Study on Spectrum Shifting and Pulse Splitting of Mode-Locked Fiber Lasers Based on NPR Technology.

We conducted a systematic investigation into the spectral and pulse characteristics of C and L-band Nonlinear Polarization Rotation (NPR) mode-locked fiber lasers effectively employing nonlinear polarization rotation technology. In our experimental setup, we achieved a stable mode-locked state at 1560.076 nm, exhibiting a 3 dB spectral bandwidth of 9.1 nm. As the pump power increased, we observed spectral shifts accompanied by shifts in the first Kelly sideband and the generation of new Kelly sidebands. In this paper, the phenomenon of spectral deviation is elucidated through the interplay of self-phase modulation, group velocity drift, and polarization-dependent isolator (PD-ISO) filter effect, with an analysis of the formation and deviation of Kelly sidebands. Notably, spectral shift persisted even when the pump power exceeded 200 mW. However, continuous pump power escalation led to soliton splitting, resulting in the formation of new soliton beams. Based on the simultaneous generation of spectral shift and pulse splitting, our study contributes to an enhanced understanding of soliton dynamics in ultrafast fiber lasers and lays a foundation for the application of high-repetition-frequency harmonic mode-locked lasers with tunable wavelengths.

Effectiveness and Safety of Pyrotinib-Based Therapy in the Treatment of HER2-Positive Breast Cancer Patients with Brain Metastases: A Multicenter Real-World Study.

BACKGROUND: Approximately 30% to 50% of patients with human epidermal growth factor receptor 2-positive metastatic breast cancer develop brain metastasis (BMs). Pyrotinib has shown promising efficacy in these patients. However, real-world evidence supporting its use is scarce. Therefore, we evaluate the efficacy and safety of pyrotinib-based regimens in the real world. MATERIALS AND METHODS: We enrolled patients with BMs from various healthcare facilities in China's Shandong region and used an updated breast-graded prognostic assessment (breast-GPA) to predict survival outcomes. RESULTS: Efficacy and toxicity were assessed in 101 patients. Overall, the median progression-free survival (PFS) was 11.0 months (95% CI, 7.6-14.4 months). PFS was shorter in patients with a breast-GPA of 0 to 2.0 (P< .001). Previous treatment with pertuzumab plus trastuzumab (P = .039) and varying numbers of BMs (P = .028) had a significant positive correlation with PFS. Additionally, radiotherapy (P = .033) for BMs, especially pyrotinib concurrent with radiotherapy (P = .013), significantly prolonged the PFS. In patients with a breast-GPA of 0 to 2.0, a significant difference in PFS was observed depending on whether the brain was the first metastatic site (P< .001). Furthermore, a breast-GPA (0-2.0 vs. 2.5-4.0), and radiotherapy for BMs were found to be independent predictors of PFS. Overall, the objective response rate was 42.6%, while the disease control rate was 88.1%. Diarrhea emerged as the most common adverse event. CONCLUSION: Pyrotinib-based therapy is effective and tolerable in human epidermal growth factor receptor 2-positive metastatic breast cancer with BMs. Patients who underwent radiotherapy for BMs, particularly those who received pyrotinib concurrently with radiotherapy, exhibited a more favorable prognosis.

Distinct roles of excitatory and inhibitory neurons in the medial prefrontal cortex in the expression and reconsolidation of methamphetamine-associated memory in male mice.

Methamphetamine, a commonly abused drug, is known for its high relapse rate. The persistence of addictive memories associated with methamphetamine poses a significant challenge in preventing relapse. Memory retrieval and subsequent reconsolidation provide an opportunity to disrupt addictive memories. However, the key node in the brain network involved in methamphetamine-associated memory retrieval has not been clearly defined. In this study, using the conditioned place preference in male mice, whole brain c-FOS mapping and functional connectivity analysis, together with chemogenetic manipulations of neural circuits, we identified the medial prefrontal cortex (mPFC) as a critical hub that integrates inputs from the retrosplenial cortex and the ventral tegmental area to support both the expression and reconsolidation of methamphetamine-associated memory during its retrieval. Surprisingly, with further cell-type specific analysis and manipulation, we also observed that methamphetamine-associated memory retrieval activated inhibitory neurons in the mPFC to facilitate memory reconsolidation, while suppressing excitatory neurons to aid memory expression. These findings provide novel insights into the neural circuits and cellular mechanisms involved in the retrieval process of addictive memories. They suggest that targeting the balance between excitation and inhibition in the mPFC during memory retrieval could be a promising treatment strategy to prevent relapse in methamphetamine addiction.

Efficacy and safety of Trastuzumab Emtansine in treating human epidermal growth factor receptor 2-positive metastatic breast cancer in Chinese population: a real-world multicenter study.

