001) without selecting resistant

mutants in vivo, but the reduction obtained with CRO against CFT073-RR Tc (pbla(CTX-M-15)) in kidneys was significantly lower than that obtained with FOX. In conclusion, FOX appears to be an effective therapeutic alternative to carbapenems for the treatment of UTIs due to CTX-M-producing E. coli.”
“The butyrogenic genes from Clostridium difficile DSM 1296(T) have been cloned and expressed HM781-36B cost in Escherichia coli. The enzymes acetyl-coenzyme A (CoA) C-acetyltransferase, 3-hydroxybutyryl-CoA dehydrogenase, crotonase, phosphate butyryltransferase, and butyrate kinase and the butyryl-CoA dehydrogenase complex composed of the dehydrogenase and two electron-transferring flavoprotein

subunits were individually produced in E. coli and kinetically characterized in vitro. While most of these enzymes were measured using well-established test systems, novel methods to determine butyrate kinase and butyryl-CoA dehydrogenase activities with respect to physiological function were developed. Subsequently, the individual genes were combined to form a single plasmid-encoded operon in a plasmid vector, which was successfully used to confer butyrate-forming capability to the host. In vitro and in vivo studies demonstrated that C. difficile possesses a bifurcating PD0332991 cost butyryl-CoA dehydrogenase which catalyzes the NADH-dependent reduction of ferredoxin coupled to the reduction of crotonyl-CoA also by NADH. Since the reoxidation of ferredoxin by a membrane-bound ferredoxin: NAD(+)-oxidoreductase enables electron transport phosphorylation, additional ATP is formed. The butyryl-CoA dehydrogenase from C. difficile is oxygen stable and apparently uses oxygen as a cooxidant of NADH in the presence of air. These properties suggest that this enzyme complex might be well suited to provide butyryl-CoA for solventogenesis in recombinant strains. The central role of bifurcating butyryl-CoA dehydrogenases and membrane-bound ferredoxin: NAD oxidoreductases (Rhodobacter nitrogen fixation [RNF]), see more which affect

the energy yield of butyrate fermentation in the clostridial metabolism, is discussed.”
“Evolutionary transitions between hermaphroditic and dioecious reproductive states are found in many groups of animals. To understand such transitions, it is important to characterize diverse modes of sex determination utilized by metazoans. Currently, little is known about how simultaneous hermaphrodites specify and maintain male and female organs in a single individual. Here we show that a sex-specific gene, Smed-dmd-1 encoding a predicted doublesex/male-abnormal-3 (DM) domain transcription factor, is required for specification of male germ cells in a simultaneous hermaphrodite, the planarian Schmidtea mediterranea. dmd-1 has a male-specific role in the maintenance and regeneration of the testes and male accessory reproductive organs.

Unilateral oophorectomy implies a significant reduction of the ovarian follicular reserve. Thus, one might expect that the time to menopause is shortened by several years in women who have

undergone unilateral oophorectomy. A retrospective cohort study of 23 580 Norwegian women who were included in the population-based HUNT2 Survey during the years 19951997. Data were obtained by two self-administered questionnaires at study inclusion. Cox proportional hazard models were used to estimate PHA-848125 inhibitor relative risks of menopause according to unilateral oophorectomy status with and without adjustment for birth cohort, parity, smoking, body mass index (BMI) and age at menarche. Women who had undergone unilateral oophorectomy were younger at

menopause [mean 49.6 years; 95 confidence interval (CI): 49.250.0] than women without unilateral oophorectomy (mean 50.7 years; 95 CI: 50.650.8) (P 0.001). The crude relative risk of menopause was 1.28 (95 CI: 1.151.42) and remained similar after adjustment for the study factors above (adjusted relative risk 1.27; 95 CI: 1.141.41). In addition, recent birth cohort and high BMI were associated with higher age at menopause. Information on unilateral oophorectomy was based on self-reports. Some women may therefore have been misclassified. Although the effect of unilateral oophorectomy on the age at menopause is similar to that of smoking, it is weaker Bucladesine than anticipated from the loss of ovarian follicular reserve. Thus, compensatory mechanisms may occur in the remaining ovary. The present study was supported by the South East Health Region Norway (grant no. 2739100). None of the authors has a conflict

