 (PRC2) proteins. We conclude that SAFB1 acts as a novel AR co-regulator at gene loci where signals from the MST1/Hippo and EZH2 pathways converge.

Hippo-like MST1 protein kinase regulates cell growth, organ size, and carcinogenesis. Reduction or loss of MST1 expression is implicated in poor cancer prognosis. However, the mechanism leading to MST1 silencing remains elusive. Here, we report that both MYC and EZH2 function as potent suppressors of MST1 expression in human prostate cancer cells. We demonstrated that concurrent overexpression of MYC and EZH2 correlated with the reduction or loss of MST1 expression, as shown by RT-qPCR and immunoblotting. Methylation sensitive PCR and bisulfite genomic DNA sequencing showed that DNA methylation caused MST1 silencing. Pharmacologic and RNAi experiments revealed that MYC and EZH2 silenced MST1 expression by inhibiting its promoter activity, and that EZH2 was a mediator of the MYC-induced silencing of MST1. In addition, MYC contributed to MST1 silencing by partly inhibiting the expression of microRNA-26a/b, a negative regulator of EZH2. As shown by ChIP assays, EZH2-induced DNA methylation and H3K27me3 modification, which was accompanied by a reduced H3K4me3 mark and RNA polymerase II occupancy on the MST1 promoter CpG region, were the underlying cause of MST1 silencing. Moreover, potent pharmacologic inhibitors of MYC or EZH2 suppressed prostate cancer cell growth in vitro, and the knockdown of MST1 caused cells' resistance to MYC and EZH2 inhibitor-induced growth retardation. These findings indicate that MYC, in concert with EZH2, epigenetically attenuates MST1 expression and suggest that the loss of MST1/Hippo functions is critical for the MYC or EZH2 mediation of cancer cell survival.

In the present research, the 20 lactobacilli isolated from children feces aged 4-15 years old were investigated for their capabilities to survive at pH 2.0, 2.5, 3.0 and in the presence of 0.25, 0.50 and 0.75% bile salts, their effect on the growth of pathogens, in addition to their sensitivity against 13 selected antibiotics. All the lactobacilli strains were able to survive in low pH and bile salt conditions at pH 2.0 and 0.25% bile salt for 2 h. Moreover, all lactobacilli strains exhibited inhibitory activity against Escherichia coli ATCC 11229, Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 29213. In addition, all lactobacilli strains indicated resistance to teicoplanin, vancomycin, and bacitracin. The amount of exopolysaccharide (EPS) produced by the strains was 70 and 290 mg/L. The capabilities to autoaggregation and coaggregate with E. coli ATCC 11229 of the strains were also evaluated. High EPS-producing strains indicated significant autoaggregation and coaggregation capability with test bacteria (p < 0.01). The maximum cholesterol removal (76.5%) was observed by strain Lactobacillus pentosus T3, producing a high amount of exopolysaccharide, in 0.3%oxgall concentration (p < 0.05). Our results demonstrate that the capability to EPS production, acid-bile tolerance, antimicrobial activity, antibiotic resistance, aggregation and cholesterol removal of lactobacilli could be utilized for preliminary screening in order to identify potentially probiotic bacteria suitable for human., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that characteristically shows overexpression of cyclin-D1 due to an alteration in the t(11;14)(q13;q32) chromosomal region. Although there are some promising treatment modalities, great majority of patients with this disease remain incurable. The B-cell antigen receptor (BCR) signaling plays a crucial role in B-cell biology and lymphomagenesis. Bruton tyrosine kinase (BTK) has been identified as a key component of the BCR signaling pathway. Evidence suggests that the blockade of BTK activity by potent pharmacologic inhibitors attenuates BCR signaling and induces cell death. Notably, the expression levels and the role of BTK in MCL survival are still elusive. Here, we demonstrated a moderate to strong BTK expression in all MCL cases (n=19) compared to benign lymphoid tissues. Treatment of MCL cell lines (Mino or Jeko-1) with a potent BTK pharmacologic inhibitor, Ibrutinib, decreased phospho-BTK-Tyr(223) expression. Consistent with this observation, Ibrutinib inhibited the viability of both Mino and JeKo-1 cells in concentration- and time-dependent manners. Ibrutinib also induced a concentration-dependent apoptosis in both cell lines. Consistently, Ibrutinib treatment decreased the levels of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1 protein. These findings suggest that BTK signaling plays a critical role in MCL cell survival, and the targeting of BTK could represent a promising therapeutic modality for aggressive lymphoma., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Mst1/Stk4, a hippo-like serine-threonine kinase, is implicated in many cancers, including prostate cancer. However, the mechanisms regulating Mst1 remain obscure. Here, we characterized the effects of phospho-Thr-120 on Mst1 in prostate cancer cells. We demonstrated that phospho-Thr-120 did not alter the nuclear localization or cleavage of Mst1 in a LNCaP or castration-resistant C4-2 prostate tumor cell model, as revealed by a mutagenesis approach. Phospho-Thr-120 appeared to be specific to cancer cells and predominantly localized in the nucleus. In contrast, phospho-Thr-183, a critical regulator of Mst1 cell death, was exclusively found in the cytoplasm. As assessed by immunohistochemistry, a similar distribution of phospho-Mst1-Thr-120/Thr-183 was also observed in a prostate cancer specimen. In addition, the blockade of PI3K signaling by a small molecule inhibitor, LY294002, increased cytoplasmic phospho-Mst1-Thr-183 without having a significant effect on nuclear phospho-Mst1-Thr-120. However, the attenuation of mammalian target of rapamycin (mTOR) activity by a selective pharmacologic inhibitor, Ku0063794 or CCI-779, caused the up-regulation of nuclear phospho-Mst1-Thr-120 without affecting cytoplasmic phospho-Mst1-Thr-183. This suggests that PI3K and mTOR pathway signaling differentially regulate phospho-Mst1-Thr-120/Thr-183. Moreover, mutagenesis and RNAi data revealed that phospho-Thr-120 resulted in C4-2 cell resistance to mTOR inhibition and reduced the Mst1 suppression of cell growth and androgen receptor-driven gene expression. Collectively, these findings indicate that phospho-Thr-120 leads to the loss of Mst1 functions, supporting cancer cell growth and survival.

