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1.  Differential expression of Mediator complex subunit MED15 in testicular germ cell tumors 
Diagnostic Pathology  2015;10:165.
Testicular germ cell tumors (TGCT) are the most common cancer entities in young men with increasing incidence observed in the last decades. For therapeutic management it is important, that TGCT are divided into several histological subtypes. MED15 is part of the multiprotein Mediator complex which presents an integrative hub for transcriptional regulation and is known to be deregulated in several malignancies, such as prostate cancer and bladder cancer role, whereas the role of the Mediator complex in TGCT has not been investigated so far. Aim of the study was to investigate the implication of MED15 in TGCT development and its stratification into histological subtypes.
Immunohistochemical staining (IHC) against Mediator complex subunit MED15 was conducted on a TGCT cohort containing tumor-free testis (n = 35), intratubular germ cell neoplasia unclassified (IGCNU, n = 14), seminomas (SEM, n = 107) and non-seminomatous germ cell tumors (NSGCT, n = 42), further subdivided into embryonic carcinomas (EC, n = 30), yolk sac tumors (YST, n = 5), chorionic carcinomas (CC, n = 5) and teratomas (TER, n = 2). Quantification of MED15 protein expression was performed through IHC followed by semi-quantitative image analysis using the Definiens software.
In tumor-free seminiferous tubules, MED15 protein expression was absent or only low expressed in spermatogonia. Interestingly, the precursor lesions IGCNU exhibited heterogeneous but partly very strong MED15 expression. SEM weakly express the Mediator complex subunit MED15, whereas NSGCT and especially EC show significantly enhanced expression compared to tumor-free testis.
In conclusion, MED15 is differentially expressed in tumor-free testis and TGCT. While MED15 is absent or low in tumor-free testis and SEM, NSGCT highly express MED15, hinting at the diagnostic potential of this marker to distinguish between SEM and NSGCT. Further, the precursor lesion IGCNU showed increased nuclear MED15 expression in the preinvasive precursor cells, which may provide diagnostic value to distinguish between benign and pre-malignant testicular specimen, and may indicate a role for MED15 in carcinogenesis in TGCT.
PMCID: PMC4573996  PMID: 26377566
2.  Flow-enhanced solution printing of all-polymer solar cells 
Nature Communications  2015;6:7955.
Morphology control of solution coated solar cell materials presents a key challenge limiting their device performance and commercial viability. Here we present a new concept for controlling phase separation during solution printing using an all-polymer bulk heterojunction solar cell as a model system. The key aspect of our method lies in the design of fluid flow using a microstructured printing blade, on the basis of the hypothesis of flow-induced polymer crystallization. Our flow design resulted in a ∼90% increase in the donor thin film crystallinity and reduced microphase separated donor and acceptor domain sizes. The improved morphology enhanced all metrics of solar cell device performance across various printing conditions, specifically leading to higher short-circuit current, fill factor, open circuit voltage and significantly reduced device-to-device variation. We expect our design concept to have broad applications beyond all-polymer solar cells because of its simplicity and versatility.
Solution printing is a desirable route for manufacturing organic solar cells, whilst the major challenge lies with morphology control. Here, Diao et al. use a microstructured blade to guide the solution flow during printing, which improves polymer crystallization and the resulting device performance.
PMCID: PMC4557117  PMID: 26264528
3.  Long-range modulation of a composite crystal in a five-dimensional superspace 
Physical review. B, Condensed matter and materials physics  2015;91(18):10.1103/PhysRevB.91.184101.
The intergrowth crystal of n-tetracosane/urea presents a misfit parameter, defined by the ratio γ = ch/cg (chost/cguest), that is very close to a commensurate value (γ ≅ 1/3). High-resolution diffraction studies presented here reveal an aperiodic misfit parameter of γ = 0.3369, which is found to be constant at all temperatures studied. A complex sequence of structural phases is reported. The high temperature phase (phase I) exists in the four-dimensional superspace group P6122(00γ). At Tc1 = 179(1) K, a ferroelastic phase transition increases the dimension of the crystallographic superspace. This orthorhombic phase (phase II) is characterized by the five-dimensional (5D) superspace group C2221(00γ)(10δ) with a modulation vector ao* + cm* = ao* + δ · ch*, in which the supplementary misfit parameter is δ = 0.025(1) in host reciprocal units. This corresponds to the appearance of a modulation of very long period (about 440 ± 16 Å). At Tc2 = 163.0(5) K, a 5D to 5D phase transition leads to the crystallographic superspace group P212121(00γ)(00δ) with a very similar value of δ. This phase transition reveals a significant hysteresis effect.
