The role of sleep quality and anxiety symptoms in the association between childhood trauma and self-harm attempt: A chain-mediated analysis in the UK Biobank.

BACKGROUND: Childhood trauma is a risk factor for self-harm/suicidal behavior, but research on the potential association linking sleep quality and anxiety symptoms to childhood trauma and self-harm attempt is limited. The aim of this study was to describe the mediating role of sleep quality and anxiety symptoms between childhood trauma and self-harm attempt, and to provide a scientific basis for the prevention of self-harm behaviors. METHODS: This study ultimately included 11,063 study participants who participated in the baseline survey of this large prospective cohort study of the UK Biobank. We used structural equation modeling (SEM) to analyze the chain mediating role of sleep quality and anxiety symptoms in childhood trauma and self-harm attempt while controlling for covariates. RESULTS: A total of 19.58 % of study participants self-reported self-harm attempt. Sleep quality was negatively correlated with childhood trauma, anxiety symptoms, and self-harm attempt (p < 0.01). Childhood trauma, anxiety symptoms, and self-harm attempt were positively correlated (p < 0.01). In addition, after adjusting for confounders, anxiety symptoms were able to partially mediate the association between childhood trauma and self-harm attempt (effect value: 0.042, p < 0.01), and sleep quality and anxiety symptoms can chain mediate the association between childhood trauma and self-harm attempt (effect value:0.002, p < 0.01), with a total mediating effect of 65.67 % of the total effect. Subgroup analyses further showed that the mediating effects of sleep quality and anxiety symptoms on childhood trauma and self-harm attempt differed across age, gender, ethnicity, and smoking and drinking subgroups. CONCLUSIONS: This study found a complex relationship between childhood trauma, sleep quality, anxiety symptoms, and self-harm attempt, with sleep quality and anxiety symptoms mediating the relationship between childhood trauma and self-harm attempt. Multiple avenues of intervention, such as the provision of professional psychological interventions and timely monitoring, should be used to improve the sleep quality and mental health of individuals with traumatic childhood experiences and to prevent the occurrence of emotionally harmful behaviors such as self-harm/suicide.

Immune checkpoint inhibitors-induced diabetes mellitus (review).

Immune checkpoint inhibitors (ICIs) have become extensively utilized in the early-stage treatment of various cancers, offering additional therapeutic possibilities for patients with advanced cancer. However, certain patient populations are susceptible to experiencing toxic adverse effects from ICIs, such as thyrotoxicosis, rashes, among others. Specifically, ICIDM, induced by immune checkpoint inhibitors, exhibits characteristics similar to insulin-dependent diabetes mellitus (Type 1 Diabetes Mellitus, T1DM). ICIDM is characterized by a rapid onset and may coincide with severe ketoacidosis. Despite a favorable response to insulin therapy, patients typically require lifelong insulin dependence. After discussing the autoimmune adverse effects and the specifics of ICIs-induced diabetes mellitus (ICIDM), it is important to note that certain patient populations are particularly susceptible to experiencing toxic adverse effects from ICIs. Specifically, ICIDM, which is triggered by immune checkpoint inhibitors, mirrors the characteristics of insulin-dependent diabetes mellitus (Type 1 Diabetes Mellitus, T1DM). This article conducts an in-depth analysis of the literature to explore the pathogenesis, disease progression, and treatment strategies applicable to diabetes induced by immune checkpoint inhibitors (ICIDM).

[EMP3 inhibits the formation of heterotypic cell-in-cell structures in hepatocellular carcinoma].

Heterotypic cell-in-cell (heCIC) structures represent a unique intercellular interaction where tumor cells internalize immune cells to enhance the killing efficiency of immune cells. However, the mechanism of heCIC structure formation remains to be fully elucidated. In this study, we explored the role of epithelial membrane protein 3 (EMP3), a PMP-22/EMP/MP20 protein family member highly expressed in the patients with hepatocellular carcinoma and poor prognosis, in the formation of the heCIC structure formed by natural killer cells and hepatocellular carcinoma cells. The analysis of monoclonal hepatocellular carcinoma cell lines revealed that EMP3 presented low expression in the cells with high capability to form heCIC structure and high expression in those with low capability. Knocking down the expression of EMP3 by gene editing promoted the formation of heCIC structures, while overexpression of EMP3 significantly inhibited this process. Additionally, the expression of factors involved in the heCIC structure formation suggested that EMP3 inhibited the formation of heCIC structures by modulating the adhesion ability and cytoskeleton of tumor cells. The findings lay a foundation for enhancing the heCIC-mediated tumor immunotherapy by targeting EMP3.

