Programmed knockout mutation of liver fluke granulin attenuates virulence of infection-induced hepatobiliary morbidity

Infection with the food-borne liver fluke Opisthorchis viverrini is the principal risk factor (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2012) for cholangiocarcinoma (CCA) in the Lower Mekong River Basin countries including Thailand, Lao PDR, Vietnam and Cambodia. We exploited this link to explore the role of the secreted growth factor termed liver fluke granulin (Ov-GRN-1) in pre-malignant lesions by undertaking programmed CRISPR/Cas9 knockout of the Ov-GRN-1 gene from the liver fluke genome. Deep sequencing of amplicon libraries from genomic DNA of gene-edited parasites revealed Cas9-catalyzed mutations within Ov-GRN-1. Gene editing resulted in rapid depletion of Ov-GRN-1 transcripts and the encoded Ov-GRN-1 protein. Gene-edited parasites colonized the biliary tract of hamsters and developed into adult flukes, but the infection resulted in reduced pathology as evidenced by attenuated biliary hyperplasia and fibrosis. Not only does this report pioneer programmed gene-editing in parasitic flatworms, but also the striking, clinically-relevant pathophysiological phenotype confirms the role for Ov-GRN-1 in virulence morbidity during opisthorchiasis.

Download Full-text

Rapid evaluation of FDG imaging alternatives using head-to-head comparisons of full ring and gamma camera based PET scanners –

Nuklearmedizin ◽

10.1055/s-0038-1625288 ◽

2002 ◽

Vol 41 (05) ◽

pp. 208-213 ◽

Cited By ~ 1

Author(s):

L. M. Haslinghuis-Bajan ◽

L. Hooft ◽

A. van Lingen ◽

M. van Tulder ◽

W. Devillé ◽

...

Keyword(s):

Methodological Quality ◽

Gamma Camera ◽

First Generation ◽

Prospective Evaluation ◽

First Approximation ◽

Variable Head ◽

Malignant Lesions ◽

The Impact ◽

Pet Scanners

SummaryAim: While FDG full ring PET (FRPET) has been gradually accepted in oncology, the role of the cheaper gamma camera based alternatives (GCPET) is less clear. Since technology is evolving rapidly, “tracker trials” would be most helpful to provide a first approximation of the relative merits of these alternatives. As difference in scanner sensitivity is the key variable, head-to-head comparison with FRPET is an attractive study design. This systematic review summarises such studies. Methods: Nine studies were identified until July 1, 2000. Two observers assessed the methodological quality (Cochrane criteria), and extracted data. Results: The studies comprised a variety of tumours and indications. The reported GC- and FRPET agreement for detection of malignant lesions ranged from 55 to 100%, but with methodological limitations (blinding, standardisation, limited patient spectrum). Mean lesion diameter was 2.9 cm (SD 1.8), with only about 20% <1.5 cm. The 3 studies with the highest quality reported concordances of 74-79%, for the studied lesion spectrum. Contrast at GCPET was lower than that of FRPET, contrast and detection agreement were positively related. Logistic regression analysis suggested that pre-test indicators might be used to predict FRPET-GCPET concordance. Conclusion: In spite of methodological limitations, “first generation” GCPET devices detected sufficient FRPET positive lesions to allow prospective evaluation in clinical situations where the impact of FRPET is not confined to detection of small lesions (<1.5 cm). The efficiency of head-to-head comparative studies would benefit from application in a clinically relevant patient spectrum, with proper blinding and standardisation of acquisition procedures.

Download Full-text

The soluble glutathione transferase superfamily: role of Mu class in triclabendazole sulphoxide challenge in Fasciola hepatica

Parasitology Research ◽

10.1007/s00436-021-07055-5 ◽

2021 ◽

Vol 120 (3) ◽

pp. 979-991

Author(s):

Rebekah B. Stuart ◽

Suzanne Zwaanswijk ◽

Neil D. MacKintosh ◽

Boontarikaan Witikornkul ◽

Peter M. Brophy ◽

...

