itor Title: Varicella zoster virus reactivation antedating ipsilateral brainstem stroke Authors: Giuliana Galassi1, Maurilio Genovese2, Marisa Meacci3, Marcella Malagoli2 Affiliations: 1Department of Biomedical, Metabolic, Neural Sciences, University Hospital of Modena, Italy, 2Neuroradiology Service, University Hospital of Modena, Italy, 3Department of Laboratory Medicine and Patholgy, Microbiology and Virology Unit, University Hospital of Modena, Italy Corresponding Author: Giuliana Galassi, MD, Department of Biomedical, Metabolic, Neural Sciences, University Hospital of Modena, Via P. Giardini 1455, Modena, Italy, Tel: 39-3497325802, Email: [email protected] Abstract: Varicella zoster virus (VZV) infection and reactivation are associated with a number of neurologic conditions. Unifocal large vessel infarcts may follow zoster in the trigeminal or cervical distribution as a result of transaxonal transport of virus from trigeminal or cervical afferent fibers that innervate vessels. Ophthalmic zoster (HZO) might cause ophthalmoplegic syndromes, with secondary optic neuritis. Mechanisms include local orbital muscle inflammation and, viral spread from the ophthalmic branch of the fifth nerve with associated vasculopathy. A 72-year-old man developed a vesicular rash in the territory of C5-T5-6. Within four weeks, the patient developed headache, dysphagia, left facial and extremity ataxic weakness. Magnetic resonance imaging (MRI) revealed a right pontine infarction. A 66-year-old woman presented with right-sided painfull HZO. One week later she developed complete external ophthalmoplegia and blurred vision. MRI showed ill-defined signal alteration in the retrobulbar tissue. Three weeks later, the patient was admitted because of dysarthria, deviated tongue, left-sided limb weakness, and tactile hypoesthesia. Spinal fluid contained 23 lymphocytes/mm3 and increased protein. The serum contained antibodies to VZV IgG and IgM in both cases. The patients received intravenously acyclovir with improvement. This report confirms unusual occurrence of ipsilateral brainstem stroke after VZV reactivation in immunocompetent subjects.

Leukemia is the most frequent malignant disease affecting children. To date, the etiology of childhood leukemia remains largely unknown. Few risk factors (genetic susceptibility, infections, ionizing radiation, etc.) have been clearly identified, but they appear to explain only a small proportion of cases. Considerably more uncertain is the role of other environmental risk factors, such as indoor and outdoor air pollution. We sought to summarize and quantify the association between traffic-related air pollution and risk of childhood leukemia, and further examined results according to method of exposure assessment, study quality, leukemia subtype, time period, and continent where studies took place. After a literature search yielded 6 ecologic and 20 case-control studies, we scored the studies based on the Newcastle-Ottawa Scale. The studies assessed residential exposure to pollutants from motorized traffic by computing traffic density in the neighboring roads or vicinity to petrol stations, or by using measured or modeled nitrogen dioxide and benzene outdoor air levels. Because heterogeneity across studies was observed, random-effects summary odds ratios (OR) and 95% confidence intervals (CI) were reported. Whenever possible we additionally conducted stratified analyses comparing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Limiting the analysis to high-quality studies (Newcastle-Ottawa Scale ≥ 7), those using traffic density as the exposure assessment metric showed an increase in childhood leukemia risk in the highest exposure category (OR = 1.07, 95% CI 0.93-1.24). However, we observed evidence of publication bias. Results for NO2 exposure and benzene showed an OR of 1.21 (95% CI 0.97-1.52) and 1.64 (95% CI 0.91-2.95) respectively. When stratifying by leukemia type, the results based upon NO2 were 1.21 (95% CI 1.04-1.41) for ALL and 1.06 (95% CI 0.51-2.21) for AML; based upon benzene were 1.09 (95% CI 0.67-1.77) for ALL and 2.28 (95% CI 1.09-4.75) for AML. Estimates were generally higher for exposures in the postnatal period compared to the prenatal period, and for European studies compared to North American studies. Overall, our results support a link between ambient exposure to traffic pollution and childhood leukemia risk, particularly due to benzene.

Scientific opinion on the relationship between selenium and the risk of cancer has undergone radical change over the years, with selenium first viewed as a possible carcinogen in the 1940s then as a possible cancer preventive agent in the 1960s-2000s. More recently, randomized controlled trials have found no effect on cancer risk but suggest possible low-dose dermatologic and endocrine toxicity, and animal studies indicate both carcinogenic and cancer-preventive effects. A growing body of evidence from human and laboratory studies indicates dramatically different biological effects of the various inorganic and organic chemical forms of selenium, which may explain apparent inconsistencies across studies. These chemical form-specific effects also have important implications for exposure and health risk assessment. Overall, available epidemiologic evidence suggests no cancer preventive effect of increased selenium intake in healthy individuals and possible increased risk of other diseases and disorders.

