Neonatal hemophagocytic lymphohistiocytosis: A meta-analysis of 205 cases.

BACKGROUND: Neonatal hemophagocytic lymphohistiocytosis (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. There have been few large descriptive studies of nHLH. OBJECTIVES: The objective of this study was to perform a meta-analysis of published cases of nHLH. METHODS: A comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age ≤30 days. Up to 70 variables were extracted from each case. RESULTS: A total of 544 studies were assessed for eligibility, and 205 cases of nHLH from 142 articles were included. The median age of symptom onset was day of life 3 (interquartile range [IQR]: 0-11, n = 141). Median age at diagnosis was day of life 15 (IQR: 6-27, n = 87). Causes of HLH included familial HLH (48%, n = 99/205), infection (26%, n = 53/205), unknown (17%, n = 35/205), macrophage activation syndrome/rheumatologic (2.9%, n = 4/205), primary immune deficiency (2.0%, n = 5/205), inborn errors of metabolism (2.4%, n = 5/205), and malignancy (2.0%, n = 4/205). Fever was absent in 19% (n = 28/147) of all neonates and 39% (n = 15/38) of preterm neonates. Bicytopenia was absent in 26% (n = 47/183) of patients. Central nervous system (CNS) manifestations were reported in 63% of cases (n = 64/102). Liver injury (68%, n = 91/134) and/or liver failure (24%, n = 32/134) were common. Flow cytometry was performed in 22% (n = 45/205) of cases. Many patients (63%, n = 121/193) died within the period of reporting. Discernable values for HLH diagnostic criteria were reported between 30% and 83% of the time. CONCLUSIONS: Evaluation of nHLH requires rapid testing for a wide range of differential diagnoses. HLH diagnostic criteria such as fever and bicytopenia may not occur as frequently in the neonatal population as in older pediatric populations. Neurologic and hepatic manifestations frequently occur in the neonatal population. Current reports of nHLH suggest a high mortality rate. Future publications containing data on nHLH should improve reporting quality by reporting all clinically relevant data.

TP53-PTEN-NF1 depletion in human brain organoids produces a glioma phenotype in vitro.

Glioblastoma (GBM) is fatal and the study of therapeutic resistance, disease progression, and drug discovery in GBM or glioma stem cells is often hindered by limited resources. This limitation slows down progress in both drug discovery and patient survival. Here we present a genetically engineered human cerebral organoid model with a cancer-like phenotype that could provide a basis for GBM-like models. Specifically, we engineered a doxycycline-inducible vector encoding shRNAs enabling depletion of the TP53, PTEN, and NF1 tumor suppressors in human cerebral organoids. Designated as inducible short hairpin-TP53-PTEN-NF1 (ish-TPN), doxycycline treatment resulted in human cancer-like cerebral organoids that effaced the entire organoid cytoarchitecture, while uninduced ish-TPN cerebral organoids recapitulated the normal cytoarchitecture of the brain. Transcriptomic analysis revealed a proneural GBM subtype. This proof-of-concept study offers a valuable resource for directly investigating the emergence and progression of gliomas within the context of specific genetic alterations in normal cerebral organoids.

An Exploratory Study of Bone Health Among Native Hawaiian Women in Rural Hawai'i.

INTRODUCTION: The purpose of this study was to obtain baseline data on bone mass density for Native Hawaiian women and to better understand the socio-cultural context for assessing bone health and risk of osteoporosis for this underserved population. METHOD: A sequential mixed-method design guided by Leininger's Culture Care Theory of Diversity and Universality consisted of two phases: (a) an initial exploratory focus group and (b) dual-energy X-ray absorptiometry (DEXA) scans and individual interviews. Data were analyzed using descriptive statistics and thematic analysis. RESULTS: Phase a (n = 12) suggested that Native Hawaiian women have limited knowledge of bone health, but recognize traditional and cultural ways of health. Phase b (n = 50) showed that Native Hawaiian women have healthy bones, according to the T-score results. The interviews suggested that perspectives of bone health are culturally anchored. DISCUSSION: Understanding cultural values and practices are vital for care. Preliminary recommendations for health professionals are included.

Nasopharyngeal Swabs in Pediatric Patients With Thrombocytopenia and Anticoagulant Use.