of interest.”
“Background: Canadians of Chinese descent, represent one of the fastest growing visible minority groups in Canada, (as well as the second largest), but relatively little is known about the clinical features of heart failure (HF) in Chinese-Canadian versus non-Chinese Canadian patients. Methods: We conducted a population-based analysis of urban patients hospitalized in Ontario, Canada for the first time with a most responsible diagnosis of HF between April 1, 1995 and March 31, 2008. Among the 99,278 patients, 1,339 (1.3%) were classified as Chinese using a previously ACY-738 mouse validated list of Chinese surnames. Through linkage to other administrative databases, we compared the clinical characteristics, pharmacological management, and outcomes of Chinese versus non-Chinese HF patients. Results: Ischemic heart disease was identified as the possible etiology of HF in a greater proportion of non-Chinese patients (47.7% vs. 35.3%; p smaller than 0.001) whereas hypertension (26.1% vs. 16.1%; p smaller than 0.001) and valvular heart disease (11.6% vs. 7.2%; p smaller than 0.001) were relatively more common in Chinese patients. Chinese patients were prescribed angiotensin-converting enzyme (ACE) inhibitors less frequently (57.5% vs. 66.4%, p smaller than 0.

Numerical experiments show that the planning strategy obtained from the optimal control model achieves maximum economic profit from raising cattle during the planning period and simultaneously improves the resilience of the system and maintains sustainable development of the rangeland. The outcomes demonstrate that resilience, sustainable development and economic profit are consistent concepts in optimal management strategy for rangeland management. (C) 2013 Elsevier Ltd. All rights reserved.”
“Shigella infection in epithelial cells induces cell death which is accompanied by

mitochondrial dysfunction. In this study the role of the mitochondrial fission protein, Drp1 during Shigella infection in HeLa cells was examined. Significant lactate dehydrogenase (LDH) release was detected in the culture supernatant when HeLa cells were infected with Shigella at a high SRT1720 datasheet multiplicity of infection. Drp1 inhibition with Mdivi-1 and siRNA knockdown significantly reduced LDH release. HeLa cell death was also accompanied by mitochondrial fragmentation. Tubular mitochondrial networks were partially restored when Drp1 was depleted with either siRNA or inhibited with Mdivi-1. Surprisingly either Mdivi-1 treatment or Drp1 siRNA-depletion of HeLa cells also reduced Shigella plague formation. The effect of Mdivi-1 on Shigella infection

was assessed using the murine Sereny model, however it had no impact on ocular inflammation. Overall our results suggest that Drp1 and the mitochondria play important roles during Shigella infection. (C) 2014 Elsevier GmbH. All rights reserved.”
“Protein disulfide isomerase Foretinib Protein Tyrosine Kinase inhibitor (PDI) and its pancreatic homolog (PDIp) buy Cilengitide are folding

catalysts for the formation, reduction, and/or isomerization of disulfide bonds in substrate proteins. However, the question as to whether PDI and PDIp can directly attack the native disulfide bonds in substrate proteins is still not answered, which is the subject of the present study. We found that RNase can be thermally unfolded at 65 degrees C under non-reductive conditions while its native disulfide bonds remain intact, and the unfolded RNase can refold and reactivate during cooling. Co-incubation of RNase with PDI or PDIp during thermal unfolding can inactivate RNase in a PDI/PDIp concentration-dependent manner. The alkylated PDI and PDIp, which are devoid of enzymatic activities, cannot inactivate RNase, suggesting that the inactivation of RNase results from the disruption of its native disulfide bonds catalyzed by the enzymatic activities of PDI/PDIp. In support of this suggestion, we show that both PDI and PDIp form stable disulfide-linked complexes only with thermally-unfolded RNase, and RNase in the complexes can be released and reactivated dependently of the redox conditions used. The N-terminal active site of PDIp is essential for the inactivation of RNase.

