The impact of maternal smoking during pregnancy and the age of smoking initiation on incident dementia: A prospective cohort study.

INTRODUCTION: The impact of early-life tobacco exposure on dementia has remained unknown. METHODS: Using the UK Biobank, the associations of maternal smoking during pregnancy (MSDP) and age of smoking initiation (ASI) with the onset time of all-cause dementia were estimated with accelerated failure time models. The effects of MSDP and ASI on brain structure and their genetic correlation to Alzheimer's disease (AD) were analyzed. A Mendelian randomization (MR) analysis was conducted. RESULTS: The time ratios for smokers starting in childhood, adolescence, and adulthood (vs never smokers) were 0.87 (0.76 to 0.99), 0.92 (0.88 to 0.96), and 0.95 (0.89 to 1.01). MSDP and smoking in adolescence altered many brain regions, including the hippocampus. In genetic analysis, MSDP was genetically and causally linked to AD, and a younger ASI was genetically correlated to a higher AD risk. DISCUSSION: Early-life smoking accelerated dementia onset and was genetically correlated to AD. MSDP demonstrated genetic and causal linkage to AD risks. HIGHLIGHTS: Unlike the commonly used Cox proportional hazards model, this article uses a parametric survival analysis method - the accelerated failure model - to explore the relationship between exposure to onset time. It can be used as an alternative method when the proportional hazards assumption is not met. Genetic analyses including genetic correlation study and MR analysis and brain structure analyses were conducted to support our findings and explore the potential mechanisms. The study reveals the relationship between different smoking initiation periods and the onset time of dementia and shows that earlier smoking exposure has a more significant impact on dementia. It emphasizes the importance of preventing early smoking. In the future, more research focusing on the relationship between early exposure and dementia is called for to provide more detailed prevention measures for dementia that cover all age groups.

Predictors for survival in patients with Alzheimer's disease: a large comprehensive meta-analysis.

The prevalence of Alzheimer's disease (AD) is increasing as the population ages, and patients with AD have a poor prognosis. However, knowledge on factors for predicting the survival of AD remains sparse. Here, we aimed to systematically explore predictors of AD survival. We searched the PubMed, Embase and Cochrane databases for relevant literature from inception to December 2022. Cohort and case-control studies were selected, and multivariable adjusted relative risks (RRs) were pooled by random-effects models. A total of 40,784 reports were identified, among which 64 studies involving 297,279 AD patients were included in the meta-analysis after filtering based on predetermined criteria. Four aspects, including demographic features (n = 7), clinical features or comorbidities (n = 13), rating scales (n = 3) and biomarkers (n = 3), were explored and 26 probable prognostic factors were finally investigated for AD survival. We observed that AD patients who had hyperlipidaemia (RR: 0.69) were at a lower risk of death. In contrast, male sex (RR: 1.53), movement disorders (including extrapyramidal signs) (RR: 1.60) and cancer (RR: 2.07) were detrimental to AD patient survival. However, our results did not support the involvement of education, hypertension, APOE genotype, Aß42 and t-tau in AD survival. Our study comprehensively summarized risk factors affecting survival in patients with AD, provided a better understanding on the role of different factors in the survival of AD from four dimensions, and paved the way for further research.

MaSMG7-Mediated Degradation of MaERF12 Facilitates Fusarium oxysporum f. sp. cubense Tropical Race 4 Infection in Musa acuminata.

