The impact of the COVID-19 pandemic and the free vaccination policy on seasonal influenza vaccination uptake among older adults in Ningbo, Eastern China.

In 2020-21, during the COVID-19 pandemic, a free influenza vaccination program was initiated among the elderly residents in Ningbo, China. The impact of the COVID-19 pandemic and free vaccination policy on influenza vaccine uptake needs to be evaluated. The influenza vaccine uptake among individuals born before 31 December, 1962 from 2017-18 to 2022-23 season in Ningbo was analyzed. Multivariate logistic regressions were used to estimate the impact of the COVID-19 pandemic and free vaccination policy. Our analysis included an average of 1,856,565 individuals each year. Influenza vaccination coverage increased from 1.14% in 2017-18 to 33.41% in 2022-23. The vaccination coverage among the free policy target population was 50.03% in 2022-23. Multivariate analysis showed that free vaccination policy increased influenza vaccine uptake most (OR = 11.99, 95%CI: 11.87-12.11). The initial phase of the pandemic was associated with a positive effect on influenza vaccination (OR = 2.09, 95%CI: 2.07-2.12), but followed by a negative effect in the subsequent two seasons(2021-22: OR = 0.75, 95%CI: 0.73-0.76; 2022-23: OR = 0.40, 95%CI: 0.39-0.40). COVID-19 vaccination in the current season was a positive predictor of influenza vaccine uptake while not completing booster COVID-19 vaccination before was negative predictor in 2022-23. Having influenza vaccine history and having ILI medical history during the last season were also positive predictors of influenza vaccine uptake. Free vaccination policies have enhanced influenza vaccination coverage among elderly population. The COVID-19 pandemic plays different roles in different seasons. Our study highlights the need for how to implement free vaccination policies targeting vulnerable groups with low vaccination coverage.

A novel LGALS1-depended and immune-associated fatty acid metabolism risk model in acute myeloid leukemia stem cells.

Leukemia stem cells (LSCs) are recognized as the root cause of leukemia initiation, relapse, and drug resistance. Lipid species are highly abundant and essential component of human cells, which often changed in tumor microenvironment. LSCs remodel lipid metabolism to sustain the stemness. However, there is no useful lipid related biomarker has been approved for clinical practice in AML prediction and treatment. Here, we constructed and verified fatty acid metabolism-related risk score (LFMRS) model based on TCGA database via a series of bioinformatics analysis, univariate COX regression analysis, and multivariate COX regression analysis, and found that the LFMRS model could be an independent risk factor and predict the survival time of AML patients combined with age. Moreover, we revealed that Galectin-1 (LGALS1, the key gene of LFMRS) was highly expressed in LSCs and associated with poor prognosis of AML patients, and LGALS1 repression inhibited AML cell and LSC proliferation, enhanced cell apoptosis, and decreased lipid accumulation in vitro. LGALS1 repression curbed AML progression, lipid accumulation, and CD8+ T and NK cell counts in vivo. Our study sheds light on the roles of LFMRS (especially LGALS1) model in AML, and provides information that may help clinicians improve patient prognosis and develop personalized treatment regimens for AML.

Metal-catalyzed Markovnikov-type selective hydrofunctionalization of terminal alkynes.

Metal-catalyzed highly Markovnikov-type selective hydrofunctionalization of terminal alkynes provides a straightforward and atom-economical route to access 1,1-disubstituted alkenes, which have a wide range of applications in organic synthesis. However, the highly Markovnikov-type selective transformations are challenging due to the electronic and steric effects during the addition process. With the development of metal-catalyzed organic synthesis, different metal catalysts have been developed to solve this challenge, especially for platinum group metal catalysts. In this perspective, we review homogeneous metal-catalyzed Markovnikov-type selective hydrofunctionalization of terminal alkynes according to the classified element types as well as reaction mechanisms. Future avenues for investigation are also presented to help expand this exciting field.

Mifepristone protects acetaminophen induced liver injury through NRF2/GSH/GST mediated ferroptosis suppression.