BACKGROUND: Nasopharyngeal (NP) swabbing is a technique that is commonly used to test pediatric patients for viral infections with increased use during the coronavirus disease 2019 pandemic. Complications from NP swabbing are rare and seem to occur more frequently in patients at risk of bleeding. Little is known about institutional or individual practices and experiences with NP swab testing in pediatric patients with risk factors for bleeding. METHODS: We conducted a survey study of pediatric hematology/oncology (PHO) attending physicians to assess practices and experiences with NP swab testing in pediatric patients with thrombocytopenia and/or on anticoagulation. RESULTS: There were 130 total respondents (5.6%, n = 130/2327) from 6 countries. Relatively few respondents (n = 17/130, 13.1%) reported that their institution had a policy specifying a lower-level platelet cutoff for patients undergoing NP swabbing. The median platelet cutoff below which NP swabs are not performed according to existing policies is 30,000×10(9)/L (interquartile range: 20,000 to 40,000). The median cutoff based on the opinion of the respondents was 10,000 (interquartile range: 10,000 to 20,000). There were 24 episodes of epistaxis among PHO patients that were NP swabbed; many adverse events (56.5%, n = 13/23) were described as persistent, severe, and/or required intervention. Three reported cases of epistaxis with anticoagulation or antiplatelet therapy occurred in patients with concomitant thrombocytopenia. Only 1 respondent (n = 1/130, 0.7%) reported an institutional policy for limiting NP swabs in patients on anticoagulant therapy. NP (66.9%) and nares (33.1%) were the most common sources of coronavirus disease 2019 testing that were reported. CONCLUSION: A small percentage of institutions in this survey have a policy restricting NP swabs in PHO patients. The discrepancy between lower platelet cutoffs proposed by experts and institutional policy suggests that existing policies may be too conservative. Expert guidelines are needed on this topic. Other bleeding risk factors (eg, aspirin use and von Willebrand disease) should be considered in policies and guidelines.

ZEB1 loss increases glioma stem cell tumorigenicity and resistance to chemoradiation.

OBJECTIVE: Glioblastoma has been known to be resistant to chemotherapy and radiation, whereas the underlying mechanisms of resistance have not been fully elucidated. The authors studied the role of the transcription factor ZEB1 (zinc finger E-box-binding homeobox 1 protein), which is associated with epithelial-mesenchymal transition (EMT) and is central to the stemness of glioblastoma, to determine its role in therapeutic resistance to radiation and chemotherapy. The authors previously demonstrated that ZEB1 is deleted in a majority of glioblastomas. METHODS: The authors explored resistance to therapy in the context of ZEB1 loss and overexpression in glioma stem cells (GSCs) and in patient data. RESULTS: Patients with ZEB1 loss had a shorter survival time than patients with wild-type ZEB1 in both the high- and low-MGMT groups. Consistent with the clinical data, mice implanted with ZEB1 knockdown GSCs showed shortened survival compared with mice inoculated with nonsilencing control (NS) short-hairpin RNA (shRNA) GSC glioblastoma. ZEB1-deleted GSCs demonstrated increased tumorigenicity with regard to proliferation and invasion. Importantly, GSCs that lose ZEB1 expression develop enhanced resistance to chemotherapy, radiotherapy, and combined chemoradiation. ZEB1 loss may lead to increased HER3 expression through the HER3/Akt pathway associated with this chemoresistance. Conversely, overexpression of ZEB1 in GSCs that are ZEB1 null leads to increased sensitivity to chemoradiation. CONCLUSIONS: The study results indicate that ZEB1 loss in cancer stem cells confers resistance to chemoradiation and uncovers a potentially targetable cell surface receptor in these resistant cells.

Efectividad de las sesiones demostrativas para mejorar el conocimiento en la prevención de la anemia en gestantes, madres lactantes De niños menores de 3 años. Centro de salud Aparicio Pomares. Huánuco ­ perú / Effectiveness of demonstration sessions to improve knowledge in the prevention of anemia in pregnant women, nursing mothers of children under 3 years. Aparicio pomares health center. Huánuco ­ Peru

El problema de la anemia está muy relacionado a los índices de pobreza, falta de cuidado de la salud y educación de la población, pero principalmente a la falta de conocimientos sobre alimentación y nutrición infantil por parte de las madres. Objetivo: Determinar la efectividad de las sesiones demostrativas para mejorar el conocimiento en la prevención de la anemia en gestantes, madres lactantes de niños menores de 3 años. Materiales y Métodos: El estudio fue de tipo experimental, descriptivo y de nivel observacional, explicativo y analítico. La población de estudio estuvo conformada por 200 gestantes, obteniendo una muestra de 30 gestantes y 20 madres lactantes de niños menores de 3 años, haciendo un total de 50 pacientes, se utilizó el cuestionario para la recolección de datos, aplicado en dos momentos; antes y después de las sesiones demostrativas, con la finalidad de comparar los resultados. Resultados: El nivel de conocimiento teórico de las madres, luego de la aplicación de las sesiones demostrativas se incrementó su nivel a un conocimiento alto. Respecto a los conocimientos prácticos luego de la aplicación de las sesiones, se logró un conocimiento alto. Conclusiones: La técnica de sesiones demostrativas en el incremento de conocimientos es efectiva(AU)

The problem of anemia is closely related to the rates of poverty, lack of care of the health and education of the population, but mainly to the lack of knowledge about food and infant nutrition by mothers. Objective: To determine the effectiveness of the demonstration sessions to improve knowledge in the prevention of anemia in pregnant women, nursing mothers of minor children 3 years old Materials and methods: The study was of type, experimental, descriptive and observational level, explanatory and analytical. The study population consisted of 200 pregnant women, obtaining a sample of 30 pregnant women and 20 lactating mothers of children under 3 years of age, making a total of 50 patients, the questionnaire was used for data collection, applied in two moments; before and after demonstration sessions, in order to compare the results. Results: The level of theoretical knowledge of the mothers, after the application of the demonstrative sessions their level to high knowledge. Regarding the practical knowledge after the application of the sessions, high knowledge was achieved. Conclusions: The technique of demonstrative sessions in the increase of knowledge is effective(AU)

Fungicide resistance characterized across seven modes of action in Botrytis cinerea isolated from Australian vineyards.

BACKGROUND: Botrytis bunch rot, caused by Botrytis cinerea, is an economically important disease of grapes in Australia and across grape-growing regions worldwide. Control of this disease relies on canopy management and the application of fungicides. Fungicide application can lead to the selection of resistant B. cinerea populations, which has an adverse effect on the management of the disease. Characterizing the distribution and severity of resistant B. cinerea populations is needed to inform resistance management strategies. RESULTS: In this study, 724 isolates were sampled from 76 Australian vineyards during 2013-2016 and were screened against seven fungicides with different modes of action (MOAs). The resistance frequencies for azoxystrobin, boscalid, fenhexamid, fludioxonil, iprodione, pyrimethanil and tebuconazole were 5%, 2.8%, 2.1%, 6.2%, 11.6%, 7.7% and 2.9%, respectively. Nearly half of the resistant isolates (43.8%) were resistant to more than one of the fungicides tested. The frequency of vineyards with at least one isolate simultaneously resistant to one, two, three, four or five fungicides was 19.7%, 7.9%, 6.6%, 10.5% and 2.6%. Resistance was associated with previously published genotypes in CytB (G143A), SdhB (H272R/Y), Erg27 (F412S), Mrr1 (D354Y), Bos1 (I365S, N373S + Q369P, I365S + D757N) and Pos5 (V273I, P319A, L412F/V). Novel genotypes were also described in Mrr1 (S611N, D616G), Pos5 (V273L) and Cyp51 (P347S). Expression analysis was used to characterize fludioxonil-resistant isolates exhibiting overexpression (6.3-9.6-fold) of the ABC transporter gene AtrB (MDR1 phenotype). CONCLUSION: Resistance frequencies were lower when compared to most previously published surveys of B. cinerea resistance in grape and other crops. Nevertheless, continued monitoring of critical MOAs used in Australian vineyards is recommended. © 2021 Society of Chemical Industry.

CD133 mRNA-transfected dendritic cells induce coordinated cytotoxic and helper T cell responses against breast cancer stem cells.

