Factors influencing self-regulatory fatigue in patients undergoing chemotherapy for gynecologic cancer: a cross-sectional study.

Objective: To understand the current status of self-regulatory fatigue among gynecologic cancer chemotherapy patients and explore influencing factors. Methods: Using convenient sampling, a total of 232 gynecological cancer chemotherapy patients from two tertiary hospitals in Zhengzhou, Henan, China, were selected as study subjects from February 2023 to April 2023. General information questionnaire, Self-Regulatory Fatigue Scale (SRF-S), Strategies Used by People to Promote Health (SUPPH) Scale, Connor-Davidson resilience scale (CD-RISC) and Perceived Social Support Scale (PSSS) were employed for data collection. The data were analyzed using SPSS 26.0 software. Chi-square test and binary logistic regression were executed to explore the correlates of self-regulatory fatigue, the significance level (α) was set at 0.05. Results: The self-regulatory fatigue score of the 232 patients was 44 (36, 56). Binary logistic regression analyses revealed significant associations, demonstrating that residing in urban areas (OR=0.241, P=0.015), having no comorbidities (OR=0.158, P=0.015), increased perceived social support (OR=0.937, P=0.001), strong self-efficacy (OR=0.959, P=0.021), and heightened psychological resilience (OR=0.895, P<0.001) acted as protective factors against self-regulatory fatigue (P < 0.05). Conclusion: Patients residing in rural areas, having more than two comorbidities, lower self-efficacy and psychological resilience levels, and lower perceived social support are indicative of higher levels of self-regulatory fatigue. Identifying these influencing factors can provide references and support for developing individualized support and intervention measures to improve patients' physical and mental well-being.

MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions.

OBJECTIVES: Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress. METHODS: ROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo. RESULTS: We found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models. DISCUSSION: our study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2.

Complete response after treatment of breast cancer with isolated liver metastasis: a case report.

Background: Breast cancer has a high incidence and is prone to metastasis, while isolated liver metastasis is rare. A growing body of evidence supports the effectiveness of treating breast cancer with anti-human epidermal growth factor receptor-2 (HER2) therapy in combination with chemotherapy. However, little is known about its impact on metastatic liver disease. There is also a lack of consensus on managing liver metastases from breast cancer, and no studies have been conducted on managing the disappearance of liver metastases after treatment. Case Description: In May 2021, a 51-year-old female patient with HER2-positive breast cancer with isolated liver metastases had immunohistochemistry of estrogen receptor (ER) (-), progesterone receptor (PR) (-), and HER2 (3+) for both her primary lesion and liver metastases. After undergoing 17 cycles of anti-HER2 therapy and chemotherapy, the patient expressed a desire for surgery. Then a preoperative examination was performed, which revealed the disappearance of both the primary breast lesion and the liver metastases. Immediately afterwards, a left mastectomy was performed, and postoperative pathology showed a complete response to the breast tumor. As for the liver, where the metastatic lesions disappeared, no relevant study has reported how to deal with this situation. Finally, after a hospital-wide discussion, the patient was given trastuzumab maintenance therapy. Until now, no obvious signs of recurrence or metastasis have been observed during regular follow-ups. Conclusions: This case suggests that maintenance therapy may be the best option for patients with breast cancer whose liver metastases disappear by medication. Also, it can be inferred that in HER2-positive metastatic breast cancer (MBC), patients with isolated liver metastases may be more likely to achieve a cure-like outcome. Nevertheless, more cases and follow-up information are needed to support these views.

m6A-methylated Lonp1 drives mitochondrial proteostasis stress to induce testicular pyroptosis upon environmental cadmium exposure.

