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The transcription factor p73 synthesizes a large number of isoforms and presents high structural and functional homology with p53, a well-known tumor suppressor and a famous "Holy Grail" of anticancer targeting. p73 has attracted increasing attention mainly because (a) unlike p53, p73 is rarely mutated in cancer, (b) some p73 isoforms can inhibit all hallmarks of cancer, and (c) it has the ability to mimic oncosuppressive functions of p53, even in p53-mutated cells. These attributes render p73 and its downstream pathways appealing for therapeutic targeting, especially in mutant p53-driven cancers. p73 functions are, at least partly, mediated by microRNAs (miRNAs), which constitute nodal components of p73-governed networks. p73 not only regulates transcription of crucial miRNA genes, but is also predicted to affect miRNA populations in a transcription-independent manner by developing protein-protein interactions with components of the miRNA processing machinery. This combined effect of p73, both in miRNA transcription and maturation, appears to be isoform-dependent and can result in a systemic switch of cell miRNomes toward either an anti-oncogenic or oncogenic outcome. In this review, we combine literature search with bioinformatics approaches to reconstruct the p73-governed miRNA network and discuss how these crosstalks may be exploited to develop next-generation therapeutics.

Metastasis is one of the most challenging issues in cancer patient management, and effective therapies to specifically target disease progression are missing, emphasizing the urgent need for developing novel anti-metastatic therapeutics. Cancer stem cells (CSCs) gained fast attention as a minor population of highly malignant cells within liquid and solid tumors that are responsible for tumor onset, self-renewal, resistance to radio- and chemotherapies, and evasion of immune surveillance accelerating recurrence and metastasis. Recent progress in the identification of their phenotypic and molecular characteristics and interactions with the tumor microenvironment provides great potential for the development of CSC-based targeted therapies and radical improvement in metastasis prevention and cancer patient prognosis. Here, we report on newly uncovered signaling mechanisms controlling CSC's aggressiveness and treatment resistance, and CSC-specific agents and molecular therapeutics, some of which are currently under investigation in clinical trials, gearing towards decisive functional CSC intrinsic or surface markers. One special research focus rests upon subverted regulatory pathways such as insulin-like growth factor 1 receptor signaling and its interactors in metastasis-initiating cell populations directly related to the gain of stem cell- and EMT-associated properties, as well as key components of the E2F transcription factor network regulating metastatic progression, microenvironmental changes, and chemoresistance. In addition, the study provides insight into systems biology tools to establish complex molecular relationships behind the emergence of aggressive phenotypes from high-throughput data that rely on network-based analysis and their use to investigate immune escape mechanisms or predict clinical outcome-relevant CSC receptor signaling signatures. We further propose that customized vector technologies could drastically enhance systemic drug delivery to target sites, and summarize recent progress and remaining challenges. This review integrates available knowledge on CSC biology, computational modeling approaches, molecular targeting strategies, and delivery techniques to envision future clinical therapies designed to conquer metastasis-initiating cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Most DNA in the genomes of higher organisms does not encode proteins, yet much is transcribed by RNA polymerase II (RNAPII) into long non-coding RNAs (lncRNAs). The biological significance of most lncRNAs is largely unclear. Here, we identify a lncRNA (SVALKA) in a cold-sensitive region of the Arabidopsis genome. Mutations in SVALKA affect CBF1 expression and freezing tolerance. RNAPII read-through transcription of SVALKA results in a cryptic lncRNA overlapping CBF1 on the antisense strand, termed asCBF1. Our molecular dissection reveals that CBF1 is suppressed by RNAPII collision stemming from the SVALKA-asCBF1 lncRNA cascade. The SVALKA-asCBF1 cascade provides a mechanism to tightly control CBF1 expression and timing that could be exploited to maximize freezing tolerance with mitigated fitness costs. Our results provide a compelling example of local gene regulation by lncRNA transcription having a profound impact on the ability of plants to appropriately acclimate to challenging environmental conditions.

Purpose: To analyze the feasibility of 2D-perfusion angiography (2D-PA) to quantify flow and perfusion changes pre- and post-transjugular intrahepatic portosystemic shunt (TIPS) revision., Materials and Methods: Fifteen consecutive patients (54 ± 14 years, seven men and eight women) scheduled for TIPS revision were included in this study. To quantify flow and perfusion changes caused by TIPS revision, digital subtraction angiography (DSA) series acquired during the revision were post-processed using a dedicated software. Reference region-of-interest (ROI) in the main portal vein (input function) and target ROIs in the TIPS lumen, the liver parenchyma and in the right atrium were placed in corresponding areas on DSA pre- and post-TIPS revision. 2D-PA evaluation included time to peak (TTP), peak density (PD), and the area under the curve (AUC) assessment. The ratios of reference ROI to target ROIs pre- and post-TIPS revision were calculated (TTP parenchyma /TTP inflow , PD parenchyma /PD inflow , AUC parenchyma /AUC inflow , TTP TIPS /TTP inflow , PD TIPS /PD inflow , AUC TIPS /AUC inflow , TTP atrium /TTP inflow , PD atrium /PD inflow , and AUC atrium /AUC inflow ). Pressure measurements pre- and post-TIPS revision were performed and correlated to the 2D-PA parameters. Reproducibility of 2D-PA was assessed by the intra-class correlation coefficient (ICC)., Results: The portosystemic pressure gradient was significantly reduced following TIPS revision (17.1 ± 6.3 vs. 8.9 ± 4.3 mmHg; p < 0.0001). PD TIPS /PD inflow (0.22 vs. 0.35; p = 0.0014) and AUC TIPS /AUC inflow (0.24 vs. 0.39; p = 0.0012) increased significantly. Likewise, PD atrium /PD inflow (0.32 vs. 0.78; p = 0.0004) and AUC atrium /AUC inflow (0.3 vs. 0.79; p < 0.0001) increased, whereas PD parenchyma /PD inflow decreased significantly (0.14 vs. 0.1; p = 0.0084). Pressure gradient changes correlated significantly with the increase in PD atrium /PD inflow (r = - 0.77, p = 0.0012) and AUC atrium /AUC inflow (r = - 0.76, p = 0.0018). ICC of the 2D-PA parameters was in the range of 0.88-0.99., Conclusion: 2D-PA offers a feasible approach to quantify flow and perfusion changes during TIPS revision. Therefore, 2D-PA may be a valuable amendment to mere pressure measurements.