Modern plant breeding relies heavily on the deployment of susceptibility and resistance genes to defend crops against diseases. The expression of these genes is usually regulated by transcription factors including members of the AP2/ERF family. While these factors are a vital component of the plant immune response, little is known of their specific roles in defense against Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4) in banana plants. In this study, we discovered that MaERF12, a pathogen-induced ERF in bananas, acts as a resistance gene against Foc TR4. The yeast two-hybrid assays and protein-protein docking analyses verified the interaction between this gene and MaSMG7, which plays a role in nonsense-mediated RNA decay. The transient expression of MaERF12 in Nicotiana benthamiana was found to induce strong cell death, which could be inhibited by MaSMG7 during co-expression. Furthermore, the immunoblot analyses have revealed the potential degradation of MaERF12 by MaSMG7 through the 26S proteasome pathway. These findings demonstrate that MaSMG7 acts as a susceptibility factor and interferes with MaERF12 to facilitate Foc TR4 infection in banana plants. Our study provides novel insights into the biological functions of the MaERF12 as a resistance gene and MaSMG7 as a susceptibility gene in banana plants. Furthermore, the first discovery of interactions between MaERF12 and MaSMG7 could facilitate future research on disease resistance or susceptibility genes for the genetic improvement of bananas.

New advances in the study of PD-1/PD-L1 inhibitors-induced liver injury.

The application of immune checkpoint inhibitors (ICIs) has made extraordinary achievements in tumor treatment. Among them, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors can improve the prognosis of advanced tumors, and have been widely used in clinical practice to treat many types of cancers. However, excessive immune response can also induce immune-related adverse events (irAEs) involving many organs. Of these, immune-related liver injury is the relatively common and carries the highest morbidity, which has attracted the attention of hepatologists all over the world. The incidence of this type of liver injury depends specifically on factors such as the type of drug being combined, viral infection, type of cancer and liver transplantation. Although there is no unanimity on the mechanism of PD-1/PD-L1 inhibitor-induced liver injury, in this review, we also summarize the current evidence that provides insights into the pathogenesis of PD-1/PD-L1 inhibitor-induced liver injury, including the fact that PD-1/PD-L1 inhibitors cause reactivation of CTLs, aberrant presentation of autoantigens, hepatic immune tolerance environment is disrupted, and cytokine secretion, among other effects. Patients usually develop liver injury after the use of PD-1/PD-L1 inhibitors, and clinical symptoms mainly include weakness, muscle pain, nausea and vomiting, and jaundice. Histologically, the main manifestation is lobular hepatitis with lobular inflammatory infiltration. Since the specific biomarkers for PD-1/PD-L1 inhibitor-associated liver injury have not been identified yet, alpha-fetoprotein, IL-6, and IL-33 have the potential to be biomarkers for predicting this type of liver injury in the future, but this requires further research. We also describe the examination and treatment of this type of liver injury, which usually includes eliminating related influencing factors, regularly monitoring liver function, temporarily retaining or permanently stopping ICIs treatment according to the severity of toxicity, and using corticosteroids. This review may provide useful information for the future clinical practice of PD-1/PD-L1 inhibitors.

MiR-522-3p Attenuates Cardiac Recovery by Targeting FOXP1 to Suppress Angiogenesis.

Angiogenesis is crucial for blood supply reconstitution after myocardial infarction in patients with acute coronary syndrome (ACS). MicroRNAs are recognized as important epigenetic regulators of endothelial angiogenesis. The purpose of this study is to determine the roles of miR-522-3p in angiogenesis after myocardial infarction. The expression levels of miR-522-3p in rats' plasma and in the upper part of the ligation of the heart tissues at 28 days after myocardial infarction were significantly higher than those of the sham group. miR-522-3p mimics inhibited cell proliferations, migrations, and tube formations under hypoxic conditions in HUVECs (human umbilical vein endothelial cells), whereas miR-522-3p inhibitors did the opposite. Furthermore, studies have indicated that the inhibition of miR-522-3p by antagomir infusion promoted angiogenesis and accelerated the recovery of cardiac functions in rats with myocardial infarction.Data analysis and experimental results revealed that FOXP1 (Forkhead-box protein P1) was the target gene of miR-522-3p. Our study explored the mechanism of cardiac angiogenesis after myocardial infarction and provided a potential therapeutic approach for the treatment of ischemic heart disease in the future.