PMCID: PMC4508869
4.  A Large Scale Test of the Effect of Social Class on Prosocial Behavior 
PLoS ONE  2015;10(7):e0133193.
Does being from a higher social class lead a person to engage in more or less prosocial behavior? Psychological research has recently provided support for a negative effect of social class on prosocial behavior. However, research outside the field of psychology has mainly found evidence for positive or u-shaped relations. In the present research, we therefore thoroughly examined the effect of social class on prosocial behavior. Moreover, we analyzed whether this effect was moderated by the kind of observed prosocial behavior, the observed country, and the measure of social class. Across eight studies with large and representative international samples, we predominantly found positive effects of social class on prosociality: Higher class individuals were more likely to make a charitable donation and contribute a higher percentage of their family income to charity (32,090 ≥ N ≥ 3,957; Studies 1–3), were more likely to volunteer (37,136 ≥N ≥ 3,964; Studies 4–6), were more helpful (N = 3,902; Study 7), and were more trusting and trustworthy in an economic game when interacting with a stranger (N = 1,421; Study 8) than lower social class individuals. Although the effects of social class varied somewhat across the kinds of prosocial behavior, countries, and measures of social class, under no condition did we find the negative effect that would have been expected on the basis of previous results reported in the psychological literature. Possible explanations for this divergence and implications are discussed.
PMCID: PMC4507988  PMID: 26193099
5.  First-Trimester Uterine Artery Doppler Analysis in the Prediction of Later Pregnancy Complications 
Disease Markers  2015;2015:679730.
Uterine artery Doppler waveform analysis has been extensively studied in the second trimester of pregnancy as a predictive marker for the later development of preeclampsia and fetal growth restriction. The use of Doppler interrogation of this vessel in the first trimester has gained momentum in recent years. Various measurement techniques and impedance indices have been used to evaluate the relationship between uterine artery Doppler velocimetry and adverse pregnancy outcomes. Overall, first-trimester Doppler interrogation of the uterine artery performs better in the prediction of early-onset than late-onset preeclampsia. As an isolated marker of future disease, its sensitivity in predicting preeclampsia and fetal growth restriction in low risk pregnant women is moderate, at 40–70%. Multiparametric predictive models, combining first-trimester uterine artery pulsatility index with maternal characteristics and biochemical markers, can achieve a detection rate for early-onset preeclampsia of over 90%. The ideal combination of these tests and validation of them in various patient populations will be the focus of future research.
PMCID: PMC4418013  PMID: 25972623
6.  Long Term Progression-Free Survival in a Patient with Locally Advanced Prostate Cancer under Low Dose Intermittent Androgen Deprivation Therapy with Bicalutamide Only 
Case Reports in Urology  2015;2015:928787.
Androgen deprivation is a common treatment option in patients with locally advanced or metastatic prostate cancer. No case of long term treatment with an intermittent approach with only low dose bicalutamide (50 mg daily) has been described yet. We report a 60-year-old patient, initially presenting with a PSA elevation of 19.2 ng/mL in 1996. After diagnosis of well to moderately differentiated prostate cancer by transrectal biopsy, the patient underwent an open radical prostatectomy. Final diagnosis was adenocarcinoma of the prostate, classified as pT3a, pR1, pV0, and pL1. Adjuvant intermittent androgen deprivation therapy with flutamide 250 mg was applied, which was changed to bicalutamide 50 mg once daily when it became available in 2001. Six on-phases were performed and PSA values never exceeded 20 ng/mL. The patient did not experience any serious side effects. To date, there are no clinical or radiological signs of progression. Current PSA value is 3.5 ng/mL.
PMCID: PMC4391157  PMID: 25883827
7.  Identification of novel long non-coding RNAs in clear cell renal cell carcinoma 
Clinical Epigenetics  2015;7(1):10.
Long non-coding RNAs (lncRNA) play an important role in carcinogenesis; knowledge on lncRNA expression in renal cell carcinoma is rudimental. As a basis for biomarker development, we aimed to explore the lncRNA expression profile in clear cell renal cell carcinoma (ccRCC) tissue.
Microarray experiments were performed to determine the expression of 32,183 lncRNA transcripts belonging to 17,512 lncRNAs in 15 corresponding normal and malignant renal tissues. Validation was performed using quantitative real-time PCR in 55 ccRCC and 52 normal renal specimens. Computational analysis was performed to determine lncRNA-microRNA (MiRTarget2) and lncRNA-protein (catRAPID omics) interactions. We identified 1,308 dysregulated transcripts (expression change >2-fold; upregulated: 568, downregulated: 740) in ccRCC tissue. Among these, aberrant expression was validated using PCR: lnc-BMP2-2 (mean expression change: 37-fold), lnc-CPN2-1 (13-fold), lnc-FZD1-2 (9-fold), lnc-ITPR2-3 (15-fold), lnc-SLC30A4-1 (15-fold), and lnc-SPAM1-6 (10-fold) were highly overexpressed in ccRCC, whereas lnc-ACACA-1 (135-fold), lnc-FOXG1-2 (19-fold), lnc-LCP2-2 (2-fold), lnc-RP3-368B9 (19-fold), and lnc-TTC34-3 (314-fold) were downregulated. There was no correlation between lncRNA expression with clinical-pathological parameters. Computational analyses revealed that these lncRNAs are involved in RNA-protein networks related to splicing, binding, transport, localization, and processing of RNA. Small interfering RNA (siRNA)-mediated knockdown of lnc-BMP2-2 and lnc-CPN2-1 did not influence cell proliferation.
We identified many novel lncRNA transcripts dysregulated in ccRCC which may be useful for novel diagnostic biomarkers.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-015-0047-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4326488  PMID: 25685243
8.  Analysis of Tissue and Serum MicroRNA Expression in Patients with Upper Urinary Tract Urothelial Cancer 
PLoS ONE  2015;10(1):e0117284.
MicroRNAs play an important role in many human malignancies; so far, their expression remains to be studied in upper urinary tract urothelial cancer (UUTUC).
Materials and Methods
The expression of eleven microRNAs (miR-10a, miR-21, miR-96, miR-135, miR-141, miR-182, miR-200b, miR-205, miR-429, miR-520b, miR-1244) formerly shown to be upregulated in urothelial bladder cancer were studied in corresponding normal and cancerous tissue samples of patients undergoing nephroureterectomy for UUTUC. Upregulated microRNAs were then measured in serum samples of patients with UUTUC and patients with non-malignant urological diseases to evaluate their potential as non-invasive biomarkers for UUTUC.
MicroRNA expression allowed differentiation of normal and cancerous tissue: miR-21, miR-96, miR-135, miR-141, miR-182, miR-205, miR-429 and miR-520b were significantly overexpressed. Furthermore, miR-205 was upregulated in poorly differentiated UUTUC. The analysis of circulating RNA in serum demonstrated an increase of miR-141 in patients with UUTUC; receiver operator characteristic analysis demonstrated an area under the curve of 0.726 for miR-141 as a diagnostic biomarker. Furthermore, we observed lower levels of miR-10a and miR-135 in UUTUC patients.
MicroRNA expression is altered in UUTUC. The analysis of circulating miR-141 may be useful to identify patients with UUTUC.
PMCID: PMC4309610  PMID: 25629698
9.  Prostaglandin receptors EP1-4 as a potential marker for clinical outcome in urothelial bladder cancer 
Prostaglandins, especially prostaglandin E2 (PGE2), and COX-2 play an important role in carcinogenesis of many tumors including bladder cancer (BCA). The PGE2 receptors EP1-4 regulate tumor cell growth, invasion and migration in different tumor entities but EP expression in BCA remains to be determined. In the present study we examined the expression of EP1-4 in non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC) and normal urothelial tissue (NU) using immunohistochemistry. Nuclear and cytoplasmic EP1-4 expression was correlated with clinicopathological parameters and survival of BCA patients. EP1, EP2 and EP3 were significantly less expressed in the cytoplasm und nucleus of NMIBC and MIBC than in NU; EP4 cytoplasmic staining in MIBC was significantly higher compared to NU. The cytoplasmic staining was significantly more abundant in MIBC than in NMIBC in all investigated receptors except EP2. The level of EP staining in NMIBC was correlated with staging and grading, especially cytoplasmic EP1. Nuclear staining of EP1 was an independent predictor of BCA recurrence-free survival in NMIBC patients. EP receptors are dysregulated in BCA. The increase of EP1 may be used as prognostic parameter in NMIBC patients and its dysregulation could be targeted by specific EP1 inhibitors.
PMCID: PMC4266727  PMID: 25520883
Bladder cancer; EP1; EP2; EP3; EP4; prostaglandin receptors; immunohistochemistry
10.  Enhancement of antitumor immunity in lung cancer by targeting myeloid-derived suppressor cell pathways 
Cancer research  2013;73(22):10.1158/0008-5472.CAN-13-0987.
Chemoresistance due to heterogeneity of the tumor microenvironment (TME) hampers the long-term efficacy of frontline therapies for lung cancer. Current combination therapies for lung cancer provide only modest improvement in survival, implicating necessity for novel approaches that suppress malignant growth and stimulate long-term anti-tumor immunity. Oxidative stress in the TME promotes immunosuppression by tumor infiltrating myeloid-derived suppressor cells (MDSC), which inhibit host protective anti-tumor immunity. Using a murine model of lung cancer, we demonstrate that a combination treatment with gemcitabine and a superoxide dismutase mimetic targets immunosuppressive MDSC in the TME and enhances the quantity and quality of both effector and memory CD8+ T cell responses. At the effector cell function level, the unique combination therapy targeting MDSC and redox signaling greatly enhanced cytolytic CD8+ T cell response and further decreased T regulatory cell infiltration. For long-term anti-tumor effects, this therapy altered the metabolism of memory cells with self-renewing phenotype and provided a preferential advantage for survival of memory subsets with long-term efficacy and persistence. Adoptive transfer of memory cells from this combination therapy prolonged survival of tumor-bearing recipients. Furthermore, the adoptively-transferred memory cells responded to tumor re-challenge exerting long-term persistence. This approach offers a new paradigm to inhibit immunosuppression by direct targeting of MDSC function, generate effector and persistent memory cells for tumor eradication, and prevent lung cancer relapse.
PMCID: PMC3854493  PMID: 24085788
Lung cancer; MDSC; Memory response; Combination therapy
11.  Online Deviation Detection for Medical Processes 
Human errors are a major concern in many medical processes. To help address this problem, we are investigating an approach for automatically detecting when performers of a medical process deviate from the acceptable ways of performing that process as specified by a detailed process model. Such deviations could represent errors and, thus, detecting and reporting deviations as they occur could help catch errors before harm is done. In this paper, we identify important issues related to the feasibility of the proposed approach and empirically evaluate the approach for two medical procedures, chemotherapy and blood transfusion. For the evaluation, we use the process models to generate sample process executions that we then seed with synthetic errors. The process models describe the coordination of activities of different process performers in normal, as well as in exceptional situations. The evaluation results suggest that the proposed approach could be applied in clinical settings to help catch errors before harm is done.
PMCID: PMC4419868  PMID: 25954343
12.  Adventitial dissection: a simple and effective way to reduce radial artery spasm in coronary bypass surgery 
Over the last two decades, the radial artery (RA) has become a routinely used conduit for coronary artery bypass graft surgery. One potential disadvantage of the radial artery is its higher susceptibility to vasospasm compared with other arterial grafts. We investigated whether adventitial dissection of the radial artery can reduce vasoconstriction and increase free blood flow.
Following harvesting, the adventitia of the radial artery was dissected using coronary scissors. Surplus distal radial artery segments (n = 35) with and without adventitial dissection of patients undergoing coronary artery bypass surgery were collected and pairwise assessment of vasoreactivity to potassium chloride, U46619 and acetylcholine was performed in organ bath experiments. Free blood flow was measured before and after adventitial dissection.
Full curve and maximal vasoconstriction of the RA to potassium chloride (P = 0.015 and 0.001) and U46619 (P = 0.048 and 0.001) was significantly reduced after adventitial dissection compared with non-adventitial dissected radial arteries. Endothelium-dependent relaxation to acetylcholine of adventitial dissected radial arteries was significantly increased (P = 0.006) compared with non-adventitial dissected radial arteries. Maximal vasorelaxation to acetylcholine was significantly increased for adventitial dissected radial arteries compared with non-adventitial dissected radial arteries (P = 0.018). Free blood flow was significantly increased after adventitial dissection (P = 0.037).
The adventitial dissected radial artery is less susceptible to vasoconstriction and more prone to vasorelaxation ex vivo and shows an increased free blood flow. Therefore, we suggest adventitial dissection of the radial artery graft to reduce vasospasm for arterial revascularization in coronary artery bypass surgery.
PMCID: PMC3805201  PMID: 23883477
Coronary artery bypass graft arterial grafts; Vascular tone and reactivity; Coronary artery bypass graft new technology; Off-pump surgery
Developmental biology  2013;382(1):268-279.
The sea urchin oral ectoderm gene regulatory network (GRN) model has increased in complexity as additional genes are added to it, revealing its multiple spatial regulatory state domains. The formation of the oral ectoderm begins with an oral-aboral redox gradient, which is interpreted by the cis-regulatory system of the nodal gene to cause its expression on the oral side of the embryo. Nodal signaling drives cohorts of regulatory genes within the oral ectoderm and its derived subdomains. Activation of these genes occurs sequentially, spanning the entire blastula stage. During this process the stomodeal subdomain emerges inside of the oral ectoderm, and bilateral subdomains defining the lateral portions of the future ciliary band emerge adjacent to the central oral ectoderm. Here we examine two regulatory genes encoding repressors, sip1 and ets4, which selectively prevent transcription of oral ectoderm genes until their expression is cleared from the oral ectoderm as an indirect consequence of Nodal signaling. We show that the timing of transcriptional de-repression of sip1 and ets4 targets which occurs upon their clearance explains the dynamics of oral ectoderm gene expression. In addition two other repressors, the direct Nodal target not, and the feed forward Nodal target goosecoid, repress expression of regulatory genes in the central animal oral ectoderm thereby confining their expression to the lateral domains of the animal ectoderm. These results have permitted construction of an enhanced animal ectoderm GRN model highlighting the repressive interactions providing precise temporal and spatial control of regulatory gene expression.
PMCID: PMC3783610  PMID: 23933172
Sea urchin; oral ectoderm; sip1; ets4; gene regulatory network
14.  Region-Specific Sensitivity of Anemophilous Pollen Deposition to Temperature and Precipitation 
PLoS ONE  2014;9(8):e104774.
Understanding relations between climate and pollen production is important for several societal and ecological challenges, importantly pollen forecasting for pollinosis treatment, forensic studies, global change biology, and high-resolution palaeoecological studies of past vegetation and climate fluctuations. For these purposes, we investigate the role of climate variables on annual-scale variations in pollen influx, test the regional consistency of observed patterns, and evaluate the potential to reconstruct high-frequency signals from sediment archives. A 43-year pollen-trap record from the Netherlands is used to investigate relations between annual pollen influx, climate variables (monthly and seasonal temperature and precipitation values), and the North Atlantic Oscillation climate index. Spearman rank correlation analysis shows that specifically in Alnus, Betula, Corylus, Fraxinus, Quercus and Plantago both temperature in the year prior to (T-1), as well as in the growing season (T), are highly significant factors (TApril rs between 0.30 [P<0.05[ and 0.58 [P<0.0001]; TJuli-1 rs between 0.32 [P<0.05[ and 0.56 [P<0.0001]) in the annual pollen influx of wind-pollinated plants. Total annual pollen prediction models based on multiple climate variables yield R2 between 0.38 and 0.62 (P<0.0001). The effect of precipitation is minimal. A second trapping station in the SE Netherlands, shows consistent trends and annual variability, suggesting the climate factors are regionally relevant. Summer temperature is thought to influence the formation of reproductive structures, while temperature during the flowering season influences pollen release. This study provides a first predictive model for seasonal pollen forecasting, and also aides forensic studies. Furthermore, variations in pollen accumulation rates from a sub-fossil peat deposit are comparable with the pollen trap data. This suggests that high frequency variability pollen records from natural archives reflect annual past climate variability, and can be used in palaeoecological and -climatological studies to bridge between population- and species-scale responses to climate forcing.
PMCID: PMC4136776  PMID: 25133631
15.  Single-Stranded DNA Catalyzes Hybridization of PCR-Products to Microarray Capture Probes 
PLoS ONE  2014;9(7):e102338.
Since its development, microarray technology has evolved to a standard method in the biotechnological and medical field with a broad range of applications. Nevertheless, the underlying mechanism of the hybridization process of PCR-products to microarray capture probes is still not completely understood, and several observed phenomena cannot be explained with current models. We investigated the influence of several parameters on the hybridization reaction and identified ssDNA to play a major role in the process. An increase of the ssDNA content in a hybridization reaction strongly enhanced resulting signal intensities. A strong influence could also be observed when unlabeled ssDNA was added to the hybridization reaction. A reduction of the ssDNA content resulted in a massive decrease of the hybridization efficiency. According to these data, we developed a novel model for the hybridization mechanism. This model is based on the assumption that single stranded DNA is necessary as catalyst to induce the hybridization of dsDNA. The developed hybridization model is capable of giving explanations for several yet unresolved questions regarding the functionality of microarrays. Our findings not only deepen the understanding of the hybridization process, but also have immediate practical use in data interpretation and the development of new microarrays.
PMCID: PMC4099319  PMID: 25025686
16.  Neural deletion of Tgfbr2 impairs angiogenesis through an altered secretome 
Human Molecular Genetics  2014;23(23):6177-6190.
Simultaneous generation of neural cells and that of the nutrient-supplying vasculature during brain development is called neurovascular coupling. We report on a transgenic mouse with impaired transforming growth factor β (TGFβ)-signalling in forebrain-derived neural cells using a Foxg1-cre knock-in to drive the conditional knock-out of the Tgfbr2. Although the expression of FOXG1 is assigned to neural progenitors and neurons of the telencephalon, Foxg1cre/+;Tgfbr2flox/flox (Tgfbr2-cKO) mutants displayed intracerebral haemorrhage. Blood vessels exhibited an atypical, clustered appearance were less in number and displayed reduced branching. Vascular endothelial growth factor (VEGF) A, insulin-like growth factor (IGF) 1, IGF2, TGFβ, inhibitor of DNA binding (ID) 1, thrombospondin (THBS) 2, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 1 were altered in either expression levels or tissue distribution. Accordingly, human umbilical vein endothelial cells (HUVEC) displayed branching defects after stimulation with conditioned medium (CM) that was derived from primary neural cultures of the ventral and dorsal telencephalon of Tgfbr2-cKO. Supplementing CM of Tgfbr2-cKO with VEGFA rescued these defects, but application of TGFβ aggravated them. HUVEC showed reduced migration towards CM of mutants compared with controls. Supplementing the CM with growth factors VEGFA, fibroblast growth factor (FGF) 2 and IGF1 partially restored HUVEC migration. In contrast, TGFβ supplementation further impaired migration of HUVEC. We observed differences along the dorso-ventral axis of the telencephalon with regard to the impact of these factors on the phenotype. Together these data establish a TGFBR2-dependent molecular crosstalk between neural and endothelial cells during brain vessel development. These findings will be useful to further elucidate neurovascular interaction in general and to understand pathologies of the blood vessel system such as intracerebral haemorrhages, hereditary haemorrhagic telangiectasia, Alzheimeŕs disease, cerebral amyloid angiopathy or tumour biology.
PMCID: PMC4222361  PMID: 24990151
17.  The Sea Urchin Genome as a Window on Function 
The Biological bulletin  2008;214(3):266-273.
The emphasis on the sequencing of genomes seems to make this task an end in itself. However, genome sequences and the genes that are predicted from them are really an opportunity to examine the biological function of the organism constructed by that genome. This point is illustrated here by examples in which the newly annotated gene complement reveals surprises about the way Strongylocentrotus purpuratus, the purple sea urchin, goes about its business. The three topics considered here are the nature of the innate immune system; the unexpected complexity of sensory function implied by genes encoding sensory proteins; and the remarkable intricacy of the regulatory gene complement in embryogenesis.
PMCID: PMC3981829  PMID: 18574103
18.  First Trimester Biomarkers in the Prediction of Later Pregnancy Complications 
BioMed Research International  2014;2014:807196.
Adverse obstetric outcomes, such as preeclampsia, preterm birth, gestational diabetes, and fetal growth restriction, are poorly predicted by maternal history and risk factors alone, especially in nulliparae. The ability to predict these outcomes from the first trimester would allow for the early initiation of prophylactic therapies, institution of an appropriate model and location of care, and recruitment of a truly “high risk” population to clinical trials of interventions to prevent or ameliorate these conditions. To this end, development of adequately sensitive and specific predictive tests for these outcomes has become a significant focus of perinatal research. This paper reviews the biomarkers involved in these multiparametric tests and also outlines the performance of these tests and issues regarding their introduction into clinical practice.
PMCID: PMC3988945  PMID: 24800250
19.  Diversification of Oral and Aboral Mesodermal Regulatory States in Pregastrular Sea Urchin Embryos 
Developmental biology  2012;375(1):92-104.
Specification of the non-skeletogenic mesoderm (NSM) in sea urchin embryos depends on Delta signaling. Signal reception leads to expression of regulatory genes that later contribute to the aboral NSM regulatory state. In oral NSM, this is replaced by a distinct oral regulatory state in consequence of Nodal signaling. Through regulome wide analysis we identify the homeobox gene not as an immediate Nodal target. not expression in NSM causes extinction of the aboral regulatory state in the oral NSM, and expression of a new suite of regulatory genes. All NSM specific regulatory genes are henceforth expressed exclusively, in oral or aboral domains, presaging the mesodermal cell types that will emerge. We have analyzed the regulatory linkages within the aboral NSM gene regulatory network. A linchpin of this network is gataE which as we show is a direct Gcm target and part of a feedback loop locking down the aboral regulatory state.
PMCID: PMC3570723  PMID: 23261933
mesoderm; nodal signaling; oral/aboral axis; not; gcm; gataE; gene regulatory network
20.  Impact of the HIV epidemic and Anti-Retroviral Treatment policy on Lymphoma incidence and subtypes seen in the Western Cape of South Africa, 2002–2009 
The Tygerberg Lymphoma Study Group was constituted in 2007 to quantify the impact of HIV on the pattern and burden of lymphoma cases in the Western Cape of South Africa which currently has an HIV prevalence of 15%. South Africa has had an Anti-Retroviral Treatment (ART) policy and roll out plan since 2004 attaining 31% effective coverage in 2009. This study is designed to qualify and establish what impact the HIV epidemic and the ARV roll-out treatment program is having on the incidence of HIV related Lymphoma (HRL). Early data documents that despite the ART roll out, cases of HRL are increasing in this geographical location, now comprising 37% of all lymphomas seen in 2009 which is an increase from 5 % in 2002. This is in contrast to trends seen in developed environments following the introduction of ART. Also noted, are the emergence of subtypes not previously seen in this location such as Burkitt and plasmablastic lymphomas. Burkitt lymphoma is now the commonest HRL seen in this population followed by diffuse large B Cell lymphoma subtypes. The reasons for this observed increase in HRL is not ascribable to improved diagnostic capacity as the tertiary institute in which these diagnosis are made, has had significant expertise in this regard for over a decade. We ascribe this paradoxical finding to an ART treatment environment that is ineffective for a diversity of reason, paramount of which are poor coverage, late commencement of ART and incomplete viral suppression.
PMCID: PMC3899789  PMID: 21402310
21.  Contemporary Clinical Management of the Cerebral Complications of Preeclampsia 
The neurological complications of preeclampsia and eclampsia are responsible for a major proportion of the morbidity and mortality arising from these conditions, for women and their infants alike. This paper outlines the evidence base for contemporary management principles pertaining to the neurological sequelae of preeclampsia, primarily from the maternal perspective, but with consideration of fetal and neonatal aspects as well. It concludes with a discussion regarding future directions in the management of this potentially lethal condition.
PMCID: PMC3893864  PMID: 24489551
22.  Direct and indirect control of oral ectoderm regulatory gene expression by Nodal signaling in the sea urchin embryo 
Developmental biology  2012;369(2):377-385.
The Nodal signaling pathway is known from earlier work to be an essential mediator of oral ectoderm specification in the sea urchin embryo, and indirectly, of aboral ectoderm specification as well. Following expression of the Nodal ligand in the future oral ectoderm during cleavage, a sequence of regulatory gene activations occurs within this territory which depends directly or indirectly on nodal gene expression. Here we describe additional regulatory genes that contribute to the oral ectoderm regulatory state during specification in Strongylocentrotus purpuratus, and show how their spatial expression changes dynamically during development. By means of system wide perturbation analyses we have significantly improved current knowledge of the epistatic relations amongst the regulatory genes of the oral ectoderm. From these studies there emerge diverse circuitries relating downstream regulatory genes directly and indirectly to Nodal signaling. A key intermediary regulator, the role of which had not previously been discerned, is the not gene. In addition to activating several genes earlier described as targets of Nodal signaling, the not gene product acts to repress other oral ectoderm genes, contributing crucially to the bilateral spatial organization of the embryonic oral ectoderm.
PMCID: PMC3423475  PMID: 22771578
nodal signaling; gene regulatory network; oral ectoderm specification
23.  Utilizing a handheld electrode array for localized muscle impedance measurements 
Muscle & nerve  2012;46(2):257-263.
Electrical impedance myography (EIM) is a non-invasive technique used for assessment of muscle health in which a high-frequency, low-amplitude electric current is applied to the skin overlying a muscle, and the resulting surface voltage is measured. We have previously used adhesive electrodes, application of which is inconvenient. We present data using a handheld electrode array (HEA) that we devised to expedite the EIM procedure in a clinical setting.