Ferroptosis is a form of iron-dependent cell death that has attracted significant attention for its potential role in numerous diseases. Targeted inhibition of ferroptosis could be of potential use in treating diseases: such as drug induced liver injury (DILI). Ferroptosis can be antagonized by the xCT/GSH/GPX4, FSP1/CoQ10, DHODH/CoQ10, GCH1/BH4, and NRF2 pathways. Identifying novel anti-ferroptosis pathways will further promote our understanding of the biological nature of ferroptosis and help discover new drugs targeting ferroptosis related human diseases. In this study, we identified the clinically used drug mifepristone (RU486) as a novel ferroptosis inhibitor. Mechanistically, RU486 inhibits ferroptosis by inducing GSH synthesis pathway, which supplies GSH for glutathione-S-transferase (GST) mediated 4-HNE detoxification. Furthermore, RU486 induced RLIP76 and MRP1 export 4-HNE conjugate contributes to its anti-ferroptosis activity. Interestingly, RU486 induced GSH/GSTs/RLIP76&MRP1 anti-ferroptosis pathway acts independent of classic anti-ferroptosis systems: including xCT/GSH/GPX4, FSP1, DHODH, GCH1, SCD1 and FTH1. Moreover, NRF2 was identified to be important for RU486's anti-ferroptosis activity by inducing downstream gene expression. Importantly, in mouse model, RU486 showed strong protection effect on acetaminophen (APAP)-induced acute liver injury, evidenced by decreased ALT, AST level and histological recovery after APAP treatment. Interestingly, RU486 also decreased oxidative markers, including 4-HNE and MDA, and induced NRF2 activation as well as GSTs, MRP1 expression. Together, these data suggest NRF2/GSH/GST/RLIP76&MRP1 mediated detoxification pathway as an important independent anti-ferroptosis pathway act both in vitro and in vivo.

Disulfidptosis-related signature elucidates the prognostic, immunologic, and therapeutic characteristics in ovarian cancer.

Introduction: Ovarian cancer (OC) is the deadliest malignancy in gynecology, but the mechanism of its initiation and progression is poorly elucidated. Disulfidptosis is a novel discovered type of regulatory cell death. This study aimed to develop a novel disulfidptosis-related prognostic signature (DRPS) for OC and explore the effects and potential treatment by disulfidptosis-related risk stratification. Methods: The disulfidptosis-related genes were first analyzed in bulk RNA-Seq and a prognostic nomogram was developed and validated by LASSO algorithm and multivariate cox regression. Then we systematically assessed the clinicopathological and mutational characteristics, pathway enrichment analysis, immune cell infiltration, single-cell-level expression, and drug sensitivity according to DRPS. Results: The DRPS was established with 6 genes (MYL6, PDLIM1, ACTN4, FLNB, SLC7A11, and CD2AP) and the corresponding prognostic nomogram was constructed based on the DRPS, FIGO stage, grade, and residual disease. Stratified by the risk score derived from DRPS, patients in high-risk group tended to have worse prognosis, lower level of disulfidptosis, activated oncogenic pathways, inhibitory tumor immune microenvironment, and higher sensitivity to specific drugs including epirubicin, stauroporine, navitoclax, and tamoxifen. Single-cell transcriptomic analysis revealed the expression level of genes in the DRPS significantly varied in different cell types between tumor and normal tissues. The protein-level expression of genes in the DRPS was validated by the immunohistochemical staining analysis. Conclusion: In this study, the DRPS and corresponding prognostic nomogram for OC were developed, which was important for OC prognostic assessment, tumor microenvironment modification, drug sensitivity prediction, and exploration of potential mechanisms in tumor development.

Lanosterol Synthase Prevents EMT During Lens Epithelial Fibrosis Via Regulating SREBP1.