This study is the first to quantify the effects of hazel (Corylus avellana) leaves on methane and urinary nitrogen emissions, digestibility, nitrogen and the energy balance of ruminants. Four experimental pellets were produced with 0, 30% and 60% hazel leaves, the latter also with 4% polyethylene glycol. Hazel leaves gradually replaced lucerne. The diet was composed of the pellets and grass hay (80%: 20%). Six adult sheep were allocated to all four treatments in a 6 × 4 crossover design. Including hazel leaves did not affect the feed intake, but it decreased the apparent digestibility of organic matter and fibre, especially at the high level. Methane emission was reduced by up to 25 to 33% per day, per unit of intake and per unit of organic matter digested. Urinary nitrogen excretion decreased by 33 to 72% with increasing levels of hazel leaves. The treatment with polyethylene glycol demonstrated that tannins in hazel leaves caused significant shares of the effects. In conclusion, the current results indicated a significant potential of hazel leaves as forage for ruminants to mitigate methane and urinary nitrogen emissions. Even high dietary hazel leaf proportions were palatable. The lower digestibility needs to be compensated with easily digestible diet ingredients.

Most DNA in the genomes of higher organisms does not code for proteins. RNA Polymerase II (Pol II) transcribes non-coding DNA into long non-coding RNAs (lncRNAs), but biological roles of lncRNA are unclear. We find that mutations in the yeast lncRNA CUT60 result in poor growth. Defective termination of CUT60 transcription causes read-through transcription across the ATP16 gene promoter. Read-through transcription localizes chromatin signatures associated with Pol II elongation to the ATP16 promoter. The act of Pol II elongation across this promoter represses functional ATP16 expression by a Transcriptional Interference (TI) mechanism. Atp16p function in the mitochondrial ATP-synthase complex promotes mitochondrial DNA stability. ATP16 repression by TI through inefficient termination of CUT60 therefore triggers mitochondrial genome loss. Our results expand the functional and mechanistic implications of non-coding DNA in eukaryotes by highlighting termination of nuclear lncRNA transcription as mechanism to stabilize an organellar genome., Competing Interests: Dd, MI, JP, SB, SM No competing interests declared, (© 2018, du Mee et al.)

High rates of lethal outcome in tumour metastasis are associated with the acquisition of invasiveness and chemoresistance. Several clinical studies indicate that E2F1 overexpression across high-grade tumours culminates in unfavourable prognosis and chemoresistance in patients. Thus, fine-tuning the expression of E2F1 could be a promising approach for treating patients showing chemoresistance. Methods: We integrated bioinformatics, structural and kinetic modelling, and experiments to study cooperative regulation of E2F1 by microRNA (miRNA) pairs in the context of anticancer chemotherapy resistance. Results: We showed that an enhanced E2F1 repression efficiency can be achieved in chemoresistant tumour cells through two cooperating miRNAs. Sequence and structural information were used to identify potential miRNA pairs that can form tertiary structures with E2F1 mRNA. We then employed molecular dynamics simulations to show that among the identified triplexes, miR-205-5p and miR-342-3p can form the most stable triplex with E2F1 mRNA. A mathematical model simulating the E2F1 regulation by the cooperative miRNAs predicted enhanced E2F1 repression, a feature that was verified by in vitro experiments. Finally, we integrated this cooperative miRNA regulation into a more comprehensive network to account for E2F1-related chemoresistance in tumour cells. The network model simulations and experimental data indicate the ability of enhanced expression of both miR-205-5p and miR-342-3p to decrease tumour chemoresistance by cooperatively repressing E2F1. Conclusions: Our results suggest that pairs of cooperating miRNAs could be used as potential RNA therapeutics to reduce E2F1-related chemoresistance., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Introduction: Coronary artery aneurysms (CAA) are rare. We present our experience with the surgical treatment of patients with CAAs., Methods: Between March 2000 and October 2016, 15 patients with CAA underwent surgery., Results: Mean age of patients was 60 ± 16 years and 47% (n = 7) were male. Kawasaki syndrome was present in two (13%) patients and 7% (n = 1) patients had Marfan syndrome. Isolated CAAs were found in 73% (n = 11) and involvement of multiple vessels was present in 27% (n = 4) of patients. Coronary arteries (CA) affected by aneurysms were: 19% (n = 4) left main stem, 33% (n = 7) left anterior descending, 14% (n = 3) left circumflex, and 33% (n = 7) right coronary artery. The majority of patients (93%, n = 14) were operated on pump with a mean cross-clamp time of 51 ± 23 min. 53% (n = 8) of patients received total arterial CA bypass grafting, while the remaining patients (47%, n = 7) received venous ± internal thoracic artery grafts. Resection/ligation of CAA was performed in 27% (n = 4) of patients. In-hospital mortality was 0% (n = 0). Follow-up was complete for 100% of patients and comprised a total of 80 patient-years. During follow-up, only one patient (7%) required re-intervention., Conclusion: Surgical treatment of CAA has good short- and long-term results., (© 2017 Wiley Periodicals, Inc.)

Purpose: To investigate the impact of the first transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) on health-related quality of life (HRQoL) and identify predictors for low HRQoL following TACE., Materials and Methods: HRQoL was prospectively evaluated in 79 patients with standardized questionnaires (QlQ-C30 and HCC18) pre- and 2 weeks post-TACE. Treatment response was evaluated using common tumour response criteria. Clinical parameters [e.g. Eastern Cooperative Oncology Group (ECOG) performance status, Model of End Stage Liver Disease (MELD) score], tumour load and pre-TACE HRQoL scores were tested for predicting HRQoL after TACE., Results: Patients showed a 12.1% decrease in global health score (GHS). Major decreases were observed for physical (-21.4%), role (-23.4%), and social (-21.5%) functioning and increases in symptom severity for fatigue (+30.1%), loss of appetite (+25.3%), pain (+19.4%) after TACE. ECOG performance status >1 was associated with increased nausea/vomiting (p = 0.002) and decreased GHS (p = 0.01). MELD score >10 was associated with increased fatigue (p = 0.021) and abdominal swelling (p < 0.001). Our study showed an increase in symptom severity in patients with no symptoms before TACE for pain (p = 0.005) and abdominal swelling (p < 0.001)., Conclusion: The first TACE for treatment of HCC does not result in a major loss of HRQoL in general. For TACE as a palliative therapy maintaining HRQoL is of critical importance and standardized HRQoL assessment can help to detect HRQoL problems.

Eukaryotic genomes are rich in transcription units encoding "long noncoding RNAs" (lncRNAs). The purpose of all this transcription is unclear since most lncRNAs are quickly targeted for destruction during synthesis or shortly thereafter. As debates continue over the functional significance of many specific lncRNAs, support grows for the notion that the act of transcription rather than the RNA product itself is functionally important in many cases. Indeed, this alternative mechanism might better explain how low-abundance lncRNAs transcribed from noncoding DNA function in organisms. Here, we highlight some of the recently emerging features that distinguish coding from noncoding transcription and discuss how these differences might have important implications for the functional consequences of noncoding transcription., (Copyright © 2017 by the Genetics Society of America.)

Background: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; hepatic CHEMOSAT ® delivery system; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyze the safety and efficacy of the second-generation CS-PHP after 54 treatments at Hannover Medical School, Germany., Methods: Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumors (RECIST1.1). Overall survival (OS), progression-free survival (PFS), and hepatic PFS (hPFS) were analyzed using the Kaplan-Meier estimation., Results: 29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors [ocular melanoma (OM) n = 11; colorectal carcinoma n = 2; pancreatic adenocarcinoma n = 2; periampular carcinoma n = 2; breast and endometrial cancer each n = 1] and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumors had durable disease stabilization (40%). Median OS, PFS, and hPFS were 261, 117, and 135 days, respectively. Tumor volume negatively correlated with OS. Complications and toxicities included thrombocytopenia, cardiovascular events, ulcerous bleeding, and edema., Conclusion: Second-generation CS-PHP seems to be effective and tolerable. Patient selection based on tumor volume and entity is of importance. Particularly, patients with OM and hepatobiliary tumors represent promising candidates for CS-PHP.

Cancer is a disease of subverted regulatory pathways. In this paper, we reconstruct the regulatory network around E2F, a family of transcription factors whose deregulation has been associated to cancer progression, chemoresistance, invasiveness, and metastasis. We integrate gene expression profiles of cancer cell lines from two E2F1-driven highly aggressive bladder and breast tumors, and use network analysis methods to identify the tumor type-specific core of the network. By combining logic-based network modeling, in vitro experimentation, and gene expression profiles from patient cohorts displaying tumor aggressiveness, we identify and experimentally validate distinctive, tumor type-specific signatures of receptor proteins associated to epithelial-mesenchymal transition in bladder and breast cancer. Our integrative network-based methodology, exemplified in the case of E2F1-induced aggressive tumors, has the potential to support the design of cohort- as well as tumor type-specific treatments and ultimately, to fight metastasis and therapy resistance.Deregulation of E2F family transcription factors is associated with cancer progression and metastasis. Here, the authors construct a map of the regulatory network around the E2F family, and using gene expression profiles, identify tumour type-specific regulatory cores and receptor expression signatures associated with epithelial-mesenchymal transition in bladder and breast cancer.

Aim: To compare need for bone augmentation, surgical complications, periodontal, radiographic, aesthetic and patient reported outcomes in subjects receiving implant placement at the time of extraction (Immediate Implant) or 12 weeks thereafter., Methods: Subjects requiring single tooth extraction in the anterior and premolar areas were recruited in seven private practices. Implant position and choice of platform were restoratively driven. Measurements were performed by calibrated and masked examiners., Results: IMI was unfeasible in 7.5% of cases. One hundred and 24 subjects were randomized. One implant was lost in the IMI group. IMI required bone augmentation in 72% of cases compared with 43.9% for delayed (p = 0.01), while wound failure occurred in 26.1% and 5.3% of cases, respectively (p = 0.02). At 1 year, IMI had deeper probing depths (4.1 ± 1.2 mm versus 3.3 ± 1.1 mm, p < 0.01). A trend for greater radiographic bone loss was observed at IMI over the initial 3-year period (p-trend < 0.01). Inadequate pink aesthetic scores were obtained in 19% of delayed and in 42% of IMI implant cases (p = 0.03). No differences in patient reported outcomes were observed., Conclusions: Immediate implant placement should not be recommended when aesthetics are important, IMI should be limited to selected cases. Longer follow-up is needed to assess differences in complication rates., (© 2016 The Authors. Journal of Clinical Periodontology Published by John Wiley & Sons Ltd.)

A 21-year-old woman with a history of psychiatric treatment was admitted to the emergency department with self-inflicted stab wounds to the neck, chest, and abdomen as the result of a suicide attempt. Inspection showed a seemingly superficial cut at the jugular fossa. The patient's mother stated that one long ceramic kitchen bread knife was totally embedded in the right thorax. Further diagnostic measures showed the missing kitchen bread knife penetrating the right chest, with the path of insertion starting 2 cm above the right clavicle and the blade in contact with the right hilum and ending next to the seventh thoracic vertebra. Retrieval the object was a challenging problem., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The absolute configuration of individual small molecules in the gas phase can be determined directly by light-induced Coulomb explosion imaging (CEI). Herein, this approach is demonstrated for ionization with a single X-ray photon from a synchrotron light source, leading to enhanced efficiency and faster fragmentation as compared to previous experiments with a femtosecond laser. In addition, it is shown that even incomplete fragmentation pathways of individual molecules from a racemic CHBrClF sample can give access to the absolute configuration in CEI. This leads to a significant increase of the applicability of the method as compared to the previously reported complete break-up into atomic ions and can pave the way for routine stereochemical analysis of larger chiral molecules by light-induced CEI., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Penile squamous cell carcinoma is a rare but aggressive cancer. Little is known about pivotal events in tumor pathogenesis and metastasis. Lymph node metastasis is the prevailing prognostic factor while clinical detection in patients remains difficult. Our aim was to identify distinct miRNAs that are differentially expressed in metastatic vs nonmetastatic penile carcinoma, which may serve as diagnostic biomarkers for disease progression., Materials and Methods: TaqMan® arrays and quantitative polymerase chain reaction were applied to analyze miRNA profiles in penile squamous cell carcinoma specimens and glans tissue from 24 patients. The prognostic value of deregulated miRNAs was analyzed using the Kaplan-Meier method. The Spearman test was applied to determine a potential linkage between distinctive miRNAs in individual patients., Results: Loss of miR-1 (p = 0.0048), miR-101 (p = 0.0001) and miR-204 (p = 0.0004) in metastasizing tumors and associated metastases (p = 0.0151, 0.0019 and 0.0003, respectively) distinguished patients with metastatic and nonmetastatic penile squamous cell carcinoma. These 3 miRNAs showed a coherent expression pattern. Consistently, patients with low levels of all 3 miRNAs had worse survival (p = 0.03). We identified a coordinately regulated miRNA target hub that is over expressed in penile squamous cell carcinoma and associated with lymphovascular invasion., Conclusions: Our results provide evidence of a novel multiple miRNA based signature associated with lymph node metastasis and unfavorable prognosis of penile squamous cell carcinoma. The integrated loss of miR-1, miR-101 and miR-204 may predict the formation of metastases in penile cancer at an early stage., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Rich democracies exhibit vast cross-national and historical variation in the socialization of health care. Yet, cross-national analyses remain relatively rare in the health policy literature, and health care remains relatively neglected in the welfare state literature. We analyze pooled time series models of the public share of total health spending for eighteen rich democracies from 1960 to 2010. Building on path dependency theory, we present a strategy for modeling the relationship between the initial 1960 public share and the current public share. We also examine two contrasting accounts for how the 1960 public share interacts with conventional welfare state predictors: the self-reinforcing hypothesis expecting positive feedbacks and the counteracting hypothesis expecting negative feedbacks. We demonstrate that most of the variation from 1960 to 2010 in the public share can be explained by a country's initial value in 1960. This 1960 value has a large significant effect in models of 1961-2010, and including the 1960 value alters the coefficients of conventional welfare state predictors. To investigate the mechanism whereby prior social policy influences public opinion about current social policy, we use the 2006 International Social Survey Programme (ISSP). This analysis confirms that the 1960 values predict individual preferences for government spending on health. Returning to the pooled time series, we demonstrate that the 1960 values interact significantly with several conventional welfare state predictors. Some interactions support the self-reinforcing hypothesis, while others support the counteracting hypothesis. Ultimately, this study illustrates how historical legacies of social policy exert substantial influence on the subsequent politics of social policy., (Copyright © 2016 by Duke University Press.)

Purpose: To assess the feasibility and diagnostic performance of contrast-enhanced, C-arm computed tomography (CACT) of the pulmonary arteries compared to digital subtraction angiography (DSA) in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH)., Materials: Fifty-two patients with CTEPH underwent ECG-gated DSA and contrast-enhanced CACT. Two readers (R1, R2) independently evaluated pulmonary artery segments and their sub-segmental branching using DSA and CACT for optimal image quality. Afterwards, the diagnostic findings, i.e., intraluminal filling defects, stenosis, and occlusion, were compared. Inter-modality and inter-observer agreement was calculated, and subsequently consensus reading was done and correlated to a reference standard representing the overall consensus of both modalities. Fisher's exact test and Cohen's Kappa were applied., Results: A total of 1352 pulmonary segments were evaluated, of which 1255 (92.8 %) on DSA and 1256 (92.9 %) on CACT were rated to be fully diagnostic. The main causes of the non-diagnostic image quality were motion artifacts on CACT (R1:37, R2:78) and insufficient contrast enhancement on DSA (R1:59, R2:38). Inter-observer agreement was good for DSA (κ = 0.74) and CACT (κ = 0.75), while inter-modality agreement was moderate (R1: κ = 0.46, R2: κ = 0.47). Compared to the reference standard, the inter-modality agreement for CACT was excellent (κ = 0.96), whereas it was inferior for DSA (κ = 0.61) due to the higher number of abnormal consensus findings read as normal on DSA., Conclusion: CACT of the pulmonary arteries is feasible and provides additional information to DSA. CACT has the potential to improve the diagnostic work-up of patients with CTEPH and may be particularly useful prior to surgical or interventional treatment.

Twelve lactating cattle × yak hybrids (B. taurus × B. grunniens) were investigated on five experimental pastures (Sites 1-5), following an up- and downward transhumance route (3,200, 4,000, 4,500, 4,000 and 2,600 m a.s.l.). Hybrids were kept in replicated groups of two (low SD) and four animals per paddock (high SD). As a control, yaks (with calves) were included at low SD at Sites 2-4. Performance was described by body weight, milk yield and composition. Herbage samples as selected by the animals were analyzed. Activity patterns of the hybrids were assessed at Sites 2-4. At similar body weight change and milk composition, the individual hybrids on average produced 26% less milk at high than at low SD. However, at high SD on average still 49% more milk/m(2) of pasture area was produced. Milk fat increased with time from 5.4 to 7.1%, milk protein decreased from 4.2 to 3.3%. At high SD, the hybrids spent less time standing and more time lying. The yaks gained weight at 4,500 m a.s.l. while the hybrids lost weight (+836 and -653 g/animal/day, respectively). In conclusion, high SD reduced individual milk yield and forced hybrids to spend more time for feeding. The yaks apparently had an advantage over the hybrids at very high altitude.

Background: Transarterial liver-directed therapies are currently not recommended as a standard treatment for colorectal liver metastases. Transarterial chemoembolization (TACE), however, is increasingly used for patients with liver-dominant colorectal metastases after failure of surgery or systemic chemotherapy. The limited available data potentially reveals TACE as a valuable option for pre- and post-operative downsizing, minimizing time-to-surgery, and prolongation of overall survival after surgery in patients with colorectal liver only metastases., Purpose: In this overview, the current status of TACE for the treatment of liver-dominant colorectal liver metastases is presented. Critical comments on its rationale, technical success, complications, toxicity, and side effects as well as oncologic outcomes are discussed. The role of TACE as a valuable adjunct to surgery is addressed regarding pre- and post-operative downsizing, conversion to resectability as well as improvement of the recurrence rate after potentially curative liver resection. Additionally, the concept of TACE for liver-dominant metastatic disease with a focus on new embolization technologies is outlined., Conclusions: There is encouraging data with regard to technical success, safety, and oncologic efficacy of TACE for colorectal liver metastases. The majority of studies are non-randomized single-center series mostly after failure of systemic therapies in the 2nd line and beyond. Emerging techniques including embolization with calibrated microspheres, with or without additional cytotoxic drugs, degradable starch microspheres, and technical innovations, e.g., cone-beam computed tomography (CT) allow a new highly standardized TACE procedure. The real efficacy of TACE for colorectal liver metastases in a neoadjuvant, adjuvant, and palliative setting has now to be evaluated in prospective randomized controlled trials.