Combination Nano-Delivery Systems Remodel the Immunosuppressive Tumor Microenvironment for Metastatic Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor microenvironment (TME) and activation of the body's immune system to fight tumors with well-designed nanoparticles have emerged as pivotal breakthroughs in tumor treatment. To simultaneously remodel the immunosuppressive TME and trigger immune responses, we designed two potential therapeutic nanodelivery systems to inhibit TNBC. First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs). Then, the biomimetic nanosystem MM@P3 was prepared by coating branched polymer poly(ß-amino ester) self-assembled NPs with melittin embedded macrophage membranes (MM). Both in vitro and in vivo, the CS@JQ1/CXB and MM@P3 NPs showed excellent immune activation efficiencies. Combination treatment exhibited synergistic cytotoxicity, antimigration ability, and apoptosis-inducing and immune activation effects on TNBC cells and effectively suppressed tumor growth and metastasis in TNBC tumor-bearing mice by activating the tumor immune response and inhibiting angiogenesis. In summary, this study offers a novel combinatorial immunotherapeutic strategy for the clinical TNBC treatment.

Systemic inflammation and risk of Parkinson's disease: A prospective cohort study and genetic analysis.

BACKGROUND: Multiple evidence has suggested the complex interplay between Parkinson's disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6 (IL-6). Nevertheless, the findings across studies have shown inconsistency, and the direction of the effect remains controversial. Here, we aimed to explore the link between CRP and IL-6 and the risk of PD. METHODS: Based on data from the UK Biobank, we investigated the association between baseline CRP and IL-6 and the risk of incident PD with Cox proportional hazards regression analysis. We further performed extensive genetic analyses including genetic correlation, polygenic risk score (PRS), and pleiotropic enrichment based on summary statistics from previous genome-wide association studies. RESULTS: A higher level of CRP at baseline was associated with a lower risk of PD (HR = 0.85, 95 % CI: 0.79-0.90, P = 4.23E-07). The results remained consistent in the subgroup analyses stratified by sex, age and body mass index. From the genetic perspective, a significant negative genetic correlation was identified between CRP and PD risk (correlation: -0.14, P = 6.31E-05). Higher PRS of CRP was associated with a lower risk of PD (P = 0.015, beta = -0.04, SE = 0.017). Moreover, we observed significant pleiotropic enrichment for PD conditional on CRP, and identified 13 risk loci for PD, some of which are implicated in immune functionality and have been linked to PD, including CTSB, HNF4A, PPM1G, ACMSD, and NCOR1. In contrast, no significant association was identified between IL-6 and PD. CONCLUSIONS: Systemic inflammation at baseline measured by CRP level is associated with decreased future risk of PD. These discoveries contribute to a deeper comprehension of the role of inflammation in the risk of PD, and hold implications for the design of therapeutic interventions in clinical trials.

A pan-cancer analysis of the prognosis and immune infiltration of eEF1A2 and its potential function in thyroid carcinoma.

Purpose: Eukaryotic translation elongation factor 1α2 (eEF1A2) promotes tumour progression in various cancers. We performed a pan-cancer analysis of eEF1A2 and explored its role in thyroid carcinoma (THCA). Methods: Databases from The Cancer Genome Atlas (TCGA), the University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), and the Human Protein Atlas (HPA) were used to investigate the differential expression of eEF1A2 in pan-cancer. The pathological stage, prognostic characteristics, tumour microenvironment (TME), tumour mutational burden (TMB), and microsatellite instability (MSI) were analysed in diverse tumours with different expression levels of eEF1A2. The expression levels in papillary thyroid carcinoma (PTC) and its specific role in cell proliferation, migration, invasion, and cell glycolysis in PTC cells were verified by quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry, cell counting kit-8, colony formation, wound healing, Transwell assay, and lactate acid and glucose assays.Results:eEF1A2 was differentially expressed in various malignant tumour tissues compared to control tissues and was associated with poor pathological stage and prognosis in most types of tumours. Moreover, eEF1A2 expression closely correlated with the infiltration of immunosuppressive cells, TMB, and MSI in some tumour types. Expression of eEF1A2 in PTC is higher than the para-carcinoma, and eEF1A2 downregulation suppressed TPC-1 and BCPAP cell proliferation, migration, invasion, and glycolysis. Conclusion: Our study suggests that the expression of eEF1A2 is related to the prognosis and immune infiltration of some tumours and may be a predictor of prognosis and immunotherapy. eEF1A2 could promote malignant behaviour of PTC cells.

