High school sports programs differentially impact participation by sex

Background： Among numerous health benefits, sports participation has been shown to reduce the risk of overweight and obesity in children and adolescents. Schools represent an ideal environment for increasing sports participation, but it is unclear how access and choice influence participation and whether characteristics of the school sports program differentially influence boys＇ and girls＇ participation. The purpose of this study was to evaluate the characteristics of high school athletic programs and determine the extent to which these characteristics influenced boys＇ and girls＇ sports team participation. Methods： Longitudinal telephone surveys were conducted with 1244 New Hampshire and Vermont students. Students self-reported their sports team participation at baseline （elementary school） and follow-up （high school）. High school personnel were surveyed to assess sports oppor- tunities, which were defined for this analysis as the number of sports offered per 100 students （i.e., choice） and the percent of sports offered that did not restrict the number of players （i.e., access）. Results： Approximately 70% of children participated on at least one sports team, including 73% of boys and 66% of girls. We detected sta- tistically significant interactions between sex and two school opportunity variables： 1） the number of sports offered per 100 students （i.e., choice） and 2） the percent of sports offered that did not restrict the number of players （i.e., access）. After controlling for children＇s baseline sports participation and other covariates, boys were more likely to play on at least one sports team per year if their school did not restrict participation in the most popular sports （relative risk, RR = 1.12, p 〈 0.01）; in contrast, girls were more likely to play on at least one sports team per year if their school offered a wider variety of sports （RR = 1.47, p 〈 0.001）. Conclusion： Sports participation has previously been shown to confer a number of health benefits; as such, school sports programs may be an important, effective, and underused target for public health efforts, including obesity prevention programs. Efforts to increase physical activity among youth should consider both access and choice in school athletic programs. Schools may need to use different strategies to increase sports participation in boys and girls.

Drug eluting biliary stents to decrease stent failure rates:Areview of the literature

Biliary stenting is clinically effective in relieving both malignant and non-malignant obstructions. However, there are high failure rates associated with tumor ingrowth and epithelial overgrowth as well as internally from biofilm development and subsequent clogging. Within the last decade, the use of prophylactic drug eluting stents as a means to reduce stent failure has been investigated. In this review we provide an overview of the current research on drug eluting biliary stents. While there is limited human trial data regarding the clinical benefit of drug eluting biliary stents in preventing stent obstruction, recent research suggests promise regarding their safety and potential efficacy.

Social Activity Patterns Drive High Rates of Latent Tuberculosis Infection among Adolescents in Urban Tanzania<br/>—Latent TB Infection in Adolescents, Tanzania

SETTING: Dar es Salaam, Tanzania. OBJECTIVE: To determine the prevalence of latent tuberculosis (TB) infection (LTBI) among adolescents in a country with a high TB burden, and examine risks of LTBI according to their social activity patterns. METHODS: A cross-sectional study nested within a phase 2b randomised, placebo controlled, double blind study and consisted of 824 adolescents, 13 - 15 years old who had received Bacillus Calmette-Guérin (BCG) vaccine, were attending public secondary schools and had no evidence of active tuberculosis (TB). Anthropometric measurements were obtained, a questionnaire administered, and phlebotomy performed for a T spot interferon-γ?release assay (IGRA) to detect LTBI. RESULTS: Among 824 subjects, 149 (18%) had a positive IGRA. After adjusting for the influence of household socioeconomic status, history of TB contact, living environment and nutritional status, LTBI risk was higher in subjects with than without regular informal encounters with traditional alcoholic beverage drinkers (AOR, 6.37 [1.84 - 22.00]). Other significant factors for LTBI risk included contact with TB patient at school (AOR, 3.34 [1.14 - 9.80]), and living close to a health facility, as was observed among those from houses within a 10 - 30-minute walking distance to the nearest health facility, who were less likely to be IGRA-positive than those who were living within a 10-minute walking distance (AOR, 0.30 [95%CI, 0.13 - 0.69]). CONCLUSION: This IGRA study revealed a high prevalence of LTBI among adolescents in Dar es Salaam, Tanzania with prior BCG immunization. Informal social encounters were identified as independent risk factors for LTBI, along with a history of contact with TB patients, living environment characteristics and household socioeconomic status. Efforts focusing on risk of MTB transmission in adolescents at informal social gatherings will improve interventions to reduce LTBI in this population and consequently the subsequent risk of developing active TB disease.

<i>In Vitro</i>Characterization of Docetaxel as a Radiosensitizer in Canine and Feline Cancer Cell Lines

An In Vitro study was conducted to investigate docetaxel as a radiation sensitizer in four canine (mammary carcinoma—CMT12 and CMT25, osteosarcoma—OS2.4, and transitional cell carcinoma—PTCC), and one feline cancer cell line (oral squamous cell carcinoma—SCCF1) to provide a basis for combination therapy in clinical patients. Cells were exposed to docetaxel followed by a single dose of radiation. The percent surviving fraction was determined by MTT assay. The combination index (CI) method determined synergistic cytotoxicity for the CMT12, CMT25 and OS2.4 cell lines with median CI values of 0.35, 0.47, 0.63 respectively. The SCCF1 cell line had moderate synergistic cytotoxicity with a median CI of 0.76, while the PTCC cell line resulted in antagonistic cytoxicity with a median CI of 2.75. The results indicated that docetaxel was a radiation sensitizer in 4 out of the 5 cancer cell lines tested.

Detecting white matter alterations in multiple sclerosis using advanced diffusion magnetic resonance imaging

Multiple sclerosis is a neurodegenerative and inflammatory disease, a hallmark of which is demyelinating lesions in the white matter. We hypothesized that alterations in white matter microstructures can be non-invasively characterized by advanced diffusion magnetic resonance imaging. Seven diffusion metrics were extracted from hybrid diffusion imaging acquisitions via classic diffusion tensor imaging, neurite orientation dispersion and density imaging, and q-space imaging. We investigated the sensitivity of the diffusion metrics in 36 sets of regions of interest in the brain white matter of six female patients(age 52.8 ± 4.3 years) with multiple sclerosis. Each region of interest set included a conventional T2-defined lesion, a matched perilesion area, and normal-appearing white matter. Six patients with multiple sclerosis(n = 5) or clinically isolated syndrome(n = 1) at a mild to moderate disability level were recruited. The patients exhibited microstructural alterations from normal-appearing white matter transitioning to perilesion areas and lesions, consistent with decreased tissue restriction, decreased axonal density, and increased classic diffusion tensor imaging diffusivity. The findings suggest that diffusion compartment modeling and q-spa ce analysis appeared to be sensitive for detecting subtle microstructural alterations between perilesion areas and normal-appearing white matter.

Sessile serrated adenomas in the proximal colon are likely to be flat,large and occur in smokers

AIM:To examine the epidemiology and the morphology of the proximal sessile serrated adenomas(SSAs).METHODS:We conducted a retrospective study to identify patients with SSAs using a university-based hospital pathology database query from January 2007to April 2011.Data collected included:age,gender,ethnicity,body mass index,diabetes,smoking,family history of colorectal cancer,aspirin,and statin use.We collected data on morphology of SSAs including site(proximal or distal),size,and endoscopic appearance(flat or protuberant).We also compared proximal SSAs to proximal tubular adenomas detected during same time period.RESULTS:One hundred and twenty patients with SSAs were identified:61%were distal and 39%were proximal SSAs.Proximal SSAs were more likely to be flat than distal(100%vs 78%respectively;P=0.0001).Proximal SSAs were more likely to occur in smokers(OR=2.63;95%CI:1.17-5.90;P=0.02)and in patients with family history of colorectal cancer(OR=4.72;95%CI:1.43-15.55;P=0.01)compared to distal.Proximal SSAs were statistically more likely to be≥6 mm in size(OR=2.94;P=0.008),and also more likely to be large(≥1 cm)(OR=4.55;P=0.0005)compared to the distal lesions.Smokers were more likely to have proximal(P=0.02),flat(P=0.01)and large(P=0.007)SSAs compared to non-smokers.Compared to proximal tubular adenomas,proximal SSAs were more likely to be large and occur in smokers.CONCLUSION:Proximal SSAs which accounted for two-fifths of all SSAs were more likely to present as flat lesions,larger SSAs,and were more likely to occur in smokers and in patients with family history of colorectal cancer.Our data has implications for colorectal cancer screening.

The Shortest Width Confidence Interval for Odds Ratio in Logistic Regression

The shortest width confidence interval (CI) for odds ratio (OR) in logistic regression is developed based on a theorem proved by Dahiya and Guttman (1982). When the variance of the logistic regression coefficient estimate is small, the shortest width CI is close to the regular Wald CI obtained by exponentiating the CI for the regression coefficient estimate. However, when the variance increases, the optimal CI may be up to 25% narrower. It is demonstrated that the shortest width CI is favorable because it has a smaller probability of covering the wrong OR value compared with the standard CI. The closed-form iterations based on the Newton's algorithm are provided, and the R function is supplied. A simulation study confirms the superior properties of the new CI for OR in small sample. Our method is illustrated with eight studies on parity as a preventive factor against bladder cancer in women.

Cancer overdiagnosis: A challenge in the era of screening

“Screening”is a search for preclinical,asymptomatic disease,including cancer.Widespread cancer screening has led to large increases in early-stage cancers and pre-cancers.Ubiquitous public messages emphasize the potential benefits to screening for these lesions based on the underlying assumption that treating cancer at early stages before spread to other organs should make it easier to treat and cure,using more tolerable interventions.The intuition is so strong that public campaigns are sometimes launched without conducting definitive trials directly comparing screening to usual care.An effective cancer screening test should not only increase the incidence of early-stage preclinical disease but should also decrease the incidence of advanced and metastatic cancer,as well as a subsequent decrease in cancer-related mortality.Otherwise,screening efforts may be uncovering a reservoir of non-progressive and very slowly progressive lesions that were not destined to cause symptoms or suffering during the person’s remaining natural lifespan:a phenomenon known as“overdiagnosis.”We provide here a qualitative review of cancer overdiagnosis and discuss specific examples due to extensive population-based screening,including neuroblastoma,prostate cancer,thyroid cancer,lung cancer,melanoma,and breast cancer.The harms of unnecessary diagnosis and cancer therapy call for a balanced presentation to people considering undergoing screening,even with a test of accepted benefit,with a goal of informed decision-making.We also discuss proposed strategies to mitigate the adverse sequelae of overdiagnosis.

基因组畸变相关基因特征预测神经母细胞瘤预后

背景与目的神经母细胞瘤(neuroblastoma,NB)是一种异质性疾病,伴有基因组畸变,且临床表现呈多样性。虽然我们对遗传畸变与临床特征之间的关系已有所了解,但对患者的预后预测和制订个体化治疗策略仍是挑战。本研究旨在建立一种有效的NB患者预后预测模型。方法我们整合了多种不同算法定义基因特征,反映MYCN活性和染色体畸变,包括染色体1p缺失(deletion of chromosome1p,Chr1p_del)、染色体11q缺失(deletion of chromosome 11q,Chr11q_del)以及染色体11q全部丢失(whole loss of chromosome 11q,Chr11q_wls)。我们评估了由RNA测序和微阵列平台产生的7个NB基因表达数据集(样本量从94到498,共2120)中这些基因特征的预后预测价值。结果MYCN活性评分是比MYCN扩增状态和表达更有效的预后标志物。同样,Chr1p_del评分是比Chr1p状态更好的预后标志物。MYCN、Chr1p_del和Chr11q_del的活性评分与预后不良相关,而Chr11q_wls评分与预后良好相关。我们整合MYCN、Chr1p_del、Chr11q_del和Chr11q_wls评分以及临床变量建立综合预测模型,该模型对NB预后预测效果比单独应用临床变量或每个基因组畸变更佳。结论加入了基因特征的预后预测模型显著提高了预测效果,可作为对NB患者进行分层以评估预后的生物标志物。

Genetic profiling of cancer with circulating tumor DNA analysis

Circulating cell-free tumor DNA（ctDNA） in the blood is DNA released from apoptotic, circulating, and living tumor cells. ctDNA is about 140 nt in length and has a half-life of about 1.5 h. ctDNA analysis provides a noninvasive means to assess the genetic profile of cancer in real time. With the advent of molecular technologies, including digital PCR and massively parallel sequencing（MPS）, ctDNA analysis has shown promise as a highly sensitive and specific alternative to conventional tissue biopsy in cancer detection, longitudinal monitoring, and precision therapy. This review provides an overview of the latest development in our understanding of the biologic characteristics, detection methodologies, and potential clinical implications of ctDNA, as well as the challenges in translating ctDNA analysis from the research arena to patient care.

Cathepsin C promotes the progression of periapical periodontitis

Although the role of cathepsin C (Cat C) in inflammation is gradually being elucidated, its function in periapical periodontitis, which is one of the most common infectious diseases worldwide, has not been studied. This study evaluated a surgically-induced model of periapical periodontitis in cathepsin C (Cat C) knock-down (KD) mice, which was constructed with a tetracycline operator, to evaluate the role of Cat C in the pathogenesis and progression of periapical periodontitis. Our results showed, for the first time, that there was a statistically significant increase in the expression of Cat C as periapical periodontitis progressed;this increase started from 1 week after surgery and reached a peak at 3 weeks after surgery, before gradually decreasing. The volume of periapical bone resorption in Cat C KD mice was significantly smaller than that in wild-type mice at 3 and 4 weeks after surgery (P<0.05). Inflammatory cell infiltration into the apical tissues of wild-type mice was also significantly higher than that of Cat C KD mice. The expression of receptor activator of nuclear factor-j B ligand (RANKL) in wild-type mice was also higher than that in Cat C KD mice. The difference in the number of osteoclasts in the apical area between the two groups was statistically significant after 2 weeks. Correlation analysis showed that there was a significant correlation between Cat C and RANKL expression (r= 0.835). Therefore, our data indicated that Cat C promoted the apical inflammation and bone destruction in mice.

Invasive <i>Aspergillus</i>Infections in a Thai Tertiary-Care Hospital during 2006-2011

From an increase in the number of immunocompromised hosts including AIDS patients, organ transplantation, solid-organ tumor, hematological malignancy, corticosteroid use, and others underlying diseases, it leads to increasing the incidence of invasive aspergillosis (IA) as one of the most prevalent opportunistic mould infections. However, the epidemiological data are still limited. Our objective is to study the epidemiology of IA, patients’ characteristics in a tertiary-care hospital, King Chulalongkorn Memorial Hospital, Bangkok, Thailand. The retrospective study of IA as principal diagnosis in both medical and laboratory records in a tertiary-care hospital, King Chulalongkorn Memorial Hospital, from January 1, 2006 to December 31, 2011, was performed. There were 69 patients who were diagnosed as IA during 2006 till 2011. They were classified as proven (45 patients), probable (3 patients), and possible (21 patients) invasive aspergillosis following the criteria of European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG), 2008. The numbers of patients in 2006 to 2011 were 3, 11, 12, 10, 10, and 23 respectively. Male patients were 58 percent. The age range was from 8 months to 87 years old. Most of patients were from Medicine ward. Others were derived from Pediatrics, Surgery, and Ear Nose Throat wards. The most common underlying disease was diabetes mellitus type 2 in the proven group. The main predisposing factors of patients were the history of pulmonary tuberculosis and using of immunosuppressive drugs. The sites of infection were lung (62%), sinus (28%), and brain (8%). Aspergillus fumigatus (69%) and Aspergillus flavus (15%) were common species from the isolated culture. The treatment used mostly was surgery and followed by amphotericin B or voriconazole. The case fatality rate of IA was 20 percent. From the epidemiological data, we can conclude that in this past ten years there is an incessant increase in the number of IA in the immunocompromised hosts especially from Aspergillus fumigatus, which is the most prevalent species found in IA. Diabetes mellitus and history of pulmonary tuberculosis will play the important role for IA in the future. The plan for prevention and treatment should be concerned about those underlying diseases and predisposing factors.

The virtual peripheral nerve academy:education for the identification and treatment of peripheral nerve disorders

Millions of people around the globe suffer peripheral nerve injuries caused by trauma and medical disorders.However,medical school curricula are profoundly deficient in peripheral nerve education.This lack of knowledge within the healthcare profession may cause inadequate patient care.We developed the Virtual Peripheral Nerve Academy(VPNA)as a reusable virtual learning environment to provide medical students with detailed education on the peripheral nervous system(PNS).Students are introduced to the PNS through virtual 3D rendering of the human body,wherein they visualize individual nerves through dissection and observe normal motor and sensory function associated with each nerve.PNS structures that are absent from traditional texts are included in this visualization,ranging from the innervation of joints to the normal anatomic variation required for differential diagnosis of pain after an injury.Detailed modules on peripheral nerve disorders allow students to observe pathophysiological mechanisms,associated symptomatology,and appropriate treatments.Students are briefed on a patient clinical case,then interact with a patient avatar to learn the appropriate diagnostics,including physical exam maneuvers and electrodiagnostic testing.Interactive modules on peripheral nerve surgeries detail surgical techniques.The VPNA data and analytics dashboards allow medical students and course instructors to assess skill improvement and identify specific learning needs.The built-in learner management system and availability on both computer-based and virtual reality platforms facilitate integration into any existing medical school curricula.Ultimately,this immersive technology enables every medical student to learn about the peripheral nervous system and gain competency in treating real-life nerve pathologies.

CD4^＋ T-cell dependence of primary CD8^＋ T-cell response against vaccinia virus depends upon route of infection and viral dose

CD4^＋ T-cell help （CD4 help） plays a pivotal role in CD8^＋ T-cell responses against viral infections. However, the role in primary CD8^＋ T-cell responses remains controversial. We evaluated the effects of infection route and viral dose on primary CD8^＋ T-cell responses to vaccinia virus （VACV） in MHC class II^-/- mice. CD4 help deficiency diminished the generation of VACV-specific CD8^＋ T cells after intraperitoneal （i.p.） but not after intranasal （i.n.） infection. A large viral dose could not restore normal expansion of VACV-specific CD8^＋ T cells in i.p. infected MHC II-/- mice. In contrast, dependence on CD4 help was observed in i.n. infected MHC II-/- mice when a small viral dose was used. These data suggested that primary CD8~ T-cell responses are less dependent on CD4 help in i.n. infection compared to i.p. infection. Activated CD8~ T cells produced more I FN-y, TNF-a and granzyme B in i.n. infected mice than those in i.p. infected mice, regardless of CD4 help. IL-2 signaling via CD25 was not necessary to drive expansion of VACV-specific CD8~ T cells in i.n. infection, but it was crucial in i.p. infection. VACV-specific CD8^＋ T cells underwent increased apoptosis in the absence of CD4 help, but proliferated normally and had cytotoxic potential, regardless of infection route. Our results indicate that route of infection and viral dose are two determinants for CD4 help dependence, and intranasal infection induces more potent effector CD8^＋ T cells than i.D. infection.

Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer

Breast cancer is one of the leading causes of death in women in the United States.In general,patients with breast cancer undergo surgical resection of the tumor and/or receive drug treatment to kill or suppress the growth of cancer cells.In this regard,small molecule kinase inhibitors serve as an important class of drugs used in clinical and research settings.However,the development of resistance to these compounds,in particular HER2 and CDK4/6 inhibitors,often limits durable clinical responses to therapy.Emerging evidence indicates that PI3K/AKT/mTOR pathway hyperactivation is one of the most prominent mechanisms of resistance to many small molecule inhibitors as it bypasses upstream growth factor receptor inhibition.Importantly,the PI3K/AKT/mTOR pathway also plays a pertinent role in regulating various aspects of cancer metabolism.Recent studies from our lab and others have demonstrated that altered lipid metabolism mediates the development of acquired drug resistance to HER2-targeted therapies in breast cancer,raising an interesting link between reprogrammed kinase signaling and lipid metabolism.It appears that,upon development of resistance to HER2 inhibitors,breast cancer cells rewire lipid metabolism to somehow circumvent the inhibition of kinase signaling.Here,we review various mechanisms of resistance observed for kinase inhibitors and discuss lipid metabolism as a potential therapeutic target to overcome acquired drug resistance.

SOPHIE: Generative Neural Networks Separate Common and Specific Transcriptional Responses

Genome-wide transcriptome profiling identifies genes that are prone to differential expression(DE)across contexts,as well as genes with changes specific to the experimental manipulation.Distinguishing genes that are specifically changed in a context of interest from common differentially expressed genes(DEGs)allows more efficient prediction of which genes are specific to a given biological process under scrutiny.Currently,common DEGs or pathways can only be identified through the laborious manual curation of experiments,an inordinately time-consuming endeavor.Here we pioneer an approach,Specific cOntext Pattern Highlighting In Expression data(SOPHIE),for distinguishing between common and specific transcriptional patterns using a generative neural network to create a background set of experiments from which a null distribution of gene and pathway changes can be generated.We apply SOPHIE to diverse datasets including those from human,human cancer,and bacterial pathogen Pseudomonas aeruginosa.SOPHIE identifies common DEGs in concordance with previously described,manually and systematically determined common DEGs.Further molecular validation indicates that SOPHIE detects highly specific but low-magnitude biologically relevant transcriptional changes.SOPHIE’s measure of specificity can complement log2 fold change values generated from traditional DE analyses.For example,by filtering the set of DEGs,one can identify genes that are specifically relevant to the experimental condition of interest.Consequently,these results can inform future research directions.All scripts used in these analyses are available at https://github.com/greenelab/generic-expression-patterns.Users can access https://github.com/greenelab/sophie to run SOPHIE on their own data.

Retinoic acid signaling acts as a rheostat to balance Treg function

Regulatory T cells(Tregs)promote immune homeostasis by maintaining self-tolerance and regulating inflammatory responses.Under certain inflammatory conditions,Tregs can lose their lineage stability and function.Previous studies have reported that ex vivo exposure to retinoic acid(RA)enhances Treg function and stability.However,it is unknown how RA receptor signaling in Tregs influences these processes in vivo.Herein,we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor(DN)RARαin all T cells.Despite the fact that DNRARαconventional T cells are hypofunctional,Tregs had increased CD25 expression,STAT5 pathway activation,mTORC1 signaling and supersuppressor function.Furthermore,DNRARαTregs had increased inhibitory molecule expression,amino acid transporter expression,and metabolic fitness and decreased antiapoptotic proteins.Supersuppressor function was observed when wild-type mice were treated with a pharmacologic pan-RAR antagonist.Unexpectedly,Treg-specific expression of DNRARαresulted in distinct phenotypes,such that a single allele of DNRARαin Tregs heightened their suppressive function,and biallelic expression led to loss of suppression and autoimmunity.The loss of Treg function was not cell intrinsic,as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARαand wild-type bone marrow maintained the enhanced suppressive capacity.Fate mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA signaling.Our findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.

The role of VISTA in the tumor microenvironment

V-domain Ig Suppressor of T cell Activation(VISTA)is a negative immune checkpoint that is expressed on multiple immune cell subsets and has been characterized in T cells,macrophages,and myeloid-derived suppressor cells.As the only immune checkpoint expressed on naïve T cells,VISTA contributes to the maintenance of T cell quiescence and tolerance.VISTA also regulates multiple myeloid cell activities such as chemotaxis,differentiation,and migration.In the context of cancer,antagonistic monoclonal antibody targeting of VISTA has been shown to aid anti-tumor immunity.Furthermore,combination therapies that include other immune checkpoints such as PD-1 or CTLA-4 with VISTA blockade may enhance therapeutic efficacy in a variety of cancers.Combination therapy may help overcome adaptive resistance to individual checkpoint therapies,thereby improving patient outcomes and survival.Here,we summarize the role of VISTA in myeloid cells and T cells within the tumor microenvironment.We discuss the proposed counter-receptors for VISTA,VISTA antibodies currently in development,and the potential for combination therapies with checkpoint inhibitors such as PD-1 and CTLA-4.

Gene signatures associated with genomic aberrations predict prognosis in neuroblastoma

Background:Neuroblastoma(NB)is a heterogeneous disease with respect to genomic abnormalities and clinical behaviors.Despite recent advances in our understanding of the association between the genetic aberrations and clinical features,it remains one of the major challenges to predict prognosis and stratify patients for determining personalized therapy in this disease.The aim of this study was to develop an effective prognosis prediction model for NB patients.Methods:We integrated diverse computational analyses to define gene signatures that reflect MYCN activity and chromosomal aberrations including deletion of chromosome 1p(Chr1p_del)and chromosome 11q(Chr11q_del)as well as chromosome 11q whole loss(Chr11q_wls).We evaluated the prognostic and predictive values of these signatures in seven NB gene expression datasets(the number of samples ranges from 94 to 498,with a total of 2120)generated from both RNA sequencing and microarray platforms.Results:MYCN signature was a more effective prognostic marker than MYCN amplification status and MYCN expression.Similarly,the Chr1p_del score was more prognostic than Chr1p status.The activity scores of MYCN,Chr1p_del and Chr11q_del were associated with poor prognosis,while the Chr11q_wls score was linked to good outcome.We integrated the activity scores of MYCN,Chr1p_del,Chr11q_del,and Chr11q_wls and clinical variables into an integrative prognostic model,which displayed significant performance over the clinical variables or each genomic aberration alone.Conclusions:Our integrative gene signature model shows a significantly improved forecast performance with prognostic and predictive information,and thereby can be served as a biomarker to stratify NB patients for prognosis evaluation and surveillance programs.

B cell infiltration is highly associated with prognosis and an immune-infiltrated tumor microenvironment in neuroblastoma

Aim:Neuroblastoma is the most common extracranial solid tumor in children.Recent advances in immunotherapy Approaches,including in neuroblastoma,have shown the important role of the immune system in mounting an effective anti-tumor response.In this study,we aimed to provide a comprehensive investigation of immune cell infiltration in neuroblastoma utilizing a large number of gene expression datasets.Methods:We inferred immune cell infiltration using an established immune inference method and evaluated the association between immune cell abundance and patient prognosis as well as common chromosomal abnormalities found in neuroblastoma.In addition,we evaluated co-infiltration patterns among distinct immune cell types.Results:The infiltration of naïve B cells,NK cells,and CD8+T cells was associated with improved patient prognosis.Naïve B cells were the most consistent indicator of prognosis and associated with an active immune tumor microenvironment.Patients with high B cell infiltration showed high co-infiltration of other immune cell types and the enrichment of immune-related pathways.The presence of high B cell infiltration was associated with both recurrence-free and overall survival,even after adjusting for clinical variables.Conclusion:In this study,we have provided a comprehensive evaluation of immune cell infiltration in neuroblastoma using gene expression data.We propose an important role for B cells in the neuroblastoma tumor microenvironment and suggest that B cells can be used as a prognostic biomarker to predict recurrence-free and overall survival independently of currently utilized prognostic variables.