Purpose: Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is a predominant pathological process underlying fibrotic cataracts. Here we investigated the role and mechanism of lanosterol synthase (LSS), a key rate-limiting enzyme in sterol biosynthesis, in EMT of LECs. Methods: Human lens epithelial explants, primary rabbit LECs, and whole rat lenses were treated with TGFß2. RNA-sequencing was conducted to explore genetic changes during fibrosis of human lens epithelial explants. Loss- and gain-of-function studies were performed in primary LECs to investigate roles and mechanisms of LSS, lanosterol and sterol regulatory element binding transcription protein 1 (SREBP1) in EMT. Rat lenses were applied to evaluate the potential effect of lanosterol on lens fibrosis. Expression of LSS, SREBP1, EMT-related regulators, and markers were analyzed by Western blot, qRT-PCR, or immunofluorescent staining. Results: LSS and steroid biosynthesis were downregulated in TGFß2-induced lens fibrosis. LSS inhibition directly triggered EMT by inducing Smad2/3 phosphorylation and nucleus translocation, an overexpression of LSS protected LECs from EMT by inhibiting Smad2/3 activation. Moreover, LSS inhibition decreased the expression of SREBP1, which regulated EMT via intervening TGFß2/Smad2/3 transduction. Furthermore, lanosterol protected LECs from EMT caused by both TGFß2 treatment and LSS inhibition via suppressing Smad2/3 activation and maintained lens transparency by preventing fibrotic plaques formation. Conclusions: We first identified that LSS protected LECs from EMT and played an antifibrotic role to maintain lens transparency. Additionally, lanosterol and sterol biosynthesis regulation might be promising strategies for preventing and treating fibrotic cataracts.

Mitophagy genes in ovarian cancer: a comprehensive analysis for improved immunotherapy.

BACKGROUND: Mitophagy is a process of selectively degrading damaged mitochondria, which has been found to be related to immunity, tumorigenesis, tumor progression, and metastasis. However, the role of mitophagy-related genes (MRGs) in the tumor microenvironment (TME) of ovarian cancer (OV) remains largely unexplored. METHODS: We analyzed the expression, prognosis, and genetic alterations of 29 MRGs in 480 OV samples. Unsupervised clustering was used to classify OV into two subtypes (clusters A and B) based on MRG changes. We compared the clinical features, differential expressed genes (DEGs), pathways, and immune cell infiltration between the two clusters. We constructed a mitophagy scoring system (MRG_score) based on the DEGs and validated its ability to predict overall survival of OV patients. RESULTS: We found that patients with high MRG_scores had better survival status and increased infiltration by immune cells. Further analysis showed that these patients may be more sensitive to immune checkpoint inhibitor (ICI) treatment. Additionally, the MRG_score significantly correlated with the sensitivity of chemotherapeutic drugs and targeted inhibitors. CONCLUSION: Our comprehensive analysis of MRGs in the TME, clinical features, and patient prognosis revealed that the MRG_score is a potentially effective prognostic biomarker and predictor of treatment. This study provides new insights into the role of MRGs in OV and identifies patients who may benefit from ICI treatment, chemotherapy, or targeted treatment.

Inhibition of CARM1 suppresses proliferation of multiple myeloma cells through activation of p53 signaling pathway.

BACKGROUND: Multiple myeloma (MM) is a malignant proliferative disease of plasma cells, the incidence of which is increasing every year and remains incurable. The enzyme co-activator-associated arginine methyltransferase 1 (CARM1) is highly expressed in a variety of cancers, such as Hodgkin's lymphoma and acute myeloid leukemia, and CARM1 is closely associated with tumor cell proliferation. However, the role of CARM1 in MM has not been elucidated. METHODS AND RESULTS: In this study, we found that CARM1 is overexpressed in MM and closely associated with poor prognosis in MM. CCK-8 and colony formation assays showed that the proliferation of MM cell lines was downregulated when CARM1 expression was knockdown by specific shRNA. Knockdown of CARM1 reduced the proportion of MM cell lines in the S phase and increased the proportion in G0/G1 phase. RNA-seq analysis of the CARM1-KD cell line revealed that it was closely associated with apoptosis and activated the p53 pathway. CCK-8 and apoptosis results showed that CARM1 knockdown made MM cells more sensitive to standard-of-care drugs. CONCLUSION: This study provides an experimental basis for elucidating the pathogenesis of multiple myeloma and searching for potential therapeutic targets.