Cadmium (Cd) is a widely distributed typical environmental pollutant and one of the most toxic heavy metals. It is well-known that environmental Cd causes testicular damage by inducing classic types of cell death such as cell apoptosis and necrosis. However, as a new type of cell death, the role and mechanism of pyroptosis in Cd-induced testicular injury remain unclear. In the current study, we used environmental Cd to generate a murine model with testicular injury and AIM2-dependent pyroptosis. Based on the model, we found that increased cytoplasmic mitochondrial DNA (mtDNA), activated mitochondrial proteostasis stress occurred in Cd-exposed testes. We used ethidium bromide to generate mtDNA-deficient testicular germ cells and further confirmed that increased cytoplasmic mtDNA promoted AIM2-dependent pyroptosis in Cd-exposed cells. Uracil-DNA glycosylase UNG1 overexpression indicated that environmental Cd blocked UNG-dependent repairment of damaged mtDNA to drive the process in which mtDNA releases to cytoplasm in the cells. Interestingly, we found that environmental Cd activated mitochondrial proteostasis stress by up-regulating protein expression of LONP1 in testes. Testicular specific LONP1-knockdown significantly reversed Cd-induced UNG1 protein degradation and AIM2-dependent pyroptosis in mouse testes. In addition, environmental Cd significantly enhanced the m6A modification of Lonp1 mRNA and its stability in testicular germ cells. Knockdown of IGF2BP1, a reader of m6A modification, reversed Cd-induced upregulation of LONP1 protein expression and pyroptosis activation in testicular germ cells. Collectively, environmental Cd induces m6A modification of Lonp1 mRNA to activate mitochondrial proteostasis stress, increase cytoplasmic mtDNA content, and trigger AIM2-dependent pyroptosis in mouse testes. These findings suggest that mitochondrial proteostasis stress is a potential target for the prevention of testicular injury.

Ocular A-to-I RNA editing signatures associated with SARS-CoV-2 infection.

Ophthalmic manifestations have recently been observed in acute and post-acute complications of COVID-19 caused by SARS-CoV-2 infection. Our precious study has shown that host RNA editing is linked to RNA viral infection, yet ocular adenosine to inosine (A-to-I) RNA editing during SARS-CoV-2 infection remains uninvestigated in COVID-19. Herein we used an epitranscriptomic pipeline to analyze 37 samples and investigate A-to-I editing associated with SARS-CoV-2 infection, in five ocular tissue types including the conjunctiva, limbus, cornea, sclera, and retinal organoids. Our results revealed dramatically altered A-to-I RNA editing across the five ocular tissues. Notably, the transcriptome-wide average level of RNA editing was increased in the cornea but generally decreased in the other four ocular tissues. Functional enrichment analysis showed that differential RNA editing (DRE) was mainly in genes related to ubiquitin-dependent protein catabolic process, transcriptional regulation, and RNA splicing. In addition to tissue-specific RNA editing found in each tissue, common RNA editing was observed across different tissues, especially in the innate antiviral immune gene MAVS and the E3 ubiquitin-protein ligase MDM2. Analysis in retinal organoids further revealed highly dynamic RNA editing alterations over time during SARS-CoV-2 infection. Our study thus suggested the potential role played by RNA editing in ophthalmic manifestations of COVID-19, and highlighted its potential transcriptome impact, especially on innate immunity.

The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans.

BACKGROUND: Autoantibody-mediated cytopenias (AICs) regularly occur in profoundly IgG-deficient common variable immunodeficiency (CVID) patients. The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear. OBJECTIVE: To determine reactivity, clonality and provenance of AIC-associated IgM autoantibodies in CVID patients. METHODS: We utilized glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan binding profiles were used to identify auto-reactive clones across B cell subsets, specifically circulating marginal zone-like (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes and responses of tonsillar MZ B cells to different T helper cell subsets were determined by confocal microscopy, RNA-sequencing, and co-cultures, respectively. RESULTS: Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen-recognizing B-cell receptors were highly enriched among CVID+AIC circulating marginal zone (MZ) B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL10/IL-21 secreting FOXP3-CD25hiTfh cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3+ regulatory T cells, and rare FOXP3-CD25+ cells that represented likely CD25hiTfh cells, all localized outside of GCs. In CVID+AIC lymph nodes, cellular positions were similar but CD25hiTfh cells greatly outnumbered regulatory cells. CONCLUSIONS: Our findings indicate glycan-reactive IgM autoantibodies produced outside of GCs may contribute to the autoimmune pathogenesis of CVID.

