Tissue compatibility of poly(hydroxypropylglutamate)-prazosin conjugates

Biocompatibility of an injectable biodegradable drug delivery system for prazosin was investigated in Sprague-Dawley rats by histological studies after subcutaneous injection ofpoly(hydroxypropyl glutamate)-prazosin (PHPG-prazosin) conjugate particles. The studies showed that (1) the acute inflammatory response to this injectable biodegradable polymeric prodrug system was mild and of only short duration, (2) the chronic inflammation was minimal to zero, (3) the fibrous capsule could be seen starting from 7 days and became more prominent at longer time periods, (4) a collagen network was formed into the injection site after 21 days, (5) the macrophages and foreign giant cells reacted to the globules of conjugate particles, and (6) no adverse reactions were identified. Focal inflammation and the formation of the fibrous capsule around the injection site were the significant histological findings in the histopathological studies. Therefore, it is concluded that the biodegradable injectable PHPG-prazosin carbamate polymeric prodrug system is tissue biocompatible

Three-Layered Atmospheric Structure in Accretion Disks Around Stellar-Mass Black Holes

Modeling of the x-ray spectra of the Galactic superluminal jet sources GRS 1915+105 and GRO J1655-40 reveal a three-layered atmospheric structure in the inner region of their accretion disks. Above the cold and optically thick disk of a temperature 0.2-0.5 keV, there is a warm layer with a temperature of 1.0-1.5 keV and an optical depth around 10. Sometimes there is also a much hotter, optically thin corona above the warm layer, with a temperature of 100 keV or higher and an optical depth around unity. The structural similarity between the accretion disks and the solar atmosphere suggest that similar physical processes may be operating in these different systems.Comment: 5 fives, 2 figures, 1 table. The online version of the paper in Science may be accessed through http://jet.uah.edu/~zhangsn/papers.htm

The Relationship Between Self-Reported Sleep Quality and Psychological Health in Undergraduates During the Home Quarantine of COVID-19

The present study aimed to investigate self-reported sleep quality and psychological well-being, specifically anxiety, depression and stress, in undergraduate students during home quarantine. A total of 7,364 students participated and completed the PSQI and DASS-21 scales. The results showed that higher-grade students were more likely to have mental health problems compared to their lower-grade students. Additionally, male students reported better sleep quality than females, and high-grade students reported more sleep problems than low-grade students. Significant correlations were observed between PSQI scores and stress, anxiety and depression scores (r=0.469, 0.458, 0.408, p＜0.01). Specifically, the PSQI score explained 22.0%, 21.0% and 16.6% of the variance in stress, anxiety and depression scores respectively. In conclusion, gender and grade differences in sleep and mental health were evident, with female students reporting lower sleep quality than males, and high-grade students experiencing worse sleep quality and mental health than their low-grade students

Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancies with a nearly equal incidence and mortality rates in patients. Pancreatic stellate cells (PSCs) are critical players in PDAC microenvironment to promote the aggressiveness and pathogenesis of the disease. Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC. Earlier, we observed a PSC-specific downregulation of miR-29a in PDAC pancreas, however, the mechanism of action of the molecule in PSCs is still to be elucidated. The current study aims to clarify the regulation of miR-29a in PSCs and identifies functionally important downstream targets that contribute to tumorigenic activities during PDAC progression. Methods In this study, using RNAseq approach, we performed transcriptome analysis of paired miR-29a overexpressing and control human PSCs (hPSCs). Enrichment analysis was performed with the identified differentially expressed genes (DEGs). miR-29a targets in the dataset were identified, which were utilized to create network interactions. Western blots were performed with the top miR-29a candidate targets in hPSCs transfected with miR-29a mimic or scramble control. Results RNAseq analysis identified 202 differentially expressed genes, which included 19 downregulated direct miR-29a targets. Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs. Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis. We further observe a regulatory role of the molecule in pathways associated with PDAC ECM remodeling and tumor-stromal crosstalk, such as INS/IGF-1, RAS/MAPK, laminin interactions and collagen biosynthesis. Conclusions Together, our study presents a comprehensive understanding of miR-29a regulation of PSCs, and identifies essential pathways associated with PSC-mediated PDAC pathogenesis. The findings suggest an anti-tumorigenic role of miR-29a in the context of PSC-cancer cell crosstalk and advocates for the potential of the molecule in PDAC targeted therapies

DNASE1L3 enhances antitumor immunity and suppresses tumor progression in colon cancer

DNASE1L3, an enzyme highly expressed in DCs, is functionally important for regulating autoimmune responses to self-DNA and chromatin. Deficiency of DNASE1L3 leads to development of autoimmune diseases in both humans and mice. However, despite the well-established causal relationship between DNASE1L3 and immunity, little is known about the involvement of DNASE1L3 in regulation of antitumor immunity, the foundation of modern antitumor immunotherapy. In this study, we identify DNASE1L3 as a potentially new regulator of antitumor immunity and a tumor suppressor in colon cancer. In humans, DNASE1L3 is downregulated in tumor-infiltrating DCs, and this downregulation is associated with poor patient prognosis and reduced tumor immune cell infiltration in many cancer types. In mice, Dnase1l3 deficiency in the tumor microenvironment enhances tumor formation and growth in several colon cancer models. Notably, the increased tumor formation and growth in Dnase1l3-deficient mice are associated with impaired antitumor immunity, as evidenced by a substantial reduction of cytotoxic T cells and a unique subset of DCs. Consistently, Dnase1l3-deficient DCs directly modulate cytotoxic T cells in vitro. To our knowledge, our study unveils a previously unknown link between DNASE1L3 and antitumor immunity and further suggests that restoration of DNASE1L3 activity may represent a potential therapeutic approach for anticancer therapy

Genome wide DNA methylation landscape reveals glioblastoma’s influence on epigenetic changes in tumor infiltrating CD4+ T cells

CD4+ helper T (Th) cells play a critical role in shaping anti-tumor immunity by virtue of their ability to differentiate into multiple lineages in response to environmental cues. Various CD4+ lineages can orchestrate a broad range of effector activities during the initiation, expansion, and memory phase of endogenous anti-tumor immune response. In this clinical corelative study, we found that Glioblastoma (GBM) induces multi- and mixed-lineage immune response in the tumor microenvironment. Whole-genome bisulfite sequencing of tumor infiltrating and blood CD4+ T-cell from GBM patients showed 13571 differentially methylated regions and a distinct methylation pattern of methylation of tumor infiltrating CD4+ T-cells with significant inter-patient variability. The methylation changes also resulted in transcriptomic changes with 341 differentially expressed genes in CD4+ tumor infiltrating T-cells compared to blood. Analysis of specific genes involved in CD4+ differentiation and function revealed differential methylation status of TBX21, GATA3, RORC, FOXP3, IL10 and IFNG in tumor CD4+ T-cells. Analysis of lineage specific genes revealed differential methylation and gene expression in tumor CD4+ T-cells. Interestingly, we observed dysregulation of several ligands of T cell function genes in GBM tissue corresponding to the T-cell receptors that were dysregulated in tumor infiltrating CD4+ T-cells. Our results suggest that GBM might induce epigenetic alterations in tumor infiltrating CD4+ T-cells there by influencing anti-tumor immune response by manipulating differentiation and function of tumor infiltrating CD4+ T-cells. Thus, further research is warranted to understand the role of tumor induced epigenetic modification of tumor infiltrating T-cells to develop effective anti-GBM immunotherapy

Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota

Restriction of methionine (MR), a sulfur-containing essential amino acid, has been reported to repress cancer growth and improve therapeutic responses in several preclinical settings. However, how MR impacts cancer progression in the context of the intact immune system is unknown. Here we report that while inhibiting cancer growth in immunocompromised mice, MR reduces T cell abundance, exacerbates tumour growth and impairs tumour response to immunotherapy in immunocompetent male and female mice. Mechanistically, MR reduces microbial production of hydrogen sulfide, which is critical for immune cell survival/activation. Dietary supplementation of a hydrogen sulfide donor or a precursor, or methionine, stimulates antitumour immunity and suppresses tumour progression. Our findings reveal an unexpected negative interaction between MR, sulfur deficiency and antitumour immunity and further uncover a vital role of gut microbiota in mediating this interaction. Our study suggests that any possible anticancer benefits of MR require careful consideration of both the microbiota and the immune system

A single-cell atlas of the healthy breast tissues reveals clinically relevant clusters of breast epithelial cells

Single-cell RNA sequencing (scRNA-seq) is an evolving technology used to elucidate the cellular architecture of adult organs. Previous scRNA-seq on breast tissue utilized reduction mammoplasty samples, which are often histologically abnormal. We report a rapid tissue collection/processing protocol to perform scRNA-seq of breast biopsies of healthy women and identify 23 breast epithelial cell clusters. Putative cell-of-origin signatures derived from these clusters are applied to analyze transcriptomes of ~3,000 breast cancers. Gene signatures derived from mature luminal cell clusters are enriched in ~68% of breast cancers, whereas a signature from a luminal progenitor cluster is enriched in ~20% of breast cancers. Overexpression of luminal progenitor cluster-derived signatures in HER2+, but not in other subtypes, is associated with unfavorable outcome. We identify TBX3 and PDK4 as genes co-expressed with estrogen receptor (ER) in the normal breasts, and their expression analyses in >550 breast cancers enable prognostically relevant subclassification of ER+ breast cancers

AT2023lli: A Tidal Disruption Event with Prominent Optical Early Bump and Delayed Episodic X-ray Emission

High-cadence, multiwavelength observations have continuously revealed the diversity of tidal disruption events (TDEs), thus greatly advancing our knowledge and understanding of TDEs. In this work, we conducted an intensive optical-UV and X-ray follow-up campaign of TDE AT2023lli, and found a remarkable month-long bump in its UV/optical light curve nearly two months prior to maximum brightness. The bump represents the longest separation time from the main peak among known TDEs to date. The main UV/optical outburst declines as $t^{-4.10}$, making it one of the fastest decaying optically selected TDEs. Furthermore, we detected sporadic X-ray emission 30 days after the UV/optical peak, accompanied by a reduction in the period of inactivity. It is proposed that the UV/optical bump could be caused by the self-intersection of the stream debris, whereas the primary peak is generated by the reprocessed emission of the accretion process. In addition, our results suggest that episodic X-ray radiation during the initial phase of decline may be due to the patched obscurer surrounding the accretion disk, a phenomenon associated with the inhomogeneous reprocessing process. The double TDE scenario, in which two stars are disrupted in sequence, is also a possible explanation for producing the observed early bump and main peak. We anticipate that the multicolor light curves of TDEs, especially in the very early stages, and the underlying physics can be better understood in the near future with the assistance of dedicated surveys such as the deep high-cadence survey of the 2.5-meter Wide Field Survey Telescope (WFST).Comment: 14 pages, 8 figures,accepted for publication by ApJ