Preoperative Contrast-Enhanced CT-Based Deep Learning Radiomics Model for Distinguishing Retroperitoneal Lipomas and Well­Differentiated Liposarcomas.

RATIONALE AND OBJECTIVES: To assess the efficacy of a preoperative contrast-enhanced CT (CECT)-based deep learning radiomics nomogram (DLRN) for predicting murine double minute 2 (MDM2) gene amplification as a means of distinguishing between retroperitoneal well-differentiated liposarcomas (WDLPS) and lipomas. METHODS: This retrospective multi-center study included 167 patients (training/external test cohort, 104/63) with MDM2-positive WDLPS or MDM2-negative lipomas. Clinical data and CECT features were independently measured and analyzed by two radiologists. A clinico-radiological model, radiomics signature (RS), deep learning and radiomics signature (DLRS), and a DLRN incorporating radiomics and deep learning features were developed to differentiate between WDLPS and lipoma. The model utility was evaluated based on the area under the receiver operating characteristic curve (AUC), accuracy, calibration curve, and decision curve analysis (DCA). RESULTS: The DLRN showed good performance for distinguishing retroperitoneal lipomas and WDLPS in the training (AUC, 0.981; accuracy, 0.933) and external validation group (AUC, 0.861; accuracy, 0.810). The DeLong test revealed the DLRN was noticeably better than clinico-radiological and RS models (training: 0.981 vs. 0.890 vs. 0.751; validation: 0.861 vs. 0.724 vs. 0.700; both P < 0.05); however, no discernible difference in performance was seen between the DLRN and DLRS (training: 0.981 vs. 0.969; validation: 0.861 vs. 0.837; both P > 0.05). The calibration curve analysis and DCA demonstrated that the nomogram exhibited good calibration and offered substantial clinical advantages. CONCLUSION: The DLRN exhibited strong predictive capability in predicting WDLPS and retroperitoneal lipomas preoperatively, making it a promising imaging biomarker that can facilitate personalized management and precision medicine.

A Multiscale Connected UNet for the Segmentation of Lung Cancer Cells in Pathology Sections Stained Using Rapid On-Site Cytopathological Evaluation.

Lung cancer is an increasingly serious health problem worldwide, and early detection and diagnosis are crucial for successful treatment. With the development of artificial intelligence and the growth of data volume, machine learning techniques can play a significant role in improving the accuracy of early detection in lung cancer. This study proposes a deep learning-based segmentation algorithm for rapid on-site cytopathological evaluation (ROSE) to enhance the diagnostic efficiency of endobronchial ultrasound-guided transbronchial needle aspiration biopsy (EBUS-TBNA) during surgery. By utilizing the CUNet3+ network model, cell clusters, including cancer cell clusters, can be accurately segmented in ROSE-stained pathological sections. The model demonstrated high accuracy, with an F1-score of 0.9604, recall of 0.9609, precision of 0.9654, and accuracy of 0.9834 on the internal testing data set. It also achieved an area under the receiver-operating characteristic curve of 0.9972 for cancer identification. The proposed algorithm saved time for on-site diagnosis, improved EBUS-TBNA efficiency, and outperformed classical segmentation algorithms in accurately identifying lung cancer cell clusters in ROSE-stained images. It effectively reduced over-segmentation, decreased network parameters, and enhanced computational efficiency, making it suitable for real-time patient evaluation during surgical procedures.

Aluminum/Graphene Thermal Interface Materials with Positive Temperature Dependence.

Graphene is widely used in excellent thermal interface materials (TIMs), thanks to its remarkably high in-plane thermal conductivity (k∥). However, the poor through-plane thermal conductivity (k⊥) limits its further application. Here, we developed a simple in situ growth method to prepare graphene-based thermal interface composites with positively temperature-dependent thermal conductivity, which loaded aluminum (Al) nanoparticles onto graphene nanoplatelets (GNPs). To evaluate the variations in thermal performance, we determined the thermal diffusivity and specific heat capacity of the composites using a laser-flash analyzer and a differential scanning calorimeter, respectively. The Al nanoparticles act as bridges between the nanoplatelets, enhancing the k⊥ of the 1.3-Al/GNPs composite to 11.70 W·m-1·K-1 at 25 °C. Even more remarkably, those nanoparticles led to a unique increase in k⊥ with temperature, reaching 20.93 W·m-1·K-1 at 100 °C. Additionally, we conducted an in-depth investigation of the thermal conductivity mechanism of the Al/GNPs composites. The exceptional heat transport property enabled the composites to exhibit a superior heat dissipation performance in simulated practical applications. This work provides valuable insights into utilizing graphene in composites with Al nanoparticles, which have special thermal conductivity properties, and offers a promising pathway to enhance the k⊥ of graphene-based TIMs.

Photochemical Strategies toward Precision Targeting against Multidrug-Resistant Bacterial Infections.

Infectious diseases pose a serious threat and a substantial economic burden on global human and public health security, especially with the frequent emergence of multidrug-resistant (MDR) bacteria in clinical settings. In response to this urgent need, various photobased anti-infectious therapies have been reported lately. This Review explores and discusses several photochemical targeted antibacterial therapeutic strategies for addressing bacterial infections regardless of their antibiotic susceptibility. In contrast to conventional photobased therapies, these approaches facilitate precise targeting of pathogenic bacteria and/or infectious microenvironments, effectively minimizing toxicity to mammalian cells and surrounding healthy tissues. The highlighted therapies include photodynamic therapy, photocatalytic therapy, photothermal therapy, endogenous pigments-based photobleaching therapy, and polyphenols-based photo-oxidation therapy. This comprehensive exploration aims to offer updated information to facilitate the development of effective, convenient, safe, and alternative strategies to counter the growing threat of MDR bacteria in the future.

Protease SfpB plays an important role in cell membrane stability and immune system evasion in Streptococcus agalactiae.

Bacteria possess the ability to develop diverse and ingenious strategies to outwit the host immune system, and proteases are one of the many weapons employed by bacteria. This study sought to identify S. agalactiae additional serine protease and determine its role in virulence. The S. agalactiae THN0901 genome features one S8 family serine peptidase B (SfpB), acting as a secreted and externally exposed entity. A S8 family serine peptidase mutant strain (ΔsfpB) and complement strain (CΔsfpB) were generated through homologous recombination. Compared to the wild-type strain THN0901, the absorption of EtBr dyes was significantly reduced (P < 0.01) in ΔsfpB, implying an altered cell membrane permeability. In addition, the ΔsfpB strain had a significantly lower survival rate in macrophages (P < 0.01) and a 61.85 % lower adhesion ability to the EPC cells (P < 0.01) compared to THN0901. In the in vivo colonization experiment using tilapia as a model, 210 fish were selected and injected with different bacterial strains at a concentration of 3 × 106 CFU/tail. At 6, 12, 24, 48, 72 and 96 h post-injection, three fish were randomly selected from each group and their brain, liver, spleen, and kidney tissues were isolated. Subsequently, it was demonstrated that the ΔsfpB strain exhibited a markedly diminished capacity for colonization in tilapia. Additionally, the cumulative mortality of ΔsfpB in fish after intraperitoneal injection was reduced by 19.92-23.85 %. In conclusion, the findings in this study have demonstrated that the SfpB plays a significant role in S. agalactiae cell membrane stability and immune evasion. The immune evasion is fundamental for the development and transmission of invasive diseases, the serine protease SfpB may be a promising candidate for the development of antimicrobial agents to reduce the transmission of S. agalactiae.

Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression.

Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression.

ZLN005 alleviates PBDE-47 induced impairment of mitochondrial translation and neurotoxicity through PGC-1α/ERRα axis.

Recent studies are identified the mitochondria as critical targets of 2, 2', 4, 4'-tetrabromodiphenyl ether (PBDE-47) induced neurotoxicity. This study aimed at examining the impact of PBDE-47 exposure on mitochondrial translation, and its subsequent effect on PBDE-47 neurotoxicity. The Sprague-Dawley (SD) rat model and neuroendocrine pheochromocytoma (PC12) cells were adopted for the measurements of mitochondrial ATP levels, mitochondrial translation products, and expressions of important mitochondrial regulators, such as required meiotic nuclear division 1 (RMND1), estrogen-related receptor α (ERRα), and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). To delve into the role of PGC-1α/ERRα axis in mitochondrial translation, 2-(4-tert-butylphenyl) benzimidazole (ZLN005) was employed. Both cellular and animal model results shown that PBDE-47 impeded PGC-1α/ERRα axis and mitochondrial translation. PBDE-47 suppressed mitochondrial function in rat hippocampus and PC12 cells by decreasing relative mitochondrial DNA (mtDNA) content, mitochondrial translation products, and mitochondrial ATP levels. Particularly, ZLN005 reversed PBDE-47 neurotoxicity by enhancing mitochondrial translation through activation of PGC-1α/ERRα axis, yet suppressing PGC-1α with siRNA attenuates its neuroprotective effect in vitro. In conclusion, this work highlights the importance of mitochondrial translation in PBDE-47 neurotoxicity by presenting results from cellular and animal models and suggests a potential therapeutic approach through activation of PGC-1α/ERRα axis. ENVIRONMENTAL IMPLICATION: PBDEs have attracted extensive attention because of their high lipophilicity, persistence, and detection levels in various environmental media. Increasing evidence has shown that neurodevelopmental disorders in children are associated with PBDE exposure. Several studies have also found that perinatal PBDE exposure can cause long-lasting neurobehavioral abnormalities in experimental animals. Our recent studies have also demonstrated the impact of PBDE-47 exposure on mitochondrial biogenesis and dynamics, leading to memory and neurobehavioral deficits. Therefore, we explore whether the pathological mechanism of PBDE-47-induced neurotoxicity involves the regulation of mitochondrial translation through the PGC-1α/ERRα axis.

Non-contact wide-field viewing system-assisted scleral buckling surgery for retinal detachment in silicone oil-filled eyes.

AIM: To evaluate scleral buckling (SB) surgery using a non-contact wide-field viewing system and 23-gauge intraocular illumination for the treatment of rhegmatogenous retinal detachment in silicone oil (SO)-filled eyes. METHODS: Totally 9 patients (9 eyes) with retinal detachment in SO-filled eyes were retrospectively analyzed. All patients underwent non-contact wide-field viewing system-assisted buckling surgery with 23-gauge intraocular illumination. SO was removed at an appropriate time based on recovery. The patients were followed up for at least 3mo after SO removal. Retinal reattachment, complications, visual acuity and intraocular pressure (IOP) before and after surgery were observed. RESULTS: Patients were followed up for a mean of 8.22mo (3-22mo) after SO removal. All patients had retinal reattachment. At the final follow-up, visual acuity showed improvement for 8 patients, and no change for 1 patient. The IOP was high in 3 patients before surgery, but it stabilized after treatment; it was not affected in the other patients. None of the patients had infections, hemorrhage, anterior ischemia, or any other complication. CONCLUSION: This new non-contact wide-field viewing system-assisted SB surgery with 23-gauge intraocular illumination is effective and safe for retinal detachment in SO-filled eyes.

Investigating the impact of cartilaginous endplate herniation on recovery from percutaneous endoscopic lumbar discectomy.

OBJECTIVE: This study aimed to evaluate the influence of herniation of cartilaginous endplates on postoperative pain and functional recovery in patients undergoing percutaneous endoscopic lumbar discectomy (PELD) for lumbar disc herniation (LDH). METHODS: A retrospective analysis was conducted on 126 patients with LDH treated with PELD at the Third Hospital of Hebei Medical University from January 2021 to January 2022. Whether cartilaginous endplates had herniated was identified by analyzing these specific findings from MRI scans: posterior marginal nodes, posterior osteophytes, mid endplate irregularities, heterogeneous low signal intensity of extruded material, and Modic changes in posterior corners and mid endplates. Patients were assessed for postoperative pain using the Visual Analogue Scale (VAS) and functional recovery using the Oswestry Disability Index (ODI) and Modified MacNab criteria. Statistical analyses compared outcomes based on the presence of herniation of cartilaginous endplates. RESULTS: Patients with herniation of cartilaginous endplates experienced higher pain scores early postoperatively but showed significant improvement in pain and functional status over the long term. The back pain VAS scores showed significant differences between the groups with and without herniation of cartilaginous endplates on postoperative day 1 and 1 month (P < 0.05). Leg pain VAS scores showed significant differences on postoperative day 1 (P < 0.05). Modic changes were significantly associated with variations in postoperative recovery, highlighting their importance in predicting patient outcomes. In patients with herniation of cartilaginous endplates, there were statistically significant differences in the back pain VAS scores at 1 month postoperatively and the ODI functional scores on postoperative day 1 between the groups with and without Modic changes (P < 0.05). There were no significant differences in the surgical outcomes between patients with and without these conditions regarding the Modified MacNab criteria (P > 0.05). CONCLUSION: Herniation of cartilaginous endplates significantly affect early postoperative pain and functional recovery in LDH patients undergoing PELD. These findings emphasize the need for clinical consideration of these imaging features in the preoperative planning and postoperative management to enhance patient outcomes and satisfaction.