Second-line therapy for patients with steroid-refractory aGVHD: systematic review and meta-analysis of randomized controlled trials.

Objective: Steroids-refractory (SR) acute graft-versus-host disease (aGVHD) is a life-threatening condition in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the optimal second-line therapy still has not been established. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of different second-line therapy regimens. Methods: Literature search in MEDLINE, Embase, Cochrane Library and China Biology Medicine databases were performed to retrieve RCTs comparing the efficacy and safety of different therapy regimens for patients with SR aGVHD. Meta-analysis was conducted with Review Manager version 5.3. The primary outcome is the overall response rate (ORR) at day 28. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated with the Mantel-Haenszel method. Results: Eight eligible RCTs were included, involving 1127 patients with SR aGVHD and a broad range of second-line therapy regimens. Meta-analysis of 3 trials investigating the effects of adding mesenchymal stroma cells (MSCs) to other second-line therapy regimens suggested that the addition of MSCs is associated with significantly improvement in ORR at day 28 (RR = 1.15, 95% CI = 1.01-1.32, P = 0.04), especially in patients with severe (grade III-IV or grade C-D) aGVHD (RR = 1.26, 95% CI = 1.04-1.52, P = 0.02) and patients with multiorgan involved (RR = 1.27, 95% CI = 1.05-1.55, P = 0.01). No significant difference was observed betwwen the MSCs group and control group in consideration of overall survival and serious adverse events. Treatment outcomes of the other trials were comprehensively reviewed, ruxolitinib showed significantly higher ORR and complete response rate at day 28, higher durable overall response at day 56 and longer failure-free survival in comparison with other regimens; inolimomab shows similar 1-year therapy success rate but superior long-term overall survial in comparison with anti-thymocyte globulin, other comparisons did not show significant differences in efficacy. Conclusions: Adding MSCs to other second-line therapy regimens is associated with significantly improved ORR, ruxolitinib showed significantly better efficacy outcomes in comparison with other regimens in patients with SR aGVHD. Further well-designed RCTs and integrated studies are required to determine the optimal treatment. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022342487.

PRMT1 inhibition promotes ferroptosis sensitivity via ACSL1 upregulation in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematological malignancy with an alarming mortality rate. The development of novel therapeutic targets or drugs for AML is urgently needed. Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation. Recently, ferroptosis has emerged as a novel method for targeting cancer, including AML. Epigenetic dysregulation is a hallmark of AML, and a growing body of evidence suggests that ferroptosis is subject to epigenetic regulation. Here, we identified protein arginine methyltransferase 1 (PRMT1) as a ferroptosis regulator in AML. The type I PRMT inhibitor GSK3368715 promoted ferroptosis sensitivity in vitro and in vivo. Moreover, PRMT1-knockout cells exhibited significantly increased sensitivity to ferroptosis, suggesting that PRMT1 is the primary target of GSK3368715 in AML. Mechanistically, both GSK3368715 and PRMT1 knockout upregulated acyl-CoA synthetase long-chain family member 1 (ACSL1), which acts as a ferroptosis promoter by increasing lipid peroxidation. Knockout ACSL1 reduced the ferroptosis sensitivity of AML cells following GSK3368715 treatment. Additionally, the GSK3368715 treatment reduced the abundance of H4R3me2a, the main histone methylation modification mediated by PRMT1, in both genome-wide and ACSL1 promoter regions. Overall, our results demonstrated a previously unknown role of the PRMT1/ACSL1 axis in ferroptosis and suggested the potential value and applications of the combination of PRMT1 inhibitor and ferroptosis inducers in AML treatment.

Effects of donor-specific antibodies on engraftment and long-term survival after allogeneic hematopoietic stem cell transplantation-A systematic review and meta-analysis.