[Pseudo-targeted metabolomics study of immune stress-mediated idiosyncratic liver injury induced by synergistic effects of bavachin and epimedin B].

Chinese patent medicine preparations containing Epimedii Folium and Psoraleae Fructus have been associated with the occurrence of idiosyncratic drug-induced liver injury(IDILI). However, the specific toxic biomarkers and mechanisms underlying these effects remain unclear. This study aimed to comprehensively assess the impact of bavachin and epimedin B, two principal consti-tuents found in Psoraleae Fructus and Epimedii Folium, on an IDILI model induced by tumor necrosis factor-α(TNF-α) treatment, both in vitro and in vivo. To evaluate the extent of liver injury, various parameters were assessed. Lactate dehydrogenase(LDH) release in the cell culture supernatant, as well as the levels of alanine aminotransferase(ALT) and aspartate transaminase(AST) in mouse plasma were measured. Additionally, histological analysis employing hematoxylin-eosin staining was performed to observe liver tissue changes indicative of the severity of liver injury. Furthermore, a pseudo-targeted metabolomics approach was employed, followed by multivariate analysis, to identify differential metabolites. These identified metabolites were subsequently subjected to Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis. The results showed that at the cellular level, after 2 hours of TNF-α stimulation, bavachin significantly increased the release of LDH in HepG2 cells compared to the normal group and the group treated alone; after the combination of bavachin and epimedin B, the release of LDH further significantly increased on the original basis. Similarly, although the individual or combination treatments of bavachin and epimedin B did not induce liver injury in normal mice, the combination of both drugs induced marked liver injury in TNF-α treated mice, leading to a significant elevation in plasma AST and ALT levels and substantial infiltration of inflammatory immune cells in the liver tissue. Pseudo-targeted metabolomics analysis identified seven common differential metabolites. Among these, D-glucosamine-6-phosphate, N1-methyl-2-pyridone-5-carboxamide, 17beta-nitro-5a-androstane, irisolidone-7-O-glucuronide, and N-(1-deoxy-1-fructosyl) valine emerged as potential biomarkers, with an area under the curve(AUC) exceeding 0.9. Furthermore, our results suggest that the metabolism of nicotinic acid and nicotinamide, as well as the linoleic acid metabolic pathway, may play pivotal roles in bavachin and epimedin B-induced IDILI. In conclusion, within an immune-stressed environment mediated by TNF-α, bavachin and epimedin B appear to induce IDILI through disruptions in metabolic processes.

Eu3+ doped ethylenediamine functionalized UiO-66 probe for fluorescence sensing of formaldehyde.

The development of probes with selectivity and prompt detection of aldehydes molecules is of great importance for protecting human health and public security. Herein, a system based on ethylenediamine (EDA) functionalized and Eu3+-doped UiO-66, namely EDA-Eu3+@UiO-66, was designed to detect formaldehyde molecules. Based on the "antenna effect" of lanthanide elements, UiO-66 transfers the absorbed energy to Eu3+ ions and emits characteristic fluorescence belonging to Eu3+. By using the fluorescence peaks of UiO-66 and Eu3+ respectively, a ratiometric fluorescence sensing probe can be constructed. Formaldehyde molecules react with the -NH2 on the surface of EDA-Eu3+@UiO-66 through an aldehyde-amine condensation reaction and connect to the functionalized surface of UiO-66. Due to the absorption of excitation light energy by formaldehyde molecules, the energy transfer efficiency from UiO-66 to Eu3+ ions is reduced, resulting in the fluorescence quenching of EDA-Eu3+@UiO-66, thus achieving selective detection of formaldehyde. The fabricated sensing platform successfully detected residual formaldehyde in frozen shrimp tail samples. The system was also used to respond to formaldehyde vapor, and a significant fluorescence quenching effect was observed. This strategy provides a sensitive, selective, and reliable method for the visual sensing of formaldehyde.

