Analysis and prediction of 5-year survival in patients with cutaneous melanoma: a model-based period analysis

BackgroundThe survival and prognosis of patients are significantly threatened by cutaneous melanoma (CM), which is a highly aggressive disease. It is therefore crucial to determine the most recent survival rate of CM. This study used population-based cancer registry data to examine the 5-year relative survival rate of CM in the US.MethodsPeriod analysis was used to assess the relative survival rate and trends of patients with CM in the Surveillance, Epidemiology, and End Results (SEER) database during 2004–2018. And based on the data stratified by age, gender, race and subtype in the SEER database, a generalized linear model was 12established to predict the 5-year relative survival rate of CM patients from 2019 to 2023.ResultsThe 5-year relative survival increased to various degrees for both total CM and CM subtypes during the observation period. The improvement was greatest for amelanotic melanoma, increasing from 69.0% to 81.5%. The 5-year overall relative survival rates of CM were 92.9%, 93.5%, and 95.6% for 2004–2008, 2009–2013, and 2014–2018, respectively. Females had a marginally higher survival rate than males for almost all subtypes, older people had lower survival rates than younger people, white patients had higher survival rates than nonwhite ones, and urban locations had higher rates of survival from CM than rural locations did. The survival rate of CM was significantly lower for distant metastasis.ConclusionThe survival rate of patients with CM gradually improved overall during 2004–2018. With the predicted survival rate of 96.7% for 2019–2023, this trend will still be present. Assessing the changes experienced by patients with CM over the previous 15 years can help in predicting the future course of CM. It also provides a scientific foundation that associated departments can use to develop efficient tumor prevention and control strategies

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol

A prognostic nomogram for the cancer-specific survival of white patients with invasive melanoma at BANS sites based on the Surveillance, Epidemiology, and End Results database

ObjectiveThe purpose of this study was to develop a comprehensive nomogram for the cancer-specific survival (CSS) of white patients with invasive melanoma at back, posterior arm, posterior neck, and posterior scalp (BANS) sites and to determine the validity of the nomogram by comparing it with the conventional American Joint Committee on Cancer (AJCC) staging system.MethodsThis study analyzed the patients with invasive melanoma in the Surveillance, Epidemiology, and End Results (SEER) database. R software was used to randomly divide the patients into training and validation cohorts at a ratio of 7:3. Multivariable Cox regression was used to identify predictive variables. The new survival nomogram was compared with the AJCC prognosis model using the concordance index (C-index), area under the receiver operating characteristic (ROC) curve (AUC), net reclassification index (NRI), integrated discrimination index (IDI), calibration plotting, and decision-curve analysis (DCA).ResultsA novel nomogram was established to determine the 3-, 5-, and 8-year CSS probabilities of patients with invasive melanoma. According to the nomogram, the Age at Diagnosis had the greatest influence on CSS in invasive melanoma, followed by Bone Metastasis, AJCC, Stage, Liver Metastasis, Histologic Subtype, Brain Metastasis, Ulceration, and Primary Site. The nomogram had a higher C-index than the AJCC staging system in both the training (0.850 versus 0.799) and validation (0.829 versus 0.783) cohorts. Calibration plotting demonstrated that the model had good calibration ability. The nomogram outperformed the AJCC staging system in terms of AUC, NRI, IDI, and DCA.ConclusionThis was the first study to develop and evaluate a comprehensive nomogram for the CSS of white patients with invasive melanoma at BANS sites using the SEER database. The novel nomogram can assist clinical staff in predicting the 3-, 5-, and 8-year CSS probabilities of patients with invasive melanoma more accurately than can the AJCC staging system

Rotational IMRT techniques compared to fixed gantry IMRT and Tomotherapy: multi-institutional planning study for head-and-neck cases

<p>Abstract</p> <p>Background</p> <p>Recent developments enable to deliver rotational IMRT with standard C-arm gantry based linear accelerators. This upcoming treatment technique was benchmarked in a multi-center treatment planning study against static gantry IMRT and rotational IMRT based on a ring gantry for a complex parotid gland sparing head-and-neck technique.</p> <p>Methods</p> <p>Treatment plans were created for 10 patients with head-and-neck tumours (oropharynx, hypopharynx, larynx) using the following treatment planning systems (TPS) for rotational IMRT: Monaco (ELEKTA VMAT solution), Eclipse (Varian RapidArc solution) and HiArt for the helical tomotherapy (Tomotherapy). Planning of static gantry IMRT was performed with KonRad, Pinnacle and Panther DAO based on step&shoot IMRT delivery and Eclipse for sliding window IMRT. The prescribed doses for the high dose PTVs were 65.1Gy or 60.9Gy and for the low dose PTVs 55.8Gy or 52.5Gy dependend on resection status. Plan evaluation was based on target coverage, conformity and homogeneity, DVHs of OARs and the volume of normal tissue receiving more than 5Gy (V_5Gy). Additionally, the cumulative monitor units (MUs) and treatment times of the different technologies were compared. All evaluation parameters were averaged over all 10 patients for each technique and planning modality.</p> <p>Results</p> <p>Depending on IMRT technique and TPS, the mean CI values of all patients ranged from 1.17 to 2.82; and mean HI values varied from 0.05 to 0.10. The mean values of the median doses of the spared parotid were 26.5Gy for RapidArc and 23Gy for VMAT, 14.1Gy for Tomo. For fixed gantry techniques 21Gy was achieved for step&shoot+KonRad, 17.0Gy for step&shoot+Panther DAO, 23.3Gy for step&shoot+Pinnacle and 18.6Gy for sliding window.</p> <p>V_5Gyvalues were lowest for the sliding window IMRT technique (3499 ccm) and largest for RapidArc (5480 ccm). The lowest mean MU value of 408 was achieved by Panther DAO, compared to 1140 for sliding window IMRT.</p> <p>Conclusions</p> <p>All IMRT delivery technologies with their associated TPS provide plans with satisfying target coverage while at the same time respecting the defined OAR criteria. Sliding window IMRT, RapidArc and Tomo techniques resulted in better target dose homogeneity compared to VMAT and step&shoot IMRT. Rotational IMRT based on C-arm linacs and Tomotherapy seem to be advantageous with respect to OAR sparing and treatment delivery efficiency, at the cost of higher dose delivered to normal tissues. The overall treatment plan quality using Tomo seems to be better than the other TPS technology combinations.</p

Comparative genomics of European Avian Pathogenic E. coli (APEC)

Background Avian pathogenic Escherichia coli (APEC) causes colibacillosis, which results in significant economic losses to the poultry industry worldwide. However, the diversity between isolates remains poorly understood. Here, a total of 272 APEC isolates collected from the United Kingdom (UK), Italy and Germany were characterised using multiplex polymerase chain reactions (PCRs) targeting 22 equally weighted factors covering virulence genes, R-type and phylogroup. Following these analysis, 95 of the selected strains were further analysed using Whole Genome Sequencing (WGS). Results The most prevalent phylogroups were B2 (47%) and A1 (22%), although there were national differences with Germany presenting group B2 (35.3%), Italy presenting group A1 (53.3%) and UK presenting group B2 (56.1%) as the most prevalent. R-type R1 was the most frequent type (55%) among APEC, but multiple R-types were also frequent (26.8%). Following compilation of all the PCR data which covered a total of 15 virulence genes, it was possible to build a similarity tree using each PCR result unweighted to produce 9 distinct groups. The average number of virulence genes was 6-8 per isolate, but no positive association was found between phylogroup and number or type of virulence genes. A total of 95 isolates representing each of these 9 groupings were genome sequenced and analysed for in silico serotype, Multilocus Sequence Typing (MLST), and antimicrobial resistance (AMR). The UK isolates showed the greatest variability in terms of serotype and MLST compared with German and Italian isolates, whereas the lowest prevalence of AMR was found for German isolates. Similarity trees were compiled using sequencing data and notably single nucleotide polymorphism data generated ten distinct geno-groups. The frequency of geno-groups across Europe comprised 26.3% belonging to Group 8 representing serogroups O2, O4, O18 and MLST types ST95, ST140, ST141, ST428, ST1618 and others, 18.9% belonging to Group 1 (serogroups O78 and MLST types ST23, ST2230), 15.8% belonging to Group 10 (serogroups O8, O45, O91, O125ab and variable MLST types), 14.7% belonging to Group 7 (serogroups O4, O24, O35, O53, O161 and MLST type ST117) and 13.7% belonging to Group 9 (serogroups O1, O16, O181 and others and MLST types ST10, ST48 and others). The other groups (2, 3, 4, 5 and 6) each contained relatively few strains. However, for some of the genogroups (e.g. groups 6 and 7) partial overlap with SNPs grouping and PCR grouping (matching PCR groups 8 (13 isolates on 22) and 1 (14 isolates on 16) were observable). However, it was not possible to obtain a clear correlation between genogroups and unweighted PCR groupings. This may be due to the genome plasticity of E. coli that enables strains to carry the same virulence factors even if the overall genotype is substantially different. Conclusions The conclusion to be drawn from the lack of correlations is that firstly, APEC are very diverse and secondly, it is not possible to rely on any one or more basic molecular or phenotypic tests to define APEC with clarity, reaffirming the need for whole genome analysis approaches which we describe here. This study highlights the presence of previously unreported serotypes and MLSTs for APEC in Europe. Moreover, it is a first step on a cautious reconsideration of the merits of classical identification criteria such as R typing, phylogrouping and serotyping

Quantitative Trait Loci for Bone Lengths on Chromosome 5 Using Dual Energy X-Ray Absorptiometry Imaging in the Twins UK Cohort

Human height is a highly heritable and complex trait but finding important genes has proven more difficult than expected. One reason might be the composite measure of height which may add heterogeneity and noise. The aim of this study was to conduct a genome-wide linkage scan to identify quantitative trait loci (QTL) for lengths of spine, femur, tibia, humerus and radius. These were investigated as alternative measures for height in a large, population–based twin sample with the potential to find genes underlying bone size and bone diseases. 3,782 normal Caucasian females, 18–80 years old, with whole body dual energy X-ray absorptiometry (DXA) images were used. A novel and reproducible method, linear pixel count (LPC) was used to measure skeletal sizes on DXA images. Intraclass correlations and heritability estimates were calculated for lengths of spine, femur, tibia, humerus and radius on monozygotic (MZ; n = 1,157) and dizygotic (DZ; n = 2,594) twins. A genome-wide linkage scan was performed on 2000 DZ twin subjects. All skeletal sites excluding spine were highly correlated. Intraclass correlations showed results for MZ twins to be significantly higher than DZ twins for all traits. Heritability results were as follows: spine, 66%; femur, 73%; tibia, 65%; humerus, 57%; radius, 68%. Results showed reliable evidence of highly suggestive linkage on chromosome 5 for spine (LOD score  =  3.0) and suggestive linkage for femur (LOD score  =  2.19) in the regions of 105cM and 155cM respectively. We have shown strong heritability of all skeletal sizes measured in this study and provide preliminary evidence that spine length is linked to the chromosomal region 5q15-5q23.1. Bone size phenotype appears to be more useful than traditional height measures to uncover novel genes. Replication and further fine mapping of this region is ongoing to determine potential genes influencing bone size and diseases affecting bone

Estrogen/progesterone Receptor and HER2 Discordance Between Primary Tumor and Brain Metastases in Breast Cancer and Its Effect on Treatment and Survival

BACKGROUND: Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). METHODS: A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. RESULTS: The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08). CONCLUSIONS: Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. KEY POINTS: 1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment

Specific requirement of NMDA receptors for long-term memory consolidation in Drosophila ellipsoid body

In humans and many other animals, memory consolidation occurs through multiple temporal phases and usually involves more than one neuroanatomical brain system. Genetic dissection of Pavlovian olfactory learning in Drosophila melanogaster has revealed multiple memory phases, but the predominant view holds that all memory phases occur in mushroom body neurons. Here, we demonstrate an acute requirement for NMDA receptors (NMDARs) outside of the mushroom body during long-term memory (LTM) consolidation. Targeted dsRNA-mediated silencing of Nmdar1 and Nmdar2 (also known as dNR1 or dNR2, respectively) in cholinergic R4m-subtype large-field neurons of the ellipsoid body specifically disrupted LTM consolidation, but not retrieval. Similar silencing of functional NMDARs in the mushroom body disrupted an earlier memory phase, leaving LTM intact. Our results clearly establish an anatomical site outside of the mushroom body involved with LTM consolidation, thus revealing both a distributed brain system subserving olfactory memory formation and the existence of a system-level memory consolidation in Drosophila