Renal Juxtaglomerular Cell Tumors Exhibit Distinct Genomic and Epigenomic Features and Lack Recurrent Gene Fusions: Comprehensive Molecular Analysis of a Multi-institutional Series.

Juxtaglomerular cell tumor (JxGCT) is a rare type of renal neoplasm demonstrating morphologic overlap with some mesenchymal tumors such as glomus tumor (GT) and solitary fibrous tumor (SFT). Its oncogenic drivers remain elusive, and only a few cases have been analyzed with modern molecular techniques. In prior studies, loss of chromosomes 9 and 11 appeared to be recurrent.

Outcome of IWGT workshop on transcriptomic biomarkers for genotoxicity: Key considerations for bioinformatics.

As a part of the International Workshop on Genotoxicity Testing (IWGT) in 2022, a workgroup was formed to evaluate the level of validation and regulatory acceptance of transcriptomic biomarkers that identify genotoxic substances. Several such biomarkers have been developed using various molecular techniques and computational approaches. Within the IWGT workgroup on transcriptomic biomarkers, bioinformatics was a central topic of discussion, focusing on the current approaches used to process the underlying molecular data to distill a reliable predictive signal; that is, a gene set that is indicative of genotoxicity and can then be used in later studies to predict potential DNA damaging properties for uncharacterized chemicals.

A 'Chiron' approach to novel phytosphingosine mimetics based on a cascade [3,3]-sigmatropic rearrangement.

Straightforward access to enantiomerically pure 3,4-diamino-3,4-dideoxyphytosphingosines, as novel analogues of natural d-ribo-phytosphingosine was accomplished, starting from two available chirons: dimethyl l-tartrate and d-isoascorbic acid. A sequential Overman rearrangement followed by late-stage introduction of the alkyl side chain moiety via olefin cross-metathesis is the cornerstone of this approach. The preliminary evaluation study of the synthesised sphingomimetics, based on their ability to inhibit a proliferation of human cancer cells, showed promising cytotoxicity against Jurkat and HeLa cells for (2R,3R,4S)-2,3,4-triaminooctadecan-1-ol trihydrochloride.

The association between histopathologic effects and liver weight changes induced in mice and rats by chemical exposures: an analysis of the data from Toxicity Reference Database (ToxRefDB).

Absolute (ALW) and relative (RLW) liver weight changes are sensitive endpoints in repeat-dose rodent toxicity studies, and their changes are often used for quantitative assessment of health effects induced by hepatotoxic chemicals using the benchmark dose-response modeling (BMD) approach. To find biologically relevant liver weight changes to chemical exposures, we evaluated all data available for liver weight changes and associated liver histopathologic findings from the Toxicity Reference Database (ToxRefDB). Our analysis of 389 subchronic mouse and rat studies for 273 chemicals found significant differences in treatment-related ALW and RLW changes between dose groups with and without liver histopathologic changes.

Homospisulosine induced apoptosis in cervical carcinoma cells is associated with phosphorylation of Bcl-2 and up-regulation of p27/Kip1.

Spisulosine (1-deoxysphinganine) is a sphingoid amino alcohol isolated from the sea clams that showed potent antiproliferative activity against a broad spectrum of solid tumors but failed in clinical trials due to neurotoxicity. However, its structural similarity to other bioactive sphingoids, interesting mode of action, and appreciable potency against cancer cells make it a suitable lead for future anticancer drug development. The present study was conducted to elucidate mechanisms of the antiproliferative/cytotoxic effects of newly synthesized spisulosine analog homospisulosine (KP7).

Ceramides and their roles in programmed cell death.

Programmed cell death plays a crucial role in maintaining the homeostasis and integrity of multicellular organisms, and its dysregulation contributes to the pathogenesis of many diseases. Programmed cell death is regulated by a range of macromolecules and low-molecular messengers, including ceramides. Endogenous ceramides have different functions, that are influenced by their localization and the presence of their target molecules.

Correlating mechanical and gene expression data on the single cell level to investigate metastatic phenotypes.

Stiffness has been observed to decrease for many cancer cell types as their metastatic potential increases. Although cell mechanics and metastatic potential are related, the underlying molecular factors associated with these phenotypes remain unknown. Therefore, we have developed a workflow to measure the mechanical properties and gene expression of single cells that is used to generate large linked-datasets.

The stringency of the containment measures in response to COVID-19 inversely correlates with the overall disease occurrence over the epidemic wave.

Non-pharmaceutical interventions (NPIs) were the only viable choice to mitigate or suppress transmission of COVID-19 in the absence of efficient and safe vaccines. In this study, we examined the association between the stringency of containment measures and cumulative incidence of the COVID-19 cases in the first wave of the pandemic across 28 European countries. Our results support the effectiveness of containment measures in the mitigation or suppression of COVID-19 epidemics.

Breast Milk as Route of Tick-Borne Encephalitis Virus Transmission from Mother to Infant.

Tick-borne encephalitis virus (TBEV) is transmitted mainly by tick bites, but humans can acquire infection through consuming unpasteurized milk from infected animals. Interhuman transmission of TBEV by breast milk has not been confirmed or ruled out. We report a case of probable transmission of TBEV from an unvaccinated mother to an infant through breast-feeding.