Background

Exposure to pesticides has been suggested as a risk factor for childhood leukemia, but definitive evidence on this relation and the specific pesticides involved is still not clear.

Objective

We carried out a population-based case-control study in a Northern Italy community to assess the possible relation between passive exposure to agricultural pesticides and risk of acute childhood leukemia.

Methods

We assessed passive pesticide exposure of 111 childhood leukemia cases and 444 matched controls by determining density and type of agricultural land use within a 100-m radius buffer around children's homes. We focused on four common crop types, arable, orchard, vineyard and vegetable, characterized by the use of specific pesticides that are potentially involved in childhood induced leukemia. The use of these pesticides was validated within the present study. We computed the odds ratios (OR) of the disease and their 95% confidence intervals (CI) according to type and density of crops around the children's homes, also taking into account traffic pollution and high-voltage power line magnetic field exposure.

Results

Childhood leukemia risk did not increase in relation with any of the crop types with the exception of arable crops, characterized by the use of 2.4-D, MCPA, glyphosate, dicamba, triazine and cypermethrin. The very few children (n=11) residing close to arable crops had an OR for childhood leukemia of 2.04 (95% CI 0.50-8.35), and such excess risk was further enhanced among children aged <5 years.

Conclusions

Despite the null association with most crop types and the statistical imprecision of the estimates, the increased leukemia risk among children residing close to arable crops indicates the need to further investigate the involvement in disease etiology of passive exposure to herbicides and pyrethroids, though such exposure is unlikely to play a role in the vast majority of cases.

Background. Some observational studies have suggested that excess dietary intake of polyunsaturated fatty acids such as linoleic acid increases cutaneous melanoma risk. We aimed at examining the association between serum fatty acids and melanoma risk by conducting a population-based case-control study in a northern Italy community. Methods. The percentage composition of 12 fatty acids was determined in 51 newly diagnosed melanoma patients and 51 age- and sex-matched population controls by extracting total lipids from serum samples using thin layer and gas chromatography. Conditional logistic regression was used to estimate the relative risk of melanoma associated with tertiles of percentage composition of each fatty acid as well as groupings including saturated, monounsaturated, and polyunsaturated fatty acids. Results. We found a slightly increased melanoma risk for stearic and arachidic acids proportion, with and without adjustment for potential confounders. For an n-3 polyunsaturated fatty acid, docosapentaenoic acid, we found a male-specific direct association with melanoma risk. No other associations emerged for the other saturated, monounsaturated, and polyunsaturated fatty acids, individually or grouped by type. Conclusions. These findings do not suggest a major role of fatty acids, including linoleic acid, on risk of cutaneous melanoma, though their evaluation is limited by the small sample size.

A few studies have suggested an association between maternal exposure to ambient air pollution from vehicular traffic and risk of congenital anomalies in the offspring, but epidemiologic evidence is neither strong nor entirely consistent. In a population-based case-control study in a Northern Italy community encompassing 228 cases of birth defects and 228 referent newborns, we investigated if maternal exposure to PM10 and benzene from vehicular traffic during early pregnancy, as estimated through a dispersion model, was associated with excess teratogenic risk. In conditional logistic regression analysis, and with adjustment for the other pollutant, we found that higher exposure to PM10 but not benzene was associated with increased risk of birth defects overall. Anomaly categories showing the strongest dose-response relation with PM10 exposure were musculoskeletal and chromosomal abnormalities but not cardiovascular defects, with Down syndrome being among the specific abnormalities showing the strongest association, though risk estimates particularly for the less frequent defects were statistically very unstable. Further adjustment in the regression model for potential confounders did not considerably alter the results. All the associations were stronger for average levels of PM10 than for their maximal level. Findings of this study give some support for an excess teratogenic risk following maternal exposure during pregnancy to PM10, but not benzene. Such association appears to be limited to some birth defect categories.

Background

Therapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative G0 state, which is difficult to capture and whose mutational drivers remain largely unknown.

Results

We develop methodology to robustly identify this state from transcriptomic signals and characterise its prevalence and genomic constraints in solid primary tumours. We show that G0 arrest preferentially emerges in the context of more stable, less mutated genomes which maintain TP53 integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We employ machine learning to uncover novel genomic dependencies of this process and validate the role of the centrosomal gene CEP89 as a modulator of proliferation and G0 arrest capacity. Lastly, we demonstrate that G0 arrest underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single-cell data.

Conclusions

We propose a G0 arrest transcriptional signature that is linked with therapeutic resistance and can be used to further study and clinically track this state.