Thirty-four healthy volunteers and 24 radiculopathy subjects underwent EIM testing using the HEA and adhesive electrodes.
The HEA was shown to have good test-retest reproducibility, with intraclass correlation coefficients as high as 0.99. HEA data correlated strongly with data from adhesive electrodes, ρ = 0.85 in healthy volunteers (p < 0.001) and ρ = 0.75 in radiculopathy subjects (p < 0.001).
These data support the potential use of a handheld array for performing rapid localized surface impedance measurements.
PMCID: PMC3400114  PMID: 22806375
electrical impedance; radiculopathy; subcutaneous fat; muscle; reproducibility
24.  Ubiquinol supplementation enhances peak power production in trained athletes: a double-blind, placebo controlled study 
To investigate the effect of Ubiquinol supplementation on physical performance measured as maximum power output in young and healthy elite trained athletes.
In this double-blind, placebo-controlled study, 100 young German well trained athletes (53 male, 47 female, age 19.9 ± 2.3 years) received either 300 mg Ubiquinol or placebo for 6 weeks. Athletes had to perform a maximum power output test and the performance in W/kg of bodyweight was measured at the 4 mmol lactate threshold on a cycling ergometer before the supplementation treatment (T1), after 3 weeks (T2) and after 6 weeks (T3) of treatment. In these 6 weeks all athletes trained individually in preparation for the Olympic Games in London 2012. The maximum power output was measured in Watt/kilogram body weight (W/kg bw).
Both groups, placebo and Ubiquinol, significantly increased their physical performance measured as maximum power output over the treatment period from T1 to T3. The placebo group increased from 3.64 ± 0.49 W/kg bw to 3.94 ± 0.47 W/kg bw which is an increase of +0.30 ± 0.18 W/kg bw or +8.5% (±5.7). The Ubiquinol group increased performance levels from 3.70 W/kg bw (±0.56) to 4.08 W/kg bw (±0.48) from time point T1 to T3 which is an increase of +0.38 ± 0.22 W/kg bw or +11.0% (±8.2). The absolute difference in the enhancement of the physical performance between the placebo and the Ubiquinol group of +0.08 W/kg bodyweight was significant (p < 0.03).
This study demonstrates that daily supplementation of 300 mg Ubiquinol for 6 weeks significantly enhanced physical performance measured as maximum power output by +0.08 W/kg bw (+2.5%) versus placebo in young healthy trained German Olympic athletes. While adherence to a training regimen itself resulted in an improvement in peak power output, as observed by improvement in placebo, the effect of Ubiquinol supplementation significantly enhanced peak power production in comparison to placebo.
PMCID: PMC3661336  PMID: 23627788
Ubiquinol; Reduced CoQ10; Peak power output; Performance; Elite athletes
25.  A comprehensive analysis of Delta signaling in pre-gastrular sea urchin embryos 
Developmental Biology  2012;364(1):77-87.
In sea urchin embryos Delta signaling specifies non-skeletogenic mesoderm (NSM). Despite the identification of some direct targets, several aspects of Delta Notch (D/N) signaling remain supported only by circumstantial evidence. To obtain a detailed and more complete image of Delta function we followed a systems biology approach and evaluated the effects of D/N perturbation on expression levels of 205 genes up to gastrulation. This gene set includes virtually all transcription factors that are expressed in a localized fashion by mid-gastrulation, and which thus provide spatial regulatory information to the embryo. Also included are signaling factors and some pigment cell differentiation genes. We show that the number of pregastrular D/N signaling targets among these regulatory genes is small and is almost exclusively restricted to non-skeletogenic mesoderm genes. However, Delta signaling also activates foxY in the small micromeres. As is the early NSM, the small micromeres are in direct contact with Delta expressing skeletogenic mesoderm. In contrast, no endoderm regulatory genes are activated by Delta signaling even during the second phase of delta expression, when this gene is transcribed in NSM cells adjacent to the endoderm. During this phase Delta provides an ongoing input which continues to activate foxY expression in small micromere progeny. Disruption of the second phase of Delta expression specifically abolishes specification of late mesodermal derivatives such as the coelomic pouches to which the small micromeres contribute.
PMCID: PMC3294105  PMID: 22306924
Delta; Notch; DAPT; FoxY; Mesoderm; Coelomic Pouch; Pigment; Small Micromeres; Sea Urchin

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