Breast cancer, a leading cause of death yearly, has been shown to be initiated and propagated by cancer stem cells. CD133, a cell surface antigen, has been shown to be present on cancer stem cells of many solid tumors, including breast cancer. A limitation to targeting CD133 is major histocompatibility complex (MHC)-restricted presentation of epitopes, leading to activation of only one arm of the immune system: either CD4+ helper T cells or CD8+ cytotoxic T cells. Thus, we hypothesized that by creating an MHC-independent vaccination, we would give rise to a sustained immune response against CD133 in triple-negative breast cancer (TNBCs). We transfected CD133 mRNA into dendritic cells and then tested this in animal models of TNBC. We showed in these models the activation of both CD8+ cytotoxic T cells and CD4+ helper T cells by dendritic cell vaccination with modified CD133 mRNA, with subsequent decrease in tumor growth. This study for the first time demonstrates in a syngeneic mouse model of TNBC that targeting CD133, in an MHC-independent manner, is an effective strategy against the cancer stem cell population, leading to tumor abrogation.

Positive Selection of Transcription Factors Is a Prominent Feature of the Evolution of a Plant Pathogenic Genus Originating in the Miocene.

Tests based on the dN/dS statistic are used to identify positive selection of nonsynonymous polymorphisms. Using these tests on alignments of all orthologs from related species can provide insights into which gene categories have been most frequently positively selected. However, longer alignments have more power to detect positive selection, creating a detection bias that could create misleading results from functional enrichment tests. Most studies of positive selection in plant pathogens focus on genes with specific virulence functions, with little emphasis on broader molecular processes. Furthermore, no studies in plant pathogens have accounted for detection bias due to alignment length when performing functional enrichment tests. To address these research gaps, we analyze 12 genomes of the phytopathogenic fungal genus Botrytis, including two sequenced in this study. To establish a temporal context, we estimated fossil-calibrated divergence times for the genus. We find that Botrytis likely originated 16-18 Ma in the Miocene and underwent continuous radiation ending in the Pliocene. An untargeted scan of Botrytis single-copy orthologs for positive selection with three different statistical tests uncovered evidence for positive selection among proteases, signaling proteins, CAZymes, and secreted proteins. There was also a strong overrepresentation of transcription factors among positively selected genes. This overrepresentation was still apparent after two complementary controls for detection bias due to sequence length. Positively selected sites were depleted within DNA-binding domains, suggesting changes in transcriptional responses to internal and external cues or protein-protein interactions have undergone positive selection more frequently than changes in promoter fidelity.

Elevated Asparagine Biosynthesis Drives Brain Tumor Stem Cell Metabolic Plasticity and Resistance to Oxidative Stress.

Asparagine synthetase (ASNS) is a gene on the long arm of chromosome 7 that is copy-number amplified in the majority of glioblastomas. ASNS copy-number amplification is associated with a significantly decreased survival. Using patient-derived glioma stem cells (GSC), we showed that significant metabolic alterations occur in gliomas when perturbing the expression of ASNS, which is not merely restricted to amino acid homeostasis. ASNS-high GSCs maintained a slower basal metabolic profile yet readily shifted to a greatly increased capacity for glycolysis and oxidative phosphorylation when needed. This led ASNS-high cells to a greater ability to proliferate and spread into brain tissue. Finally, we demonstrate that these changes confer resistance to cellular stress, notably oxidative stress, through adaptive redox homeostasis that led to radiotherapy resistance. Furthermore, ASNS overexpression led to modifications of the one-carbon metabolism to promote a more antioxidant tumor environment revealing a metabolic vulnerability that may be therapeutically exploited. IMPLICATIONS: This study reveals a new role for ASNS in metabolic control and redox homeostasis in glioma stem cells and proposes a new treatment strategy that attempts to exploit one vulnerable metabolic node within the larger multilayered tumor network.

Impacts of fludioxonil resistance on global gene expression in the necrotrophic fungal plant pathogen Sclerotinia sclerotiorum.

