Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Interaction of Ras Binding Domain (RBD) by chemotherapeutic zinc oxide nanoparticles: Progress towards RAS pathway protein interference.

Zinc oxide (ZnO) NP is considered as a nanoscale chemotherapeutic. Thus, the drug delivery of this inorganic NP is of considerable importance. Ras mutations are common in cancer and the activation of this signaling pathway is a hallmark in carcinoma, melanoma and many other aggressive malignancies. Thus, here we examined the binding and delivery of Ras binding domain (RBD), a model cancer-relevant protein and effector of Ras by ZnO NP. Shifts in zeta potential in water, PBS, DMEM and DMEM supplemented with FBS supported NP interaction to RBD. Fluorescence quenching of the NP was concentration-dependent for RBD, Stern-Volmer analysis of this data was used to estimate binding strength which was significant for ZnO-RBD (Kd 50%) zone of killing as shown by light and fluorescence microscopy after intra-vital staining. ZnO 100 nm was superior to ZnO 14 nm in terms of anticancer activity. When bound to ZnO NP, the anticancer activity of RBD was enhanced. These data indicate the potential diagnostic application or therapeutic activity of RBD-NP complexes in vivo which demands further investigation

Delivering Therapeutics to Glioblastoma: Overcoming Biological Constraints

Glioblastoma multiforme is the most lethal intrinsic brain tumor. Even with the existing treatment regimen of surgery, radiation, and chemotherapy, the median survival time is only 15–23 months. The invasive nature of this tumor makes its complete removal very difficult, leading to a high recurrence rate of over 90%. Drug delivery to glioblastoma is challenging because of the molecular and cellular heterogeneity of the tumor, its infiltrative nature, and the blood–brain barrier. Understanding the critical characteristics that restrict drug delivery to the tumor is necessary to develop platforms for the enhanced delivery of effective treatments. In this review, we address the impact of tumor invasion, the molecular and cellular heterogeneity of the tumor, and the blood–brain barrier on the delivery and distribution of drugs using potential therapeutic delivery options such as convection-enhanced delivery, controlled release systems, nanomaterial systems, peptide-based systems, and focused ultrasound

Image_1_Efficacy of Chlorine, Chlorine Dioxide, and Peroxyacetic Acid in Reducing Salmonella Contamination in Wash Water and on Mangoes Under Simulated Mango Packinghouse Washing Operations.pdf

<p>Salmonellosis associated with consumption of mangoes have been traced back to the use of contaminated wash water. This highlights the critical role of wash water disinfection in mango processing, affecting its quality, and safety. Moreover, steps unique to the post-harvest handling of mangoes also create a conducive environment for internalization of pathogens into the fruit pulp. Currently, no effective treatment exists to eliminate internalized pathogens from mangoes. Therefore, it is critical to prevent contamination on the fruit to avert pathogen internalization. So the present study evaluated the efficacy of chlorine (200 ppm), peroxyacetic acid (80 ppm), and chlorine dioxide (5 ppm) for reducing Salmonella populations on mangoes and in wash water under simulated mango packing house conditions. Nalidixic-acid resistant isolates of Salmonella Montevideo, S. Newport, S. Baildon, S. Braenderup, and S. Poona were used in this study. Disinfectants were added to inoculated wash water (ca. 7 log CFU/ml) and mangoes (var. Atualfo and Tommy Atkins) were washed under simulated dump tank wash (24°C for 2 min), hot water treatment (46°C for 75 and 110 min), and hydrocooling conditions (21°C for 30 min). Wash water and mangoes were collected at different times for microbiological analysis. Additionally, residual disinfectant concentration was monitored throughout the study. All the three disinfectant tested were effective in significantly reducing Salmonella populations in wash water and on mangoes during dump tank wash, hot water treatment, and hydrocooling (p ≤ 0.05). Specifically, no Salmonella was detected from samples treated with 200 ppm chlorine and 80 ppm PAA. On the other hand, Salmonella was consistently recovered from mango and water samples treated with chlorine dioxide (5 ppm). This reduced antimicrobial efficacy can be attributed to the sharp decline in residual chlorine dioxide concentrations in wash water. Further, reductions in residual chlorine and PAA concentrations were also observed over time. Therefore, to ensure the sustained antimicrobial activity of chlorine and PAA, it is critical to regularly monitor and replenish the disinfectant in wash water. However, given the laboratory scale of these experiments, further validation of these results on a commercial scale are warranted.</p

Image_2_Efficacy of Chlorine, Chlorine Dioxide, and Peroxyacetic Acid in Reducing Salmonella Contamination in Wash Water and on Mangoes Under Simulated Mango Packinghouse Washing Operations.pdf