Immunotherapy for patients with advanced non-small cell lung cancer harboring oncogenic driver alterations other than EGFR: a multicenter real-world analysis.

Background: The administration of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) with oncogenic driver alterations other than epidermal growth factor receptor (EGFR) aroused a heated discussion. We thus aimed to evaluate ICI treatment in these patients in real-world routine clinical practice. Methods: A multicenter, retrospective study was conducted for NSCLC patients with at least one gene alteration (KRAS, HER2, BRAF, MET, RET, ALK, ROS1) receiving ICI monotherapy or combination treatment. The data regarding clinicopathologic characteristics, clinical efficacy, and safety were investigated. Results: A total of 216 patients were included, the median age was 60 years, 72.7% of patients were male, and 46.8% had a smoking history. The molecular alterations involved KRAS (n=95), HER2 (n=42), BRAF (n=22), MET (n=21), RET (n=14), ALK (n=14), and ROS1 (n=8); 56.5% of patients received immunotherapy in the first-line, and the rest 43.5% were treated as a second-line and above. For the entire cohort who received immunotherapy-based regimens in the first-line, the median progression-free survival (PFS) was 7.5 months and the median overall survival (OS) was 24.8 months. For the entire cohort who received immunotherapy-based regimens in the second-line and above, the median PFS was 4.7 months and median OS was 17.1 months. KRAS mutated NSCLC treated with immunotherapy-based regimens in the first-line setting had a median PFS and OS were 7.8 and 26.1 months, respectively. Moreover, the median PFS and OS of immunotherapy-based regimens for KRAS-mutant NSCLC that progressed after chemotherapy were 5.9 and 17.1 months. Programmed death ligand 1 (PD-L1) expression level was not consistently associated with response to immunotherapy across different gene alteration subsets. In the KRAS group, PD-L1 positivity [tumor proportion score (TPS) ≥1%] was associated with better PFS and OS according to the multivariate Cox analysis. No statistically significant association was found for smoking status, age, or gender with clinical efficacy in any gene group analyses. Conclusions: KRAS-mutant NSCLC could obtain clinical benefits from ICIs either for treatment-naive patients or those who have experienced progression after chemotherapy, and PD-L1 positive expression (TPS >1%) may be a potential positive predictor. For NSCLC with ALK, RET and ROS1 rearrangement, MET exon 14 skipping mutation, or BRAF V600E mutation, effectiveness of single or combined ICI therapy remains limited, therefore, targeted therapies should be considered prior to immunotherapy regimens. Future studies should address the investigation of better predictive biomarkers for immunotherapy response in oncogene-driven NSCLC.

First-Principles Predictions of MoS2-WS2 In-Plane Heterostructures for Sensing Dissolved Gas Species in Oil-Immersed Transformers.

This work from first-principles insight uses a MoS2-WS2 in-plane heterostructure as a potential sensing material for detection of CO and C2H2, two typical dissolved gases in oil-immersed transformers, in order to evaluate the operation status. The adsorption performance of the MoS2-WS2 heterostructure upon two gas species is assessed via three adsorption sites and compared with isolated MoS2 and WS2. Results indicate that MoS2-WS2 performs with a much stronger binding force and charge-transfer for adsorptions of CO and C2H2 in comparison to the isolated counterpart, which gives rise to more obvious deformation in the electronic property of MoS2-WS2 as well as a much larger resistance-based sensing response. The recovery time of MoS2-WS2 for desorption of CO and C2H2 molecules is also appropriate to allow the reusability of such a sensor. The findings in this work uncover the admirable sensing potential of transition metal dichalcogenides (TMDs)-based heterostructures upon oil dissolved gases, which opens up a new way to explore novel 2D nanomaterials as resistive gas sensors for dissolved gas analysis in electrical oil-immersed transformers.

Radiation-primed TGF-ß trapping by engineered extracellular vesicles for targeted glioblastoma therapy.

