Is 6-Shogaol a Beneficial Phytochemical for Patients with Lower-Risk Myelodysplastic Syndrome? A Narrative Review

Myelodysplastic syndrome (MDS) evolves due to genomic instability, dysregulated signalling pathway and overproduction of inflammatory markers. Reactive oxygen species contribute to the inflammatory response, which causes gene damage, cellular remodelling and fibrosis. MDS can be a debilitating condition, and management options in patients with MDS aim to improve cytopenias, delay disease progression, and enhance quality of life. High serum ferritin levels, a source of iron for reactive oxygen species production, correlate with a higher risk of progression to acute myeloid leukaemia, and iron overload is compounded by blood transfusions given to improve anaemia. 6-shogaol is a natural phenolic compound formed when ginger is exposed to heat and/or acidic conditions, and it has been shown to possess anti-tumour activity against leukaemia cell lines and antioxidant effects. This narrative review assessed the potential benefits of this phytochemical in lower-risk MDS patients through examining the current evidence on the pharmacological and therapeutic properties of ginger and 6-shogaol.

Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition

The characterization of germline genetic variation affecting cancer risk, known as cancer predisposition, is fundamental to preventive and personalized medicine. Studies of genetic cancer predisposition typically identify significant genomic regions based on family-based cohorts or genome-wide association studies (GWAS). However, the results of such studies rarely provide biological insight or functional interpretation. In this study, we conducted a comprehensive analysis of cancer predisposition in the UK Biobank cohort using a new gene-based method for detecting protein-coding genes that are functionally interpretable. Specifically, we conducted proteome-wide association studies (PWAS) to identify genetic associations mediated by alterations to protein function. With PWAS, we identified 110 significant gene-cancer associations in 70 unique genomic regions across nine cancer types and pan-cancer. In 48 of the 110 PWAS associations (44%), estimated gene damage is associated with reduced rather than elevated cancer risk, suggesting a protective effect. Together with standard GWAS, we implicated 145 unique genomic loci with cancer risk. While most of these genomic regions are supported by external evidence, our results also highlight many novel loci. Based on the capacity of PWAS to detect non-additive genetic effects, we found that 46% of the PWAS-significant cancer regions exhibited exclusive recessive inheritance. These results highlight the importance of recessive genetic effects, without relying on familial studies. Finally, we show that many of the detected genes exert substantial cancer risk in the studied cohort determined by a quantitative functional description, suggesting their relevance for diagnosis and genetic consulting.

The interaction effects of FEN1 rs174538 polymorphism and polycyclic aromatic hydrocarbons exposure on damage in exon 19 and 21 of EGFR gene in coke oven workers

Mutagenesis is a multifactor process associated with increased risk of cancer. Polycyclic aromatic hydrocarbons (PAHs) exposure and genetic susceptibility were conductive to genotoxic effects including gene damage, which can increase mutational probability and are potential carcinogenic etiology. We aimed to explore the dose-effect associations of PAHs exposure with damage of exons of epidermal growth factor receptor (EGFR) and breast cancer susceptibility gene 1 (BRCA1), as well as their associations whether modified by Flap endonuclease 1 (FEN1) genotype. 288 coke oven male workers were recruited and we detected the concentration of 1-hydroxypyrene (1-OH-pyr) as PAHs exposure biomarker in urine and examined base modification in exons of EGFR and BRCA1 respectively, and genotyped FEN1 rs174538 polymorphism in plasma by PCR methods. Compared to low exposure group, the high exposed workers had significantly higher urinary concentrations of 1-OH-pyr, after adjustment for multiple covariates (P < 0.001). We found that the damage index of exon 19 and 21 of EGFR (EGFR-19 and EGFR-21) were both significantly associated with increased urinary 1-OH-pyr (both Ptrend < 0.001). The multiple linear regression analysis showed that the levels of urinary 1-OH-pyr were both significantly associated with increased EGFR-19 and EGFR-21 in both smokers and nonsmokers (both P < 0.001). Additionally, we observed that the urinary 1-OH-pyr concentrations were both linearly associated with EGFR-19 and EGFR-21 only in rs174538 GA + AA genotype carriers (both P < 0.001). Moreover, FEN1rs rs174538 showed modifying effects on the associations of urinary 1-OH-pyr with EGFR-19 and EGFR-21 (both Pinteraction< 0.05). Our findings revealed the linear dose-effect association between exon damage of EGFR and PAHs exposure and highlight differences in genetic contributions to exon damage and have the potential to identify at-risk subpopulations who are susceptible to adverse health effects induced by PAH exposure.