<p>Salmonellosis associated with consumption of mangoes have been traced back to the use of contaminated wash water. This highlights the critical role of wash water disinfection in mango processing, affecting its quality, and safety. Moreover, steps unique to the post-harvest handling of mangoes also create a conducive environment for internalization of pathogens into the fruit pulp. Currently, no effective treatment exists to eliminate internalized pathogens from mangoes. Therefore, it is critical to prevent contamination on the fruit to avert pathogen internalization. So the present study evaluated the efficacy of chlorine (200 ppm), peroxyacetic acid (80 ppm), and chlorine dioxide (5 ppm) for reducing Salmonella populations on mangoes and in wash water under simulated mango packing house conditions. Nalidixic-acid resistant isolates of Salmonella Montevideo, S. Newport, S. Baildon, S. Braenderup, and S. Poona were used in this study. Disinfectants were added to inoculated wash water (ca. 7 log CFU/ml) and mangoes (var. Atualfo and Tommy Atkins) were washed under simulated dump tank wash (24°C for 2 min), hot water treatment (46°C for 75 and 110 min), and hydrocooling conditions (21°C for 30 min). Wash water and mangoes were collected at different times for microbiological analysis. Additionally, residual disinfectant concentration was monitored throughout the study. All the three disinfectant tested were effective in significantly reducing Salmonella populations in wash water and on mangoes during dump tank wash, hot water treatment, and hydrocooling (p ≤ 0.05). Specifically, no Salmonella was detected from samples treated with 200 ppm chlorine and 80 ppm PAA. On the other hand, Salmonella was consistently recovered from mango and water samples treated with chlorine dioxide (5 ppm). This reduced antimicrobial efficacy can be attributed to the sharp decline in residual chlorine dioxide concentrations in wash water. Further, reductions in residual chlorine and PAA concentrations were also observed over time. Therefore, to ensure the sustained antimicrobial activity of chlorine and PAA, it is critical to regularly monitor and replenish the disinfectant in wash water. However, given the laboratory scale of these experiments, further validation of these results on a commercial scale are warranted.</p

Image_3_Efficacy of Chlorine, Chlorine Dioxide, and Peroxyacetic Acid in Reducing Salmonella Contamination in Wash Water and on Mangoes Under Simulated Mango Packinghouse Washing Operations.pdf

<p>Salmonellosis associated with consumption of mangoes have been traced back to the use of contaminated wash water. This highlights the critical role of wash water disinfection in mango processing, affecting its quality, and safety. Moreover, steps unique to the post-harvest handling of mangoes also create a conducive environment for internalization of pathogens into the fruit pulp. Currently, no effective treatment exists to eliminate internalized pathogens from mangoes. Therefore, it is critical to prevent contamination on the fruit to avert pathogen internalization. So the present study evaluated the efficacy of chlorine (200 ppm), peroxyacetic acid (80 ppm), and chlorine dioxide (5 ppm) for reducing Salmonella populations on mangoes and in wash water under simulated mango packing house conditions. Nalidixic-acid resistant isolates of Salmonella Montevideo, S. Newport, S. Baildon, S. Braenderup, and S. Poona were used in this study. Disinfectants were added to inoculated wash water (ca. 7 log CFU/ml) and mangoes (var. Atualfo and Tommy Atkins) were washed under simulated dump tank wash (24°C for 2 min), hot water treatment (46°C for 75 and 110 min), and hydrocooling conditions (21°C for 30 min). Wash water and mangoes were collected at different times for microbiological analysis. Additionally, residual disinfectant concentration was monitored throughout the study. All the three disinfectant tested were effective in significantly reducing Salmonella populations in wash water and on mangoes during dump tank wash, hot water treatment, and hydrocooling (p ≤ 0.05). Specifically, no Salmonella was detected from samples treated with 200 ppm chlorine and 80 ppm PAA. On the other hand, Salmonella was consistently recovered from mango and water samples treated with chlorine dioxide (5 ppm). This reduced antimicrobial efficacy can be attributed to the sharp decline in residual chlorine dioxide concentrations in wash water. Further, reductions in residual chlorine and PAA concentrations were also observed over time. Therefore, to ensure the sustained antimicrobial activity of chlorine and PAA, it is critical to regularly monitor and replenish the disinfectant in wash water. However, given the laboratory scale of these experiments, further validation of these results on a commercial scale are warranted.</p

Polygenic risk scores for prediction of breast cancer and breast cancer subtypes

Abstract Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs