Children's lead exposure in the U.S.: Application of a national-scale, probabilistic aggregate model with a focus on residential soil and dust lead (Pb) scenarios.

Lead (Pb) exposures from soil and dust ingestion contribute to children's blood lead levels (BLLs) in the United States. The U.S. Environmental Protection Agency (EPA)'s Strategy to Reduce Lead Exposures and Disparities in U.S. Communities and the Federal Action Plan to Reduce Childhood Lead Exposure describe multi-pronged collaborative approaches. These include reducing multi-media lead exposures nationally using analytical tools such as EPA's Stochastic Human Exposure and Dose Simulation model for lead [SHEDS-Pb; formerly known as SHEDS-IEUBK (Integrated Exposure Uptake Biokinetic model)], which was initially developed and applied with a focus on children's drinking water exposures. In this study we applied SHEDS-Pb to determine what residential soil Pb and dust Pb concentrations (individually and their sum) can keep BLLs of potentially exposed young children in the general U.S. population below specified values, considering aggregate exposures from water, soil, dust, food, and air. We considered two age groups (1 to <2 years and 2 to <6 years), two BLL values (5 µg/dL and 3.5 µg/dL), and two population percentiles (95th and 97.5th). Sensitivity analyses were conducted using several alternative model inputs and data sets, yielding 15 scenarios summarized in the paper. Of those scenarios, we focused on ones with the most recent science and available data. Modeled soil Pb concentrations by age group, population percentile and reference BLL scenarios for the focus scenarios ranged from 70 ppm to 220 ppm; and modeled dust Pb concentrations ranged from 110 ppm to 240 ppm. These results are consistent with current soil and dust Pb concentrations in the U.S. general population and are lower than most of the current U.S. Federal standards. Estimated BLLs compared well with measured BLLs from CDC's NHANES 2009-2016 (0-27 % relative error for focus scenarios). This analysis can be used to inform EPA and other federal Pb efforts.

Monitoring EBV infection, MSI, PDL-1 expression, Her-2/neu amplification as a biomarker for PD-1 inhibition in gastric cancer.

BACKGROUND: The anti-PD-1 monoclonal antibody pembrolizumab has been shown to be associated with a good response in patients with metastatic gastric cancer. Excellent therapeutic results of pembrolizumab have been shown in patients with tumours showing a high microsatellite instability (MSI) and Epstein-Barr virus (EBV) positivity. GOAL: This is a retrospective study of 40 bioptic specimens from the patients, who underwent gastrectomy for gastric carcinoma. The goal of the study was to identify biomarkers (EBV, MLH-1, PDL-1 expression) that are potentially relevant for selecting the patients, who may benefit from PD-1 inhibition therapy. METHODS: Immunohistochemical (IHC) expression of PDL-1 and MSI, cytogenetic FISH amplification of the HER-2/neu gene and polymerase chain reaction of EBV RNA, including charge quantification, were performed in selected patients with metastatic or advanced gastric cancer. RESULTS: EBV-encoded RNA was detected in nine patients. None of them exhibited Her-2 overexpression or CMV infection. PD-L1 was detected in twelve patients. Ten patients were MLH1 positive. All nine cases of EBV infection showed a high expression of PD-L1 and MLH-1 (Tab. 1, Ref. 14).

Molecular and IHC analysis of head and neck carcinomas associated with HPV infection.

Head and neck squamous cell carcinomas (HNSCC) are a highly heterogenous disease which can be induced by two main carcinogens - tobacco and/or alcohol, or by HR HPV infection. This work examined 60 paraffin-embedded biopsies of head and neck carcinomas after histological verification. HPV infection, including its specific types in various HNSCC areas, was studied using multiplex qPCR. Expression levels of p16INK4A and p53 were detected by subsequent IHC analysis as being potential diagnostic markers. Based on the assumption that patients with HNSCC could benefit from anti-EGFR therapy (cetuximab), but the predictors are not yet defined, analyses of point mutations of ras genes (Kras, Nras) were carried out using multiplex qPCR and sequence analysis of the Braf gene. All statistical data were processed by Chí-x2 test.HPV infection was detected in 23.34 % of cases with HNSCC, of which 100 % were HPV 16, which is the most frequently infection found in the oropharyngeal region. Using IHC analysis, a positive expression of P16INK4A was detected in 100 % of HPV-positive HNSCC while this expression was discovered to be highly correlated with HPV infection. Furthermore, a correlation between p53 and HPV-negative HNSCC was proved. The mutation incidence was the highest in the Kras gene (codon 12 and codon 146), Nras (codon 12) and Braf. A correlation between tumor location in the oropharyngeal region and Kras mutations was proved. The HPV infection correlated with Kras mutations in case of codon 146 but on the grounds of low amount of output data, these figures could be irrelevant. In one case, c.1808 G>A, protein 603 Arg>Gln mutation was found in the Braf gene but its correlation with head and neck carcinomas has not been described yet (Tab. 2, Fig. 2, Ref. 24). Keywords: head and neck carcinomas, biopsy, HPV types, PCR, p16INK4A, p53, molecular predictors, Kras, Nras, Braf.

Absence of BRAF mutation in pheochromocytoma and paraganglioma.