The presence of donor-specific antibodies (DSAs) have been reported to be associated with an increased risk of primary graft failure following allogeneic hematopoietic stem cell transplantation (allo-HSCT), but its effects on the time to engraftment and long-term outcomes remain unclear. We performed a systematic review and meta-analysis of studies investigating the impact of DSAs on engraftment and long-term survival of patients undergoing allo-HSCT. We systematically searched PubMed, Embase, the Cochrane Library, and CBM. Data were analyzed using RevMan5.4. Pooled hazard ratio (HR), standard mean difference (SMD) or odds ratio (OR) and corresponding 95% confidence interval (CI) are calculated for time-to-event data, continuous data, discontinuous data respectively. 17 eligible studies were included, involving 2169 patients main receiving haploidentical SCT (haplo-SCT) or umbilical cord blood transplantation (UCBT). Meta-analysis showed that DSAs-positive patients are associated with significantly higher risk of GF(OR = 12.87, 95%CI, 6.45-25.70; P < 0.00001; OR = 4.76, 95%CI, 2.88-7.87), poorer neutrophil engraftment (HR = 2.20, 95%CI, 1.02-4.73; P = 0.04; HR = 1.83, 95%CI, 1.46-2.30; P < 0.00001), worse OS (HR = 3.19, 95%CI, 1.85-5.50; P < 0.0001; HR = 1.68, 95%CI, 1.04-2.71; P = 0.03), and inferior PFS (HR = 4.25, 95%CI, 1.59-11.40; P = 0.004; HR = 4.83, 95%CI, 1.65-14.12; P = 0.004) in haplo-SCT and UCBT, respectively.

Targeting positive cofactor 4 induces autophagic cell death in MYC-expressing diffuse large B-cell lymphoma.

MYC-expressing diffuse large B-cell lymphoma (DLBCL) is one of the refractory lymphomas. Currently, the pathogenesis of MYC-expressing DLBCL is still unclear, and there is a lack of effective therapy. We characterized positive cofactor 4 (PC4) as an upstream regulator of c-Myc, and PC4 is overexpressed in DLBCL and is closely related to clinical staging, prognosis, and c-Myc expression. Furthermore, our in vivo and in vitro studies revealed that PC4 knockdown can induce autophagic cell death and enhance the therapeutic effect of doxorubicin in MYC-expressing DLBCL. Inhibition of c-Myc-mediated aerobic glycolysis and activation of the AMPK/mTOR signaling pathway are responsible for the autophagic cell death induced by PC4 knockdown in MYC-expressing DLBCL. Using dual-luciferase reporter assay and electrophoretic mobility shift assay assays, we also found that PC4 exerts its oncogenic functions by directly binding to c-Myc promoters. To sum up, our study provides novel insights into the functions and mechanisms of PC4 in MYC-expressing DLBCL and suggests that PC4 may be a promising therapeutic target for MYC-expressing DLBCL.

Myeloablative conditioning regimens in adult patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission: a systematic review and network meta-analysis.

The optimal myeloablative conditioning (MAC) regimens in adult patients with acute myeloid leukemia (AML) undergoing allogeneic hemopoietic stem cell transplantation (allo-HSCT) in complete remission (CR) remain unclear. We performed a systematic review and network meta-analysis to compare the effects of different MAC regimens. Bayesian network meta-analysis was performed using WinBUGS version 1.4.3. The commonly used MAC regimen Bu/Cy (4-day busulfan for toal 16 mg/kg orally or 12.8 mg/kg intravenously, plus 2-day cyclophosphamide for toal 120 mg/kg intravenously) is chosen as the common comparator. Pooled hazard ratios (HRs) with the associated 95% credibility interval (95% CrI) are obtained for all comparisons. We included 19 eligible studies, involving 8104 AML patients and 9 MAC regimens. Compared with Bu/Cy, 3-day busulfan plus fludarabine and thiotepa (Bu3/Flu/TT) is associated with significantly better overall survival (HR, 0.70; 95% CrI, 0.51 to 0.96) and lower risk of relapse (HR, 0.59; 95% CrI, 0.35 to 0.98). Bu3/Flu/TT is also associated with superior overall survival than Cy/TBI (cyclophosphamide plus total body irradiation), and lower risk of relapse than Bu4/Flu (4-day busulfan plus fludarabine). These results suggest that thiotepa-based new MAC regimen Bu3/Flu/TT is associated with improved outcomes in AML patients undergoing allo-HSCT in CR and worth further investigation.