Association between self-reported oral health and Parkinson's disease: evidence from UK biobank.

Objectives Oral health problem is prevalent in the elderly population which is also at high risk of Parkinson's disease (PD). However, the association between self-reported oral health and PD is still unclear. We aimed to explore the association between baseline self-reported oral health (mouth ulcers, painful gums, bleeding gums, loosen teeth, toothache, dentures) and future incidence of PD. Methods Participants were enrolled in the UK biobank from 2006 to 2010 and those without PD at baseline were included in the current study. We used Cox regression analysis to explore the question and adjusted for age, sex, body mass index, smoking, drinking, ethnicity, education, socioeconomic status, and average total household income before tax. Results We included 421180 participants with a mean age of 56.26 years old and 46.5% of them were male. And 2339 participants were diagnosed with PD in the follow-up. Mouth ulcers, loosen teeth, dentures, toothache, and bleeding gums were not related to the risk of PD. Painful gums were related to a higher risk of PD (HR: 1.39, 95%CI: 1.12-1.72, P = 0.003), and similar results were reached after adjusting for gene risk (HR: 1.39, 95%CI: 1.12-1.73, P = 0.003), or source of diagnosis (HR: 1.39, 95%CI: 1.12-1.72, P = 0.002), and time of diagnosis (HR: 1.29, 95%CI: 1.03-1.63, P = 0.02). Conclusions Our study has demonstrated a substantial correlation between painful gums and elevated susceptibility to PD, underscoring the potential advantages of implementing oral health interventions for decreasing the risk of PD.

Evaluating distinct KRAS subtypes as potential biomarkers for immune checkpoint inhibitor efficacy in lung adenocarcinoma.

Background: Despite the acknowledged predictive value of KRAS in immune checkpoint inhibitor (ICI) responses, the heterogeneous behavior of its mutations in this sphere remains largely unexplored. As of now, no studies have definitively categorized KRAS subtype variations as independent prognostic indicators for ICI responses in lung cancer patients. Methods: We analyzed a cohort of 103 patients, all harboring different KRAS mutation subtypes, and complemented this data with information from TCGA and GEO databases. Our research focused on delineating the relationships between KRAS mutation subtypes and factors like immunotherapy markers and immune cell composition, in addition to examining survival rates, drug sensitivity, and PD-L1 responses corresponding to distinct KRAS subtypes. Results: We found that the G12V and G12D subtypes demonstrated elevated expressions of immunotherapy markers, implying a potentially enhanced benefit from immunotherapy. Significant variations were identified in the distribution of naive B cells, activated CD4+ memory T cells, and regulatory T cells (Tregs) across different KRAS mutant subtypes. A notable difference was observed in the Tumor Mutation Burden (TMB) levels across the four KRAS subtypes, with the G12D subtype displaying the lowest TMB level. Furthermore, G12C subtype showcased the worst prognosis in terms of progression-free intervals (PFI), in stark contrast to the more favorable outcomes associated with the G12A subtype. Conclusion: Our study reveals that KRAS mutations exhibit considerable variability in predicting outcomes for LUAD patients undergoing ICI treatment. Thus, the evaluation of KRAS as a biomarker for ICIs necessitates recognizing the potential diversity inherent in KRAS mutations.

Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia: a single-arm, phase 2 study.