BACKGROUND: The fungicide fludioxonil over-stimulates the fungal response to osmotic stress, leading to over-accumulation of glycerol and hyphal swelling and bursting. Fludioxonil-resistant fungal strains that are null-mutants for osmotic stress response genes are easily generated through continual sub-culturing on sub-lethal fungicide doses. Using this approach combined with RNA sequencing, we aimed to characterise the effects of mutations in osmotic stress response genes on the transcriptional profile of the important agricultural pathogen Sclerotinia sclerotiorum under standard laboratory conditions. Our objective was to understand the impact of disruption of the osmotic stress response on the global transcriptional regulatory network in an important agricultural pathogen. RESULTS: We generated two fludioxonil-resistant S. sclerotiorum strains, which exhibited growth defects and hypersensitivity to osmotic stressors. Both had missense mutations in the homologue of the Neurospora crassa osmosensing two component histidine kinase gene OS1, and one had a disruptive in-frame deletion in a non-associated gene. RNA sequencing showed that both strains together differentially expressed 269 genes relative to the parent during growth in liquid broth. Of these, 185 (69%) were differentially expressed in both strains in the same direction, indicating similar effects of the different point mutations in OS1 on the transcriptome. Among these genes were numerous transmembrane transporters and secondary metabolite biosynthetic genes. CONCLUSIONS: Our study is an initial investigation into the kinds of processes regulated through the osmotic stress pathway in S. sclerotiorum. It highlights a possible link between secondary metabolism and osmotic stress signalling, which could be followed up in future studies.

CD133 mRNA-Loaded Dendritic Cell Vaccination Abrogates Glioma Stem Cell Propagation in Humanized Glioblastoma Mouse Model.

Cancer stem cells are initiating cells of cancer and propagate its growth through self-renewal and differentiation of its daughter cells. CD133 is a cell surface antigen that is present on glioma stem cells and has been used to prospectively isolate glioma stem cells. We hypothesized that a major histocompatibility complex (MHC)-independent and long-lasting immune response against CD133 could be generated by transfecting CD133 mRNA into dendritic cells and vaccinating animals with experimental gliomas. To test this hypothesis, we developed a novel humanized mouse model using CD34-positive hematopoietic stem cells. We confirmed the robust simultaneous activation of CD8- and CD4-positive T cells by dendritic cell vaccination with modified CD133 mRNA leading to a potent and long-lived immune response, with subsequent abrogation of CD133-positive glioma stem cell propagation and tumor growth. This study for the first time demonstrates in both a humanized mouse model and in a syngeneic mouse model of glioblastoma that targeting a glioma stem cell-associated antigen is an effective strategy to target and kill glioma stem cells. This novel and simple humanized mouse model for immunotherapy is a significant advance in our ability to test human-specific immunotherapies for glioblastoma.

A Long-Term Time Series of Dinophysis acuminata Blooms and Associated Shellfish Toxin Contamination in Port Underwood, Marlborough Sounds, New Zealand.

Blooms of the dinoflagellate Dinophysis acuminata occur every year in an important mussel cultivation area in Port Underwood, Marlborough Sounds, New Zealand. Annual maximum cell numbers range from 1500⁻75,000 cells L-1 and over 25 years of weekly monitoring the D. acuminata bloom has never failed to exhibit peaks in abundance at some time between spring and autumn. During winter (June⁻August) the dinoflagellate is often undetectable, or at low levels (≤100 cells L-1), and the risk of diarrhetic shellfish poisoning (DSP)-toxin contamination over this period is negligible. Bloom occurrence may be coupled to the abundance of D. acuminata prey (Mesodinium sp.) but the mechanism by which it maintains its long-term residence in this hydrologically dynamic environment is unknown. The toxin profile of D. acuminata is dominated by pectenotoxin-2 (PTX-2) and dinophysistoxin-1 (DTX-1), but the cellular toxin content is low. It is rare that free DTX-1 is detected in mussels as this is invariably exclusively present as fatty acid-esters. In only five out of >2500 mussel samples over 16 years have the levels of total DTX-1 marginally exceeded the regulated level of 0.16 mg kg-1. It is also rare that free PTX-2 is detected in mussels, as it is generally only present in its hydrolysed non-toxic PTX-2 seco acid form. The D. acuminata alert level of 1000 cells L-1 is often exceeded without DTX-1 residues increasing appreciably, and this level is considered too conservative.

Is sleep position associated with glenohumeral shoulder pain and rotator cuff tendinopathy: a cross-sectional study.

BACKGROUND: Glenohumeral pain and rotator cuff tendinopathy (RCT) are common musculoskeletal complaints with high prevalence among working populations. The primary proposed pathophysiologic mechanisms are sub-acromial RC tendon impingement and reduced tendon blood flow. Some sleep postures may increase subacromial pressure, potentially contributing to these postulated mechanisms. This study uses a large population of workers to investigate whether there is an association between preferred sleeping position and prevalence of: (1) shoulder pain, and (2) rotator cuff tendinopathy. METHODS: A cross-sectional analysis was performed on baseline data from a multicenter prospective cohort study. Participants were 761 workers who were evaluated by questionnaire using a body diagram to determine the presence of glenohumeral pain within 30 days prior to enrollment. The questionnaire also assessed primary and secondary preferred sleep position(s) using 6 labeled diagrams. All workers underwent a structured physical examination to determine whether RCT was present. For this study, the case definition of RCT was glenohumeral pain plus at least one of a positive supraspinatus test, painful arc and/or Neer's test. Prevalence of glenohumeral pain and RCT were individually calculated for the primary and secondary sleep postures and odds ratios were calculated. RESULTS: Age, sex, Framingham cardiovascular risk score and BMI had significant associations with glenohumeral pain. For rotator cuff tendinopathy, increasing age, Framingham risk score and Hand Activity Level (HAL) showed significant associations. The sleep position anticipated to have the highest risk of glenohumeral pain and RCT was paradoxically associated with a decreased prevalence of glenohumeral pain and also trended toward being protective for RCT. Multivariable logistic regression showed no further significant associations. CONCLUSION: This cross-sectional study unexpectedly found a reduced association between one sleep posture and glenohumeral pain. This cross-sectional study may be potentially confounded, by participants who are prone to glenohumeral pain and RCT may have learned to avoid sleeping in the predisposing position. Longitudinal studies are needed to further evaluate a possible association between glenohumeral pain or RCT and sleep posture as a potential risk factor.

Physical activity level and body composition in a multiethnic sample of school children in Hawaii.

BACKGROUND: Obesity, particularly in Native Hawaiians, is an important health risk. A possible contributing factor to obesity is reduced physical activity levels. AIM: This study investigates the relationship between measured levels of physical activity and body composition in two grade cohorts of school children of Native Hawaiian/Pacific Islander (NHPI) and non-NHPI ethnicity. METHODS: A sample of 105 Kindergarteners and third graders were measured for adiposity, physical fitness, and physical activity levels. Ethnicity was determined from genealogical surveys. BMI, waist circumference (WC) and body fat percentage derived from air displacement plethysmography were used to evaluate adiposity. Maximal oxygen consumption (VO2max/kg) was estimated and total energy expenditure (TEE), physical activity level (PAL) and percentage of time inactive (PTI) were determined using the Flex-heart rate method. RESULTS: VO2max, but not TEE, PAL or PTI, was significantly correlated with BMI in Kindergarteners; while VO2max and PAL were negatively correlated with BMI, PAL was significantly negatively correlated with WC and PTI was positively correlated with fat percentage among third graders. There were no significant ethnic differences in VO2max, TEE, PAL or PTI. CONCLUSIONS: PAL and PTI are moderately related to adiposity measures, and there are no ethnic differences in physical activity or fitness measures in this sample.

The Curious Case of ZEB1.

The Zinc Finger E-box binding homeobox (ZEB1/TCF8 or DeltaEF1) is at the forefront of transcription factors involved in controlling epithelial-to-mesenchymal transitions (EMT). Essentially, EMT allows for the reorganization of epithelial cells to become migratory cells with a mesenchymal phenotype.  In addition to ZEB1 being involved in embryonic development, ZEB1 has also been linked to processes involving micro-RNAs, long non-coding RNAs and stem cells. In recent years there has been an accumulation of evidence with regard to ZEB1 in various cancers. Although increased ZEB1 expression has largely been associated with EMT, cancer invasion, and tumorigenicity, there have been some episodic reports that have gone against the traditional reporting of the role of ZEB1. Indicating that the function of ZEB1 and the mechanisms by which ZEB1 facilitates its activities is more complex than was once appreciated. This complexity is further exacerbated by the notion that ZEB1 can act not only as a transcriptional repressor but a transcriptional activator as well. This review seeks to shed light on the complexity of ZEB1 with respect to cancer.

ZEB1 Is a Transcription Factor That Is Prognostic and Predictive in Diffuse Gliomas.