In conclusion, silymarin exerts beneficial effects on the early stages of liver pathogenesis, preventing and delaying liver carcinogenesis. This drug should be considered as a potential chemopreventive agent for HBV-related hepatocarcinogenesis.”
“A case of intracranial malignant peripheral nerve sheath tumor (MPNST) with uncommon features due to recurrence is reported. The primary tumor showed typical histopathological features of MPNST with wavy nuclei and S-100 positivity. The patient’s latest

recurrent tumor resembled undifferentiated sarcoma with lipoblast-like multivacuolated cells and hyaline globules (HGs). Ultrastructurally, the vacuolated spaces contained granular materials derived from cystic dilation of the rough endoplasmic reticulum. The HG consisted of round osmophilic inclusions with or without a limiting membrane. The HGs and lipoblast-like multivacuolated cells may have been caused by the degeneration of tumor CBL0137 supplier cells in myxoid stroma

and abundant vasculature.”
“Despite substantial investments since the events of 2001, much work remains to prepare IWR-1-endo in vitro the nation for a chemical, biological, radiological or nuclear (CBRN) attack or to respond to an emerging infectious disease threat. Following a 2010 review of the US Public Health Emergency Medical Countermeasures Enterprise, FDA launched its Medical Countermeasures initiative (MCMi) to facilitate the development and availability of medical products to counter CBRN and emerging disease threats. As a regulatory agency, FDA has a unique and critical part to play in this national undertaking. Using a three-pillar approach, FDA is addressing key challenges associated Cl-amidine order with the regulatory review process for medical countermeasures; gaps in regulatory science for MCM development and evaluation; and issues related to the legal, regulatory and policy framework for an effective public health response. Filling the gaps in the MCM Enterprise is a huge national undertaking, requiring the collaboration of all stakeholders, including federal partners, current and prospective developers of medical countermeasures,

relevant research organizations, and state and local responders. Especially critical to success are an appreciation of the long timelines, risks and high costs associated with developing medical countermeasures and the systems to deliver them and the requisite support of all stakeholders, including national leadership.”
“Crotalaria pallida (Fabaceae) is a pantropical plant with extrafloral nectaries (EFNs) near the reproductive structures. EFN-visiting ants attack and remove arctiid moth Utetheisa ornatrix larvae, the main pre-dispersal seed predator, but the impact of ants on C pallida fitness is unknown. To assess this impact, we controlled ant presence on plants and evaluated the reproductive output of C pallida with and without ants. Predatory wasps also visit EFNs, prey upon U.

302; P = 0.015). After adjustment for BMI, left atrium (LA) size, epicardial fat, and interatrial septum width, interatrial fat independently associated with the P-f on Z lead (-coefficient 0.009 [95%CI 0.0003-0.019]; P = 0.043).\n\nConclusionsInfiltrated atrial fat correlates with discontinuous conduction on posterior LA wall and represents AF early substrate.”
“Background: Numerous molecular markers of sinonasal inverted papillomas (IP) were investigated in the past; however, significance of angiogenesis and inhibition of apoptosis were not well documented. This study was designed to determine expression

of angiogenic marker CD34 antigen, antiapoptotic marker Bcl-2 oncoprotein, and proliferative marker Ki-67 antigen in the group of patients with IP. We matched up these findings to the group of patients PF-00299804 nmr with sinonasal carcinoma (SNC) and used chronic rhinosinusitis (CRS) patients as control group. In addition, we compared expression of the markers among IP patients who displayed distinctly different patterns of clinical behavior. Methods: Tissue samples were obtained from 46 surgically treated patients; 18 of them had a diagnosis of IP, 9 had documented SNC, and the remaining 19 patients had CRS. All specimens were stained using immunohistochemistry

techniques for CD34 (mean vessel density [MVD]), Bcl-2, and Ki-67 antigens. Morphometry was evaluated by computer image analysis system. Results: We noted statistically significant differences in expression

of CD34 antigen, Bcl-2 protein, and Ki-67 antigen (for all groups, ANOVA p smaller than 0.001) among the investigated groups. The mean value of CD34 antigen was significantly selleck inhibitor SYN-117 supplier higher in the IP group than in the CRS group, but it was below the levels of the SNC group. Compared with the cases not complicated by recurrence, the patients with recurrent IP exhibited higher MVD levels, while levels of bcl-2 and Ki67 protein expression did not differ in a significant way between recurrent and nonrecurrent cases. The significant positive correlations were observed between Bcl-2 protein and Ki-67 antigen in IP and SNC groups and between Bcl-2 protein and CD34 antigen in the CRS group. Conclusion: Our findings underscore importance of angiogenesis in the development and prognosis of IP and support further investigation of this aspect of IP tumor growth.”
“P>An invariable feature of Helicobacter pylori-infected gastric mucosa is the persistent infiltration of inflammatory cells. The neutrophil-activating protein (HP-NAP) has a pivotal role in triggering and orchestrating the phlogistic process associated with H. pylori infection. Aim of this study was to address whether HP-NAP might further contribute to the inflammation by increasing the lifespan of inflammatory cells. We report that HP-NAP is able to prolong the lifespan of monocytes, in parallel with the induction of the anti-apoptotic proteins A1, Mcl-1, Bcl-2 and Bcl-X(L).