Abstract Background TOP2A encodes for topoisomerase IIα, a nuclear enzyme that controls DNA topological structure and cell cycle progression. This enzyme is a marker of cell proliferation in normal and neoplastic tissues; however, little information is available about its expression in prostate cancer (PCa). Methods Immunohistochemistry (IHC) was automated using mouse monoclonal antibody against TOP2A (clone SWT3D1; DAKO, Carpenteria, CA, USA) at dilution 1:800 and Flex Plus detection system in autostainer 48Ultra (DAKO). FISH was performed using TOP2A (17q21)/ CEP17 probe kit (Kreateck Biotechnology, San Diego, CA, USA). Biochemical and pathological data from 193 patients with PCa were retrieved for the analysis, whose significance was considered when p < 0.05. Also, fractal analysis was performed in a subset of 20 randomly selected cases. Results TOP2A protein expression correlated with higher Gleason scores and higher levels of preoperative PSA (p = 0.018 and p = 0.011). Patients with higher levels of TOP2A presented shorter biochemical recurrence-free survival (BRFS) (p = 0.001). In multivariate analysis, we found that TOP2A remained an independent prognostic factor of BRFS, with a relative risk of 1.98 (p = 0.001; 95% CI, 1.338–2.93); thus, cases that expressed high levels of this enzyme had a shorter BRFS compared with TOP2A-negative or TOP2A-low cases. No alterations in TOP2A gene status nor correlation between FISH and IHC results were observed. Concerning fractal analysis, patients who expressed higher levels of TOP2A have angiolymphatic invasion and presented higher Gleason scores (p = 0.033 and p = 0.025, respectively). Also, patients with higher expression of TOP2A presented shorter BRFS (p = 0.001). Conclusions This is the first study to perform TOP2A protein and gene digital assessment and fractal analysis in association with BRFS in a large series of PCa. Also, we show that TOP2A gene copy number alterations are not observed in this type of tumor. So, higher protein expression of TOP2A is not related to gene amplification in PCa. Furthermore, TOP2A protein assessment has prognostic importance and, due to its relation with poor outcome, TOP2A IHC evaluation in the biopsy can represent an important tool for selecting the most suitable surgical and clinical approach for patients with PCa.

We are currently in the midst of the most aggressive and fulminating outbreak of Ebola-related disease, commonly referred to as "Ebola", ever recorded. In less than a year, the Ebola virus (EBOV, Zaire ebolavirus species) has infected over 10,000 people, indiscriminately of gender or age, with a fatality rate of about 50%. Whereas at its onset this Ebola outbreak was limited to three countries in West Africa (Guinea, where it was first reported in late March 2014, Liberia, where it has been most rampant in its capital city, Monrovia and other metropolitan cities, and Sierra Leone), cases were later reported in Nigeria, Mali and Senegal, as well as in Western Europe (i.e., Madrid, Spain) and the US (i.e., Dallas, Texas; New York City) by late October 2014. World and US health agencies declared that the current Ebola virus disease (EVD) outbreak has a strong likelihood of growing exponentially across the world before an effective vaccine, treatment or cure can be developed, tested, validated and distributed widely. In the meantime, the spread of the disease may rapidly evolve from an epidemics to a full-blown pandemic. The scientific and healthcare communities actively research and define an emerging kaleidoscope of knowledge about critical translational research parameters, including the virology of EBOV, the molecular biomarkers of the pathological manifestations of EVD, putative central nervous system involvement in EVD, and the cellular immune surveillance to EBOV, patient-centered anthropological and societal parameters of EVD, as well as translational effectiveness about novel putative patient-targeted vaccine and pharmaceutical interventions, which hold strong promise, if not hope, to curb this and future Ebola outbreaks. This work reviews and discusses the principal known facts about EBOV and EVD, and certain among the most interesting ongoing or future avenues of research in the field, including vaccination programs for the wild animal vectors of the virus and the disease from global translational science perspective.

MicroRNA-31 (miR-31) is overexpressed in esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary Zn deficiency and inflammation. In a Zn deficiency-promoted rat ESCC model with miR-31 up-regulation, cancer-associated inflammation, and a high ESCC burden following N-nitrosomethylbenzylamine (NMBA) exposure, systemic antimiR-31 delivery reduced ESCC incidence from 85 to 45% (P = 0.038) and miR-31 gene knockout abrogated development of ESCC (P = 1 × 10^-6). Transcriptomics, genome sequencing, and metabolomics analyses in these Zn-deficient rats revealed the molecular basis of ESCC abrogation by miR-31 knockout. Our identification of EGLN3, a known negative regulator of nuclear factor κB (NF-κB), as a direct target of miR-31 establishes a functional link between oncomiR-31, tumor suppressor target EGLN3, and up-regulated NF-κB-controlled inflammation signaling. Interaction among oncogenic miR-31, EGLN3 down-regulation, and inflammation was also documented in human ESCCs. miR-31 deletion resulted in suppression of miR-31-associated EGLN3/NF-κB-controlled inflammatory pathways. ESCC-free, Zn-deficient miR-31^-/- rat esophagus displayed no genome instability and limited metabolic activity changes vs. the pronounced mutational burden and ESCC-associated metabolic changes of Zn-deficient wild-type rats. These results provide conclusive evidence that miR-31 expression is necessary for ESCC development.