Epigenetic Mechanisms in Hematologic Aging and Premalignant Conditions.

Hematopoietic stem cells (HSCs) are essential for maintaining overall health by continuously generating blood cells throughout an individual's lifespan. However, as individuals age, the hematopoietic system undergoes significant functional decline, rendering them more susceptible to age-related diseases. Growing research evidence has highlighted the critical role of epigenetic regulation in this age-associated decline. This review aims to provide an overview of the diverse epigenetic mechanisms involved in the regulation of normal HSCs during the aging process and their implications in aging-related diseases. Understanding the intricate interplay of epigenetic mechanisms that contribute to aging-related changes in the hematopoietic system holds great potential for the development of innovative strategies to delay the aging process. In fact, interventions targeting epigenetic modifications have shown promising outcomes in alleviating aging-related phenotypes and extending lifespan in various animal models. Small molecule-based therapies and reprogramming strategies enabling epigenetic rejuvenation have emerged as effective approaches for ameliorating or even reversing aging-related conditions. By acquiring a deeper understanding of these epigenetic mechanisms, it is anticipated that interventions can be devised to prevent or mitigate the rates of hematologic aging and associated diseases later in life. Ultimately, these advancements have the potential to improve overall health and enhance the quality of life in aging individuals.

Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer.

Clonal hematopoiesis (CH) is defined as clonal expansion of mutant hematopoietic stem cells absent diagnosis of a hematologic malignancy. Presence of CH in solid tumor patients, including colon cancer, correlates with shorter survival. We hypothesized that bone marrow-derived cells with heterozygous loss-of-function mutations of DNMT3A, the most common genetic alteration in CH, contribute to the pathogenesis of colon cancer. In a mouse model that combines colitis-associated colon cancer (CAC) with experimental CH driven by Dnmt3a+/Δ, we found higher tumor penetrance and increased tumor burden compared with controls. Histopathological analysis revealed accentuated colonic epithelium injury, dysplasia, and adenocarcinoma formation. Transcriptome profiling of colon tumors identified enrichment of gene signatures associated with carcinogenesis, including angiogenesis. Treatment with the angiogenesis inhibitor axitinib eliminated the colon tumor-promoting effect of experimental CH driven by Dnmt3a haploinsufficiency and rebalanced hematopoiesis. This study provides conceptually novel insights into non-tumor-cell-autonomous effects of hematopoietic alterations on colon carcinogenesis and identifies potential therapeutic strategies.

ECM2 and GLT8D2 in human pulmonary artery hypertension: fruits from weighted gene co-expression network analysis.

BACKGROUND: Pulmonary artery hypertension (PAH) is an incurable disease with a high mortality rate. Current medications ameliorate symptoms but cannot target adverse vascular remodeling. New therapeutic strategies for PAH need to be established. METHODS: Using the weighted gene coexpression network analysis (WGCNA) algorithm, we constructed a coexpression network of dataset GSE117261 from the Gene Expression Omnibus (GEO) database. Key modules were identified by the relationship between module eigengenes and clinical traits. Hub genes were screened out based on gene significance (GS), module membership (MM), and mean pulmonary artery pressure (mPAP). External validations were conducted in GSE48149 and GSE113439. Functional enrichment and immune cell infiltration were analyzed using Metascape and CIBERSORTx. RESULTS: The WGCNA analysis revealed 13 coexpression modules. The pink module had the highest correlation with PAH in terms of module eigengene (r=0.79; P=2e-18) and module significance (MS =0.43). Functional enrichment indicated genes in the pink module contributed to the immune system process and extracellular matrix (ECM). In the pink module, ECM2 (GS =0.65, MM =0.86, ρ=0.407, P=0.0019) and GLT8D2 (GS =0.63, MM =0.85, ρ=0.443, P=0.006) were identified as hub genes. For immune cells infiltration in PAH lung tissue, hub genes were positively correlated with M2 macrophages and resting mast cells, and were negatively correlated with monocytes, neutrophils, and CD4-naïve T cells. CONCLUSIONS: Our research identified 2 hub genes ECM2 and GLT8D2 related to PAH. The functions of these hub genes were involved in the immune process and ECM, indicating that they might serve as candidate therapeutic targets for PAH.