The pulsatility index was increased in the EA1 and EA2 on postoperative days 1 and 2, showing decrease in the similar preoperative value on postoperative day 10, but decreased pulsatility index was continuous in the EA3 during the postoperative day 10. The resistance index was significantly different between preoperative and postoperative day 10 especially in the EA2 and EA3. Ultramicroscopic findings in the EA3 group showed an increase in tunica media necrosis, convolution of the internal elastic lamina, and densely packed platelets, fibrins, and erythrocytes.”
“Nonlinear sparse sensing (NSS) techniques have been adopted for realizing compressive sensing in many applications

such as radar imaging. Unlike the NSS, in this paper, we propose an adaptive sparse sensing (ASS) approach using the reweighted zero-attracting normalized least mean fourth (RZA-NLMF) algorithm which depends on several given parameters, i.e., reweighted Selleck Bioactive Compound Library factor, regularization parameter, and initial step size. First, based on the independent assumption, Cramer-Rao lower bound (CRLB) is derived as for the performance comparisons. In addition, reweighted factor selection method is proposed

for achieving robust estimation performance. Finally, to verify the algorithm, Monte Carlo-based computer simulations are given to show that the ASS achieves much better mean square error (MSE) performance than the NSS.”
“BackgroundNon-alcoholic fatty liver disease (NAFLD) is a comorbidity of childhood obesity. ObjectiveWe examined whole-body substrate metabolism and metabolic characteristics in obese adolescents with vs. without NAFLD. SubjectsTwelve learn more obese (BMI 95th percentile) adolescents with and without NAFLD [intrahepatic triglyceride (IHTG) 5.0% vs. smaller than 5.0%] were pair-matched for race, gender, age and % body fat. MethodsInsulin sensitivity (IS) was assessed by a 3-h hyperinsulinemic-euglycemic clamp and whole-body substrate oxidation by indirect calorimetry during fasting and insulin-stimulated conditions. ResultsAdolescents with NAFLD had increased (p smaller than 0.05) abdominal fat, lipids, and liver enzymes compared with those without NAFLD. Fasting glucose concentration

was not different between groups, but fasting insulin concentration was higher (p smaller than 0.05) in the NAFLD group compared with those without. Fasting hepatic glucose Selleck MGCD0103 production and hepatic IS did not differ (p bigger than 0.1) between groups. Adolescents with NAFLD had higher (p smaller than 0.05) fasting glucose oxidation and a tendency for lower fat oxidation. Adolescents with NAFLD had lower (p smaller than 0.05) insulin-stimulated glucose disposal and lower peripheral IS compared with those without NAFLD. Although respiratory quotient (RQ) increased significantly from fasting to insulin-stimulated conditions in both groups (main effect, p smaller than 0.001), the increase in RQ was lower in adolescents with NAFLD vs.

“
“Objective: This study

examined the strength of the therapeutic alliance in the early stages of cognitive-behavioral therapy (CBT) for the eating disorders, and whether the strength of that allianceis associated with early eating characteristics, comorbid Axis 1 and 2 features.\n\nMethod: Forty-four eating-disordered patients completed measures of eating and Axis 1 and 2 characteristics at the start of therapy, and measures DZNeP chemical structure of the therapeutic alliance and eating characteristics at the sixth session of CBT.\n\nResults: The therapeutic alliance was strong, including in the domain of attachment. It was unrelated to initial eating pathology and early changes in eating cognitions and behaviors. However, there were links between initial emotional and interpersonal features and therapeutic alliance by the sixth session.\n\nDiscussion: The findings counter suggestions that CBT for eating disorders PF477736 concentration is characterized by a poor therapeutic relationship. The therapeutic alliance is likely to be enhanced by addressing high levels of emotional distress and difficulties in interpersonal function where appropriate. This research needs to be extended to other therapies, other domains of function and different time points in therapy, to build a fuller picture of the role of the therapeutic relationship in working with the eating disorders. (C) 2011 by Wiley Periodicals, Inc.”
“Background and purposeThe ankle-brachial

