Here we show the importance of these reefs and the main stressors

Here we show the importance of these reefs and the main stressors to which they are exposed. We explain the criteria to account this ecological corridor under the figure of a network of marine protected areas. To arrive at this proposal, we conducted a qualitative approach at different spatial scales. First, we considered the large region which includes the Gulf of Mexico (GoM). The GoM was divided according to their geological characteristics and the presence of reef systems. With this, we identified the factors that group these reef systems into two sets, according to the type of continental shelf, either carbonated or sedimentary. At a smaller

spatial scale for sedimentary platform reefs, we integrate information about the presence of scleractinian coral species, the main environmental mTOR inhibitor characteristics, the relationship with human uses and the pressures Selleck Neratinib to which they are subjected. This information was obtained from published data for different reef systems and expert knowledge in each of

the areas. Evidence of connectivity between different reef systems was collected from the scientific literature, considering existing data on benthic organisms. We must emphasize that the main purpose of this paper is to set the conceptual basis to coordinate research efforts and management of this Reef Corridor, and the establishment of the first Mexican Marine Protected Area Network in the Gulf of Mexico. The Gulf

of Mexico is a Large Marine Ecosystem (Sherman, 1991) with a mixture of ecological characteristics of temperate and tropical environments. It is an inland sea whose basin of 1.5 × 106 km2 (Bryant et al., 1991) receives discharges from rivers that led to the formation of environmentally and biologically diverse coastal systems. Coral reefs require particular oceanographic and environmental conditions such as shallow, oligotrophic, and warm (>20° C) marine Janus kinase (JAK) waters, with an optimum between 26 and 28 °C, with salinities of 33–36 ups, minimal turbidity and sedimentation, well lit and with low wave energy (Hubbard, 1997; Carricart-Ganivet, 2004). However, in the Gulf of Mexico, some reefs developed despite the conditions of turbidity, sedimentation, temperature and organic inputs, produced by natural disturbances and human activities (Salas-Pérez and Granados-Barba, 2008, Salas-Pérez and Arenas, 2010, Pérez-España et al., 2012, Tunnell, 1992, Godínez-Ortega et al., 2009, Gutiérrez-Ruiz et al., 2011 and Ortiz-Lozano, 2012). In the Gulf of Mexico, reefs are distributed in two major groups linked to the environmental features of the continental shelf were they are located: the terrigenous platform present in West and North, and the Southeastern carbonate platform (Fig. 1).

There was a main effect of supplemental SMSC on increasing fastin

There was a main effect of supplemental SMSC on increasing fasting blood glucose (P < .05) ( Table 2). Within the HIF groups, SMSC caused a significant increase in fasting blood glucose (P < .05), and within the LIF groups, a trend was apparent for the effect of SMSC (P = .075). Fasting insulin levels were not different between groups (data not shown). Supplementing mice with 3 mg/kg SMSC did not result in a significant difference in the response

to a glucose challenge as determined by the area under the curve (AUC) for the glucose tolerance test (GTT); however, a trend was apparent (main effect of SMSC, P = .08) ( Fig. 1). This trend for increased IR is consistent with the impaired fasting blood glucose in these animals ( Table 2). The glucose tolerance pattern BKM120 price observed in the absence of increased dietary IF also tended to be higher

with supplemental LDK378 clinical trial SMSC (P = .08), whereas no such effect was apparent in the animals consuming high IF ( Fig. 1). Basal AMPK activation was determined via immunoblot for pAMPK in muscle and liver samples. Surprisingly, the HIF diet had a main effect of decreased AMPK phosphorylation in red quadriceps (RQ) (Fig. 2B) and white quadriceps (WQ) (Fig. 2A) and tibialis anterior (TA) muscles (Fig. 2C). The basal level of pAMPK in the liver remained unchanged in all groups (Fig. 2D). To investigate AMPK activation in muscle more thoroughly, we also measured the protein expression of the upstream kinase LKB1 (Fig. 3) and the downstream target of AMPK, ACC in the same tissues (Fig. 4). A main effect for decreased LKB1 protein in the HIF groups was consistent PtdIns(3,4)P2 with decreased AMPK phosphorylation in the RQ (Fig. 3C) and mixed fiber-type TA muscle (Fig. 3B). Moreover, in both the TA and the RQ muscles, where we observed reduced AMPK phosphorylation and LKB1 content, there were no significant differences or trends for reduced ACC phosphorylation (Fig. 4B and C). As both Cyt C and UCP3 are markers of mitochondrial content and AMPK is known to affect mitochondrial content, we measured protein expression via immunoblot to