Anti-ATR001 monoclonal antibody ameliorates atherosclerosis through beta-arrestin2 pathway.

BACKGROUND: Our previous study developed ATRQß-001 vaccine, which targets peptide ATR001 from angiotensin Ⅱ (Ang Ⅱ) receptor type 1 (AT1R). The ATRQß-001 vaccine could induce the production of anti-ATR001 monoclonal antibody (McAb-ATR) and inhibit atherosclerosis without feedback activation of the renin-angiotensin system (RAS). This study aims at investigating the underexploited mechanisms of McAb-ATR in ameliorating atherosclerosis. METHODS: AT1R-KO HEK293T cell lines were constructed to identify the specificity of McAb-ATR and key sites of ATRQß-001 vaccine. Beta-arrestin1 knock-out (Arrb1-/-) mice, Beta-arrestin2 knock-out (Arrb2-/-) mice, and low-density lipoprotein receptor knock-out (LDLr-/-) mice were used to detect potential signaling pathways affected by McAb-ATR. The role of McAb-ATR in beta-arrestin and G proteins (Gq or Gi2/i3) signal transduction events was also investigated. RESULTS: McAb-ATR could specifically bind to the Phe182-His183-Tyr184 site of AT1R second extracellular loop (ECL2). The anti-atherosclerotic effect of McAb-ATR disappeared in LDLr-/- mice transplanted with Arrb2-/- mouse bone marrow (BM) and BM-derived macrophages (BMDMs) from Arrb2-/- mice. Furthermore, McAb-ATR inhibited beta-arrestin2-dependent extracellular signal regulated kinase1/2 (ERK1/2) phosphorylation, and promoted beta-arrestin2-mediated nuclear factor kappa B p65 (NFκB p65) inactivity. Compared with conventional AT1R blockers (ARBs), McAb-ATR did not inhibit Ang Ⅱ-induced uncoupling of heterotrimeric G proteins (Gq or Gi2/i3) and Gq-dependent intracellular Ca2+ release, nor cause RAS feedback activation. CONCLUSIONS: Through regulating beta-arrestin2, McAb-ATR ameliorates atherosclerosis without affecting Gq or Gi2/i3 pathways. Due to high selectivity for AT1R and biased interaction with beta-arrestin2, McAb-ATR could serve as a novel strategy for treating atherosclerosis.

Immunotherapy against angiotensin II receptor ameliorated insulin resistance in a leptin receptor-dependent manner.

The angiotensin II type 1 receptor (AT1R) signaling pathway is reported to modulate glucose metabolism. Targeting AT1R, our group invented ATRQß-001 vaccine, a novel immunotherapeutic strategy to block the activation of AT1R. Here, we evaluated the therapeutic efficacy of ATRQß-001 vaccine in insulin resistance, and investigated the mechanism. Our results showed that ATRQß-001 vaccine and specific monoclonal antibody against epitope ATR-001 (McAb-ATR) decreased fasting serum insulin concentration and improved glucose and insulin tolerance in ob/ob mice. These beneficial effects were verified in high-fat diet-induced obese mice. McAb-ATR activated insulin signaling in skeletal muscle and insulin-resistant C2C12 myotubes without affecting liver or white adipose tissue of ob/ob mice. Mechanistically, the favorable impact of McAb-ATR on insulin resistance was abolished in db/db mice and in C2C12 myotubes with leptin receptor knockdown. AT1R knockdown also eradicated the effects of McAb-ATR in C2C12 myotubes. Furthermore, McAb-ATR treatment was able to activate the leptin receptor-mediated JAK2/STAT3 signaling in skeletal muscle of ob/ob mice and C2C12 myotubes. Additionally, angiotensin II downregulated the leptin signaling in skeletal muscle of ob/ob and diet-induced obese mice. We demonstrated that ATRQß-001 vaccine and McAb-ATR improved whole-body insulin resistance and regulated glucose metabolism in skeletal muscle in a leptin receptor-dependent manner. Our data suggest that immunotherapy targeting AT1R is a novel strategy for treating insulin resistance.