BACKGROUND: Relapses frequently occur following CD19-directed chimeric antigen receptor (CAR) T-cell treatment for relapsed or refractory B-cell acute lymphocytic leukaemia in children. We aimed to assess the activity and safety of sequential CD19-directed and CD22-directed CAR T-cell treatments. METHODS: This single-centre, single-arm, phase 2 trial, done at Beijing GoBroad Boren Hospital, Beijing, China, included patients aged 1-18 years who had relapsed or refractory B-cell acute lymphocytic leukaemia with CD19 and CD22 positivity greater than 95% and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were initially infused with CD19-directed CAR T cells intravenously, followed by CD22-directed CAR T-cell infusion after minimal residual disease-negative complete remission (or complete remission with incomplete haematological recovery) was reached and all adverse events (except haematological adverse events) were grade 2 or better. The target dose for each infusion was 0·5 × 106 to 5·0 × 106 cells per kg. The primary endpoint was objective response rate at 3 months after the first infusion. Secondary endpoints were duration of remission, event-free survival, disease-free survival, overall survival, safety, pharmacokinetics, and B-cell quantification. The prespecified activity analysis included patients who received the target dose and the safety analysis included all treated patients. This study is registered with ClinicalTrials.gov, NCT04340154, and enrolment has ended. FINDINGS: Between May 28, 2020, and Aug 16, 2022, 81 participants were enrolled, of whom 31 (38%) were female and 50 (62%) were male. Median age was 8 years (IQR 6-10), all patients were Asian. All 81 patients received the first infusion and 79 (98%) patients received sequential infusions, CD19-directed CAR T cells at a median dose of 2·7 × 106 per kg (IQR 1·1 × 106 to 3·7 × 106) and CD22-directed CAR T cells at a median dose of 2·2 × 106 per kg (1·1 × 106 to 3·7 × 106), with a median interval of 39 days (37-41) between the two infusions. 62 (77%) patients received the target dose, including two patients who did not receive CD22 CAR T cells. At 3 months, 60 (97%, 95% CI 89-100) of the 62 patients who received the target dose had an objective response. Median follow-up was 17·7 months (IQR 11·4-20·9). 18-month event-free survival for patients who received the target dose was 79% (95% CI 66-91), duration of remission was 80% (68-92), and disease-free survival was 80% (68-92) with transplantation censoring; overall survival was 96% (91-100). Common adverse events of grade 3 or 4 between CD19-directed CAR T-cell infusion and 30 days after CD22-directed CAR T-cell infusion included cytopenias (64 [79%] of 81 patients), cytokine release syndrome (15 [19%]), neurotoxicity (four [5%]), and infections (five [6%]). Non-haematological adverse events of grade 3 or worse more than 30 days after CD22-directed CAR T-cell infusion occurred in six (8%) of 79 patients. No treatment-related deaths occurred. CAR T-cell expansion was observed in all patients, with a median peak at 9 days (IQR 7-14) after CD19-directed and 12 days (10-15) after CD22-directed CAR T-cell infusion. At data cutoff, 35 (45%) of 77 evaluable patients had CAR transgenes and 59 (77%) had B-cell aplasia. INTERPRETATION: This sequential strategy induced deep and sustained responses with an acceptable toxicity profile, and thus potentially provides long-term benefits for children with this condition. FUNDING: The National Key Research & Development Program of China, the CAMS Innovation Fund for Medical Sciences (CIFMS), and the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Genome-wide comprehensive characterization and transcriptomic analysis of AP2/ERF gene family revealed its role in seed oil and ALA formation in perilla (Perilla frutescens).