The poor outcome of glioblastoma multiforme (GBM) treated with immunotherapy is attributed to the profound immunosuppressive tumor microenvironment (TME) and the lack of effective delivery across the blood-brain barrier. Radiation therapy (RT) induces an immunogenic antitumor response that is counteracted by evasive mechanisms, among which transforming growth factor-ß (TGF-ß) activation is the most prominent factor. We report an extracellular vesicle (EV)-based nanotherapeutic that traps TGF-ß by expressing the extracellular domain of the TGF-ß type II receptor and targets GBM by decorating the EV surface with RGD peptide. We show that short-burst radiation dramatically enhanced the targeting efficiency of RGD peptide-conjugated EVs to GBM, while the displayed TGF-ß trap reversed radiation-stimulated TGF-ß activation in the TME, offering a synergistic effect in the murine GBM model. The combined therapy significantly increased CD8+ cytotoxic T cells infiltration and M1/M2 macrophage ratio, resulting in the regression of tumor growth and prolongation of overall survival. These results provide an EV-based therapeutic strategy for immune remodeling of the GBM TME and eradication of therapy-resistant tumors, further supporting its clinical translation.

Small extracellular vesicles derived from human mesenchymal stem cells prevent Th17-dominant neutrophilic airway inflammation via immunoregulation on Th17 cells.

Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation is critical in the pathogenesis of steroid-resistant airway inflammation such as severe asthma. Small extracellular vesicles (sEV) derived from human mesenchymal stem cells (MSCs) display extensive therapeutic effects and advantages in many diseases. However, the role of MSC-sEV in Th17-dominant neutrophilic airway inflammation and the related mechanisms are still poorly studied. Here we found that MSC-sEV significantly alleviated the infiltration of inflammatory cells in peribronchial interstitial tissues and reduced levels of inflammatory cells, especially neutrophils, in bronchoalveolar lavage fluids (BALF) of mice with neutrophilic airway inflammation. Consistently, MSC-sEV significantly decreased levels of IL-17A in BALF and Th17 in lung tissues. Furthermore, we found that labelled MSC-sEV were taken up by human CD4+ T cells most obviously at 12 h after incubation, and distributed mostly in mouse lungs. More importantly, potential signaling pathways involved in the MSC-sEV mediated inhibition of Th17 polarization were found using RNA sequencing. Using Western blot, JAK2-STAT3 pathway was identified as an important role in the inhibition of Th17 polarization by MSC-sEV. We found that proteins in MSC-sEV were mostly involved in the therapeutic effects of MSC-sEV. In total, our study suggested that MSC-sEV could be a potential therapeutic strategy for the treatment of neutrophilic airway inflammation.

The oncogenic role and regulatory mechanism of ACAA2 in human ovarian cancer.

Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial ß oxidation, which plays an important role in fatty acid metabolism. The expression of ACAA2 is closely related to the occurrence and malignant progression of tumors. However, the function of ACAA2 in ovarian cancer is unclear. The expression level and prognostic value of ACAA2 were analyzed by databases. Gain and loss of function were carried out to explore the function of ACAA2 in ovarian cancer. RNA-seq and bioinformatics methods were applied to illustrate the regulatory mechanism of ACAA2. ACAA2 overexpression promoted the growth, proliferation, migration, and invasion of ovarian cancer, and ACAA2 knockdown inhibited the malignant progression of ovarian cancer as well as the ability of subcutaneous tumor formation in nude mice. At the same time, we found that OGT can induce glycosylation modification of ACAA2 and regulate the karyoplasmic distribution of ACAA2. OGT plays a vital role in ovarian cancer as a function of oncogenes. In addition, through RNA-seq sequencing, we found that ACAA2 regulates the expression of DIXDC1. ACAA2 regulated the malignant progression of ovarian cancer through the WNT/ß-Catenin signaling pathway probably. ACAA2 is an oncogene in ovarian cancer and has the potential to be a target for ovarian cancer therapy.

Global, Regional and National Burden of Human Cystic Echinococcosis from 1990 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019.