index (ABI) has been defined as an important factor associated with vascular Apoptosis inhibitor events. Our objective was to analyze the prognostic value of the ABI as a predictive factor of new vascular events and functional status at 1year in patients with non-cardioembolic ischaemic stroke. MethodsA prospective, longitudinal, observational and multicenter study was performed, including

consecutive patients 50years old who had suffered from a non-cardioembolic ischaemic stroke. Pathological ABI (PI) was defined when the value was 0.9. The logistic regression model, survival analysis and the Cox proportional hazard regression model were used to identify factors independently associated with functional outcome and occurrence of new vascular events, including recurrent stroke. ResultsIn all, 977 patients were evaluated. The mean age was 69.19.5 years. 40.5% patients had PI. Stroke recurrence and new vascular events global rates were 9% and 20% respectively at 1year. PI was independently associated with new vascular events [hazard ratio 1.764 (1.274-2.444), P=0.001]. A cut-off point of ABI0.8 (14% vs. 7%, P=0.002) independently predicted stroke recurrence in an adjusted regression model [hazard ratio 1.807 (1.102-2.963), P=0.019]. PI was also associated with functional dependence [odds ratio 1.490 (1.011-2.196), P=0.044]. ConclusionsIn non-cardioembolic ischaemic stroke patients, PI was an independent predictive factor of new vascular events and functional outcome after 1year of follow-up.

\n\nResults We completed interviews of 1,219 breast cancer patients and found almost half (46%) had at least one severe symptom (any of the following: nausea/vomiting, arm problems, hot flashes, vaginal dryness,

difficulty sleeping) that interfered with her daily functioning or mood. Multi-variate analysis controlling for patient characteristics and treatment showed that older (OR = 0.90; P < 0.000), black (OR = 0.50; P < 0.000), Hispanic Spanish-speaking (OR = 0.37; P < 0.000), widowed or never married (OR = 0.68; Linsitinib ic50 P = 0.049), and working (OR = 0.72; P = 0.024) women were less likely to report severe symptoms than other women. Number of comorbid conditions (OR = 1.21; P < 0.000) and receipt of chemotherapy (OR = 1.48; P = 0.040) were positively associated with reporting symptoms.\n\nConclusion These findings estimate the prevalence of several mutable symptoms in breast cancer patients that can be addressed by appropriate treatments.

Comorbidity is a significant predictor of symptoms, especially amongst those receiving chemotherapy. Variation in symptom reporting occurred by race/ethnicity and other sociodemographic characteristics, raising questions of different thresholds for reporting symptoms or truly fewer symptoms for some sociodemographic groups. Population-based estimates of the probability of symptoms in women with incident breast cancer can be used to provide patient education about potential JAK inhibitor outcomes following the treatment of breast cancer.”
“Scientific data provide BVD-523 cost the evidence that secondary K-RAS mutations do not occur during anti-epidermal growth factor receptor therapy in colorectal cancer patients. This multicenter phase II prospective study aims to investigate the activity of a retreatment with a cetuximab-based therapy.\n\nWe enrolled 39 irinotecan-refractory patients who had a clinical benefit after a line of cetuximab- plus irinotecan-based therapy and then a progression of disease for which underwent a
chemotherapy and finally, after a clear new progression of disease, were retreated with the same cetuximab- plus irinotecan-based

therapy.\n\nMedian number of therapeutic lines before accrual was 4. Median interval time between last cycle of first cetuximab-based therapy and first cycle of the retreatment was 6 months. Overall response rate was 53.8% with 19 partial responses (48.7%) and 2 complete responses (5.1%). Disease stabilization was obtained in 35.9% of patients and progression in four patients (10.2%). Median progression-free survival was 6.6 months. The correlation between skin toxicity during first cetuximab therapy and during cetuximab rechallenge was significant (P = 0.01).\n\nRechallenge with the same cetuximab-based therapy may achieve a new important clinical benefit further delaying the progression of disease and improving the therapeutic options.