further investigate metabolic response to SMSC and IF. No differences were observed in skeletal muscle expression of either Cyt C (Fig. 5A, C, and E) or UCP3 (Fig. 5B, D, and F). We investigated changes in total GLUT4 protein expression in the WQ, TA, and RQ muscles. Despite increased fasting glucose and a trend for reduced glucose tolerance in mice given SMSC, GLUT4 protein levels were unchanged compared with mice that received dietary IF alone (Fig. 6A-C). The primary focus of this study was to examine the impact of SMSC supplementation with or without HIF intake on basal glucose management. Based on previous work and available information from human studies, we hypothesized that (1) SMSC would have a negative impact on basal glucose management and (2) increasing the dietary content of IF would attenuate this effect.

, 2010; restricted to not extend

beyond the atlas definit

, 2010; restricted to not extend

beyond the atlas definition of the fusiform gyrus), a property of the pOTS reported in previous studies (Bruno et al., 2008 and Kronbichler et al., 2004). Finally, although our hypotheses primarily concern posterior temporo-parietal regions thought to be involved in the computation of orthography, phonology, and semantics leading up to word pronunciation (i.e., the regions in Fig. 4), an ROI located primarily in the pars opercularis and triangularis of the inferior frontal gyrus (IFG) was also included. This ROI was defined based on word-frequency related activation in the IFG from Graves et SB203580 manufacturer al. (2010; masked to ensure it did not extend beyond the atlas definition of the IFG). There is ample evidence suggesting a role for this region in aspects of phonological processing (Bookheimer, 2002, Katz et al., 2005 and Sandak et al., 2004), although the degree to which activations in

this region are distinguishable from effects of working memory or time-on-task is unclear (Binder et al., 2005, Cattinelli et al., 2013, Graves et al., 2010 and Taylor et al., 2013). The participants considered here are a subset of those involved in a previous fMRI study (N = 20; Graves et al., 2010). DTI data were collected on 18 (12 female) healthy, literate adults who spoke English as a first language. Their mean age was 23.1 (SD: 3.6), mean years of education 16.6 (SD: 3.3). All had normal or corrected-to-normal vision and were right-handed on the Edinburgh handedness inventory ( Oldfield, 1971). AC220 A verbal IQ estimate from the Wechsler Test of Adult Reading ( Wechsler, 2001) Quinapyramine showed a mean standard score of 109.3 (SD: 8.4). All participants provided written consent and were paid an hourly stipend

according to local Institutional Review Board protocols. Details of the stimuli and task are provided in Graves et al. (2010). The most relevant points to emphasize for the current analysis are that the task was reading aloud, and the stimuli consisted of 465 words for which length in letters, spelling-sound consistency, word frequency, imageability, bigram frequency, and biphone frequency were all uncorrelated. Graves et al. reported that imageability of the stimuli was uncorrelated with word frequencies from a large text-based corpus (Baayen, Piepenbrock, & Gulikers, 1995); it is also uncorrelated with frequencies from a corpus of spoken English (Brysbaert & New, 2009), (r = 0.08, p > 0.05). To address whether skilled readers differ in the degree to which they use semantic information in reading aloud, we analyzed RTs using multiple linear regression with the following 6 explanatory variables: length in letters, word frequency, consistency, imageability, the multiplicative interaction of word frequency and consistency, and the multiplicative interaction of consistency and imageability.

Negative controls were incubated in medium

lacking TdT en

Negative controls were incubated in medium

lacking TdT enzyme. The specimens were examined and photographed in an OLYMPUS BX-60 microscope. No quantification has Enzalutamide chemical structure been carried out in TUNEL-labelled sections because it has been concluded that quantification produces uneven results due to the variable number of apoptotic bodies present in a given tissue. 21 Upper alveolar processes from 4 alendronate-treated and 4 control rats from each time point were fixed and decalcified as described. Then, they were post-fixed in 0.1 M cacodylate-buffered 1% osmium tetroxide for 2 h at room temperature, dehydrated in graded concentrations of ethanol, and embedded in Spurr epoxy resin (EMS). Toluidine blue-stained 1-μm thick sections were examined in a light microscope, and cervical regions of the tooth germ/alveolar bony crypt were selected for ultrathin sectioning. Sections 80-nm thick were obtained with a Thiazovivin molecular weight diamond knife on a Leica Ultracut R ultramicrotome (Leica, Buffalo, NY, USA), collected