Pheochromocytomas and Paragangliomas (PHEO/PARA) are rare endocrine tumors originating from the adrenal medulla. More than 20 genes are involved in the tumorigenesis of these tumors, but a substantial part of the causative genetic events remains unexplained. A recent study has reported the presence of the activating BRAF V600E mutation in PCC, suggesting a role for BRAF activation in tumor development. Other studies have not find this mutation. This study investigates the occurrence of the BRAF V600E mutation in these tumors.A cohort of 64 PHEO/PARA were screened for the BRAF V600E mutation using direct Sanger sequencing and QRT-PCR.All cases investigated displayed wild-type without V600E BRAF mutationTaken together with all previously screened tumors up to date, only 1 V600E BRAF mutation has been found among 427 PCCs. These findings imply that the V600E BRAF mutation is a rare event in PHEO/PARA.

Aggressive acute myeloid leukemia in PU.1/p53 double-mutant mice.

PU.1 downregulation within hematopoietic stem and progenitor cells (HSPCs) is the primary mechanism for the development of acute myeloid leukemia (AML) in mice with homozygous deletion of the upstream regulatory element (URE) of PU.1 gene. p53 is a well-known tumor suppressor that is often mutated in human hematologic malignancies including AML and adds to their aggressiveness; however, its genetic deletion does not cause AML in mouse. Deletion of p53 in the PU.1(ure/ure) mice (PU.1(ure/ure)p53(-/-)) results in more aggressive AML with shortened overall survival. PU.1(ure/ure)p53(-/-) progenitors express significantly lower PU.1 levels. In addition to URE deletion we searched for other mechanisms that in the absence of p53 contribute to decreased PU.1 levels in PU.1(ure/ure)p53(-/-) mice. We found involvement of Myb and miR-155 in downregulation of PU.1 in aggressive murine AML. Upon inhibition of either Myb or miR-155 in vitro the AML progenitors restore PU.1 levels and lose leukemic cell growth similarly to PU.1 rescue. The MYB/miR-155/PU.1 axis is a target of p53 and is activated early after p53 loss as indicated by transient p53 knockdown. Furthermore, deregulation of both MYB and miR-155 coupled with PU.1 downregulation was observed in human AML, suggesting that MYB/miR-155/PU.1 mechanism may be involved in the pathogenesis of AML and its aggressiveness characterized by p53 mutation.

Perceptions of underweight images: are women with anorexia nervosa perceived as attractive and healthy?

The current study examined the impact of receiving information about a woman's eating disorder status on perceptions of the woman's health and attractiveness. A total of 99 females and 84 males viewed a photo of a model who had disclosed her diagnosis of anorexia nervosa. Participants were randomly divided into three groups: model (M) group (those who were informed that the photo showed a model), eating disorders (ED) group (those who were informed that the photo showed a woman with an eating disorder), and no description control (C) group. Male and female participants in the ED group rated the woman in the photo as less healthy than did participants in the M and C groups. However, there were no differences between groups for ratings of attractiveness or the participants' desire to achieve a similar look (for females). Additionally, male participants rated the photo as less attractive than female participants had predicted. Finally, internalization of the thin ideal was a significant predictor of ratings of health and attractiveness of the woman in the photo.

Comparison of the IHC, FISH, SISH and qPCR methods for the molecular diagnosis of breast cancer.

Her2 proto-oncogene amplification and protein overexpression is observed in 20-40% of patients with breast cancer and plays a crucial role in invasive breast cancer and its treatment. In the present study, we investigated samples from 131 patients with invasive breast carcinoma. In all cases, the overexpression/amplification level of Her2 was determined using manual immunohistochemistry (IHC) and/or automatic IHC, fluorescence in situ hybridization (FISH), silver in situ hybridization (SISH) and quantitative polymerase chain reaction (qPCR). Using various methods, we demonstrated candidate methods for Her2 detection and their dependability. Our results demonstrate that these methods are highly comparable for the detection of Her2 overexpression/amplification. It was also revealed that qPCR is a valuable tool for the evaluation of Her2 gene overexpression/amplification. The results from pPCR analysis positively correlated with the results from IHC and FISH analysis. Moreover, in contrast to IHC or SISH/FISH, the results obtained by qPCR were not encumbered with any subjective error on the part of the evaluator.

Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories.

Brain-derived neurotrophic factor (BDNF) is known to play a critical role in the synaptic plasticity underlying the acquisition and/or consolidation of certain forms of memory. Additionally, a role has been suggested for neurotrophin function within the hippocampus in protection from anxiety and depressive disorders. Understanding the function of this important gene in adult animals has been limited however, because standard knockouts are confounded by gene effects during development. There are no BDNF receptor-specific pharmacological agents, and infusions of neuropeptides or antibodies have other significant limitations. In these studies, we injected a lentivirus expressing Cre recombinase bilaterally into the dorsal hippocampus in adult mice floxed at the BDNF locus to facilitate the site-specific deletion of the BDNF gene in adult animals. Significant decreases in BDNF mRNA expression are demonstrated in the hippocampi of lenti-Cre-infected animals compared with control lenti-GFP-infected animals. Behaviorally, there were no significant effects of BDNF deletion on locomotion or baseline anxiety measured with startle. In contrast, hippocampal-specific BDNF deletions impair novel object recognition and spatial learning as demonstrated with the Morris water maze. Although there were no effects on the acquisition or expression fear, animals with BDNF deletions show significantly reduced extinction of conditioned fear as measured both with fear-potentiated startle and freezing. These data suggest that the cognitive deficits and impairment in extinction of aversive memory found in depression and anxiety disorders may be directly related to decreased hippocampal BDNF.