Perilla (Perilla frutescens) is a potential specific oilseed crop with an extremely high α-linolenic acid (ALA) content in its seeds. AP2/ERF transcription factors (TFs) play important roles in multiple biological processes. However, limited information is known about the regulatory mechanism of the AP2/ERF family in perilla's oil accumulation. In this research, we identified 212 AP2/ERF family members in the genome of perilla, and their domain characteristics, collinearity, and sub-genome differentiation were comprehensively analyzed. Transcriptome sequencing revealed that genes encoding key enzymes involved in oil biosynthesis (e.g., ACCs, KASII, GPAT, PDAT and LPAAT) were up-regulated in the high-oil variety. Moreover, the endoplasmic reticulum-localized FAD2 and FAD3 were significantly up-regulated in the high-ALA variety. To investigate the roles of AP2/ERFs in lipid biosynthesis, we conducted a correlation analysis between non-redundant AP2/ERFs and key lipid metabolism genes using WGCNA. A significant correlation was found between 36 AP2/ERFs and 90 lipid metabolism genes. Among them, 12 AP2/ERFs were identified as hub genes and showed significant correlation with lipid synthase genes (e.g., FADs, GPAT and ACSL) and key regulatory TFs (e.g., LEC2, IAA, MYB, UPL3). Furthermore, gene expression analysis identified three AP2/ERFs (WRI, ABI4, and RAVI) potentially playing an important role in the regulation of oil accumulation in perilla. Our study suggests that PfAP2/ERFs are important regulatory TFs in the lipid biosynthesis pathway, providing a foundation for the molecular understanding of oil accumulation in perilla and other oilseed crops.

Angelicin inhibits cell growth and promotes apoptosis in oral squamous cell carcinoma by negatively regulating DUSP6/cMYC signaling pathway.

Angelicin has been reported to have antitumor effects on many types of cancer. However, few studies on angelicin in oral squamous cell carcinoma (OSCC) have been performed. We performed cell cycle and apoptosis analyses to assess the effect of angelicin on OSCC cells. We conducted RNA-seq studies to reveal differentially expressed genes (DEGs). Dual-specificity phosphatase 6 (DUSP6) and c-MYC were strongly down-regulated differential genes. Silencing RNA (siRNA) was used to knockdown DUSP6. The mouse xenograft model was used to mimic OSCC. Angelicin inhibited OSCC in vitro. We found that DUSP6 interacted with c-MYC. DUSP6 knockdown group and DUSP6 knockdown + angelicin group had similar effects of OSCC cells. Angelicin could reduce tumor formation, DUSP6, and c-MYC expression in vivo. Compared with paclitaxel, the tumor inhibition effect of the two drugs was similar. However, angelicin did not cause weight loss and had lower toxicity. In sum, Angelicin has antitumor effects on OSCC in vitro and vivo by negatively regulating the DUSP6 mediated c-MYC signaling pathway.

Sijunzi Tang improves gefitinib resistance by regulating glutamine metabolism.

Lung cancer is a major health concern and significant barrier to human well-being and social development. Although targeted therapy has shown remarkable progress in the treatment of lung cancer, the emergence of drug resistance has limited its clinical efficacy. Sijunzi Tang (SJZ) is a classical Chinese herbal formula known for tonifying qi and nourishing the lungs, has been recognized for its potential in lung cancer management. However, the underlying mechanism of its combined use with anti-cancer drugs remains unclear. Here, we investigated the anti-lung cancer efficacy and underlying mechanisms of the combination of gefitinib and SJZ in gefitinib-resistant human lung adenocarcinoma cells (PC-9/GR). We conducted in vitro and in vivo experiments using histopathology and targeted metabolomics approaches. Our results demonstrated that the combination of SJZ and gefitinib exhibited synergistic effects on tumor growth inhibition in PC-9/GR-bearing nude mice. Notably, the co-administration of SJZ and gefitinib synergistically promoted tumor cell apoptosis, potentially through the regulation of BAX and BCL-2 expression. Immunohistochemistry and western blot analysis found down-regulation of GLS, GS, and SLC1A5 expression in the co-administration group compared to the control and the individual treatment groups. Targeted metabolomics revealed significant alterations in the plasma glutamine metabolic markers glutamine, alanine, succinate, glutamate, and pyruvate. Of the glutamine metabolism markers measured in tumor tissues, glutamine and pyruvate demonstrated significant differences across the treatment groups. These findings suggest that administration of SJZ improves gefitinib resistance in the treatment of lung cancer without toxic effects. Moreover, SJZ may affect glutamine metabolism by regulating key targets involved in glutamine metabolism (SLC1A5, GLS, and GS) and modulating the levels of related metabolic markers, ultimately reducing gefitinib resistance.