BACKGROUND: Cystic echinococcosis (CE) is a neglected tropical parasitic disease that poses huge disease, social and economic burdens worldwide; however, there has been little knowledge on the global morbidity, mortality and disability-adjusted life years (DALYs) of CE until now. This study aimed to collect the most up-to-date data about the global, regional and national disease burden due to CE from 1990 to 2019 and to project trends in the next 10 years. METHODS: We measured the global, regional and national morbidity, mortality and DALYs of CE from 1990 to 2019 based on the Global Burden of Disease Study 2019 (GBD 2019) data, and we examined the correlation between socioeconomic development levels and the disease burden of CE. In addition, the disease burden due to CE was projected from 2020 to 2030. RESULTS: The age-standardized incidence rate (ASIR) of CE reduced from 2.65/105 [95% UI: (1.87/105 to 3.7/105)] in 1990 to 2.6/105 [95% UI: (1.72/105 to 3.79/105)] in 2019 (EAPC = -0.18%). The number of deaths, DALYs, age-standardized mortality rate (ASMR) and age-standardized DALY rate due to CE all showed a tendency to decline from 1990 to 2019. A higher disease burden of CE was measured in women than in men in 2019. There was a significant difference in the ASMR of CE by region according to the socio-demographic index (SDI), and lower burdens of CE were estimated in high-SDI regions. The global ASIR of CE is projected to decline from 2020 to 2030; however, the ASMR and age-standardized DALY rate are projected to rise. CONCLUSIONS: The global burden of CE remains high, and it is recommended that more health resources are allocated to low-SDI regions, women and the elderly aged 55 to 65 years to reduce the disease burden of CE.

Generation of Metastatic Cholangiocarcinoma Patient-Derived Xenograft Models.

Cholangiocarcinoma (CCA) poses a substantial clinical hurdle as it is often detected at advanced metastatic stages with limited therapeutic options. To enhance our understanding of advanced CCA, it is imperative to establish preclinical models that faithfully recapitulate the disease's characteristics. Patient-derived xenograft (PDX) models have emerged as a valuable approach in cancer research, offering an avenue to reproduce and study the genomic, histologic, and molecular features of the original human tumors. By faithfully preserving the heterogeneity, microenvironmental interactions, and drug responses observed in human tumors, PDX models serve as highly relevant and predictive preclinical tools. Here, we present a comprehensive protocol that outlines the step-by-step process of generating and maintaining PDX models using biopsy samples from patients with advanced metastatic CCA. The protocol encompasses crucial aspects such as tissue processing, xenograft transplantation, and subsequent monitoring of the PDX models. By employing this protocol, we aim to establish a robust collection of PDX models that accurately reflect the genomic landscape, histologic diversity, and therapeutic responses observed in advanced CCA, thereby enabling improved translational research, drug development, and personalized treatment strategies for patients facing this challenging disease.

Cost-Effectiveness of First-Line Atezolizumab versus Chemotherapy in Non-Small-Cell Lung Cancer Patients Ineligible for Platinum-Containing Regimens.

Purpose: The IPSOS study provided evidence supporting the efficacy and tolerability of first-line atezolizumab compared to single-agent chemotherapy for non-small-cell lung cancer (NSCLC) patients ineligible for treatment with a platinum-containing regimen. This study aimed to assess the cost-effectiveness of atezolizumab specifically in this population, considering the perspective of the Chinese healthcare system. Patients and Methods: In this analysis, a three-state Markov model was utilized. The survival data were derived from the IPSOS clinical trial. Direct medical costs and utility values were collected from national authoritative database and published literature. The primary outcomes were costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). To ensure the robustness of our model, both one-way and probabilistic sensitivity analyses were conducted. Results: Atezolizumab monotherapy led to an increase in costs of $4139.23 compared to single-agent chemotherapy. Additionally, it resulted in a gain of 0.14 QALYs, leading to an ICER of $29,365.79 per QALY, which was below the willingness-to-pay threshold of $36,066 per QALY used in the model. One-way sensitivity analyses revealed cost of atezolizumab and utility of progressive disease (PD) as major influencing factors for ICER. Furthermore, probabilistic sensitivity analyses confirmed our base-case results. Conclusion: From the perspective of the Chinese healthcare system, atezolizumab emerges as a cost-effective choice for the first-line treatment of NSCLC patients ineligible for platinum-based chemotherapy.