SARS-CoV-2 disinfection in aqueous solution by UV222 from a krypton chlorine excilamp

ABSTRACTThere is an urgent need for evidence-based development and implementation of engineering controls to reduce transmission of SARS-CoV-2, the etiological agent of COVID-19. Ultraviolet (UV) light can inactivate coronaviruses, but the practicality of UV light as an engineering control in public spaces is limited by the hazardous nature of conventional UV lamps, which are Mercury (Hg)-based and emit a peak wavelength (254 nm) that penetrates human skin and is carcinogenic. Recent advances in the development and production of Krypton Chlorine (KrCl) excimer lamps hold promise in this regard, as these emit a shorter peak wavelength (222 nm) and are recently being produced to filter out emission above 240 nm. However, the disinfection kinetics of KrCl UV excimer lamps against SARS-CoV-2 are unknown. Here we provide the first dose response report for SARS-CoV-2 exposed to a commercial filtered KrCl excimer light source emitting primarily 222 nm UV light (UV222), using multiple assays of SARS-CoV-2 viability. Plaque infectivity assays demonstrate the pseudo-first order rate constant of SARS-CoV-2 reduction of infectivity to host cells to be 0.64 cm2/mJ (R2 = 0.95), which equates to a D90 (dose for 1 log10 or 90% inactivation) of 1.6 mJ/cm2. Through RT-qPCR assays targeting the nucleocapsid (N) gene with a short (<100 bp) and long (∼1000 bp) amplicon in samples immediately after UV222 exposure, the reduction of ability to amplify indicated an approximately 10% contribution of N gene damage to disinfection kinetics. Through ELISA assay targeting the N protein in samples immediately after UV222 exposure, we found no dose response of the ability to damage the N protein. In both qPCR assays and the ELISA assay of viral outgrowth supernatants collected 3 days after incubation of untreated and UV222 treated SARS-CoV-2, molecular damage rate constants were similar, but lower than disinfection rate constants. These data provide quantitative evidence for UV222 doses required to disinfect SARS-CoV-2 in aqueous solution that can be used to develop further understanding of disinfection in air, and to inform decisions about implementing UV222 for preventing transmission of COVID19.ABSTRACT ART / TOC GRAPHIC

CompoundHetVIP: Compound Heterozygous Variant Identification Pipeline

Compound Heterozygous (CH) variant identification requires distinguishing maternally from paternally derived nucleotides, a process that requires numerous computational tools. Using such tools often introduces unforeseen challenges such as installation procedures that are operating-system specific, software dependencies that must be installed, and formatting requirements for input files. To overcome these challenges, we developed Compound Heterozygous Variant Identification Pipeline (CompoundHetVIP), which uses a single Docker image to encapsulate commonly used software tools for file aggregation (BCFtools or GATK4), VCF liftover (Picard Tools), joint-genotyping (GATK4), file conversion (Plink2), phasing (SHAPEIT2, Beagle, and/or Eagle2), variant normalization (vt tools), annotation (SnpEff), relational database generation (GEMINI), and identification of CH, homozygous alternate, and de novo variants in a series of 13 steps. To begin using our tool, researchers need only install the Docker engine and download the CompoundHetVIP Docker image. The tools provided in CompoundHetVIP, subject to the limitations of the underlying software, can be applied to whole-genome, whole-exome, or targeted exome sequencing data of individual samples or trios (a child and both parents), using VCF or gVCF files as initial input. Each step of the pipeline produces an analysis-ready output file that can be further evaluated. To illustrate its use, we applied CompoundHetVIP to data from a publicly available Ashkenazim trio and identified two genes with a candidate CH variant and two genes with a candidate homozygous alternate variant after filtering based on user-set thresholds for global minor allele frequency, Combined Annotation Dependent Depletion, and Gene Damage Index. While this example uses genomic data from a healthy child, we anticipate that most researchers will use CompoundHetVIP to uncover missing heritability in human diseases and other phenotypes. CompoundHetVIP is open-source software and can be found at https://github.com/dmiller903/CompoundHetVIP; this repository also provides detailed, step-by-step examples.

Is 6-Shogaol an Effective Phytochemical for Patients With Lower-risk Myelodysplastic Syndrome? A Narrative Review

Myelodysplastic syndrome (MDS) evolves due to genomic instability, dysregulated signaling pathways, and overproduction of inflammatory markers. Reactive oxygen species contribute to the inflammatory response, which causes gene damage, cellular remodeling, and fibrosis. MDS can be a debilitating condition, and management options in patients with MDS aim to improve cytopenias, delay disease progression, and enhance quality of life. High serum ferritin levels, a source of iron for reactive oxygen species production, correlate with a higher risk of progression to acute myeloid leukemia, and iron overload is compounded by blood transfusions given to improve anemia. 6-shogaol is a natural phenolic compound formed when ginger is exposed to heat and/or acidic conditions, and it has been shown to possess anti-tumor activity against leukemia cell lines and antioxidant effects. This narrative review assessed the potential benefits of this phytochemical in lower-risk MDS patients through examining the current evidence on the pharmacological and therapeutic properties of ginger and 6-shogaol.

DDB2 Genetic Risk Factor for Ocular Squamous Cell Carcinoma Identified in Three Additional Horse Breeds

Squamous cell carcinoma (SCC) is the most common cancer affecting the equine eye. A missense variant within the gene damage-specific DNA binding protein 2 (DDB2 c.1013C>T, p.Thr338Met) was previously identified as a causal recessive genetic risk factor for the development of ocular SCC within Haflingers, Belgian Draft horses, and Rocky Mountain Horses, but not in the Appaloosa or Arabian breeds. This study aimed to evaluate three cases of ocular SCC in additional breeds and determine if DNA testing for the DDB2 variant in warmblood horses and Connemara ponies is warranted. Histopathology confirmed ocular SCC in all three cases and DNA testing confirmed each horse was homozygous for the DDB2 risk factor. The DDB2 risk allele frequency was estimated to be 0.0043 for Holsteiners (N = 115), 0.014 for Belgian Warmbloods (N = 71), and 0.22 for Connemara Ponies (N = 86). Taken together these data support using DNA testing for DDB2 in Connemara Ponies to assist in mate selection and clinical management. Given the low observed allele frequencies in both the Holsteiner and Belgian Warmblood breeds and that the case under investigation was a warmblood cross-bred, evaluating additional SCC affected warmbloods is warranted to fully determine the importance of DDB2 genotyping as a risk factor in warmblood breeds.

Natural Products: Implication in Cancer Prevention and Treatment through Modulating Various Biological Activities

Cancer is one of the most leading causes of death worldwide. It is one of the primary global diseases that cause morbidity and mortality in millions of people. It is usually caused by different carcinogenic agents that damage the genetic material and alter the cell signaling pathways. Carcinogens are classified into two groups as genotoxic and non-genotoxic agents. Genotoxic carcinogens are capable of directly altering the genetic material, while the non-genotoxic carcinogens are capable of producing cancer by some secondary mechanisms not related to direct gene damage. There is undoubtedly the greatest need to utilize some novel natural products as anticancer agents, as these are within reach everywhere. Interventions by some natural products aimed at decreasing the levels and conditions of these risk factors can reduce the frequency of cancer incidences. Cancer is conventionally treated by surgery, radiation therapy and chemotherapy, but such treatments may be fast-acting and causes adverse effects on normal tissues. Alternative and innovative methods of cancer treatment with the least side effects and improved efficiency are being encouraged. In this review, we discuss the different risk factors of cancer development, conventional and innovative strategies of its management and provide a brief review of the most recognized natural products used as anticancer agents globally.

Toxic effects of dechlorane plus on the common carp (Cyprinus carpio) embryonic development

Dechlorane Plus (DP) is a widely using chlorinated flame retardant, and has been detected extensively in the environment. Even though the DP content in the surface water is low, it can pose a continuous exposure risk to aquatic organisms due to its strong bioaccumulation. Since related researches on the toxicity mechanism of DP exposure on carp embryo development are limited, we carried out the evaluation of DP effect on carp. In this study, Carp embryos were exposed to DP of 0, 30, 60, and 120 µg/L at 3h post fertilization (hpf). The expression of genes associated with the neural and skeletal development such as sox2, sox19a, Mef2c, and BMP4 were evaluated using quantitative PCR (qPCR), and analysis of different developmental toxicity endpoints changes were observed with microscopy. Our results demonstrated that the expression of sox2, sox19a, Mef2c, and BMP4 were significantly changed and several developmental defects were observed in the exposed carps embryo, such as DNA damage, increased mortality rate, delayed hatching time, decreased hatching rate, decreased body length, increased morphological deformities. In addition, reactive oxygen species (ROS) and malondialdehyde (MDA) were significantly increased with DP exposure at 60µg/L and 120 µg/L. Altogether, our results suggest that DP may have an unique modes of action, which results in aberration occurrence in the early development stage of common carps, that may relates to some gene damage and oxidative stress. Besides, the parameters evaluated here can be used as tools to access the environmental risk for biota and humans exposed to DP.

Oxidative Stress and the Kidney in the Space Environment

In space, the special conditions of hypogravity and exposure to cosmic radiation have substantial differences compared to terrestrial circumstances, and a multidimensional impact on the human body and human organ functions. Cosmic radiation provokes cellular and gene damage, and the generation of reactive oxygen species (ROS), leading to a dysregulation in the oxidants–antioxidants balance, and to the inflammatory response. Other practical factors contributing to these dysregulations in space environment include increased bone resorption, impaired anabolic response, and even difficulties in detecting oxidative stress in blood and urine samples. Enhanced oxidative stress affects mitochondrial and endothelial functions, contributes to reduced natriuresis and the development of hypertension, and may play an additive role in the formation of kidney stones. Finally, the composition of urine protein excretion is significantly altered, depicting possible tubular dysfunction.