onto 200-mesh copper grids, stained with uranyl acetate and lead citrate, and examined in a Jeol 1010 transmission electron microscope operated at 80 kV. The upper first molar germs of CON rats at 9 days presented normal morphology; the enamel matrix was almost completely secreted. They did not present immunolabelling to Smad-4 antibody (Fig. 1a, b). The first molar germs of ALN specimens at day 9 presented contacting bone trabeculae adjacent to ameloblasts and cells of the HERS. Weak immunolabelling was observed in some dental follicle cells (Fig. 1c, ADP ribosylation factor d). At day 12, CON specimens presented elongation of the root dentine that was still being formed, and the epithelial diaphragm was intact. They presented positive immunolabelling in the inner enamel organ epithelium. The fibroblasts and cementoblasts adjacent to the forming root were strongly immunopositive to Smad-4 (Fig. 1e, f). At the same time point, ALN-treated specimens presented ankylosis sites between the maturing enamel matrix and bone trabeculae from

the crypt. The bone trabeculae also contacted the cells of the cervical portion of the tooth germ. Immunopositive cells were detected at the inner enamel organ. Some epithelial cells of the cervical portion of the tooth germ were also immunopositive (Fig. 1g, h). At day 30, the CON specimens at day 30 presented normal root formation and eruption. Immunopositive cementoblasts were detected over the entire root surface of CON specimens (Fig. 1i, j). No tooth eruption and root elongation occurred until the thirtieth day in ALN specimens, and several ankylosis sites were observed over the first molar germ. They presented some immunopositive cells adjacent to the enamel organ (Fig. 1k, l). TUNEL labelling was carried out in the ALN specimens at 30 days (Fig. 2). The CON specimens at the same time point were not shown because their root development occurred normally.

The quantitative data were not suitable for meta-analysis, as the

The quantitative data were not suitable for meta-analysis, as the study designs lacked appropriate control groups and the data from the 2 comparable randomized controlled trials (RCTs) on the garden intervention would have had limited generalizability. Therefore, the quantitative data were tabulated and summarized narratively. A process of thematic analysis was used to synthesize across the qualitative studies, as they were largely descriptive in

nature with little additional interpretation of findings. Data in the form of quotes (first-order concepts) and themes and concepts identified by the study authors (second-order concepts) were extracted. The articles and the extracted data were read and re-read and the findings organized into third-order concepts by the

reviewers. We have Dasatinib supplier used participant quotes to illustrate the concepts in the synthesis. The electronic searches identified 1295 articles of which 85 were retrieved as full text. Seventeen studies met the inclusion criteria (see Figure 1 for reasons for exclusion): 9 quantitative, 7 qualitative, and 1 mixed methods. Fourteen included articles reported on gardens, 3 reported on horticultural therapy, http://www.selleckchem.com/products/chir-99021-ct99021-hcl.html and 1 reported on both interventions16 (Supplementary Table 1). The description of the interventions was generally poor in all studies, lacking detail of the garden designs and the nature of resident engagement. One garden Interleukin-2 receptor was designed with specific characteristics, such as memory boxes, continuous wandering paths, scented but nontoxic plants, and viewing platforms, to enhance the experience of residents with dementia.17 The remaining gardens were not specifically designed for residents with dementia but contained features such as a mixture of grass, concrete, and decking; raised beds (of flowers or vegetables); gazebos; fish ponds; and benches (Supplementary Table 2). In some studies, residents were allowed to be in the garden for only approximately 30 minutes per day18 and 19 accompanied by nursing home staff or a researcher, with the doors to the garden otherwise locked. In other

studies, residents were allowed to wander unaccompanied17, 18, 20 and 21 and in some it was unclear if the residents were accompanied or not.16, 22, 23, 24, 25, 26 and 27 The components of horticultural therapy varied across the studies in structure, duration, content, frequency, and length of follow-up. Therapy sessions varied from 30 minutes to approximately 1 hour per day, were one-to-one or group based, and were followed-up from 2 to 78 weeks. Sessions involved activities such as seeding, planting and flower arranging, singing, and making jam. Details of the personnel running the sessions were provided in only one study,28 in which a specialized horticultural therapist was involved (Supplementary Table 2).

Manifestations of toxicity are frequently mediated by regulatory

Manifestations of toxicity are frequently mediated by regulatory macromolecules such as

enzymes, receptors, ion channels or DNA. These targets represent complex and flexible three-dimensional entities that attempt to optimize their interaction with a small molecule (e.g., a xenobiotic) by adapting their 3D conformation, a mechanism referred to as “induced fit”. Protein-bound solvent molecules are frequently involved in stabilizing small-molecule ligands or, upon release to the “bulk solvent” contribute favorably to the binding entropy. Accounting and quantifying selleck antibody these effects belongs to the most challenging tasks in the computational sciences. In this account, we present the more recent developments of the VirtualToxLab—most noticeably, the change

from multi-dimensional QSAR (mQSAR) to 4D Boltzmann scoring for computing binding affinities based on the three-dimensional structure of protein–ligand complexes. By avoiding the training of a model against a set of compounds with known effects (such as in QSARs) but using an “ab initio” approach instead, the bias of a prediction from any training set is removed as the changes in free energy of ligand binding, ΔG, are computed by direct comparison of a compound’s “behavior” in aqueous solution (mimicking the this website cytoplasm) with those at the target protein employing the same directional force field. Moreover, the risk of extrapolation—occurring when attempting to predict properties of compounds not truly represented TNF-alpha inhibitor in a QSAR’s training set—is purged. The new protocol has been validated with a total of 1288 test compounds and employed to estimate the toxic potential of more than 2500 drugs, chemicals and natural products. All results are posted on http://www.virtualtoxlab.org. We explicitly invite all interested non-profit organizations to freely access/utilize the technology, and share their results with the scientific community

at http://www.biograf.ch/data/projects/OpenVirtualToxLab.php. The technology underlying the VirtualToxLab has recently been described in great detail ( Vedani et al., 2012). In this account, we therefore focus on the most recent extensions and the freely accessible platform—the OpenVirtualToxLab. The flow chart of the VirtualToxLab is shown in Fig. 1. The technology consists of two distinct modules: the user interface (light green) and the server backend (light blue) which communicate through an SSH protocol. The user interface features an embedded 3D viewer for inspecting both input (compounds to be uploaded) and output structures (resulting protein–ligand complexes) and a 3D model builder to readily generate the three-dimensional structure of any small molecule of interest. In a first step (blue borders) the compound’s behavior in aqueous solution is simulated.

, 2012) The

, 2012). The Akt inhibitor high diversity, widespread occurrence and relative sensitivity make foraminifera good bioindicator organisms to evaluate phytotoxic stress on coral reefs. Further up the food chain, the exposure of juveniles of the tropical reef fish Acanthochromis to the insecticide

chlorpyrifos resulted in elevated oxidative stress biomarkers in liver tissue ( Botté et al., 2012). This set of papers illustrates clearly that on-going exposure to pollutants, particularly herbicides, can affect GBR biota through a number of impact pathways. To prioritise management action for the GBR, managers require information from all aspects of the catchment to reef continuum including the studies described above. To date, a small number of studies have attempted to undertake a risk analysis of land-based pollutants to GBR ecosystems. Most recently, Waterhouse et al. (2012) completed a relative risk assessment of priority pollutants in the GBR catchments based on current pollutant loads, reef condition and estimates of the exposure of the reef to these pollutants. The Wet Tropics and Mackay Whitsunday regions, dominated by sugarcane cultivation, were considered as high risk areas due to high loads of pesticide and dissolved inorganic nitrogen

(DIN). The Burdekin and Fitzroy regions were ranked medium to high risk due to their suspended sediment inputs from grazing lands, and DIN and pesticide inputs from sugarcane farming in the lower Burdekin catchment. Early results of this research informed the selection of priority areas and priority land Selleckchem IWR 1 uses for a number of GBR management initiatives including the State government’s Reef Protection Package. In all, this Special Issue has brought together authors from several different research and management agencies, all working towards a sustainable and resilient reef. The role of research in guiding positive management outcomes for the iconic Great Barrier Reef depends on cross-agency all communication,

engaged research users and robust collaborative research across the catchment to reef continuum. All these factors have been addressed in the selection of research papers in this Special Issue to provide a useful baseline upon which to build further ecosystem understanding and the continuous improvement of resource management and conservation efforts. “
“They lie in parallel rows, In an article in the Sunday Times on 13 June 2010, the journalist Charles Clover exhorted us to “Wake up, the mackerel war has started”! In the article, Clover pointed out that because the annual migration of the mackerel (Scomber scombrus) – our striped tiger of the sea – has shifted north, a new group of fishermen are out to catch them. Never having fished for mackerel before, in the summer of 2009, Iceland unilaterally declared for itself a quota of 112,000 tonnes. In 2010, it declared a quota of 130,000 tonnes.

, using the same dose range of BPA as in the present study, but w

, using the same dose range of BPA as in the present study, but without fructose. The Marmugi study showed an impact on the hepatic transcriptome, particularly on genes involved in lipid synthesis and that various transcription

factors followed a non monotonic dose–response curve (Marmugi et al., 2012). In addition, also in line with the Marmugi study, the most significant effects were observed within one magnitude around the current TDI. However, Marmugi et al. used mice and did not combine BPA with fructose, so our study is not entirely comparable with theirs. Low-dose effects of BPA are currently highlighted and under discussion worldwide (Rhomberg and Goodman, 2012, Richter et al., 2007, http://www.selleckchem.com/epigenetic-reader-domain.html Ryan et al., 2010 and Vandenberg et al., 2012) and therefore three dosages were used, of which the medium dose corresponded to the defined human TDI, as established by the U.S. Environmental Protection Agency (EPA) and the European Food Safety Authority (EFSA) at 50 μg/kg and day. TDI is equal to NOAEL (5000 μg/kg http://www.selleckchem.com/products/PD-0332991.html and

day, this is the highest dose which did not induce any adverse effect in animal testing), divided by a factor of 100 to compensate for possible species differences in sensitivity. The current TDI is assumed to be considerably higher than the calculated human exposure. However, in the present study and others, effects are seen in rats and mice at doses close to the current TDI and even at lower doses (Richter et al., 2007). Low dose effects of environmental contaminants have previously been suggested based on epidemiological studies, as well as in experimental settings using BPA (Lee et Grape seed extract al., 2011, Marmugi et al., 2012, Rubin et al., 2001 and Soriano et al., 2012). Also non monotonic relationships are suggested in e.g. a study by Wei et al. where pregnant Wistar rats were exposed to BPA (50, 250 or 1250 μg/kg bw and day) and their offspring given normal or high fat diet after weaning. Only the lowest dose (50 μg/kg and day) resulted in such effects as increased body weight, elevated serum insulin and impaired glucose tolerance in adult offspring. In the rats fed a

high fat diet the effects were exacerbated and included metabolic syndrome (obesity, dyslipidemia, hyperleptindemia, hyperglycemia, hyperinsulinemia and glucose intolerance). Rats perinatally exposed to the higher doses did not show any of the adverse effects regardless of diet (Wei et al., 2011). A similar study has been performed with CD-1 mice by Ryan et al. but with a different conclusion. In this experiment the mice exposed to BPA (approximately 0.25 μg/kg bw and day via the diet) during gestation and lactation had heavier and longer pups at weaning than pups from the control groups, but the differences did not persist until adulthood, regardless of a high fat or low fat diet given from 9 weeks of age. As in our study MRI was used to determine body composition and no increase in body fat was seen in the BPA exposed rats (Ryan et al.

The CDEIS and the SES-CD are both validated for Crohn’s disease

The CDEIS and the SES-CD are both validated for Crohn’s disease. The Rutgeerts Postoperative Endoscopic Index is useful for the prediction of postoperative recurrence in those patients who have had an ileocolic resection. “
“Split-dose bowel regimens should be used in

patients without increased risk for gastric retention or aspiration. Patients with inflammatory bowel disease (IBD) are at increased selleck chemical risk of developing colorectal cancer. Compared with sporadic cases, IBD-related colorectal cancers occur at a younger age,1 are more likely multifocal or synchronous,2 and 3 and have a more aggressive phenotype with worsened mortality.3 and 4 In light of the increased risk of colorectal cancer, regular colonoscopy is advised every 1 to 3 years in patients for surveillance of colorectal neoplasia. Candidates for surveillance are those with Obeticholic Acid chemical structure disease duration of 8 years or more who have either ulcerative colitis extending beyond the rectum or Crohn’s disease involving one-third or more of the colon. Strong, albeit indirect, data5, 6, 7 and 8 suggest a benefit to colonoscopic surveillance. It is therefore