Feasibility and tolerability of eribulin-based chemotherapy versus other chemotherapy regimens for patients with metastatic triple-negative breast cancer: a single-centre retrospective study.

Background: Patients with Triple-negative breast cancer (TNBC) face a poor prognosis and limited therapeutic options. Current data on eribulin usage to treat TNBC is scarce. Therefore, we sought to compare the feasibility and tolerability of eribulin-based regimens with other chemotherapy regimens in patients with TNBC. Method: This retrospective study was conducted at Fujian Medical University Cancer Hospital and included 159 patients with TNBC enrolled between October 2011 and January 2023. Patients underwent treatment with eribulin-based and other chemotherapy regimens. The study's primary endpoints were progression-free survival (PFS) and overall survival (OS), while its secondary endpoint was objective response rate (ORR), disease control rate (DCR), and safety. Tumour response was assessed using RECIST V.1.1 criteria. Results: Of the 159 participants in the study, 42 individuals (26.4%) received treatment with eribulin, whereas 117 participants (73.6%) were administered alternative chemotherapy regimens, which included nab-paclitaxel-based therapy (n = 45) and platinum-based therapy (n = 51). The follow-up period for all patients ended on 31 December 2022, and the median follow-up time was 18.3 months (range:0.7-27.5). Following propensity score matching (PSM), eribulin-based treatment resulted in longer median progression-free survival compared to platinum-based (hazard ratio (HR) = 0.41, p = 0.006), nab-paclitaxel-based (hazard ratio = 0.36, p = 0.001) and other chemotherapy (HR = 0.39, p < 0.001). Also, eribulin induced a remarkable prolongation of the median overall survival duration in all three comparative groups. The group receiving eribulin treatment showed significantly reduced incidences of any grade of anaemia, peripheral neuropathy, nausea and vomiting, and hair loss compared to other chemotherapy groups. Conclusion: For the salvage treatment of advanced TNBC, treatment with eribulin produced longer median PFS and OS than other chemotherapy regimens, with a well-tolerated safety profile. Therefore, further investigation of eribulin-based treatment in larger randomized trials for patients with advanced TNBC is warranted.

Deep learning on tertiary lymphoid structures in hematoxylin-eosin predicts cancer prognosis and immunotherapy response.

Tertiary lymphoid structures (TLSs) have been associated with favorable immunotherapy responses and prognosis in various cancers. Despite their significance, their quantification using multiplex immunohistochemistry (mIHC) staining of T and B lymphocytes remains labor-intensive, limiting its clinical utility. To address this challenge, we curated a dataset from matched mIHC and H&E whole-slide images (WSIs) and developed a deep learning model for automated segmentation of TLSs. The model achieved Dice coefficients of 0.91 on the internal test set and 0.866 on the external validation set, along with intersection over union (IoU) scores of 0.819 and 0.787, respectively. The TLS ratio, defined as the segmented TLS area over the total tissue area, correlated with B lymphocyte levels and the expression of CXCL13, a chemokine associated with TLS formation, in 6140 patients spanning 16 tumor types from The Cancer Genome Atlas (TCGA). The prognostic models for overall survival indicated that the inclusion of the TLS ratio with TNM staging significantly enhanced the models' discriminative ability, outperforming the traditional models that solely incorporated TNM staging, in 10 out of 15 TCGA tumor types. Furthermore, when applied to biopsied treatment-naïve tumor samples, higher TLS ratios predicted a positive immunotherapy response across multiple cohorts, including specific therapies for esophageal squamous cell carcinoma, non-small cell lung cancer, and stomach adenocarcinoma. In conclusion, our deep learning-based approach offers an automated and reproducible method for TLS segmentation and quantification, highlighting its potential in predicting immunotherapy response and informing cancer prognosis.

Molecular targets of cisplatin in HeLa cells explored through competitive activity-based protein profiling strategy.

Cisplatin is widely used as anticancer drugs, and DNA is considered as the main target. Considering its high affinity towards cysteines and the important role of cystine containing proteins, we applied a competitive activity-based protein profiling strategy to identify protein cysteines that bind with cisplatin in HeLa cells. Living cells were treated with cisplatin at cytotoxic concentrations, then the protein was extracted. After labeling with desthiobiotin iodoacetamide (DBIA) probe, protein was precipitated, digested and isotopically labeled, subsequently the peptides were combined, and the biotinylated cysteine-containing peptides were enriched and quantified by LC-MS/MS. A total of 3571 peptides which originated from 1871 proteins were identified using the DBIA probe. Among them, 46 proteins were screened as targets, including proteins that have been identified as binding proteins by previous study. A novel cisplatin target, calpain-1 (CAPN1), was identified and validated as binding with cisplatin in vitro.

A real-world study of the effectiveness and safety of apatinib-based regimens in metastatic triple-negative breast cancer.

PURPOSE: This investigation sought to examine the efficacy and safety of low-dose apatinib used alongside chemotherapy in the clinical management of patients with metastatic triple-negative breast cancer (TNBC) within a real-world setting, whilst comparing the outcomes with those treated solely with chemotherapy. METHODS: This case series study analyzed clinical data and treatment outcomes of 163 patients with metastatic TNBC who underwent rescue treatment at the Medical Oncology Department of Clinical Oncology, Fujian Cancer Hospital, School of Fujian Medical University, China, between October 2011 and January 2023. All the patients underwent rescue treatment with either chemotherapy alone or apatinib (250 mg/day) combined with chemotherapy. The study's primary outcome was progression-free survival (PFS), whereas the secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety profiles. RESULTS: The study was designed to compare two groups [1]. Out of the 163 TNBC patients who participated in the study, 107 individuals (65.6%) received treatment based on chemotherapy, whereas 56 patients (34.4%) were given treatment based on a combination of low-dose apatinib (250 mg/day) and other treatments, including chemotherapy. After propensity score matching (PSM), the objective response rate (ORR) and disease control rate (DCR) of patients with advanced triple-negative breast cancer (TNBC) who received apatinib-based treatment were 50.0 and 90.0%, respectively, while they were 6.7 and 20.0%, respectively, for the chemotherapy-based group (P < 0.001). The group that received apatinib-based treatment showed superior results in both PFS and OS compared to the group that received chemotherapy. The median PFS and OS for the apatinib-based group were 7.8 and 20.3 months, respectively, while they were only 2.2 months and 9.0 months, respectively, for the chemotherapy-based group (P < 0.001) [2]. Patients who were administered combo therapies, including PD-1 inhibitors, were excluded. In total, 97 patients received chemotherapy alone, while 34 patients were treated with apatinib in combination with chemotherapy. After propensity score matching (PSM), the ORR and DCR for the total group who received combo therapies were 44.4 and 81.5%, respectively, while they were 11.1 and 22.2%, respectively, for the chemotherapy alone group (P < 0.001). The group receiving both apatinib and chemotherapy displayed notable advantages over the group solely receiving chemotherapy in regards to PFS and OS for the entirety of the population. The PFS was found to be 7.8 months in comparison to 2.1 months (P < 0.001) and the OS was 21.1 months in contrast to 9.0 months (P < 0.001). Apatinib combined with chemotherapy induced grade 3/4 hematological toxicities, including neutropenia (8.8%) and thrombocytopenia (2.9%). Additionally, non-hematological toxicities were commonly observed, such as Hand-foot syndrome (35.3%), proteinuria (26.5%), hypertension (61.8%), higher alanine aminotransferase levels (26.5%), and fatigue (35.3%). The most frequent non-hematological grade 3/4 toxicities were Hand-foot syndrome (2.9%) and hypertension (5.9%). The study did not report any fatal adverse effects. CONCLUSIONS: The combination of low-dose apatinib with chemotherapy has proven to be more effective than chemotherapy alone in treating metastatic triple-negative breast cancer (TNBC). Additionally, the occurrence of grade 3/4 non-hematologic toxicities was significantly lower compared to the recommended dose of apatinib.