(C) 2014 Elsevier GmbH. All rights reserved.”
“We and others have identified FGFR4 as a direct transcriptional target of the alveolar rhabdomyosarcoma (ARMS) specific fusion protein, PAX3-FOXO1. We hypothesized fibroblast growth factor receptor 4 (FGFR4) may act as an effector of PAX3-FOXO1, contributing to PAX3-FOXO1 tumorigenic phenotypes. However, we demonstrate that LCL161 enhanced expression of FGFR4 does not contribute to inhibited differentiation, enhanced proliferation, or transformation downstream of PAX3-FOXO1

in primary mouse myoblasts. Therefore we were unable to identify any contribution of up regulation of wild type FGFR4 to PAX3-FOXO1 driven tumorigenesis. Conversely, a constitutively active mutant of FGFR4 can enhance CP868596 primary myoblast proliferation and transformation, indicating activating mutations of FGFR4 could contribute to the development and progression of ARMS. We sequenced the FGFR4 mRNA from five ARMS cell lines and identified no somatic mutations,

nor any association with any human single nucleotide polymorphism within the FGFR4 coding region. (c) 2011 Wiley Periodicals, Inc.”
“The present study was designed to assess the synergistic antitumor effects of anthracenylmethyl homospermidine (ANTMHspd), a novel polyamine conjugate, with alpha-difluoromethylornithine (DFMO) and to elucidate the mechanism of these effects on human leukemia HL60 cells. Cell proliferation was assessed by the MTT assay. Cell cycle, apoptosis and mitochondria membrane potential (MMP) were evaluated by flow cytometry. Caspases and cytochrome c were detected by Western Blot analysis. The combination treatment strongly inhibited cell proliferation, induced cell apoptosis and caused an accumulation

in the G(1) phase with an accompaniment decrease in S phase. Moreover, reduction of MMP, release of cytochrome c and activation of caspase-3 and caspase-9 but not caspase-8 were observed during the combination-mediated apoptosis. All these findings demonstrated that the combination treatment with DFMO and ANTMHspd resulted in synergistic antitumor effects on HL60 cells. (C) 2007 Elsevier Ltd. All rights reserved.”
“Background: Lentinula edodes, known as shiitake, has been utilized as food, as well as, in popular medicine, moreover, compounds isolated from its mycelium learn more and fruiting body have shown several therapeutic properties. The aim of this study was to determine the antiviral activity of aqueous (AqE) and ethanol (EtOHE) extracts and polysaccharide (LeP) from Lentinula edodes in the replication of poliovirus type 1 (PV-1) and bovine herpes virus type 1 (BoHV-1).\n\nMethods: The time-of-addition assay was performed at the times -2, -1, 0, 1 and 2 h of the infection. The virucidal activity and the inhibition of viral adsorption were also evaluated. Plaque assay was used to monitor antiviral activity throughout.

Our molecular modeling with the assistance of ab Selleckchem SBE-β-CD initio suggested the coupling of NP likely proceeded via covalent bonding between two NP radicals at their unsubstituted carbons in phenolic rings. Data from acute immobilization tests with Daphnia confirm that NP toxicity is effectively eliminated by LiP/HRP-catalyzed NP removal. The findings in this study provide useful information for understanding LiP/HRP-mediated NP reactions, and comparison of enzymatic performance can present their advantages for

up-scale applications in water/wastewater treatment.”
“We and others previously showed that p38 mitogen-activated protein kinase is indispensable for myogenic differentiation. However, it is less clear which of the

four p38 isoforms in the mouse genome participates in this process. Using C2C12 myogenic cells as a model, we showed here that p38 alpha, beta, and gamma are expressed with distinct expression patterns during differentiation. Knockdown of any of them by small interfering RNA inhibits myogenic differentiation, which suggests that the functions of the three p38 isoforms are not completely redundant. To further elucidate the AZD1080 unique role of each p38 isoform in myogenic differentiation, we individually knocked down one p38 isoform at a time in C2C12 cells, and we compared the whole-genome gene expression profiles by microarrays. We found that some genes are coregulated by all three p38 isoforms, whereas others are uniquely regulated by one particular p38 isoform. Furthermore,

several novel p38 target genes (i.e., E2F2, cyclin D3, and WISP1) are found to be required for myogenin expression, which provides a molecular basis to explain why different p38 isoforms are required for myogenic differentiation.”
“Melanoma DZNeP inhibitor is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life(1). To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)-a PTEN-interacting protein and negative regulator of PTEN in breast cancer(2)-as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo.