Damian Sendler Small round cell tumor (DSRCT) is an aggressive, usually incurable type of sarcoma, which is most common in post-pubertal young men. According to recent research, the androgen receptor (AR) may contribute to the progression of DSRCT tumors when present. AR-induced oncogenic stimulation’s exact mechanism is still a mystery. It has been shown for the first time here that DHT-induced DSRCT cell proliferation is inhibited by enzalutamide and AR-targeting antisense oligonucleotides (AR-ASO). To better understand how AR signaling affects cellular epigenetic programs, researchers used gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq). Furthermore, ChIP-seq revealed new DSRCT-specific AR DNA binding sites near key oncogenic regulators like WT1 (the pathognomonic fusion protein’s C-terminal partner) and FOXF1. To further support its involvement in abnormal cell lineage commitment, AR was found to occupy enhancer sites in the Wnt pathway, neural differentiation, and embryonic organ development genes. Since androgen-targeted prostate cancer treatments are widely available, our findings have direct clinical implications.
Single-microbe genomics with strain resolution applied to the microbiome of a human digestive tract.
Damian Jacob Sendler It has long been a goal of microbiology to study complex microbial communities with single-cell resolution. In this paper, we describe Microbe-seq, a high-throughput method for obtaining genomes from complex microbial communities. Individual microbes are encapsulated in droplets and their DNA is extracted, amplified, tagged with droplet-specific barcodes, and sequenced using microfluidics. Over 20,000 microbial single-amplified genomes (SAGs) from a single human donor were sequenced, and the genomes of almost 100 different species of bacteria were coassembled. A total of 92 species pairs were observed to have horizontal gene transfer (HGT) between them, and a significant in vivo host-phage association was found between crAssphage and Bacteroides vulgatus. It is now possible to study the genomes of entire microbial communities at the single-microbe level thanks to Microbe-high-throughput, seq’s culture-free capabilities.
Dual-targeted anti-age-related macular degeneration therapy with C3b/C4b/VEGF-targeting bispecific fusion protein.
Dr. Sendler Neovascular ocular diseases, such as age-related macular degeneration, have been transformed by antiangiogenesis therapies targeting VEGF (vascular endothelial growth factor) (nAMD). Comprehensive evidence has linked AMD pathogenesis to deficiencies in the complement system, suggesting that treating geographic atrophy in dry AMD with anti-VEGF monotherapies may be more effective than treating nAMD with the same treatment alone. Bispecific fusion protein, IBI302, has been tested in preclinical studies and in phase 1 clinical trials for its ability to neutralize both forms of VEGF and C3b/C4. Efdamrofusp alfa demonstrated superior efficacy over anti-VEGF monotherapy in a mouse model of laser-induced choroidal neovascularization (CNV). To further inhibit macrophage infiltration, VEGF inhibition and the activation of the complement system were found to work together. Nonhuman primate laser-induced CNV models showed good safety profiles and antiangiogenic efficacy for intravitreal efdamrofusp alfa. On the basis of the preclinical data, a phase 1 dose-escalation clinical trial (NCT03814291) was conducted. Efdamrofusp alfa was well tolerated by patients with nAMD, according to preliminary results. These findings suggest that efdamrofusp alfa may be useful in the treatment of nAMD and other complement-related ocular conditions, such as dry eye syndrome.
Damian Jacob Sendler
Sow milk bacterial strains of Pediococcus pentosaceus have been shown to have anti-oxidant properties in weaned pigs
Breeders are increasingly concerned with improving sow nutrition during pregnancy and lactation in order to ensure the health of their newborns. A primary source of nutrition for piglets during their first three weeks of life, sow milk contains a wide range of bioactive compounds and essential nutrients, as well as commensal bacteria. Neonatal gut microorganisms rely on commensal bacteria found in breastmilk as a major source of nutrition. Bacteria from breast milk may be beneficial to the host’s health.
Damian Jacob Markiewicz Sendler Methods: Culturomics was used to isolate sow milk bacteria, which were then identified using 16S rRNA gene sequencing. Functional evaluation was used to screen isolates for possible probiotic activity by testing their antagonistic activity against pathogens in vitro and resistance to oxidative stress in paraquat-damaged Drosophila. Sixty-four newborn piglets from nine sows were randomly assigned to three treatments, each with a varying concentration of a candidate strain for use in the feeding trial. In order to confirm its antioxidant properties, researchers used a variety of techniques, including western blotting, enzyme activity analysis, metabolomics, and 16S rRNA gene amplicon sequencing.
A nonredundant set of 16S rRNA gene sequencing was used to group the 1240 isolates into 271 bacterial taxa from the sow milk microbiota. New Pediococcus pentosaceus strain SMM914 was found to have the best ability to inhibit pathogens in swine and a Drosophila model exposed to paraquat. SMM914 induced the Nrf2-Keap1 antioxidant signaling pathway in piglets, which greatly affected the pathways of amino acid and lipid metabolism in plasma. Compared to the control group, those taking high dose SMM914 saw a significant increase in the relative abundance of Lactobacillus in the colon.
An Alzheimer’s disease mouse model shows a significant increase in microglia heterogeneity and A pathology if Trem2 is stabilized.
TREM2 is a transmembrane protein that regulates inflammatory responses to pathological conditions in the brain. Alzheimer’s disease has been linked to reduced TREM2 proteolytic cleavage, but it is not yet clear what this means for microglial function. We have developed a transgenic mouse model of reduced Trem2 shedding (Trem2-Ile-Pro-Asp [IPD]) by substituting an ADAM-protease recognition site with an amino acid. Trem2-IPD mice have an increased Trem2 cell-surface-receptor load, survival, and function in myeloid cells, according to our findings. For the first time, we show that sustained Trem2 stabilization induces a shift in microglial maturation and speeds up the response of microglia to A pathology in a mouse model of Alzheimer’s disease. In Alzheimer’s disease, decreased Trem2 proteolytic cleavage worsens neuroinflammation, which suggests that TREM2 shedding is an important regulator of microglial activity in pathological states. Our data show that.