Objective: To address the unmet medical need to better prognosticate patients with diffuse gliomas and to predict responses to chemotherapy regimens. Methods: ZEB1 alterations were retrospectively identified from a cohort of 1,160 diffuse glioma patients. Epigenome-wide association scans (EWAS) were performed on available data. We determined the utility of ZEB1 as a prognostic indicator of patient survival in diffuse gliomas and assessed the value of ZEB1 to predict the efficacy of treating diffuse glioma patients with procarbazine, CCNU, and vincristine along with radiation at diagnosis. Decision curve analysis (DCA) was used to determine if ZEB1 added benefit to clinical decision-making over and above conventional methods. Results: Fifteen percent of diffuse glioma patients had a ZEB1 deletion. ZEB1 deletion was associated with poor overall survival (OS) with and without adjustment for age and tumor grade (adjusted HR: 4.25; 95% CI: 2.35 to 7.66; P < 0.001). Decision curve analysis confirmed that ZEB1 status with or without IDH1 was more beneficial to clinical decision making than conventional information such as age and tumor grade. We showed that ZEB1 regulates TERT expression, and patients with ZEB1 deletions likely subsume patients with mutant TERT expression in diffuse gliomas. ZEB1 influenced clinical decision making to initiate procarbazine, CCNU, and vincristine treatment. Conclusion: We demonstrate the prognostic value of ZEB1 in diffuse glioma patients. We further determine ZEB1 to be a vital and influential molecular marker in clinical decisions that exceed conventional methods regarding whether to treat or not treat patients with diffuse glioma.

ZEB1 regulates glioma stemness through LIF repression.

The identification of a stem cell regulatory gene which is aberrantly expressed in glioma and associated with patient survival would increase the understanding of the role of glioma cancer stem cells (GCSCs) in the virulence of gliomas. Interrogating the genomes of over 4000 brain cancers we identified ZEB1 deletion in ~15% (grade II and III) and 50% of glioblastomas. Meta-analysis of ZEB1 copy number status in 2,988 cases of glioma revealed disruptive ZEB1 deletions associated with decreased survival. We identified ZEB1 binding sites within the LIF (stemness factor) promoter region, and demonstrate LIF repression by ZEB1. ZEB1 knockdown in GCSCs caused LIF induction commensurate with GCSC self-renewal and inhibition of differentiation. IFN-γ treatment to GCSCs induced ZEB1 expression, attenuating LIF activities. These findings implicate ZEB1 as a stem cell regulator in glioma which when deleted leads to increased stemness, tumorigenicity and shortened patient survival.

Discussion of "Representation of People's Decisions in Health Information Systems: A Complementary Approach for Understanding Health Care Systems and Population Health".

This article is part of a For-Discussion-Section of Methods of Information in Medicine about the paper "Representation of People's Decisions in Health Information Systems: A Complementary Approach for Understanding Health Care Systems and Population Health" written by Fernan Gonzalez Bernaldo de Quiros, Adriana Ruth Dawidowski, and Silvana Figar. It is introduced by an editorial. This article contains the combined commentaries invited to independently comment on the paper of de Quiros, Dawidowski, and Figar. In subsequent issues the discussion can continue through letters to the editor.

The Draft Genome Sequence of the Yersinia entomophaga Entomopathogenic Type Strain MH96T.

Here we report the draft genome of Yersinia entomophaga type strain MH96T. The genome shows 93.8% nucleotide sequence identity to that of Yersinia nurmii type strain APN3a-cT, and comprises a single chromosome of approximately 4,275,531 bp. In silico analysis identified that, in addition to the previously documented Y. entomophaga Yen-TC gene cluster, the genome encodes a diverse array of toxins, including two type III secretion systems, and five rhs-associated gene clusters. As well as these multicomponent systems, several orthologs of known insect toxins, such as VIP2 toxin and the binary toxin PirAB, and distant orthologs of some mammalian toxins, including repeats-in-toxin, a cytolethal distending toxin, hemolysin-like genes and an adenylate cyclase were identified. The genome also contains a large number of hypothetical proteins and orthologs of known effector proteins, such as LopT, as well as genes encoding a wide range of proteolytic determinants, including metalloproteases and pathogen fitness determinants, such as genes involved in iron metabolism. The bioinformatic data derived from the current in silico analysis, along with previous information on the pathobiology of Y. entomophaga against its insect hosts, suggests that a number of these virulence systems are required for survival in the hemocoel and incapacitation of the insect host.