recommended by numerous professional guidelines9, 10, 11 and 12 and has become widely adopted in standard practice. The purpose of surveillance colonoscopy in IBD is to detect neoplasia (ie, cancer or precancerous dysplasia). Until recently, common surveillance technique has entailed a combination of targeted and random biopsies. All visible lesions receive targeted biopsy or resection (via polypectomy or endoscopic mucosal resection) to determine the histology and, most especially, the presence of dysplasia or cancer. In addition, by US guidelines,

at least 33 additional random biopsies are taken throughout the colon to detect the presence of flat, endoscopically invisible dysplasia. However, with the advent of enhanced endoscopic imaging, it is increasingly recognized that most IBD-related dysplasia is visible with careful mucosal inspection using high-definition endoscopes and chromoendoscopy. In chromoendoscopy, a solution Niclosamide containing dilute indigo carmine or methylene blue is applied to the mucosal surface via the forward wash jet or biopsy channel to enhance lesion detection (Fig. 1). Augmented lesion recognition via chromoendoscopy may supplant the need for random biopsy. A meta-analysis by Soetikno and colleagues13 confirmed that chromoendoscopy with targeted biopsies of visualized lesions resulted in increased dysplasia detection rates compared with standard white light endoscopy and random biopsies. Several guidelines12, 14 and 15 now endorse the routine use of chromoendoscopy and question any incremental benefit of random biopsies to detect invisible dysplasia.

Tumor diameters were measured with digital calipers, and tumor vo

Tumor diameters were measured with digital calipers, and tumor vol- ume was calculated by the following formula: tumor volume (mm3) = shorter diameter2 × longer diameter/2. The tumor volume data are pre- sented as means ± SD (n = 15). Our study was approved by the Animal Care and Use Committee of the Renji Hospital affiliated selleck inhibitor to Shanghai Jiao Tong University School of Medicine. All animal procedures were performed according to the guidelines developed by the China Council on Animal Care and

the protocol approved by the Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine. The genomic sequencing and survival data analyzed in this study were obtained from The Cancer Genome Atlas (TCGA) GSK2118436 in vivo GBM data set [16].

The published versions of these data sets include 586 cancer cases with sequencing data and clinical information. The corresponding reverse phase protein array (RPPA) data of TCGA GBM data set were obtained using the cBioPortal online data portal (Memorial Sloan-Kettering Cancer Center, New York, NY) [17], which include quantified expression of 122 proteins and 43 phosphoproteins involved in various signaling pathways. Exam- ples of such pathways include p53 signaling, retinoblastoma (RB), AMP-activated protein kinase (AMPK), PTEN, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB), receptor tyrosine kinase (RTK)/RAS GTPase, and epidermal growth factor receptor signaling, and other sequences. A complete list of antibodies in the protein micro- array can be accessed from TCGA data portal (http://tcga-data.nci.nih. gov/tcga/, Memorial Sloan-Kettering Cancer Center). The patients with upper or lower quarter

Pten protein expression were determined according to the levels detected by RPPA (respectively ranked as 25% highest or 25% lowest). We obtained the sensitivity profiles of 59 human brain tumor only cell lines to 131 anticancer drugs from the Cancer Cell Line Encyclo- pedia (CCLE; Broad Institute, Cambridge, MA) database [18]. The half-maximal inhibitory concentration (IC50) was used as a measure of the effectiveness of a drug on the cell lines. The mutation spectrum of TP53 in these cell lines was similar with that in the TCGA data sets. Survival analysis was carried out in R program using the “survival” package as described previously [19]. In the Kaplan-Meier (log-rank) survival test and Cox regression models, the censored status is in- dicated when the patient was still alive (or cancer free) at the time of follow-up. The Cox regression model included cancer type as a covariant, and the P value for mutation type is calculated after adjustment for the factor of cancer type. The hazard ratios (HRs) and 95% confidence intervals (CIs) were also determined for each mutation. The effects of different p53 mutations were compared to nonsense mutations as an indication of gain-of-function (GOF) effect.