Genotypic Characterization of a Chinese Family with Osteogenesis Imperfecta and Generation of Disease-Specific Induced Pluripotent Stem Cells.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by recurring bone fractures. Some OI patients have other clinical manifestations such as growth retardation, dental abnormalities, blue sclera, and hearing loss. The relationship between the phenotype and genotype of OI is indistinct, and there is no cure for OI. Therefore, an appropriate disease model is urgently needed to understand the pathophysiology of OI. Induced pluripotent stem cells (iPSCs) are capable of developing into three germ layers and have the same genetic background as the donor cells they were derived from; thus, they are an appropriate disease model. METHODS: Blood samples collected from the proband and her affected children and one unaffected child were used forgenotyping by whole genome sequencing. A patient-specific iPSC line and a healthy donor iPSC line were generated by reprogramming peripheral blood mononuclear cells with episomal plasmids containing seven transcription factors, namely, OCT4, SOX2, NANOG, LIN28, cMYC, KLF4, and SV40LT. RESULTS: The proband and her two affected children were homozygous for a mutation in collagen type I alpha 1 exon 10, c.725G>T, predicting a p.G242V substitution. A patient-specific iPSC line and a healthy donor iPSC line were generated and characterized in terms of their human embryonic stem cell-like morphology, expression of pluripotency markers, and the ability to differentiate into cells of three germ layers. CONCLUSIONS: Here, we report the phenotyping and iPSC disease modeling of an OI family. The detailed phenotyping of the OI family and establishment of iPSCs from an OI patient and healthy family member will provide a powerful tool to evaluate the pathophysiology of OI and develop targeted therapies.

The prognostic impact of the immune microenvironment in small-cell neuroendocrine carcinoma of the uterine cervix: PD-L1 and immune cell subtypes.

BACKGROUND: We investigate the correlation between programmed cell death-ligand 1 (PD-L1) and tumor-associated immune cell (TAIC) density in small-cell neuroendocrine carcinoma of the uterine cervix (SCNEC) and their correlation with clinicopathologic features. METHODS: PD-L1 and mismatch repair protein (MMR) expression in cancer cells and the density of TAIC were evaluated by immunohistochemistry in 89 SCNEC patients. The combined positive score (CPS), tumor proportion score (TPS), and immune cell score (ICS) of PD-L1 were measured, along with their correlation with clinicopathologic features in SCNEC patients using statistical analyses. RESULTS: CPS of PD-L1 ≥ 1 was seen in 68.5% of patients, positive TPS and ICS of PD-L1 were detected in 59.6% and 33.7% of patients, respectively. PD-L1CPS was higher in tumor-infiltrating immune cells (r = 0.387, p = 0.001) and positively correlated with programmed cell death-1 and forkhead box P3 + regulatory T cell (FOXP3 + Treg) infiltration (r = 0.443, p < 0.001; r = 0.532, p < 0.001). There was no statistical correlation between PD-L1 and MMR status. PD-L1CPS and PD-L1ICS positivity were independent prognostic factors, correlating with a favorable survival (HR (95%CI) = 0.363(0.139-0.950), p = 0.039 and HR (95% CI) = 0.199(0.050-0.802), p = 0.023, respectively). PD-L1ICS positivity was an independent indicator of recurrence in SCNEC patients and associated with better disease-free survival (HR (95% CI) = 0.124(0.036-0425), p = 0.001). TAIC and MMR levels had no statistical impact on survival results. CONCLUSIONS: PD-L1 positivity was seen in over half of SCNEC tumors. It may work synergistically with FOXP3 + Treg and other infiltrating immune cells to support an adaptive immune response. PD-L1 positivity may be a favorable prognostic factor in SCNEC.