Purpose: To assess the impact of anatomical, procedural, and operator skill factors on the success and duration of fluoroscopy-guided transjugular intrahepatic portoystemic shunt following standard operating procedure (SOP)., Material and Methods: During a 32-month period, 102 patients underwent transjugular intrahepatic portosystemic shunt creation (TIPS) by two interventional radiologists (IR) following our institutional SOP based on fluoroscopy guidance. Both demographic and procedural data were assessed. The duration of the intervention (D(Int)) and of the portal vein puncture (D(Punct)) was analyzed depending on the skill level of the IR as well as the anatomic or procedural factors., Results: In 99 of the 102 patients, successful TIPS without peri-procedural complications was performed. The mean D(Int) (IR1: 77 min; IR2: 51 min, P < 0.005) and the mean D(Punct) (IR1: 19 min; IR2: 13 min, P < 0.005) were significantly higher in TIPS performed by IR1 (with 2 years of clinical experience performing TIPS, n = 38) than by IR2 (>10 years of clinical experience performing TIPS, n = 61), (P < 0.005 both, Mann-Whitney U test). D Int showed a higher correlation with D(Punct) for IR2 (R(2) = 0.63) than for IR1 (R(2) = 0.13). There was no significant difference in the D(Punct )for both IRs with regard to the success of the wedged portography (P = 0.90), diameter of the portal vein (P = 0.60), central right portal vein length (P = 0.49), or liver function (MELD-Score before the TIPS procedure; P = 0.14)., Conclusion: TIPS following SOP is safe, fast, and reliable. The only significant factor for shorter D(Punct) and D(Int) was the clinical experience of the IR. Anatomic variability, successful portography, or liver function did not alter the duration or technical success of TIPS.

Malignant melanoma is highly lethal due to its aggressive invasive properties and metastatic dissemination. The transcription factor E2F1 is crucial for melanoma progression through poorly understood mechanisms. Here, we show that the miR-224/miR-452 cluster is significantly increased in advanced melanoma and invasive/metastatic cell lines that express high levels of E2F1. miR-224/miR-452 expression is directly activated by E2F1 through transactivation of the GABRE gene. Ectopic expression of miR-224/miR-452 in less aggressive cells induces EMT and cytoskeletal rearrangements and enhances migration/invasion. Conversely, miR-224/miR-452 depletion in metastatic cells induces the reversal of EMT, inhibition of motility, loss of the invasive phenotype and an absence of lung metastases in mice. We identify the metastasis suppressor TXNIP as new target of miR-224/miR-452 that induces feedback inhibition of E2F1 and show that miR-224/452-mediated downregulation of TXNIP is essential for E2F1-induced EMT and invasion. The E2F1-miR-224/452-TXNIP axis constitutes a molecular signature that predicts patient survival and may help to set novel therapies., (© 2014 The Authors.)

Antisense transcription is widespread in many genomes; however, how much is functional is hotly debated. We are investigating functionality of a set of long noncoding antisense transcripts, collectively called COOLAIR, produced at Arabidopsis FLOWERING LOCUS C (FLC). COOLAIR initiates just downstream of the major sense transcript poly(A) site and terminates either early or extends into the FLC promoter region. We now show that splicing of COOLAIR is functionally important. This was revealed through analysis of a hypomorphic mutation in the core spliceosome component PRP8. The prp8 mutation perturbs a cotranscriptional feedback mechanism linking COOLAIR processing to FLC gene body histone demethylation and reduced FLC transcription. The importance of COOLAIR splicing in this repression mechanism was confirmed by disrupting COOLAIR production and mutating the COOLAIR proximal splice acceptor site. Our findings suggest that altered splicing of a long noncoding transcript can quantitatively modulate gene expression through cotranscriptional coupling mechanisms., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Mouth-to-mouth ventilation is often refused by laypersons because of hygienic reasons. Supraglottic airway devices (SADs) might reduce the adverse effects of mouth-to-mouth ventilation. We tried to verify the possibility for untrained laypersons to use SADs properly after having read written instructions only. The participants were told to ventilate a manikin using a laryngeal tube (LT). The time to ventilation and the rate of success were recorded. After a practical skill demonstration, a second placement of the LT was performed. A successful placement of the LT was achieved by 53% after the first and 98% after the second attempt. Time to ventilation was 124 s (±45 s) for the first attempt and 12 s (±2.75 s) for the second attempt. Delivering ventilation through an SAD is a reasonable way for laypersons. After a prior hands-on training, the placement can be performed in an adequate time frame with high success rates.

Species distribution models (SDMs), which are well established in many fields of biological research, are still uncommon in the agricultural risk analysis of pest insects. To exemplify the use of SDMs, we investigated the influence of environmental factors on the occurrence of Hyalesthes obsoletus Signoret (Hemiptera: Cixiidae). The planthopper is the only known vector of the grapevine yellows disease 'bois noir'. The study was conducted in 145 locations in the Baden region of southwest Germany. The planthopper was surveyed on host plant patches, consisting of stinging nettle and/or bindweeds. We used a stratified modelling framework where (1) species presence-absence data were related to an extensive environmental dataset using logistic regressions; and (2) different types of average models were developed based on an information theoretic method. The results show that the incidence of H. obsoletus is associated to above- as well as below-ground environmental factors, particularly to the amount of fine soil and average annual precipitation. This result was consistent across all average models. The relative importance of other environmental variables was dependent upon the average model under consideration and thus may vary according to their intended use, either the explanation of habitat requirements or the prediction and mapping of occurrence risks. The study showed that SDMs offer a quantification of species' habitat requirements and thus, could represent a valuable tool for pest management purposes. By providing examples of current issues of grapevine pests in viticulture, we discuss the use of SDMs in agricultural risk analysis and highlight their advantages and caveats.

Purpose: Evaluation of the potential usability of an iPad 3 with a high-resolution display in CT emergency diagnosis compared to a 3 D PACS workstation., Materials and Methods: 3 readers used a 5-point Likert scale to evaluate 40 CCT scans and 40 CTPA scans to determine the detectability of early signs of infarction in CCT or segmental and subsegmental pulmonary embolisms in CT angiography of the pulmonary arteries (CTPA) on the iPad 3 (Apple Inc., USA) using an application for image viewing (Visage Ease, Visage Imaging GmbH, Berlin) and on a 3 D PACS workstation (Visage 7.1, Visage Imaging, Berlin) using a certified monitor for image viewing. The results were compared using the Wilcoxon rank sum test, Spearman's correlation coefficient, and a kappa statistic., Results: There was no significant difference in the median evaluations for the readings of both the CCT scans and the CTPA scans on the iPad 3 and on the workstation (p > 0.05) for all three readers. The mean Spearman's correlation coefficient for CCT and CTPA was 0.46 (± 0.2) and 0.69 (± 0.16), respectively, for the comparison iPad/PACS, 0.41 (± 0.16) and 0.68 (± 0.06), respectively, for the interobserver agreement on the iPad, and 0.35 (± 0.05) and 0.68 (± 0.10), respectively, for the interobserver agreement on the PACS. Mean kappa values for CCT of 0.52 (± 0.17) for the comparison iPad/PACS and 0.33 (± 0.16) and 0.32 (± 0.16), respectively, for the interobserver agreement on the iPad and the PACS were achieved. For CTPA average kappa values of 0.67 (± 0.19) were calculated for the comparison iPad/PACS and 0.69 (± 0.08) and 0.60 (± 0.14), respectively, for the interobserver concordance on the iPad 3 and the PACS. All differences were not statistically significant (p > 0.05)., Conclusion: The variability of the interpretation of typical emergency scans on an iPad 3 with a high-resolution display and on a 3 D PACS workstation does not differ from the interobserver variability., (© Georg Thieme Verlag KG Stuttgart · New York.)

Bijvoet's method, which makes use of anomalous x-ray diffraction or dispersion, is the standard means of directly determining the absolute (stereochemical) configuration of molecules, but it requires crystalline samples and often proves challenging in structures exclusively comprising light atoms. Herein, we demonstrate a mass spectrometry approach that directly images the absolute configuration of individual molecules in the gas phase by cold target recoil ion momentum spectroscopy after laser ionization-induced Coulomb explosion. This technique is applied to the prototypical chiral molecule bromochlorofluoromethane and the isotopically chiral methane derivative bromodichloromethane.

Background: Connecting willing patients with dementia to suitable clinical research studies has been historically challenging. The United Kingdom Dementia and Neurodegenerative Research Network (DeNDRoN) was established to link patients into high-quality studies. One component is DemReg, a register of dementia patients and their carers who have agreed to be approached regarding future research studies. The limited literature highlights the predominance of altruism mediating research register participation. The objective of this study was to understand the motivations of patients and carers to participate in DemReg., Methods: There were 107 participants in the study, interviewed using a questionnaire to determine which factors were important in their decision to be on the register. The study compared the proportion of the altruistic motivations articulated with the proportion of the other answers offered., Results: The two most important motivators for registering on DemReg were to help others (44%; p < 0.001) or themselves (29%; p < 0.001) and altruistic motives took precedence over those for personal benefit. Participants were not motivated by the prospect of payment or by concern that they would be letting down their clinician if they did not register., Conclusions: There are currently major projects within the United Kingdom to increase the number of patients on dementia registers and to further involvement in dementia research. This study, to the best of our knowledge, is the first to assess the motivations of patients and carers for joining a dementia research register in the United Kingdom, and the findings highlight the importance of altruistic motives.

Feeding plants containing elevated levels of polyphenols may reduce ruminal CH₄ emissions, but at the expense of nutrient utilisation. There might, however, be non-additive effects when combining high-phenolic plants with well-digestible, high-nutrient feeds. To test whether non-additive effects exist, the leaves of Carica papaya (high in dietary quality, low in polyphenols), Clidemia hirta (high in hydrolysable tannins), Swietenia mahagoni (high in condensed tannins) and Eugenia aquea (high in non-tannin phenolics) were tested alone and in all possible mixtures (n 15 treatments). An amount of 200 mg DM of samples was incubated in vitro (24 h; 39°C) with buffered rumen fluid using the Hohenheim gas test apparatus. After the incubation, total gas production, CH₄ concentration and fermentation profiles were determined. The levels of absolute CH₄, and CH₄:SCFA and CH₄:total gas ratios were lower (P< 0·05) when incubating a combination of C. papaya and any high-phenolic plants (C. hirta, S. mahagoni and E. aquea) than when incubating C. papaya alone. Additionally, mixtures resulted in non-additive effects for all CH₄-related parameters of the order of 2-15 % deviation from the expected value (P< 0·01). This means that, by combining these plants, CH₄ in relation to the fermentative capacity was lower than that predicted when assuming the linearity of the effects. Similar non-additive effects of combining C. papaya with the other plants were found for NH₃ concentrations but not for SCFA concentrations. In conclusion, using mixtures of high-quality plants and high-phenolic plants could be one approach to CH₄ mitigation; however, this awaits in vivo confirmation.