TOK-001 and abiraterone are potent 17-heteroarylsteroid (17-HAS) inhibitors of Cyp17, one of the rate-limiting enzymes in the biosynthesis of testosterone from cholesterol in prostate cancer cells. Nevertheless, the molecular mechanism underlying the prevention of prostate cell growth by 17-HASs still remains elusive. Here, we assess the effects of 17-HASs on androgen receptor (AR) activity in LNCaP and LAPC-4 cells. We demonstrate that both TOK-001 and abiraterone reduced AR protein and mRNA expression, and antagonized AR-dependent promoter activation induced by androgen. TOK-001, but not abiraterone, is an effective apparent competitor of the radioligand [(3)H]R1881 for binding to the wild type and various mutant AR (W741C, W741L) proteins. In agreement with these data, TOK-001 is a consistently superior inhibitor than abiraterone of R1881-induced transcriptional activity of both wild type and mutant AR. However, neither agent was able to trans-activate the AR in the absence of R1881. Our data demonstrate that phospho-4EBP1 levels are significantly reduced by TOK-001 and to a lesser extent by abiraterone alcohol, and suggest a mechanism by which cap-dependent translation is suppressed by blocking assembly of the eIF4F and eIF4G complex to the mRNA 5' cap. Thus, the effects of these 17-HASs on AR signaling are complex, ranging from a decrease in testosterone production through the inhibition of Cyp17 as previously described, to directly reducing both AR protein expression and R1881-induced AR trans-activation.

The MST1 serine-threonine kinase, a component of the RASSF1-LATS tumor suppressor network, is involved in cell proliferation and apoptosis and has been implicated in cancer. However, the physiologic role of MST1 in prostate cancer (PCa) is not well understood. Here, we investigated the possibility of a biochemical and functional link between androgen receptor (AR) and MST1 signaling. We showed that MST1 forms a protein complex with AR and antagonizes AR transcriptional activity as shown by coimmunoprecipitation (co-IP), promoter reporter analysis, and molecular genetic methods. In vitro kinase and site-specific mutagenesis approaches indicate that MST1 is a potent AR kinase; however, the kinase activity of MST1 and its proapoptotic functions were shown not to be involved in inhibition of AR. MST1 was also found in AR-chromatin complexes, and enforced expression of MST1 reduced the binding of AR to a well-characterized, androgen-responsive region within the prostate-specific antigen promoter. MST1 suppressed PCa cell growth in vitro and tumor growth in mice. Because MST1 is also involved in regulating the AKT1 pathway, this kinase may be an important new link between androgenic and growth factor signaling and a novel therapeutic target in PCa.

Two novel proton transfer compounds were prepared between 2,4-dichloro-5-sulphamoylbenzoic acid (lasamide) (Hsba) and ethylenediamine (en), namely ethane-1,2-diaminium 2,4-dichloro-5-sulphamoylbenzoate (1), and also between Hsba and 2-amino-3-methylpyridine (2-amino-3-picoline) (amp), namely 2-amino-3-methylpyridinium 2,4-dichloro-5-sulphamoylbenzoate (2). All these were characterised by elemental, spectral (IR and UV-vis), thermal analyses, and single crystal X-ray diffraction studies. Compounds 1 and 2 crystallised in the P-1 and P21/c space groups, respectively. Intermolecular non-covalent interactions, such as ion pairing, hydrogen bonding, and π-π stacking were observed for these ionic compounds. The free ligands Hsba, en and amp, the products 1 and 2, and acetazolamide (AAZ) as the control compound, were also evaluated for their in vitro inhibitor effects on the human carbonic anhydrase isoenzymes (hCA I and hCA II) purified from erythrocyte cells by affinity chromatography for their hydratase and esterase activities. The half maximal inhibitory concentration (IC(50)) values for products 1 and 2 with respect to hydratase activity are 0.15 and 0.32 μM for hCA I and 0.06 and 0.15 μM for hCA II, respectively. The IC(50) values of the same inhibitors for esterase activity are 0.13 and 0.8 μM for hCA I and 0.14 and 0.1 μM for hCA II, respectively. In relation to esterase activities, the inhibition equilibrium constants (Ki) were also determined and found to be 0.137 and 0.99 μM on hCA I and 0.157 and 0.075 μM on hCA II for 1 and 2, respectively. The comparison of the inhibition studies of the newly synthesised compounds 1 and 2 to the parent compounds Hsba and amp and also to AAZ indicated that 1 and 2 have an effective inhibitory activity on hCA I and II, and might be used as potential inhibitors.

Behçet's disease is a chronic systemic inflammatory disorder associated with recurrent oral and genital ulcers and iritis. Vascular lesions are encountered in 7%-29% of patients, gravely affecting the course of the disease. Extracranial carotid aneurysms due to Behçet's disease are extremely rare. We describe a surgically treated case of Behçet's disease in a 28-year-old man who presented with a rapidly enlarging left common carotid artery aneurysm.

Open surgical repair of complex aortic pathologies using cardiopulmonary bypass and deep hypothermic circulatory arrest still carries a substantial rate of mortality and morbidity. Endovascular stent-graft placement has developed as a safe and effective treatment modality for various diseases of the aorta. We report on the case of a 65-year-old female presenting with symptomatic type B aortic dissection with aneurysm of the ascending aorta and the aortic root. The patient was treated with a flanged composite graft custom made from a branched 24-mm Dacron graft for entire prosthetic transposition of the supra-aortic branches. Metachronously, the patient underwent endovascular stent-grafting of the descending aorta. She was discharged free of complications on day 10.

Background and Aim of the Study: Emergency re-revascularization and invasive/noninvasive interventions in intensive care unit (ICU) are two main treatment methods in cardiac arrest following coronary artery bypass grafting (CABG). We evaluated the short- and long-term consequences of these two methods and discussed the indications for re-revascularization., Methods: Between 1998 and 2004, a total of 148 CABG patients, who were complicated with cardiac arrest, were treated with emergency re-revascularization (n = 36, group R) and ICU procedures (n = 112, group ICU). Re-revascularizations are mostly blind operations depending on clinical/hemodynamic criteria. These are: no response to resuscitation, recurrent tachycardia/fibrillation, and severe hemodynamic instability after resuscitation. Re-angiography could only be performed in 3.3% of the patients. Event-free survival of the groups was calculated by the Kaplan-Meier method. Events are: death, recurrent angina, myocardial infarction, functional capacity, and reintervention., Results: Seventy percent of patients, who were complicated with cardiac arrest, had perioperative myocardial infarction (PMI). This rate was significantly higher in group R (p = 0.013). The major finding in group R was graft occlusion (91.6%). During in-hospital period, no difference was observed in mortality rates between the two groups. However, hemodynamic stabilization time (p = 0.012), duration of hospitalization (p = 0.00006), and mechanical support use (p = 0.003) significantly decreased by re-revascularization. During the mean 37.1 +/- 25.1 months of follow-up period, long-term mortality (p = 0.03) and event-free survival (p = 0.029) rates were significantly in favor of group R., Conclusion: Better short- and long-term results were observed in the re-revascularization group.

Ankyloglossia is a congenital anomaly of the tongue that is usually characterized by a short and thick lingual frenulum. The genetic mutations such as in TBox genes and other foetal mechanism have still been under investigation as possible causes of ankyloglossia. This study describes morphology of anklyoglossia phenotype found in members of two closely bred Kangal dog families. Morphology of ankyloglossia and immunohistochemical localization of alphaB-crystallin, an anti-apoptotic protein, in the frenulum tissue collected during frenectomy was described. Grossly, the lingual frenulum was observed as it extended up to the tip or near the tip of the tongue. The tip of the tongue was often notched and appeared in 'W' shape. No other craniofacial anomalies were associated with ankyloglossia. Histologically, the frenulum tissue was covered by stratified squamous epithelia of variable thickness. Skeletal muscle fibres were often scattered in the vicinity of collagen fibres of the lamina propria. alphaB-crystallin was immunolocalized exclusively in skeletal muscle fibres. In conclusion, ankyloglossia in the dog generally occurs as a sole anomaly. The presence of alphaB-crystallin immunoreactivity exclusively in skeletal muscle fibres suggests that there may be a connection between occurrences of ankyloglossia in the dog and a delay or interference with apoptosis of the skeletal fibres in the frenulum tissue.

The regulation of androgen receptor (AR) expression in prostate cancer is still poorly understood. The activation of the epidermal growth factor receptor (EGFR) in prostate cancer cells was previously shown to lower AR expression by a rapamycin-sensitive, posttranscriptional mechanism involving the AR mRNA 5'-untranslated region (5'-UTR). In a search for an intermediate within the EGFR/phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway that regulates AR at this site, we identified the nucleic acid-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNP-K), by mass spectrometric analysis of Akt immune complexes from lipid raft-enriched subcellular fractions. We show here that hnRNP-K is a novel inhibitor of AR mRNA translation that regulates androgen-responsive gene expression and prostate cancer cell proliferation. A functional hnRNP-K binding site involved in down-regulating AR protein levels was identified in the AR mRNA 5'-UTR. Further analysis revealed that hnRNP-K is also able to inhibit AR translation in the absence of the 5'-UTR, consistent with the presence of additional predicted hnRNP-K binding sites within the AR open reading frame and in the 3'-UTR. Immunohistochemical analysis of a human prostate cancer tissue microarray revealed an inverse correlation between hnRNP-K expression and AR protein levels in organ-confined prostate tumors and a substantial decline in cytoplasmic hnRNP-K in metastases, despite an overall increase in hnRNP-K levels in metastatic tumors. These data suggest that translational inhibition of AR by hnRNP-K may occur in organ-confined tumors but possibly at a reduced level in metastases. HnRNP-K is the first protein identified that directly interacts with and regulates the AR translational apparatus.

Background: This study aims to assess any clustering between obesity, number of decayed, missing, and filled teeth (DMFT), television (TV) viewing, and lifestyle factors among pre-adolescents living in 2 countries with different developmental status and oral health care systems - Turkey and Finland., Patients and Methods: A cross-sectional study of Finnish (n = 338) and Turkish (n = 611) preadolescents, 10-12 years old, was undertaken with preadolescent oral health data and health behavior questionnaires for pre-adolescents and their mothers. The parameters examined were DMFT, body mass index (BMI), leisure time activities (TV viewing), and lifestyle factors (family dinners and dietary habits) of pre-adolescents. Data analysis included factor analysis, Student's t-test, and Chi-square tests by cross tabulation., Results: Turkish pre-adolescents were more obese and had poorer dental health than their Finnish counterparts (p < 0.05). Turkish and Finnish pre-adolescents drinking fizzy drinks more than 3 times a week were more likely to watch TV for >or= 2 h/school day (odds ratio (OR) = 1.51, 95% confidence interval (CI) 1.00-2.28) than those consuming them once a week or less (OR = 3.06, 95% CI 1.39-6.75; p < 0.05). Factor analysis revealed that DMFT and obesity shared the same cluster among Turkish and Finnish pre-adolescents., Conclusion: Both medical and dental examination of any pediatric patient should include BMI, leisure time activities, and dietary habits as well as socio-economic status., (Copyright (c) 2008 S. Karger AG, Basel.)

Akt kinases mediate cell growth and survival. Here, we report that a pro-apoptotic kinase, Mst1/STK4, is a physiological Akt1 interaction partner. Mst1 was identified as a component of an Akt1 multiprotein complex isolated from lipid raft-enriched fractions of LNCaP human prostate cancer cells. Endogenous Mst1, along with its paralog, Mst2, acted as inhibitors of endogenous Akt1. Surprisingly, mature Mst1 as well as both of its caspase cleavage products, which localize to distinct subcellular compartments and are not structurally homologous, complexed with and inhibited Akt1. cRNAs encoding full-length Mst1, and N- and C-terminal caspase Mst1 cleavage products, reverted an early lethal phenotype in zebrafish development induced by expression of membrane-targeted Akt1. Mst1 and Akt1 localized to identical subcellular sites in human prostate tumors. Mst1 levels declined with progression from clinically localized to hormone refractory disease, coinciding with an increase in Akt activation with transition from hormone naïve to hormone-resistant metastases. These results position Mst1/2 within a novel branch of the phosphoinositide 3-kinase/Akt pathway and suggest an important role in cancer progression.

The serine-threonine kinase, Akt1/protein kinase Balpha is an important mediator of growth, survival, and metabolic signaling. Recent studies have implicated cholesterol-rich, lipid raft microdomains in survival signals mediated by Akt1. Here we address the role of lipid raft membranes as a potential site of intersection of androgenic and Akt1 signaling. A subpopulation of androgen receptor (AR) was found to localize to a lipid raft subcellular compartment in LNCaP prostate cancer cells. Endogenous AR interacted with endogenous Akt1 preferentially in lipid raft fractions and androgen substantially enhanced the interaction between the two proteins. The association of AR with Akt1 was inhibited by the anti-androgen, bicalutamide, but was not affected by inhibition of phosphoinositide 3-kinase (PI3K). Androgen promoted endogenous Akt1 activity in lipid raft fractions, in a PI3K-independent manner, within 10 min of treatment. Fusion of a lipid raft targeting sequence to AR enhanced localization of the receptor to rafts, and stimulated Akt1 activity in response to androgen, while reducing the cells' dependence on constitutive signaling through PI3K for cell survival. These findings suggest that signals channeled through AR and Akt1 intersect by a mechanism involving formation within lipid raft membranes of an androgen-responsive, extranuclear AR/Akt1 complex. Our results indicate that cholesterol-rich membrane microdomains play a role in transmitting non-genomic signals involving androgen and the Akt pathway in prostate cancer cells.

Background: Previous studies have reported a circadian variation of ventricular tachyarrhythmias. However, there is no detailed information of the daily distribution of ventricular tachycardia (VT) and ventricular fibrillation (VF) episodes. The purpose of this study was to evaluate the daily distribution of episodes of ventricular tachyarrhythmia in patients with implantable cardioverter defibrillators., Material/methods: We used data stored by last-generation implantable cardioverter-defibrillators (ICD) to retrospectively evaluate the circadian distribution of VT and VF in 70 patients with ICD. The distribution of tachyarrhythmias was categorized into four time zones: zone 1 (06:00-11:59), zone 2 (12:00-17:59), zone 3 (18:00-23:59), and zone 4 (00:00-05:59)., Results: During a follow-up of a mean of 3.1+/-1.3 years, a total of 791 ventricular arrhythmias were recorded from which 631 events were VT and 160 VF. A circadian variation of episodes of ventricular tachyarrhythmia was evident. The incidence of ventricular arrhythmia sharply increased in zone 1 (8.82+/-2.13, p<0.0001). Episodes of VT had peaks in zones 1 and 2 (7.44+/-2.03 and 2.70+/-0.65, p<0.001) and episodes of VF had peaks in zones 1 and 4 (1.38+/-0.39 and 1.30+/-0.51, p<0.011). No difference was observed between patients who used betablocker and those who did not., Conclusions: Malignant ventricular tachyarrhythmias have a circadian distribution. VT peaks occur in the morning and noon hours and VF peaks occurs at the night and morning hours. Betablocker and/or amiodarone usage do not alter this distribution.

Androgen receptor (AR) plays an important role in normal prostate function as well as in the etiology of prostate cancer. Activation of AR is dictated by hormone binding and by interactions with coregulators. Several of these coregulators are known targets of Ras-related signals. Recent evidence suggests that Ras activation may play a causal role in the progression of prostate cancer toward a more malignant and hormone-insensitive phenotype. In the present study, we used a transcription factor-transcription factor interaction array method to identify the zinc finger protein Ras-responsive element binding protein (RREB-1) as a partner and coregulator of AR. In LNCaP prostate cancer cells, RREB-1 was found to be present in a complex with endogenous AR as determined by coimmunoprecipitation, glutathione S-transferase pull down, and immunofluorescence analyses. RREB-1 bound to the prostate-specific antigen (PSA) promoter as assessed by chromatin immunoprecipitation. Transient expression of RREB-1 down-regulated AR-mediated promoter activity and suppressed expression of PSA protein. The repressor activity of RREB-1 was significantly attenuated by cotransfection of activated Ras. Moreover, expression of the dominant-negative N-17-Ras or, alternatively, use of the MAPK kinase inhibitor PD98059 [2-(2-amino-3-methyoxyphenyl)-4H-1-benzopyran-4-one] abolished the effect of Ras in attenuating RREB-1-mediated repression. Furthermore, inhibition of RREB-1 expression by RNA interference enhanced the effect of Ras on PSA promoter activity and PSA expression. In addition, activation of the Ras pathway depleted AR from the RREB-1/AR complex. Collectively, our data for the first time identify RREB-1 as a repressor of AR and further implicate the Ras/MAPK kinase pathway as a likely antagonist of the inhibitory effects of RREB-1 on androgenic signaling.

The serine-threonine kinase, Akt, has been linked to cholesterol-sensitive signaling mechanisms, suggesting a possible means whereby cholesterol might affect tumor cell growth and survival. However, it has not been shown whether Akt itself, as distinct from upstream components of the pathway (e.g., membrane phosphoinositides), can be directly responsible for cholesterol-mediated effects. Consistent with this possibility, we identified an Akt1 subpopulation in cholesterol-rich lipid raft fractions prepared from LNCaP human prostate cancer cells. Phosphorylation of this Akt subspecies was ablated with methyl-beta-cyclodextrin, a cholesterol-binding compound, under conditions where nonlipid raft-resident Akt was unaffected. A myristoylated Akt1 (MyrAkt1) fusion protein expressed in LNCaP cells was found to be highly enriched in lipid rafts, indicating that oncogenic Akt is overrepresented in cholesterol-rich membranes compared with wild-type Akt. Notably, lipid raft-resident MyrAkt1 exhibited a markedly distinct substrate preference compared with MyrAkt1 immunoprecipitated from cytosol and nonraft membrane fractions, suggesting a redirection of signal transduction when the protein is present in cholesterol-rich membranes. Expression of MyrAkt1 in LNCaP cells overcame their characteristic dependence on constitutive signaling through the phosphoinositide 3'-kinase pathway. This protective effect was substantially diminished with cyclodextrin treatment. Phosphorylation of Akt substrates in lipid raft fractions, but not in cytosol/nonraft membrane fractions, was ablated with cyclodextrin. In addition, in control (LacZ transfected) cells, lipid raft fractions were relatively enriched in phosphorylated Akt substrates. Collectively, these data show that a subpopulation of Akt is cholesterol sensitive and that the oncogenic effects conferred by myristoylation arise, in part, from the tendency of the membrane-targeted form of the protein to reside in cholesterol-rich membrane microdomains.

Aneurysms of the renal artery are rare and have an estimated incidence of 0.09% in the general population. They may be diagnosed incidentally or during the evaluation of related symptoms. They may be followed up or treated either surgically or endovascularly. We present a successful percutaneous treatment of a renal artery aneurysm with stenosis by a stent-graft in a 55-year-old woman, who was diagnosed during the evaluation of labile hypertension. Follow-up was for 6 months.