Effects of long-term no-tillage and different stover mulching amounts on soil carbon and nitrogen contents and enzyme activities of carbon and nitrogen cycle in Mollisols.

To understand the effects of different stover mulching amounts in no-tillage on soil carbon and nitrogen contents and enzyme activities, finding a stover mulching amount which can meet the requirement of soil carbon and nitrogen accumulation while maximizing economic benefits, we conducted a long-term conservation tillage field experiment since 2007 in Mollisols area of Northeast China. We analyzed soil carbon and nitrogen contents, enzyme activities and economic benefits under conventional tillage (Control, CT), no-tillage without stover mulching (NT0), no-tillage with 33% stover mulching (NT33), no-tillage with 67% stover mulching (NT67), and no-tillage with 100% stover mulching (NT100) before planting in May 2020. The results showed that compared with CT, NT0 did not affect soil organic carbon (SOC) and total nitrogen (TN) contents, but increased soil organic carbon recalcitrance and decreased the availability of dissolved organic nitrogen (DON) and ammonium nitrogen. Compared with NT0, no-tillage with stover mulching significantly increased SOC contents in 0-10 cm layer and increased with the amounts of stover. In addition, NT67 and NT100 significantly increased SOC stocks, facilitating the accumulation of soil organic matter. The effects of different stover mulching amounts on soil nitrogen content in 0-10 cm layer were different. Specifically, NT33 increased DON content and DON/TN, NT67 increased DON content, while NT100 increased TN content. Compared with CT, NT0 decreased peroxidase (POD) activity in 0-10 cm layer. Compared with NT0, NT33 increased ß-glucosidase (ßG), cellobiase (CB), 1,4-ß-N-acetylglucosaminidase (NAG), polyphenol oxidase (PPO) and POD activities, while NT67 only increased CB, NAG and POD activities in 0-10 cm soil layer, both alleviated microbial nutrient limitation. NT100 increased PPO activity in 10-20 cm layer. NT33 increased carbon conversion efficiency of stover compared with NT100, and had the highest economic benefit. In all, no-tillage with 33% stover mulching was the optimal strategy, which could promote nutrient circulation, boost stover utilization efficiency, improve the quality of Mollisols, and maximize guaranteed income.

UFL1 triggers replication fork degradation by MRE11 in BRCA1/2-deficient cells.

The stabilization of stalled forks has emerged as a crucial mechanism driving resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient tumors. Here, we identify UFL1, a UFM1-specific E3 ligase, as a pivotal regulator of fork stability and the response to PARP inhibitors in BRCA1/2-deficient cells. On replication stress, UFL1 localizes to stalled forks and catalyzes the UFMylation of PTIP, a component of the MLL3/4 methyltransferase complex, specifically at lysine 148. This modification facilitates the assembly of the PTIP-MLL3/4 complex, resulting in the enrichment of H3K4me1 and H3K4me3 at stalled forks and subsequent recruitment of the MRE11 nuclease. Consequently, loss of UFL1, disruption of PTIP UFMylation or overexpression of the UFM1 protease UFSP2 protects nascent DNA strands from extensive degradation and confers resistance to PARP inhibitors in BRCA1/2-deficient cells. These findings provide mechanistic insights into the processes underlying fork instability in BRCA1/2-deficient cells and offer potential therapeutic avenues for the treatment of BRCA1/2-deficient tumors.

Transcription factor C/EBPα is required for the development of Ly6Chi monocytes but not Ly6Clo monocytes.