Mutation Is Associated with Increased Risk of Adult-Type Ovarian Granulosa Cell Tumors.

Pathogenic germline mutations c.1100delC and p.I157T in the CHEK2 gene have been associated with increased risk of breast, colon, kidney, prostate, and thyroid cancers; however, no associations have yet been identified between these two most common European founder mutations of the CHEK2 gene and ovarian cancers of any type.

Inferred inactivation of the Cftr gene in the duodena of mice exposed to hexavalent chromium (Cr(VI)) in drinking water supports its tumor-suppressor status and implies its potential role in Cr(VI)-induced carcinogenesis of the small intestines.

Carcinogenicity of hexavalent chromium [Cr (VI)] has been supported by a number of epidemiological and animal studies; however, its carcinogenic mode of action is still incompletely understood. To identify mechanisms involved in cancer development, we analyzed gene expression data from duodena of mice exposed to Cr(VI) in drinking water. This analysis included (i) identification of upstream regulatory molecules that are likely responsible for the observed gene expression changes, (ii) identification of annotated gene expression data from public repositories that correlate with gene expression changes in duodena of Cr(VI)-exposed mice, and (iii) identification of hallmark and oncogenic signature gene sets relevant to these data.

Design and synthesis of novel tacrine-indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease.

The authors report on the synthesis and biological evaluation of new compounds whose structure combines tacrine and indole moieties. Tacrine-indole heterodimers were designed to inhibit cholinesterases and β-amyloid formation, and to cross the blood-brain barrier. The most potent new acetylcholinesterase inhibitors were compounds and (IC = 25 and 39 nM, respectively).

Targeted next generation sequencing of MLH1-deficient, MLH1 promoter hypermethylated, and BRAF/RAS-wild-type colorectal adenocarcinomas is effective in detecting tumors with actionable oncogenic gene fusions.

Oncogenic gene fusions represent attractive targets for therapy of cancer. However, the frequency of actionable genomic rearrangements in colorectal cancer (CRC) is very low, and universal screening for these alterations seems to be impractical and costly. To address this problem, several large scale studies retrospectivelly showed that CRC with gene fusions are highly enriched in groups of tumors defined by MLH1 DNA mismatch repair protein deficiency (MLH1d), and hypermethylation of MLH1 promoter (MLH1ph), and/or the presence of microsatellite instability, and BRAF/KRAS wild-type status (BRAFwt/KRASwt).

The sensitivity of transcriptomics BMD modeling to the methods used for microarray data normalization.

Whole-genome expression data generated by microarray studies have shown promise for quantitative human health risk assessment. While numerous approaches have been developed to determine benchmark doses (BMDs) from probeset-level dose responses, sensitivity of the results to methods used for normalization of the data has not yet been systematically investigated. Normalization of microarray data converts raw hybridization signals to expression estimates that are expected to be proportional to the amounts of transcripts in the profiled specimens.

Risk of Alzheimer's Disease in Cancer Patients: Analysis of Mortality Data from the US SEER Population-Based Registries.

Previous studies have reported an inverse association between cancer and Alzheimer's disease (AD), which are leading causes of human morbidity and mortality. We analyzed the SEER (Surveillance, Epidemiology, and End Results) data to estimate the risk of AD death in (i) cancer patients relative to reference populations stratified on demographic and clinical variables, and (ii) female breast cancer (BC) patients treated with chemotherapy or radiotherapy, relative to those with no/unknown treatment status. Our results demonstrate the impact of race, cancer type, age and time since cancer diagnosis on the risk of AD death in cancer patients.

Solitary fibrous tumors of the head and neck region revisited: a single-institution study of 20 cases and review of the literature.

A solitary fibrous tumor (SFT) is a rare, NAB2-STAT6 fusion gene-associated mesenchymal neoplasm. It most commonly arises in the pleural site, but it can occur at many other sites, and rarely also in the head and neck (H&N) region. STFs may show many growth patterns and therefore can be easily mistaken for other more common H&N spindle cell or epithelial lesions.

The use of evidence from high-throughput screening and transcriptomic data in human health risk assessments.

High throughput screening (HTS) and functional genomics (toxicogenomics) have opened new avenues in toxicity testing. Their advantages include the potential for developing short-term in vivo bioassays and in vitro assays in order to keep pace with the growing backlog of chemicals that need to be evaluated for potential human health risk. In addition, these approaches have the potential to address some of the difficulties that arise with interpreting traditional rodent bioassays, such as the relevance of apical outcomes induced by chemical exposure in animals to humans.

Chronic dissecting aneurysm of ascending aorta with a large intramural thrombus and isolated aortic defects.

We present macroscopic and microscopic findings in a case of chronic dissecting aneurysm of ascending aorta and aortic arch associated with isolated tears of aortic wall without its rupture in a 71-year-old female presenting with minimal clinical symptomatology. Aneurysmal dilation of the aorta was caused not only by the bridging of the vascular wall based on the presence of an organizing intramural thrombus in the false lumen between the separated layers, but also by a wide flat defect in the aortic intima and media with the preservation of the aortic wall integrity due to fibrotical alteration of tunica adventicia. Histologic examination of the thoracic aorta detected cystic medial degeneration with mild atherosclerosis.