Adipogenic and osteogenic effects of OBS and synergistic action with PFOS via PPARγ-RXRα heterodimers.

Sodium p-perfluorous nonenoxybenzenesulfonate (OBS) is a novel alternative to perfluorooctane sulfonate (PFOS), with environmental health risks largely unknown. The present study aims to unravel the adipogenesis effects and underlying molecular initiating events of OBS, which are crucial for understanding and predicting its adverse outcome. In undifferentiated human mesenchymal stem cells (hMSCs), exposure to 1-100 nM of OBS for 7 days stimulated reactive oxygen species production. In the subsequent multipotent differentiation, hMSCs favored adipogenesis and repressed osteogenesis. The point of departure (PoD) for cellular responses of OBS was 38.85 nM, higher than PFOS (0.39 nM). Notably, OBS/PFOS co-exposure inhibited osteogenesis and synergistically promoted adipogenesis. Consistently, the expression of adipogenic marker genes was up-regulated, while that of osteogenic marker genes was down-regulated. The decreased adiponectin and elevated tumor necrosis factor α (TNFα) secretion were observed in differentiated cells exposed to the mixture of OBS and PFOS. The co-treatment of a peroxisome proliferator-activated receptor γ (PPARγ) antagonist alleviated the adipogenic effects of PFOS and its combination with OBS. Moreover, OBS/PFOS co-exposure induced peroxisome PPARγ activation in reporter gene assays, and increased formation of PPARγ - retinoid X receptor α (RXRα) heterodimers measured by co-immunoprecipitation assays. Molecular docking showed interaction energy of OBS (-20.7 kcal/mol) with intact PPARγ-RXRα complex was lower than that of PFOS (-25.9 kcal/mol). Overall, single OBS exhibited lower potency in inducing adipogenesis but is comparable to PFOS in repressing osteogenesis, whereas OBS/PFOS co-exposure increases interaction with PPARγ-RXRα heterodimers, resulting in the synergistic activation of PPARγ, ultimately enhancing adipogenesis at the expense of osteogenic differentiation. The results indicate the potential health risks of increased obesity and decreased bone density caused by OBS and its co-exposure with PFOS, as well as other perfluorinated alkylated substances mixtures.

A Comparative Analysis of Major Cell Wall Components and Associated Gene Expression in Autotetraploid and Its Donor Diploid Rice (Oryza sativa L.) under Blast and Salt Stress Conditions.

Whole-genome duplication is a significant evolutionary mechanism in plants, with polyploid plants often displaying larger organs and enhanced adaptability to unfavorable conditions compared to their diploid counterparts. The cell wall acts as a primary defense for plant cells against external stresses, playing an essential role in the plant's resistance to various stressors. In this study, we utilized both autotetraploid and its donor diploid rice (Oryza sativa L.) to analyze their phenotypic differences comparatively, the composition of key cell wall components, and the expression of related genes under normal conditions, as well as under stress from Magnaporthe oryzae (M. oryzae) and salt. Our findings indicated that autotetraploid rice exhibits significantly larger phenotypic characteristics under normal conditions than diploid rice. At the seedling stage, the lignin, cellulose, hemicellulose, and pectin levels in autotetraploid rice were markedly lower than in diploid rice. Additionally, 24 genes associated with major cell wall components showed differential expression between diploid and tetraploid rice. At the filling stage, the lignin and pectin content in autotetraploid rice were significantly higher than in diploid rice, while the levels of cellulose and hemicellulose were notably lower. Under M. oryzae stress or salt stress, autotetraploid rice showed smaller lesion areas and less wilting than diploid rice. The increased lignin content in autotetraploid rice under M. oryzae stress suggested a stronger adaptive capacity to adverse conditions. Compared to salt stress, M. oryzae stress induced more differential expression of genes related to major cell wall components. In this study, we explored the differences in the major cell wall components of diploid and homologous tetraploid rice under various treatment conditions. This study provides valuable insights into understanding the cell wall's adaptive mechanisms in autotetraploid rice when facing blast disease and salt stress, and it reveals the differential gene expression linked to these adaptive capabilities.