Keyword(s):

In Vitro Culture ◽

Liver Fluke ◽

Glutathione Transferase ◽

Fasciola Hepatica ◽

Affinity Purification ◽

Economic Loss ◽

Differential Abundance ◽

Parasitic Helminths

AbstractFasciola hepatica (liver fluke), a significant threat to food security, causes global economic loss for the livestock industry and is re-emerging as a foodborne disease of humans. In the absence of vaccines, treatment control is by anthelmintics; with only triclabendazole (TCBZ) currently effective against all stages of F. hepatica in livestock and humans. There is widespread resistance to TCBZ and its detoxification by flukes might contribute to the mechanism. However, there is limited phase I capacity in adult parasitic helminths with the phase II detoxification system dominated by the soluble glutathione transferase (GST) superfamily. Previous proteomic studies have demonstrated that the levels of Mu class GST from pooled F. hepatica parasites respond under TCBZ-sulphoxide (TCBZ-SO) challenge during in vitro culture ex-host. We have extended this finding by exploiting a sub-proteomic lead strategy to measure the change in the total soluble GST profile (GST-ome) of individual TCBZ-susceptible F. hepatica on TCBZ-SO-exposure in vitro culture. TCBZ-SO exposure demonstrated differential abundance of FhGST-Mu29 and FhGST-Mu26 following affinity purification using both GSH and S-hexyl GSH affinity. Furthermore, a low or weak affinity matrix interacting Mu class GST (FhGST-Mu5) has been identified and recombinantly expressed and represents a new low-affinity Mu class GST. Low-affinity GST isoforms within the GST-ome was not restricted to FhGST-Mu5 with a second likely low-affinity sigma class GST (FhGST-S2) uncovered. This study represents the most complete Fasciola GST-ome generated to date and has supported the potential of subproteomic analyses on individual adult flukes.

Download Full-text

112 How Will the Purebred Association Adapt to a Changing Beef Industry?

Journal of Animal Science ◽

10.1093/jas/skab054.068 ◽

2021 ◽

Vol 99 (Supplement_1) ◽

pp. 39-39

Author(s):

Mark McCully

Keyword(s):

Supply Chains ◽

Genetic Information ◽

Gene Editing ◽

Value Added ◽

Beef Industry ◽

Breed Improvement ◽

Pull Through ◽

Optimum Production ◽

Selection Tools

Abstract The role of the breed association has historically been to keep a registry of a pure breed, aggregate the performance data surrounding that one breed, develop breeding and selection tools, and conduct breed promotion. Larger associations have been able to augment that with operating magazines and other media, running branded beef programs, feeder calf marketing programs, and genetic evaluation for other breeds. The relevance of breed associations is being and will continue to be challenged as genomics and large commercial databases develop and allow for breeding and selection tools to be developed independently by large breeders or private entities. Gene editing and other such technology will also challenge the traditional seedstock models and opens the door for proprietary genetic lines. Breed associations may need to modify their traditional policies to incorporate these innovations. Supply chains will continue to become far more sophisticated and will incorporate more genetic information to guide management decisions and potentially validate brand promises around sustainability. To stay relevant, breed associations of the future will need to do the following: Balance the needs of diverse membership (show, hobby, lifestyle, etc.) with commercial industry value and significance. Have access to large amounts of data and be leaders in adopting the most current technologies. Deliver tools for breeders that enhance the profitability of commercial producers – identify optimum production levels vs maximum outputs. Work collaboratively with multiple supply chains providing the needed genetic information. Be a significant educational resource to breeders and commercial producers. Be a leader in research on breed improvement and genetic advancement. Have value-added programs that create real and sustained pull-through demand for the end product.

Download Full-text

Cancer Stem Cells Are Possible Key Players in Regulating Anti-Tumor Immune Responses: The Role of Immunomodulating Molecules and MicroRNAs

Cancers ◽

10.3390/cancers13071674 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1674

Author(s):

Sara Tomei ◽

Ola Ibnaof ◽

Shilpa Ravindran ◽

Soldano Ferrone ◽

Cristina Maccalli

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Immune Responses ◽

Antigen Processing ◽

Aberrant Expression ◽

Immunological Profile ◽

Malignant Lesions ◽

Novel Therapeutic Strategies ◽

Antigen Processing And Presentation

Cancer cells endowed with stemness properties and representing a rare population of cells within malignant lesions have been isolated from tumors with different histological origins. These cells, denominated as cancer stem cells (CSCs) or cancer initiating cells (CICs), are responsible for tumor initiation, progression and resistance to therapies, including immunotherapy. The dynamic crosstalk of CSCs/CICs with the tumor microenvironment orchestrates their fate and plasticity as well as their immunogenicity. CSCs/CICs, as observed in multiple studies, display either the aberrant expression of immunomodulatory molecules or suboptimal levels of molecules involved in antigen processing and presentation, leading to immune evasion. MicroRNAs (miRNAs) that can regulate either stemness properties or their immunological profile, with in some cases dual functions, can provide insights into these mechanisms and possible interventions to develop novel therapeutic strategies targeting CSCs/CICs and reverting their immunogenicity. In this review, we provide an overview of the immunoregulatory features of CSCs/CICs including miRNA profiles involved in the regulation of the interplay between stemness and immunological properties.

Download Full-text

A Statewide Assessment of the Role of Norwalk Virus in Outbreaks of Food-Borne Gastroenteritis

The Journal of Infectious Diseases ◽

10.1093/infdis/151.3.568 ◽

1985 ◽

Vol 151 (3) ◽

pp. 568-568 ◽

Cited By ~ 21

Author(s):

J. N. Kuritsky ◽

M. T. Osterholm ◽

J. A. Korlath ◽

K. E. White ◽

J. E. Kaplan

Keyword(s):

Norwalk Virus ◽

Food Borne ◽

Statewide Assessment

Download Full-text

Role of diffusion-weighted magnetic resonance imaging in assessment of mammographically detected asymmetric densities

Egyptian Journal of Radiology and Nuclear Medicine ◽

10.1186/s43055-020-00361-5 ◽

2020 ◽

Vol 51 (1) ◽

Author(s):

Mohamed Zidan ◽

Shimaa Ali Saad ◽

Eman Abo Elhamd ◽

Hosam Eldin Galal ◽

Reem Elkady

Keyword(s):

Positive Predictive Value ◽

Negative Predictive Value ◽

Predictive Value ◽

Benign Lesions ◽

Adc Value ◽

Dce Mri ◽

Diffusion Weighted ◽

Breast Asymmetries ◽

Malignant Lesions

Abstract Background Asymmetric breast density is a potentially perplexing finding; it may be due to normal hormonal variation of the parenchymal pattern and summation artifact or it may indicate an underlying true pathology. The current study aimed to identify the role of diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) values in the assessment of breast asymmetries. Results Fifty breast lesions were detected corresponding to the mammographic asymmetry. There were 35 (70%) benign lesions and 15 (30%) malignant lesions. The mean ADC value was 1.59 ± 0.4 × 10–3 mm2/s for benign lesions and 0.82 ± 0.3 × 10–3 mm2/s for malignant lesions. The ADC cutoff value to differentiate between benign and malignant lesions was 1.10 × 10–3 mm2/s with sensitivity 80%, specificity 88.6%, positive predictive value 75%, negative predictive value 91%, and accuracy 86%. Best results were achieved by implementation of the combined DCE-MRI and DWI protocol, with sensitivity 93.3%, specificity 94.3%, positive predictive value 87.5%, negative predictive value 97.1%, and accuracy 94%. Conclusion Dynamic contrast-enhanced MRI (DCE-MRI) was the most sensitive method for the detection of the underlying malignant pathology of breast asymmetries. However, it provided a limited specificity that may cause improper final BIRADS classification and may increase the unnecessary invasive procedures. DWI was used as an adjunctive method to DCE-MRI that maintained high sensitivity and increased specificity and the overall diagnostic accuracy of breast MRI examination. Best results can be achieved by the combined protocol of DCE-MRI and DWI.

Download Full-text

C/EBPα Is Critical for the Neonatal Acute-Phase Response to Inflammation

Molecular and Cellular Biology ◽

10.1128/mcb.18.12.7269 ◽

1998 ◽

Vol 18 (12) ◽

pp. 7269-7277 ◽

Cited By ~ 52

Author(s):

Bonnie L. Burgess-Beusse ◽

Gretchen J. Darlington

Keyword(s):

Dna Binding ◽

Acute Phase ◽

Acute Phase Response ◽

Northern Blot Analysis ◽

Protein Gene ◽

Phase Response ◽

Wild Type ◽

Neonatal Mice ◽

Enhancer Binding Protein

ABSTRACT Members of the C/EBP (CCAAT/enhancer binding protein) family of transcription factors play important roles in mediating the acute-phase response (APR), an inflammatory process resulting from infection and/or tissue damage. Among the C/EBP family of proteins, C/EBPβ and -δ were thought to be the primary mediators of the APR. The function of C/EBPα in the APR has not been fully characterized to date. Here, we investigate the role of C/EBPα in the APR by using neonatal mice that lack C/EBPα expression. Northern blot analysis of acute-phase protein gene expression in neonatal mice treated with purified bacterial lipopolysaccharide or recombinant interleukin 1β as an inflammation stimulus showed a strong APR in wild-type mice, but a response in C/EBPα null animals was completely lacking. The C/EBPα knockout and wild-type mice demonstrated elevations in C/EBPβ and -δ mRNA expression and DNA binding as well as increased DNA binding of NF-κB, all of which are known to be important in the APR. Null mice, however, failed to activate STAT3 binding in response to lipopolysaccharide. Our results provide the first evidence that C/EBPα is absolutely required for the APR in neonatal mice, is involved in STAT3 regulation, and cannot be compensated for by other C/EBP family members.

Download Full-text

Taxonomic revisions of Altigena laticeps and A. lippa (Cyprinidae: Labeoninae) from the Mekong River Basin

Zootaxa ◽

10.11646/zootaxa.4941.2.7 ◽

2021 ◽

Vol 4941 (2) ◽

pp. 271-280

Author(s):

PATRICK J. CICCOTTO ◽

FENG LIN ◽

XIAO-YONG CHEN

Keyword(s):

River Basin ◽

Lateral Line ◽

Lao Pdr ◽

Junior Synonym ◽

Mekong River ◽

Type Material ◽

Mekong River Basin

Altigena laticeps, previously considered a junior synonym of A. lippa, is revalidated and re-described based on morphological examinations of type and non-type material. This species, found in the Upper Mekong River basin in China, can be distinguished from A. lippa based on higher numbers of lateral-line scales (40–42 vs. 34–39), predorsal scales (14–16 vs. 9–12), and circumpeduncular scales (20 vs. 16). Altigena lippa, from the Lower Mekong River basin in Lao PDR, Myanmar, Thailand, and Vietnam is also re-described. Four species of Altigena are herein recognized in the Mekong River basin: A. elegans, A. laticeps, A. lippa, and A. yunnanensis.

Download Full-text

Let Us Assume That Gene Editing is Safe—The Role of Safety Arguments in the Gene Editing Debate

Cambridge Quarterly of Healthcare Ethics ◽

10.1017/s0963180118000439 ◽

2018 ◽

Vol 28 (1) ◽

pp. 100-111 ◽

Cited By ~ 3

Author(s):

SØREN HOLM

Keyword(s):

Gene Editing ◽

Legal Principle ◽

Rhetorical Function ◽

Made In

Abstract:This paper provides an analysis of the statement, made in many papers and reports on the use of gene editing in humans, that we should only use the technology when it is safe. It provides an analysis of what the statement means in the context of nonreproductive and reproductive gene editing and argues that the statement is inconsistent with the philosophical commitments of some of the authors, who put it forward in relation to reproductive uses of gene editing, specifically their commitment to Parfitian nonidentity considerations and to a legal principle of reproductive liberty.But, if that is true it raises a question about why the statement is made. What is its discursive and rhetorical function? Five functions are suggested, some of which are more contentious and problematic than others. It is argued that it is possible, perhaps even likely, that the “only when it is safe” rider is part of a deliberate obfuscation aimed at hiding the full implications of the arguments made about the ethics of gene editing and their underlying philosophical justifications.

Download Full-text