Animal and vegetal materials of mouse oocytes segregate at first zygotic cleavage: a simple mechanism that makes the 2-cell blastomeres differ reciprocally from the start.

Recent advances in embryology have shown that the sister blastomeres of 2-cell mouse and human embryos differ reciprocally in potency. An open question is whether the blastomeres became different as opposed to originating as different. Here we wanted to test two conflicting models: one proposing that each blastomere contains both animal and vegetal materials in balanced proportions because the plane of first cleavage runs close to the animal-vegetal axis of the fertilized oocyte; and the other model proposing that each blastomere contains variable proportions of animal and vegetal materials because the plane of the first cleavage can vary depending on the topology of fertilization.

Characterization of an Uncommon Finding in the Basal Nuclei in Beagle Dogs: A Novel Potential Background Lesion in the Canine Brain.

Degenerative lesions specific to the basal nuclei have not been described as a background finding in Beagle dogs. This report comprises a documentation of seven cases. In the context of a nonclinical safety studies, the authors suggest documenting the lesion descriptively as as it is characterized by (1) vacuolation, neuropil; (2) gliosis (astro- and/or microgliosis); and (3) demyelination.

ICH S1 prospective evaluation study and weight of evidence assessments: commentary from industry representatives.

Industry representatives on the ICH S1B(R1) Expert Working Group (EWG) worked closely with colleagues from the Drug Regulatory Authorities to develop an addendum to the ICH S1B guideline on carcinogenicity studies that allows for a weight-of-evidence (WoE) carcinogenicity assessment in some cases, rather than conducting a 2-year rat carcinogenicity study. A subgroup of the EWG composed of regulators have published in this issue a detailed analysis of the Prospective Evaluation Study (PES) conducted under the auspices of the ICH S1B(R1) EWG. Based on the experience gained through the Prospective Evaluation Study (PES) process, industry members of the EWG have prepared the following commentary to aid sponsors in assessing the standard WoE factors, considering how novel investigative approaches may be used to support a WoE assessment, and preparing appropriate documentation of the WoE assessment for presentation to regulatory authorities.

A Minimal Approach to Demonstrate Concordance of Digital and Conventional Microscopy in Toxicologic Pathology.

Digitalization of pathology workflows has undergone a rapid evolution and has been widely established in the diagnostic field but remains a challenge in the nonclinical safety context due to lack of regulatory guidance and validation experience for good laboratory practice (GLP) use. One means to demonstrate that digital slides are fit for purpose, that is, provide sufficient quality for pathologists to reach a diagnosis, is conduction of comparison studies, which have been published both, for veterinary and human diagnostic pathology, but not for toxicologic pathology. Here, we present an approach that uses study material from nonclinical safety studies and that allows for the statistical comparison of concordance rates for glass and digital slide evaluation while minimizing time and effort for the involved personnel.

Intracellular fraction of zona pellucida protein 3 is required for the oocyte-to-embryo transition in mice.

In oocyte biology, the zona pellucida has long been known to operate three extracellular functions downstream of the secretory pathway, namely, encasing the oocytes in ovarian follicles, mediating sperm-oocyte interaction, and preventing premature embryo contact with oviductal epithelium. The present study uncovers a fourth function that is fundamentally distinct from the other three, being critical for embryonic cell survival in mice. Intriguingly, the three proteins of the mouse zona pellucida (ZP1, ZP2, ZP3) were found abundantly present also inside the embryo 4 days after fertilization, as shown by mass spectrometry, immunoblotting, and immunofluorescence.

Evaluation of Pharmacobezoar Formation from Suspensions of Spray-Dried Amorphous Solid Dispersions: An MRI Study in Rats.

Spray-dried amorphous solid dispersions of new chemical entities and pH-dependent soluble polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were found to form solid agglomerates in the gastrointestinal tract of rodents after oral administration. These agglomerates, referring to descriptions of intra-gastrointestinal aggregated oral dosage forms termed pharmacobezoars, represent a potential risk for animal welfare. Previously, we introduced an in vitro model to assess the agglomeration potential of amorphous solid dispersions from suspensions and how it can be reduced.

An In Vitro Model to Investigate the Potential of Solid Dispersions to Form Pharmacobezoars.

The formation of pharmacobezoars from suspensions of spray-dried amorphous solid dispersions (SD-ASDs) of new chemical entities (NCEs) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) represents a non-compound related adverse effect in preclinical oral toxicity studies in rodents. Whereas the contribution of the insolubility of the carrier polymer to this process taking place in the acidic environment of the rodent stomach is conclusive, unawareness of the extent of in vivo pharmacobezoar formation is adverse. In order to evaluate the risk of pharmacobezoar formation before in vivo administration, we subsequently introduce an in vitro model to assess the agglomeration potential of solid dispersions.

Pharmacobezoar Formation From HPMC-AS-Containing Spray-Dried Formulations in Nonclinical Safety Studies in Rats.

Changing the physical state from crystalline to amorphous is an elegant method to increase the bioavailability of poorly soluble new chemical entity (NCE) drug candidates. Subsequently, we report findings from repeat-dose toxicity studies of an NCE formulated as a spray-dried amorphous solid dispersion (SD-ASD) based on hydroxypropyl methylcellulose acetate succinate (HPMC-AS) in rats. At necropsy, agglomerates of SD-ASD were found in the stomach and small intestine, which in reference to literature were termed pharmacobezoars.

Corrigendum: Task Roadmaps: Speeding Up Task Replanning.

[This corrects the article DOI: 10.3389/frobt.2022.

Task Roadmaps: Speeding up Task Replanning.

Modern industrial robots are increasingly deployed in dynamic environments, where unpredictable events are expected to impact the robot's operation. Under these conditions, runtime task replanning is required to avoid failures and unnecessary stops, while keeping up productivity. Task replanning is a long-sighted complement to path replanning, which is mostly concerned with avoiding unexpected obstacles that can lead to potentially unsafe situations.

Quantification of Hepatocellular Mitoses in a Toxicological Study in Rats Using a Convolutional Neural Network.

Convolutional neural networks (CNNs) have been recognized as valuable tools for rapid quantitative analysis of morphological changes in toxicologic histopathology. We have assessed the performance of CNN-based (Halo-AI) mitotic figure detection in hepatocytes in comparison with detection by pathologists. In addition, we compared with Ki-67 and 5-bromodesoxyuridin (BrdU) immunohistochemistry labeling indices (LIs) obtained by image analysis.

The gatekeeper of Yersinia type III secretion is under RNA thermometer control.

Many bacterial pathogens use a type III secretion system (T3SS) as molecular syringe to inject effector proteins into the host cell. In the foodborne pathogen Yersinia pseudotuberculosis, delivery of the secreted effector protein cocktail through the T3SS depends on YopN, a molecular gatekeeper that controls access to the secretion channel from the bacterial cytoplasm. Here, we show that several checkpoints adjust yopN expression to virulence conditions.

The prospective GermanVasc cohort study.

Previous observational studies reported a wide variation and possible room for improvement in the treatment of patients suffering from symptomatic peripheral artery disease (PAD). Yet, systematic assessment of everyday clinical practice is lacking. A General Data Protection Regulation (GDPR) compliant registry was developed and used to collect comprehensive data on clinical treatment and outcomes regarding PAD in Germany.

Proceedings of the 2020 Classic Examples in Toxicologic Pathology XXVII.

The histopathology slide seminar "Classic Examples in Toxicologic Pathology XXVII" was held on February 21 and 22, 2020, at the Department of Pathology at the University of Veterinary Medicine in Hannover, Germany, with joint organization by the European Society of Toxicologic Pathology. The goal of this annual seminar is to present and discuss classical and actual cases of toxicologic pathology. This article summarizes the presentations given during the seminar, including images of representative lesions.

Long-term outcomes of the Ovation Stent Graft System investigational device exemption trial for endovascular abdominal aortic aneurysm repair.

Objective: The objective of this study was to report the 5-year outcomes of the Food and Drug Administration investigational device exemption clinical trial of endovascular aneurysm repair (EVAR) with the Ovation stent graft (Endologix, Irvine, Calif) for elective treatment of abdominal aortic aneurysm (AAA).