The m6A-Related mRNA Signature Predicts the Prognosis of Pancreatic Cancer Patients.

N6-methyladenosine (m6A) has an important epitranscriptomic modification that controls cancer self-renewal and cell fate. The addition of m6A to mRNA is a reversible modification. The deposition of m6A is encoded by a methyltransferase complex involving three homologous factors, jargonized as "writers," "erasers," and "readers." However, their roles in pancreatic adenocarcinoma (PAAD) are underexploited. With the use of The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases, we provided an mRNA signature that may improve the prognostic prediction of PAAD patients based on the genetic status of m6A regulators. PAAD patients with genetic alteration of m6A regulators had worse disease-free and overall survival. After comparing PAAD groups with/without genetic alteration of m6A regulators, we identified 196 differentially expressed genes (DEGs). Then, we generated a 16-mRNA signature score system through least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Multivariate cox regression analysis demonstrated that a high-risk score significantly correlates with poor prognosis. Moreover, time-dependent receiver operating characteristic (ROC) curves revealed it was effective in predicting the overall survival in both training and validation sets. PAH, ZPLD1, PPFIA3, and TNNT1 from our signature also exhibited an independent prognostic value. Collectively, these findings can improve the understanding of m6A modifications in PAAD and potentially guide therapies in PAAD patients.

Pulmonary papillary squamous cell carcinoma: a population-based analysis of incidence, treatment, and prognosis.

BACKGROUND: Pulmonary papillary squamous cell carcinoma (PSCC) is a rare variant of pulmonary squamous cell carcinoma (SCC). This study aims to improve relevant understanding and demonstrate the incidence, treatment, and prognosis of pulmonary PSCC using a population-based database. METHODS: The Surveillance, Epidemiology and End Results (SEER) database was used to extract data of cases diagnosed with PSCC from 1973 to 2015 and analyze the incidence, treatment, and prognosis. RESULTS: A total of 151 pulmonary PSCC cases were identified. The incidence of pulmonary PSCC cases in 2015 was 0.009 per 100,000 persons. The tumor grade of pulmonary PSCC cases was significantly lower than that of SCC cases (P<0.001). Both cancer-specific (CSS) and overall survival (OS) of pulmonary PSCC were significantly higher than those of other pulmonary SCCs (P<0.001). The outcomes of pulmonary PSCC cases receiving surgery were significantly better than cases without surgery (P<0.001). On the contrary, patients with radiotherapy had a worsened prognosis compared with those without radiotherapy (P<0.05). As expected, the prognosis of pulmonary PSCC cases receiving surgery was significantly better than that of pulmonary PSCC cases receiving chemotherapy and radiotherapy (both P<0.05). CONCLUSIONS: Our population-based evidence shows that pulmonary PSCC, as a rare cancer, has a better prognosis compared with other pulmonary SCCs. Surgery was the only effective treatment to improve CSS and OS, while chemotherapy was ineffective and radiotherapy worsened prognosis.

Sacrificial oxidation of a self-metal source for the rapid growth of metal oxides on quantum dots towards improving photostability.

Growth of metal oxide layers on quantum dots (QDs) has been regarded as a good way to improve the photostability of QDs. However, direct growth of metal oxides on individual QD remains a great challenge. Here we report a novel approach to rapidly anchor metal oxides on QD surfaces through a sacrificial oxidation of a self-metal source strategy. As typical core/shell QDs, CdSe/CdS or aluminum doped CdSe/CdS (CdSe/CdS:Al) QDs were chosen and treated with peroxide (benzoyl peroxide). Self-metal sources (cadmium or/and aluminum) can be easily sacrificially oxidized, leading to the quick growth of cadmium oxide (CdO) or aluminum/cadmium hybrid oxides (Al2O3/CdO) on the surface of individual QD for improved photostability. Compared with CdO, Al2O3 possesses excellent barrier properties against moisture and oxygen. Therefore, CdSe/CdS QDs with the protection of an Al2O3/CdO hybrid layer show much superior photostability. Under strong illumination with blue light, the QDs coated with the Al2O3/CdO hybrid layer retained 100% of the original photoluminescence intensity after 70 h, while that of the untreated CdSe/CdS:Al, the treated CdSe/CdS and the CdSe/CdS QDs dropped to 65%, 45%, and 5%, respectively. Furthermore, we demonstrate that this method can be extended to other metal-doped QD systems, even including some inactive metals difficult to be oxidized spontaneously in an ambient atmosphere, which provides a new way to stabilize QDs for diverse optoelectronic applications.

Prognostic and Immunological Role of FUN14 Domain Containing 1 in Pan-Cancer: Friend or Foe?

Background: FUN14 domain containing 1 (FUNDC1) plays a pivotal role in mitochondrial autophagy (mitophagy), which is closely associated with human immunity. However, the role of FUNDC1 in cancers remains unclear. This study aimed to visualize the prognostic landscape of FUNDC1 in pan-cancer and investigate the relationship between FUNDC1 expression and immune infiltration. Methods: In this study, we explored the expression pattern and prognostic value of FUNDC1 in pan-cancer across multiple databases, including ONCOMINE, PrognoScan, GEPIA, and Kaplan-Meier Plotter. Then, using the GEPIA and TIMER databases, we investigated the correlations between FUNDC1 expression and immune infiltration in cancers, especially liver hepatocellular carcinoma (LIHC), and lung squamous cell carcinoma (LUSC). Results: In general, compared with that in normal tissue, tumor tissue had a higher expression level of FUNDC1. Although FUNDC1 showed a protective effect on pan-cancer, a high expression level of FUNDC1 was detrimental to the survival of LIHC patients. Although different from what was found for LUSC, for LIHC, there were significant positive correlations between FUNDC1 expression and immune infiltrates, including B cells, CD8+ T cells, CD4+ T cells, neutrophils, macrophages, and dendritic cells. Furthermore, markers of infiltrating immune cells, such as tumor-associated-macrophages (TAMs), exhibited different FUNDC1-related immune infiltration patterns. Conclusion: The mitophagy regulator FUNDC1 can serve as a prognostic biomarker in pan-cancer and is correlated with immune infiltrates.

Enhancing the stability of CsPbBr3 nanocrystals by sequential surface adsorption of S2- and metal ions.

A sequential surface adsorption method for improving the photostability of perovskite nanocrystals (NCs) at room temperature was proposed. Firstly, S2- was decorated on the surface of CsPbBr3 NCs by adding didodecyl dimethylammonium sulfide (S2--DDA+), and then In3+ ions, which diffused from the salt powder of In(Ac)3, were slowly adsorbed by the pre-loaded S2-. Through this process, the photoluminescence quantum yield of the CsPbBr3 NCs increases from 57% to 80%, and their photostability, thermal stability, and colloidal stability were all drastically improved. The resultant CsPbBr3·S-In NCs remained stable for 188 h under strong LED light illumination (450 nm and 175 mW cm-2), while pristine CsPbBr3 NCs totally quenched in 2 h, which shows the great potential of CsPbBr3·S-In NCs in lighting and display applications. We also demonstrated that this method could be extended to many other metal salts to form stable perovskite·S-X (X = Ni, Mn and Zn) nanocrystals.

High-performance humidity sensor based on a polyvinyl alcohol-coated photonic crystal cavity.

We demonstrate a high-performance relative humidity (RH) sensor by coating a photonic crystal (PC) cavity with polyvinyl alcohol (PVA). Because a PC cavity's evanescent field strongly interacts with the coated moisture-sensitive PVA film, the resonant wavelength is modified remarkably under varying RH levels ranging from 30% to 90%. In a PC cavity coated with a 720 nm thick PVA, the sensor exhibits a linear spectrum sensitivity exceeding 129 pm/%RH over 40-90%RH, and the power interrogation presents a high sensitivity as 0.77 dB/%RH. The resolvable humidity variation could be much less than 0.1%RH. Relying on the sub-micron thick PVA, the sensor promises a response time less than 300 ms and good repeatability. The dependence of the sensor performances on the PVA thickness is studied as well, indicating a tradeoff between the sensing dynamic range and the response time.