The functional consequences of changes in membrane lipid composition that coincide with malignant growth are poorly understood. Sufficient data have been acquired from studies of lipid binding proteins, post-translational modifications of signaling proteins, and biochemical inhibition of lipidogenic pathways to indicate that growth and survival pathways might be substantially re-directed by alterations in the lipid content of membranes. Cholesterol and glycosphingolipids segregate into membrane patches that exhibit a liquid-ordered state in comparison to membrane domains containing relatively lower amounts of these classes of lipids. These "lipid raft" structures, which may vary in size and stability in different cell types, both accumulate and exclude signaling proteins and have been implicated in signal transduction through a number of cancer-relevant pathways. In prostate cancer cells, signaling from epidermal growth factor receptor (EGFR) to the serine-threonine kinase Akt1, as well as from IL-6 to STAT3, have been demonstrated to be influenced by experimental interventions that target cholesterol homeostasis. The recent finding that classical steroid hormone receptors also reside in these microdomains, and thus may function within these structures in a signaling capacity independent of their role as nuclear factors, suggests a novel means of cross-talk between receptor tyrosine kinase-derived and steroidogenic signals. Potential points of intersection between components of the EGFR family of receptor tyrosine kinases and androgen receptor signaling pathways, which may be sensitive to disruptions in cholesterol metabolism, are discussed. Understanding the manner in which these pathways converge within cholesterol-rich membranes may present new avenues for therapeutic intervention in hormone-dependent cancers.

Aim: Mortality and morbidity of abdominal aortic aneurysm surgery have decreased significantly in time and transperitoneal approach (TPA) still preserves its popularity although retroperitoneal approach (RPA) is known to cause lower incidence and shortened duration of ileus, shorter intensive care unit (ICU) and hospital stay, earlier oral intake and less patient discomfort or pain., Methods: One hundred and fifty patients that underwent abdominal aortic aneurysm repair at our Cardiovascular Surgery Center between January, 1990 and March, 2000 were reviewed and analyzed based on the elective/emergent nature of the surgery and the type of the incision as either TPA or RPA., Results: Significantly shorter mechanical ventilation (15.2+/-3.8 vs 10.1+/-2.3 hours) and nasogastric decompression periods (40.6+/-10.7 vs 9.1+/-2.2 hours), less need for intravenous fluid supplementation and shorter ICU stay (29.5+/-14.8 vs 18.6+/-1.9 hours) were observed with the retroperitoneal approach (P<0.001). Need for allogeneic blood transfusion was, similar (1.3+/-1.4 vs0.9+/-0.4, P>0.05). Analysis of mortality and morbidity revealed bleeding as the major cause of mortality for ruptured aneurysm. A similar comparison between TPA and RPA groups, however, revealed no significant difference (P>0.05)., Conclusions: | Retroperitoneal approach is a reliable technique causing less fluid-electrolyte imbalance with rapid restoration of gastrointestinal physiology. It causes less discomfort to patients with reduced need for analgesia. A shorter weaning period from mechanical ventilation is among the benefits for patients with co-morbid states.

The androgen receptor (AR) plays a key role in the development and function of male reproductive organs. Using a high-throughput transcription factor-transcription factor (TF-TF) interaction array method, we captured the AR interactomes in androgen-responsive LNCaP cells. Several known and unknown partners of AR, including AP-2, Pax 3/5 (BSAP), c-Rel, RREB-1, LIII BP, and NPAS2 were identified. We investigated one unreported AR-associated transcription factor, the proto-oncoprotein c-Rel, in detail. C-Rel belongs to the NF-kB/Rel families and is persistently active in a number of diseases, including cancer. The presence of c-Rel transcript, protein, and its in vitro and in vivo association with AR was determined. Co-localization of c-Rel with AR both in cytoplasm and nucleus was confirmed by indirect immunofluorescence analysis. Chromatin immunoprecipitation data indicated that c-Rel, like AR, is a part of the nucleoprotein complex regulating the androgen-responsive prostate-specific antigen (PSA) promoter. Overexpression of c-Rel downregulated the promoter activity of both PSA and GRE4-TATA-Luc plasmids in LNCaP and COS cells. Analysis of AR and c-Rel protein levels indicated that the promoter downregulation was not due to reciprocal decrease in the amounts of AR or c-Rel. In summary, we have identified several new partners of AR by using the TF-TF array method and have provided the first evidence of a functional role for c-Rel in androgen-responsive human prostate cancer cells.