Monocytes comprise two major subsets, Ly6Chi classical monocytes and Ly6Clo nonclassical monocytes. Notch2 signaling in Ly6Chi monocytes triggers transition to Ly6Clo monocytes, which require Nr4a1, Bcl6, Irf2, and Cebpb. By comparison, less is known about transcriptional requirements for Ly6Chi monocytes. We find transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) is highly expressed in Ly6Chi monocytes, but down-regulated in Ly6Clo monocytes. A few previous studies described the requirement of C/EBPα in the development of neutrophils and eosinophils. However, the role of C/EBPα for in vivo monocyte development has not been understood. We deleted the Cebpa +37 kb enhancer in mice, eliminating hematopoietic expression of C/EBPα, reproducing the expected neutrophil defect. Surprisingly, we also found a severe and selective loss of Ly6Chi monocytes, while preserving Ly6Clo monocytes. We find that BM progenitors from Cebpa +37-/- mice rapidly progress through the monocyte progenitor stage to develop directly into Ly6Clo monocytes even in the absence of Notch2 signaling. These results identify a previously unrecognized role for C/EBPα in maintaining Ly6Chi monocyte identity.

Glutathionylation of a glycolytic enzyme promotes cell death and vigor loss during aging of elm seeds.

Seed deterioration during storage is a major problem in agricultural and forestry production and for germplasm conservation. Our previous studies have shown that a mitochondrial outer membrane protein VOLTAGE-DEPENDENT ANION CHANNEL (VDAC) is involved in programmed cell death (PCD)-like viability loss during the controlled deterioration treatment (CDT) of elm (Ulmus pumila L.) seeds, but its underlying mechanism remains unclear. In this study, we demonstrate that the oxidative modification of GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE (GAPDH) is functioned in the gate regulation of VDAC during the CDT of elm seeds. Through biochemical and cytological methods and observations of transgenic material [Arabidopsis (Arabidopsis thaliana), Nicotiana benthamiana, and yeast (Saccharomyces cerevisiae)], we demonstrate that cysteine S-glutathionylated UpGAPDH1 interacts with UpVDAC3 during seed aging, which leads to a mitochondrial permeability transition and aggravation of cell death, as indicated by the leakage of the mitochondrial pro-apoptotic factor cytochrome c and the emergence of apoptotic nucleus. Physiological assays and inductively coupled plasma mass spectrometry (ICP-MS) analysis revealed that GAPDH glutathionylation is mediated by increased glutathione, which might be caused by increases in the concentrations of free metals, especially Zn. Introduction of the Zn-specific chelator TPEN [(N, N, N', N'-Tetrakis (2-pyridylmethyl)ethylenediamine)] significantly delayed seed aging. We conclude that glutathionylated UpGAPDH1 interacts with UpVDAC3 and serves as a pro-apoptotic protein for VDAC-gating regulation and cell death initiation during seed aging.

Surface-enhanced Raman scattering-based identification of breast cancer progression using extracellular vesicles-derived integrin α6ß4.

Detection of progression is of great importance to breast cancer treatment and can benefit patients. Limited by current detection technologies and biomarkers, early breast cancer progression diagnosis remains challenging. Researchers have found blood extracellular vesicles (EVs)-derived integrin α6ß4 directly facilitate progression in breast cancer, enabling cancer detection. However, EVs size and heterogeneity hinder protein detection, masked by abundant background EVs. Hence, novel tools for efficient detection of EVs with high selectivity and low interference are significantly desired. Here, a new silver-coated gold nanorods SERS probe, termed as Au@Ag@IDA-B/4MSTP, based on DNA aptamer was established for the detection of integrin α6ß4 derived from EVs. Validation of the Au@Ag@IDA-B/4MSTP probes using cell-culture-derived EVs revealed a LOD of 23 particles/µL for EVs detection. This tool was further confirmed to mimic the real state of cancer with subcutaneous tumor model and lung metastasis model in mice. With 10 µL of blood plasma and simple Raman analysis process, the test achieved 85.7 % sensitivity and 83.3 % specificity. Moreover, our method achieves a simplified approach that expedites the detection process. These results demonstrate the good detection performance of Au@Ag@IDA-B/4MSTP probes for EVs integrin α6ß4, and suggest that this non-invasive approach could be a promising tool for early detection of breast cancer progression.