The influence of neighborhood quality on tourism in China: Using Baidu Street View pictures and deep learning techniques.

Previous studies have investigated the determinants of urban tourism development from the various attributes of neighborhood quality. However, traditional methods to assess neighborhood quality are often subjective, costly, and only on a small scale. To fill this research gap, this study applies the recent development in big data of street view images, deep learning algorithms, and image processing technology to assess quantitatively four attributes of neighborhood quality, namely street facilities, architectural landscape, green or ecological environment, and scene visibility. The paper collects more than 7.8 million Baidu SVPs of 232 prefecture-level cities in China and applies deep learning techniques to recognize these images. This paper then tries to examine the influence of neighborhood quality on regional tourism development. Empirical results show that both levels of street facilities and greenery environment promote tourism. However, the construction intensity of the landscape has an inhibitory influence on the development of tourism. The threshold test shows that the intensity of the influence varies with the city's overall economic level. These conclusions are of great significance for the development of China's urban construction and tourism economy, and also provide a useful reference for policymakers. The methodological procedure is reduplicative and can be applied to other challenging cases.

Inducement of ER Stress by PAD Inhibitor BB-Cl-Amidine to Effectively Kill AML Cells.

OBJECTIVE: Acute myeloid leukemia (AML) is a highly heterogeneous and recurrent hematological malignancy. Despite the emergence of novel chemotherapy drugs, AML patients' complete remission (CR) remains unsatisfactory. Consequently, it is imperative to discover new therapeutic targets or medications to treat AML. Such epigenetic changes like DNA methylation and histone modification play vital roles in AML. Peptidylarginine deminase (PAD) is a protein family of histone demethylases, among which the PAD2 and PAD4 expression have been demonstrated to be elevated in AML patients, thus suggesting a potential role of PADs in the development or maintenance of AML and the potential for the identification of novel therapeutic targets. METHODS: AML cells were treated in vitro with the pan-PAD inhibitor BB-Cl-Amidine (BB-Cl-A). The AML cell lines were effectively induced into apoptosis by BB-Cl-A. However, the PAD4-specific inhibitor GSK484 did not. RESULTS: PAD2 played a significant role in AML. Furthermore, we found that BB-Cl-A could activate the endoplasmic reticulum (ER) stress response, as evidenced by an increase in phosphorylated PERK (p-PERK) and eIF2α (p-eIF2α). As a result of the ER stress activation, the BB-Cl-A effectively induced apoptosis in the AML cells. CONCLUSION: Our findings indicated that PAD2 plays a role in ER homeostasis maintenance and apoptosis prevention. Therefore, targeting PAD2 with BB-Cl-A could represent a novel therapeutic strategy for treating AML.

RAD21 amplification epigenetically suppresses interferon signaling to promote immune evasion in ovarian cancer.

Prevalent copy number alteration is the most prominent genetic characteristic associated with ovarian cancer (OV) development, but its role in immune evasion has not been fully elucidated. In this study, we identified RAD21, a key component of the cohesin complex, as a frequently amplified oncogene that could modulate immune response in OV. Through interrogating the RAD21-regulated transcriptional program, we found that RAD21 directly interacts with YAP/TEAD4 transcriptional corepressors and recruits the NuRD complex to suppress interferon (IFN) signaling. In multiple clinical cohorts, RAD21 overexpression is inversely correlated with IFN signature gene expression in OV. We further demonstrated in murine syngeneic tumor models that RAD21 ablation potentiated anti-PD-1 efficacy with increased intratumoral CD8+ T cell effector activity. Our study identifies a RAD21-YAP/TEAD4-NuRD corepressor complex in immune modulation, and thus provides a potential target and biomarker for precision immunotherapy in OV.