Methods: The study comprised 161 patients who underwent EVAR as part of the prospective, international, multicenter pivotal Ovation stent graft trial. The main inclusion criteria were AAA diameter ≥5 cm, proximal neck length ≥7 mm, neck angulation ≤60 degrees, and bilateral iliac fixation length ≥10 mm.

Cross-sectional study on viraemia and shedding of porcine circovirus type 2 in a subclinically infected multiplier sow herd.

Vertical and horizontal transmission of porcine circovirus type 2 (PCV2) plays an important role for the spread of PCV2 within piglet-producing farms and following production steps. Further information is crucial to learn about the principles of PCV2 circulation among sows in piglet-producing farms to improve preventive healthcare concerning porcine circovirus diseases (PCVD) in downstream production steps. The present study was conducted as a cross-sectional study in a 400 sow multiplier herd in Germany with no PCV2 vaccination.

Best Practice Approach for Assessment of Microchip-associated Tumors in Preclinical Safety Studies: Position of the Registry of Industrial Toxicology Animal-data (RITA).

Microchip (passive radio-frequency identification device) implantation is a common and widely employed means of animal identification in laboratory animal facilities. However, these devices have been associated with tumors of the skin and subcutis in rodents. While microchip-associated tumors are rare, they pose a challenge for accurate diagnosis and documentation in preclinical toxicity studies.

Self-Expanding Versus Balloon-Expandable Stents for Iliac Artery Occlusive Disease: The Randomized ICE Trial.

Objectives: Atherosclerosis of iliac arteries is widespread. As inflow vessels, they are of great clinical significance and increasingly being treated by endovascular means. Most commonly, stents are implanted.

Proceedings of the 2016 National Toxicology Program Satellite Symposium.

The 2016 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri" was held in San Diego, CA, at the Society of Toxicologic Pathology's (STP) 35th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks, along with select images that were used by the audience for voting and discussion.

Women and men derive comparable benefits from an ultra-low-profile endograft: 1-year results of the European OVATION registry.

Background: Female patients are underrepresented in most stent-graft (EVAR) trials due to a reduced anatomical eligibility for endovascular treatment. The purpose of this analysis was to determine the performance of the Ovation® and Ovation Prime® stent graft in women versus men for elective abdominal aortic aneurysm (AAA) repair.

Methods: From May 2011 to December 2013, 501 patients (86% men, mean age 73 years) from 30 sites were prospectively enrolled in the OVATION Registry and electively treated with endovascular aneurysm repair.

Nonproliferative and Proliferative Lesions of the Gastrointestinal Tract, Pancreas and Salivary Glands of the Rat and Mouse.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature and diagnostic criteria for nonproliferative and proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and diagnostic criteria for classifying lesions in the digestive system including the salivary glands and the exocrine pancreas of laboratory rats and mice. Most lesions are illustrated by color photomicrographs.

Recommendations from the INHAND Apoptosis/Necrosis Working Group.

Historically, there has been confusion relating to the diagnostic nomenclature for individual cell death. Toxicologic pathologists have generally used the terms "single cell necrosis" and "apoptosis" interchangeably. Increased research on the mechanisms of cell death in recent years has led to the understanding that apoptosis and necrosis involve different cellular pathways and that these differences can have important implications when considering overall mechanisms of toxicity, and, for these reasons, the separate terms of apoptosis and necrosis should be used whenever differentiation is possible.

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) progress to date and future plans.

The INHAND Proposal (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) has been operational since 2005. A Global Editorial Steering Committee (GESC) manages the overall objectives of the project and the development of harmonized terminology for each organ system is the responsibility of the Organ Working Groups (OWG), drawing upon experts from North America, Europe and Japan.Great progress has been made with 9 systems published to date - Respiratory, Hepatobiliary, Urinary, Central/Peripheral Nervous Systems, Male Reproductive and Mammary, Zymbals, Clitoral and Preputial Glands in Toxicologic Pathology and the Integument and Soft Tissue and Female Reproductive System in the Journal of Toxicologic Pathology as supplements and on a web site - www.