Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions.

Senolytics, small molecules targeting cellular senescence, have emerged as potential therapeutics to enhance health span. However, their impact on epigenetic age remains unstudied. This study aimed to assess the effects of Dasatinib and Quercetin (DQ) senolytic treatment on DNA methylation (DNAm), epigenetic age, and immune cell subsets. In a Phase I pilot study, 19 participants received DQ for 6 months, with DNAm measured at baseline, 3 months, and 6 months. Significant increases in epigenetic age acceleration were observed in first-generation epigenetic clocks and mitotic clocks at 3 and 6 months, along with a notable decrease in telomere length. However, no significant differences were observed in second and third-generation clocks. Building upon these findings, a subsequent investigation evaluated the combination of DQ with Fisetin (DQF), a well-known antioxidant and antiaging senolytic molecule. After one year, 19 participants (including 10 from the initial study) received DQF for 6 months, with DNAm assessed at baseline and 6 months. Remarkably, the addition of Fisetin to the treatment resulted in non-significant increases in epigenetic age acceleration, suggesting a potential mitigating effect of Fisetin on the impact of DQ on epigenetic aging. Furthermore, our analyses unveiled notable differences in immune cell proportions between the DQ and DQF treatment groups, providing a biological basis for the divergent patterns observed in the evolution of epigenetic clocks. These findings warrant further research to validate and comprehensively understand the implications of these combined interventions.

OMICmAge: An integrative multi-omics approach to quantify biological age with electronic medical records.

Biological aging is a multifactorial process involving complex interactions of cellular and biochemical processes that is reflected in omic profiles. Using common clinical laboratory measures in ~30,000 individuals from the MGB-Biobank, we developed a robust, predictive biological aging phenotype, EMRAge, that balances clinical biomarkers with overall mortality risk and can be broadly recapitulated across EMRs. We then applied elastic-net regression to model EMRAge with DNA-methylation (DNAm) and multiple omics, generating DNAmEMRAge and OMICmAge, respectively. Both biomarkers demonstrated strong associations with chronic diseases and mortality that outperform current biomarkers across our discovery (MGB-ABC, n=3,451) and validation (TruDiagnostic, n=12,666) cohorts. Through the use of epigenetic biomarker proxies, OMICmAge has the unique advantage of expanding the predictive search space to include epigenomic, proteomic, metabolomic, and clinical data while distilling this in a measure with DNAm alone, providing opportunities to identify clinically-relevant interconnections central to the aging process.

Zebrafish Cancer Avatars: A Translational Platform for Analyzing Tumor Heterogeneity and Predicting Patient Outcomes.

The increasing number of available anti-cancer drugs presents a challenge for oncologists, who must choose the most effective treatment for the patient. Precision cancer medicine relies on matching a drug with a tumor's molecular profile to optimize the therapeutic benefit. However, current precision medicine approaches do not fully account for intra-tumoral heterogeneity. Different mutation profiles and cell behaviors within a single heterogeneous tumor can significantly impact therapy response and patient outcomes. Patient-derived avatar models recapitulate a patient's tumor in an animal or dish and provide the means to functionally assess heterogeneity's impact on drug response. Mouse xenograft and organoid avatars are well-established, but the time required to generate these models is not practical for clinical decision-making. Zebrafish are emerging as a time-efficient and cost-effective cancer avatar model. In this review, we highlight recent developments in zebrafish cancer avatar models and discuss the unique features of zebrafish that make them ideal for the interrogation of cancer heterogeneity and as part of precision cancer medicine pipelines.

An invertebrate model in examining the effect of acute ferric iron exposure on proprioceptive neurons.

Iron is an essential element for plant and animal life and is found in soil, fresh waters and marine waters. The Fe3+ ion is a vital prosthetic group and cofactor to mitochondrial electron transport complexes and numerous proteins involved in normal functioning. Despite its importance to life-sustaining processes, overexposure results in toxicity. For example, ferric iron (Fe3+) accumulation in the mammalian central nervous system is associated with various neurological disorders. Although current literature addresses the long-term effects of Fe3+ overload, fewer studies exist examining the effects of acute exposure. Using the blue crab (Callinectes sapidus), we investigate the effects of acute Fe3+ overload on proprioception within the propodite-dactylopodite (PD) nerve. For proprioceptive studies, 10- and 20-mM ferric chloride and ferric ammonium citrate solutions were used at 5- and 20- min exposure times. Exposure to 20 mM concentrations of ferric chloride and ferric ammonium citrate reduced excitability in proprioceptive neurons. Thus, Fe3+ likely blocks stretch-activated channels or voltage-gated Na+ channels. The depressive effects of Fe3+ are partly reversible following saline washout, indicating cells are not acutely damaged. Gadolinium (GdCl3, 1 and 10 mM) was used to examine the effects of an additional trivalent ion comparator. Gd3+ depressed PD nerve compound action potential amplitude while increasing the compound action potential duration. This study is relevant in demonstrating the dose-dependent effects of acute Fe3+ and Gd3+ exposure on proprioception and provides a model system to further investigate the mechanisms by which metals act on the nervous system.

De novo transcriptomes for two species of snappers from the Western Atlantic (Lutjanus griseus and Lutjanus synagris).

Transcriptomes are appropriate resources for studying species that lack sequenced genomes, as they can serve as references for a broad suite of genetic applications, including: phylogenetic assessments, population genomics, and evaluate responses to environmental fluctuations. Here, we present the transcriptomes of two species of marine fishes of commercial and ecological relevance in the Western Atlantic: Lutjanus griseus and L. synagris. This project represents a step forward on developing genomic resources for important species of the Atlantic Ocean.

Range expansion and complete mitochondrial genome of the highfin blenny (Lupinoblennius nicholsi).

BACKGROUND: The highfin blenny, Lupinoblennius nicholsi, is a marine fish species reported in reef and rocky inshore habitats with a disjunct distribution in the southern Gulf of Mexico. Overall, there are very few studies on this species and there is a scarcity of molecular resources for genetic comparisons. We set out to report the first mitochondrial genome for L. nicholsi and report a range expansion for the species. METHODS AND RESULTS: An individual of L. nicholsi was collected from the coast of Dauphin Island, Alabama. The mitochondrial genome was sequenced, assembled, and annotated. The fragment corresponding to cytochrome oxidase I (COI) was used to compare this sample to other cryptobenthic species of the Atlantic. Finding a mature individual in the coast of Alabama implies this species has a continuous distribution throughout the northern Gulf of Mexico. The mitochondrial genome of L. nicholsi is 16,416 bp in length and comprised of 13 protein coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and a non-coding D-loop. Comparisons using COI support the species is L. nicholsi and separate it from other cryptobenthic fishes found in the area. CONCLUSIONS: This study represents the first mitochondrial genome for this L. nicholsi, serving as a reference for future comparative studies with marine fishes. By reporting the range expansion of this species, this study provides insights on the fish diversity of the Gulf of Mexico.

Innovative 19-minute rapid cytokeratin immunostaining of nonmelanoma skin cancer in Mohs micrographic surgery.

BACKGROUND: Dense inflammation can obscure nonmelanoma skin cancer (NMSC) on frozen sections, prompting removal of additional layers to ensure negative margins. Cytokeratin (CK) immunostaining in Mohs micrographic surgery (MMS) has been examined and found to be useful but is limited by lengthy 1-hour processing. OBJECTIVE: Our objective was to develop an effective ultrarapid CK frozen section immunostain to be used during MMS in cases of NMSC with dense or perineural inflammation. METHODS: An ultrarapid immunostain with a mixture of AE1/AE3 monoclonal antibodies was performed in 21 MMS cases and compared with permanent sections prepared from the same material. RESULTS: The ultrarapid CK protocol stained all of the cells in each of the 21 examples of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in frozen tissue in a way equivalent to immunostains being applied to permanent sections. CONCLUSION: The 19-minute CK immunohistochemistry protocol in frozen tissue appears to be as effective at labeling tumor cells of SCC and BCC as methods requiring permanent sections. It is hopeful that this technique may prevent recurrences after MMS and limit the number of Mohs layers required to obtain free margins when inflammation is abundant. It also is effective in uncovering subtle perineural invasion.

Use of environmentally enriched housing for rats with spinal cord injury: the need for standardization.

A variety of rehabilitation methods that increase social interaction and locomotor activity are reported to yield positive benefits in humans and animals with spinal cord injury (SCI). Environmental enrichment often incorporates group housing, increased cage size, and objects to increase social interaction and stimulate locomotor activity of animals. Others have reported that adult rats housed in enriched environments immediately after moderate contusion thoracic SCI show improvements in locomotion, but not in neurotransmission through or anatomy at the SCI site. In the present study, in contrast to previous reports, environmental enrichment did not improve the locomotion of rats with contusion thoracic SCI. Furthermore, as in previous reports, improvements were not observed for either electrophysiologic measures of neurotransmission through (transcranial magnetic motor-evoked potentials) and caudal to (magnetic-evoked interlimb reflex) the injury site or the amount of spared white matter at the epicenter. Determining the effectiveness of environmental enrichment to improve locomotor recovery in the SCI model requires standardization of housing procedures, outcome measures, and analyses.