The essential helicase-like protein Sen1 mediates termination of RNA Polymerase II (Pol II) transcription at snoRNAs and other noncoding RNAs in yeast. A mutation in the Pol II subunit Rpb1 that increases the elongation rate increases read-through transcription at Sen1-mediated terminators. Termination and growth defects in sen1 mutant cells are partially suppressed by a slowly transcribing Pol II mutant and are exacerbated by a faster-transcribing Pol II mutant. Deletion of the nuclear exosome subunit Rrp6 allows visualization of noncoding RNA intermediates that are terminated but not yet processed. Sen1 mutants or faster-transcribing Pol II increase the average lengths of preprocessed snoRNA, CUT, and SUT transcripts, while slowed Pol II transcription produces shorter transcripts. These connections between transcription rate and Sen1 activity support a model whereby kinetic competition between elongating Pol II and Sen1 helicase establishes the temporal and spatial window for early Pol II termination., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Plants growing on alpine meadows are reported to be rich in phenols. Such compounds may affect ruminal fermentation and reduce the plants' methanogenic potential, making alpine grazing advantageous in this respect. The objective of this study was to quantify nutrients and phenols in Alpine forage grasses, herbs and trees collected over 2 years and, in a 24 h in vitro incubation, their effects on ruminal fermentation parameters., Results: The highest in vitro gas production, resulting in metabolisable energy values around 10 MJ kg⁻¹, were found with Alchemilla xanthochlora and Crepis aurea (herbaceous species) and with Sambucus nigra leaves and flowers (tree species). Related to the amount of total gas production, methane formation was highest with Nardus stricta, and lowest with S. nigra and A. xanthochlora. In addition, Castanea sativa leaves led to an exceptional low methane production, but this was accompanied by severely impaired ruminal fermentation. When the data were analysed by principal component analysis, phenol concentrations were negatively related with methane proportion in total gas., Conclusion: Variation in methane production potential across the investigated forages was small. The two goals of limited methane production potential and high nutritive value for ruminants were met best by A. xanthochlora and S. nigra., (Copyright © 2011 Society of Chemical Industry.)

Non-coding transcripts originating from bidirectional promoters have been reported in a wide range of organisms. In yeast, these divergent transcripts can be subdivided into two classes. Some are designated Cryptic Unstable Transcripts (CUTs) because they are terminated by the Nrd1-Nab3-Sen1 pathway and then rapidly degraded by the nuclear exosome. This is the same processing pathway used by yeast snoRNAs. Whereas CUTs are only easily observed in cells lacking the Rrp6 or Rrp47 subunits of the nuclear exosome, Stable Uncharacterized Transcripts (SUTs) are present even in wild-type cells. Here we show that SUTs are partially susceptible to the nuclear exosome, but are primarily degraded by cytoplasmic 5' to 3' degradation and nonsense-mediated decay (NMD). Therefore, SUTs may be processed similarly to mRNAs. Surprisingly, both CUTs and SUTs were found to produce 3' extended species that were also subject to cytoplasmic degradation. The functions, if any, of these extended CUTs and SUTs are unknown, but their discovery suggests that yeasts generate transcripts reminiscent of long non-coding RNAs found in higher eukaryotes.

Bacteria comprehensively reorganize their global gene expression when faced with starvation. The alarmone ppGpp facilitates this massive response by co-ordinating the downregulation of genes of the translation apparatus, and the induction of biosynthetic genes and the general stress response. Such a large reorientation requires the activities of multiple regulators, yet the regulatory network downstream of ppGpp remains poorly defined. Transcription profiling during isoleucine depletion, which leads to gradual starvation (over > 100 min), allowed us to identify genes that required ppGpp, Lrp and RpoS for their induction and to deduce the regulon response times. Although the Lrp and RpoS regulons required ppGpp for their activation, they were not induced simultaneously. The data suggest that metabolic genes, i.e. those of the Lrp regulon, require only a low level of ppGpp for their induction. In contrast, the RpoS regulon was induced only when high levels of ppGpp accumulated. We tested several predictions of a model that explains how bacteria allocate transcriptional resources between metabolism and stress response by discretely tuning two regulatory circuits to different levels of ppGpp. The emergent regulatory structure insures that stress survival circuits are only triggered if homeostatic metabolic networks fail to compensate for environmental deficiencies., (© 2010 Blackwell Publishing Ltd.)

One of the predominant cell-cycle programs found in mature tissues is endoreplication, also known as endoreduplication, that leads to cellular polyploidy. A key question for the understanding of endoreplication cycles is how oscillating levels of cyclin-dependent kinase activity are generated that control repeated rounds of DNA replication. The APC/C performs a pivotal function in the mitotic cell cycle by promoting anaphase and paving the road for a new round of DNA replication. However, using marker lines and plants in which APC/C components are knocked down, we show here that outgrowing and endoreplicating Arabidopsis leaf hairs display no or very little APC/C activity. Instead we find that RBX1-containing Cullin-RING E3 ubiquitin-Ligases (CRLs) are of central importance for the progression through endoreplication cycles; in particular, we have identified CULLIN4 as a major regulator of endoreplication in Arabidopsis trichomes. We have incorporated our findings into a bio-mathematical simulation presenting a robust two-step model of endoreplication control with one type of cyclin-dependent kinase inhibitor function for entry and a CRL-dependent oscillation of cyclin-dependent kinase activity via degradation of a second type of CDK inhibitor during endoreplication cycles.

Noncoding RNA is emerging as an important regulator of gene expression in many organisms. We are characterizing RNA-mediated chromatin silencing of the Arabidopsis major floral repressor gene, FLC. Through suppressor mutagenesis, we identify a requirement for CstF64 and CstF77, two conserved RNA 3'-end-processing factors, in FLC silencing. However, FLC sense transcript 3' processing is not affected in the mutants. Instead, CstF64 and CstF77 are required for 3' processing of FLC antisense transcripts. A specific RNA-binding protein directs their activity to a proximal antisense polyadenylation site. This targeted processing triggers localized histone demethylase activity and results in reduced FLC sense transcription. Targeted 3' processing of antisense transcripts may be a common mechanism triggering transcriptional silencing of the corresponding sense gene.

The role of RNA metabolism in chromatin silencing is now widely recognized. We have studied the Arabidopsis RNA-binding protein FCA that down-regulates an endogenous floral repressor gene through a chromatin mechanism involving histone demethylase activity. This mechanism needs FCA to interact with an RNA 3' processing/polyadenylation factor (FY/Pfs2p), but the subsequent events leading to chromatin changes are unknown. Here, we show that this FCA-FY interaction is required for general chromatin silencing roles where hairpin transgenes induce DNA methylation of an endogenous gene. We also show 2 conserved RNA processing factors, AtCPSF100 and AtCPSF160, but not FCA, are stably associated with FY in vivo and form a range of different-sized complexes. A hypomorphic fy allele producing a shorter protein, able to provide some FY functions but unable to interact with FCA, reduces abundance of some of the larger MW complexes. Suppressor mutants, which specifically disrupt the FY motif through which FCA interacts, also lacked these larger complexes. Our data support a model whereby FCA, perhaps after recognition of a specific RNA feature, transiently interacts with FY, an integral component of the canonical RNA 3' processing machinery, changing the interactions of the different RNA processing components. These altered interactions would appear to be a necessary step in this RNA-mediated chromatin silencing.