Fusaric acid inhibits proliferation and induces apoptosis through triggering endoplasmic reticulum stress in MCF-7 human breast cancer cells.

Breast cancer has replaced lung cancer to be the leading cancer in the world. Currently, chemotherapy is still the major method for breast cancer therapy, but its overall effect remains unsatisfactory. Fusaric acid (FSA), a mycotoxin derived from fusarium species, has shown potency against the proliferation of several types of cancer cells, but its effect on breast cancer cells has not been examined. Therefore, we explored the possible effect of FSA on the proliferation of MCF-7 human breast cancer cells and uncovered the underlying mechanism in the present study. Our results showed that FSA has a strong anti-proliferative effect on MCF-7 cells through inducing ROS production, apoptosis and arresting cell cycle at G2/M transition phase. Additionally, FSA triggers endoplasmic reticulum (ER) stress in the cells. Notably, the cell cycle arrest and apoptosis inducing effect of FSA can be attenuated by ER stress inhibitor, tauroursodeoxycholic acid. Our study provide evidence that FSA is a potent proliferation inhibition and apoptosis inducing agent against human breast cancer cells, and the possible mechanism involves the activation of ER stress signaling pathways. Our study may highlight that FSA is promising for the future in vivo study and development of potential agent for breast cancer therapy.

The recent progress of endocrine therapy-induced osteoporosis in estrogen-positive breast cancer therapy.

Breast cancer is a significant global health concern, and the discovery of endocrine therapy has played a crucial role in the treatment of estrogen-positive breast cancer. However, these therapies are often associated with osteoporosis-related adverse events, which increase the risk of fractures in breast cancer patients and can result in limited mobility and reduced quality of life. Previous studies have shown that osteoporosis is essential side effects of the breast cancer therapy, although the exact mechanisms remain mostly unclear. Current clinical treatments, such as bisphosphonates, cause side effects and may impact the therapeutic response to endocrine drugs. In this review, we explore the likelihood of endocrine therapy-induced osteoporosis in estrogen-positive breast cancer therapy and discuss the involved mechanisms as well as the therapeutic potential of drugs and drug combination strategies.

Multi-view radiomics and deep learning modeling for prostate cancer detection based on multi-parametric MRI.

Introduction: This study aims to develop an imaging model based on multi-parametric MR images for distinguishing between prostate cancer (PCa) and prostate hyperplasia. Methods: A total of 236 subjects were enrolled and divided into training and test sets for model construction. Firstly, a multi-view radiomics modeling strategy was designed in which different combinations of radiomics feature categories (original, LoG, and wavelet) were compared to obtain the optimal input feature sets. Minimum-redundancy maximum-relevance (mRMR) selection and least absolute shrinkage selection operator (LASSO) were used for feature reduction, and the next logistic regression method was used for model construction. Then, a Swin Transformer architecture was designed and trained using transfer learning techniques to construct the deep learning models (DL). Finally, the constructed multi-view radiomics and DL models were combined and compared for model selection and nomogram construction. The prediction accuracy, consistency, and clinical benefit were comprehensively evaluated in the model comparison. Results: The optimal input feature set was found when LoG and wavelet features were combined, while 22 and 17 radiomic features in this set were selected to construct the ADC and T2 multi-view radiomic models, respectively. ADC and T2 DL models were built by transferring learning from a large number of natural images to a relatively small sample of prostate images. All individual and combined models showed good predictive accuracy, consistency, and clinical benefit. Compared with using only an ADC-based model, adding a T2-based model to the combined model would reduce the model's predictive performance. The ADCCombinedScore model showed the best predictive performance among all and was transformed into a nomogram for better use in clinics. Discussion: The constructed models in our study can be used as a predictor in differentiating PCa and BPH, thus helping clinicians make better clinical treatment decisions and reducing unnecessary prostate biopsies.