The REMPI spectra of anisole-h8, anisole-d3 and anisole-d8 have been measured. The assignment of the fundamental vibrations of anisole in the S(1) state is supported by quantum chemical model calculations, the isotopic shifts, the comparison with the frequencies of corresponding vibrations in other monosubstituted benzenes, especially phenol, and the overtones, combinations and progressions observed in the spectrum of anisole-h8. The frequencies of the 42 fundamental vibrations of anisole in the S(1) state are evaluated and compared with the frequencies of the corresponding vibrations in the electronic ground state. Some assignments given earlier in the literature have been revised.

The cell-damaging effects of N-tert-butoxypyridine-2-thione (tBuOPT), which generates alkoxyl and thiyl radicals on photolysis, have been investigated in L5178Y mouse lymphoma cells. The UVA irradiation of 2.5 microM tBuOPT inhibits strongly cell growth and cell viability, causes pronounced membrane damage, and induces micronuclei. Without irradiation, tBuOPT does not cause any cell damage at 2.5 microM concentration. The phototoxicity of tBuOPT is effectively inhibited by the radical scavenger glutathione, while the photogenotoxicity (micronuclei induction) is not affected by this strong hydrogen-atom donor. Thus, for the cytotoxicity and genotoxicity different reactive species seems to be responsible. The cytotoxicity is presumably caused by oxyl radicals, which are derived from tert-butoxyl radicals generated by photocleavage of tBuOPT, while in the genotoxicity the less reactive pyridyl-2-thiyl radicals appear to play a role. These results demonstrate that N-alkoxypyridinethiones are useful photochemical sources of oxyl and thiyl radicals to elucidate biological effects caused by these free radicals.

In animals, cyclin-dependent kinase inhibitors (CKIs) are important regulators of cell cycle progression. Recently, putative CKIs were also identified in plants, and in previous studies, Arabidopsis thaliana plants misexpressing CKIs were found to have reduced endoreplication levels and decreased numbers of cells consistent with a function of CKIs in blocking the G1-S cell cycle transition. Here, we demonstrate that at least one inhibitor from Arabidopsis, ICK1/KRP1, can also block entry into mitosis but allows S-phase progression causing endoreplication. Our data suggest that plant CKIs act in a concentration-dependent manner and have an important function in cell proliferation as well as in cell cycle exit and in turning from a mitotic to an endoreplicating cell cycle mode. Endoreplication is usually associated with terminal differentiation; we observed, however, that cell fate specification proceeded independently from ICK1/KRP1-induced endoreplication. Strikingly, we found that endoreplicated cells were able to reenter mitosis, emphasizing the high degree of flexibility of plant cells during development. Moreover, we show that in contrast with animal CDK inhibitors, ICK1/KRP1 can move between cells. On the one hand, this challenges plant cell cycle control with keeping CKIs locally controlled, and on the other hand this provides a possibility of linking cell cycle control in single cells with the supracellular organization of a tissue or an organ.

The Arabidopsis GNOM gene encodes an ARF GDP/GTP exchange factor involved in embryonic axis formation and polar localisation of the auxin efflux regulator PIN1. To examine whether GNOM also plays a role in post-embryonic development and to clarify its involvement in auxin transport, we have characterised newly isolated weak gnom alleles as well as trans-heterozygotes of complementing strong alleles. These genotypes form a phenotypic series of GNOM activity in post-embryonic development, with auxin-related defects, especially in the maintenance of primary root meristem activity and in the initiation and organisation of lateral root primordia. Our results suggest a model for GNOM action mediating auxin transport in both embryogenesis and post-embryonic organ development.

UVA-irradiation of the photo-Fenton reagents N-isopropoxypyridone 2b and N-isopropoxythiazole-2(3H)-thione 3b releases radicals which induce strand breaks. Transient spectroscopy establishes N-O bond scission [Phi(N)(-)(O) = (75 +/- 8)% for 2b and (65 +/- 7)% 3b] as the dominating primary photochemical process to afford the DNA-damaging radicals. Product studies and laser-flash experiments reveal that the thiazolethione 3b leads primarily to the disulfide 5, from which through C-S bond breakage, the bithiazyl 6, the thiazole 7, and the isothiocyanate 8 are derived. Upon irradiation of pyridone 2b (300 nm) in aqueous media, a mixture of isopropoxyl and 2-hydroxyprop-2-yl radicals is formed, as confirmed by trapping with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and EPR spectroscopy. In contrast, the photolysis of the thiazolethione 3b (350 nm) affords exclusively the DMPO adducts of the isopropoxyl radicals. Control experiments disclose that the thiazolethione-derived photoproduct disulfide 5, or the intermediary thiyl radicals B, scavenge the carbon-centered 2-hydroxyprop-2-yl radicals, which are generated from the isopropoxyl radicals by hydrogen shift. With supercoiled pBR 322 DNA in a 60:40 mixture of H(2)O-MeCN, the pyridone 2b and the thiazolethione 3b display moderate strand-break activity (17% open-circular DNA for 2b and 12% for 3b). In pure water, however, the pyridone 2b photoinduces substantially more DNA cleavage (32% open-circular DNA), which is attributed to the peroxyl radicals generated from the 2-hydroxyprop-2-yl radicals by oxygen trapping. The lower strand-break activity of the thiazolethione 3b derives presumably from isopropoxyl radicals, because only these are detected in the photolysis of this photo-Fenton reagent.

In aqueous solution, UV irradiation of the photo-Fenton-type reagents perester 1 and N-tert-butoxypyridone 2 leads to the formation of tert-butoxyl radicals and methyl radicals as confirmed by product studies and by spin trapping with 5,5-dimethyl-1-pyrroline N-oxide (DMPO), followed by EPR spectroscopy. The methyl radicals result from the initially released tert-butoxyl radicals through beta-cleavage, a fragmentation pathway, which dominates at lower DMPO concentrations. In the presence of 2'-deoxyguanosine (dG), both photochemical radical sources afford 8-MedG [(2.3 +/- 0.3)%] and N7-MedG [(0.27 +/- 0.05)%] as modified products, whereas the direct reaction of the tert-butoxyl radicals with dG cannot compete with this beta-cleavage process.