Background: Trastuzumab emtansine (T-DM1) has been approved worldwide for treating metastatic breast cancer (mBC) in patients who have received first-line therapy, shown disease progression, and are human epidermal growth factor receptor 2 (HER2)-positive. T-DM1 received approval in China to treat early-stage breast cancer (BC) in 2020 and for mBC in 2021. In March 2023, T-DM1 was included in medical insurance coverage, significantly expanding the eligible population. Materials and methods: This post-marketing observational study aimed to assess the safety and effectiveness of T-DM1 in real-world clinical practice in China. This study enrolled 31 individuals with HER2-positive early-stage BC and 70 individuals with HER2-positive advanced BC from 8 study centers in Shandong Province, China. The T-DM1 dosage was 3.6 mg/kg injected intravenously every 3 weeks until the disease advanced or the drug toxicity became uncontrollable, whichever occurred earlier. Additionally, efficacy and safety information on T-DM1 were collected. Results: During the 7-month follow-up period, no recurrence or metastases were observed in patients who had early-stage BC. The disease control rate was 31.43% (22/70) in patients with advanced BC. The most common adverse effect of T-DM1 was thrombocytopenia, with an incidence of 69.31% (70/101), and the probability of Grade ≥ 3 thrombocytopenia was 11.88% (12/101). Conclusion: This real-world study demonstrated that T-DM1 had good efficacy and was well tolerated by both HER2-positive early-stage BC and mBC patients.

Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Pleuromutilin Derivatives Containing Thiazole.

In this study, we designed and synthesized a series of pleuromutilin derivatives containing thiazole. The in vitro antimicrobial efficacy of these synthesized compounds was examined by using four strains. Compared with tiamulin (MIC = 0.25 µg/mL), compound 14 exhibited potency in inhibiting MRSA growth (MIC = 0.0625 µg/mL) in these derivatives. Meanwhile, the time-killing kinetics further demonstrated that compound 14 could efficiently inhibit the MRSA growth. After exposure at 4 × MIC, the postantibiotic effect (PAE) of compound 14 was 1.29 h. Additionally, in thigh-infected mice, compound 14 exhibited a more potent antibacterial efficacy (-1.78 ± 0.28 log10 CFU/g) in reducing MRSA load compared to tiamulin (-1.21 ± 0.23 log10 CFU/g). Moreover, the MTT assay on RAW 264.7 cells demonstrated that compound 14 (8 µg/mL) had no significant cytotoxicity. Docking studies indicated the strong affinity of compound 14 toward the 50S ribosomal subunit, with a binding free energy of -9.63 kcal/mol. Taken together, it could be deduced that compound 14 was a promising candidate for treating MRSA infections.

Roles of negative emotions and personality traits in psoriasis vulgaris: A mendelian randomization study.

BACKGROUND: Many studies have indicated that negative emotions and personality traits are related to psoriasis, though few have provided causal evidence. METHODS: Our analysis utilized 15 genome-wide association study datasets to identify instrumental variables associated with negative emotions, personality traits and psoriasis vulgaris. Two-sample Mendelian randomization was conducted to identify the causal associations of negative emotions and personality traits with psoriasis vulgaris. To mitigate bias from multiple tests, we adjusted p-values using the Benjamini-Hochberg method. RESULTS: Our study revealed causal links between negative emotions and psoriasis vulgaris, including depressed affect, worry too long, feeling hurt, guilty feelings, mood swings, unenthusiasm, miserableness, fed-up feelings. However, there was no significant evidence of a causal relationship between feeling lonely and psoriasis vulgaris. Additionally, personality traits including neuroticism and openness to experience were found to have causal effects on psoriasis vulgaris. However, no significant evidence supported a causal relationship between agreeableness, conscientiousness, and extraversion with psoriasis vulgaris. CONCLUSION: Our findings suggest that experiencing negative emotions including depressed affect, worrying excessively, feeling hurt, guilty feelings, mood swings, lack of enthusiasm, miserableness and fed-up feelings may pose risks for psoriasis vulgaris. Additionally, neuroticism is associated with a risk of psoriasis vulgaris. Conversely, the openness trait may serve a protective role against psoriasis vulgaris.

Experimental investigation of acoustic moiré effect controlled by twisted bilayer gratings.

Recently, the moiré pattern has attracted lots of attention by superimposing two planar structures of regular geometries, such as two sets of metasurfaces or gratings. Here, we show the experimental investigation of acoustic moiré effect by using twisted bilayer gratings (i.e., one grating twisted with respect to the other). We observed the guided resonance that occurred when the incident ultrasound beam was coupled with the guiding modes in a meta-grating, significantly influencing the reflection and transmission. Tunable guided resonances from the moiré effect with complete ultrasound reflection at different frequencies were further demonstrated in experiments. Combining the measurements of transmission spectra and the Fast Fourier Transform analyses, we reveal the guided resonance frequencies of moiré ultrasonic metasurface can be effectively controlled by adjusting the twisting angle of the bilayer gratings. Our results can be explained in a simplified model based on the band folding theory, providing a reliable prediction on the precise control of ultrasound reflection via the twisting angle adjustment. Our work extends the moiré metasurface from optics into acoustics, which shows more possibilities for the ultrasound beam engineering from the moiré effect and enables the exploration of functional acoustic devices for ultrasound imaging, treatment and diagnosis.

Autism patient-derived SHANK2BY29X mutation affects the development of ALDH1A1 negative dopamine neuron.

Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions. Different mutations on a single ASD gene contribute to heterogeneity of disease phenotypes, possibly due to functional diversity of generated isoforms. SHANK2, a causative gene in ASD, demonstrates this phenomenon, but there is a scarcity of tools for studying endogenous SHANK2 proteins in an isoform-specific manner. Here, we report a point mutation on SHANK2, which is found in a patient with autism, located on exon of the SHANK2B transcript variant (NM_133266.5), hereby SHANK2BY29X. This mutation results in an early stop codon and an aberrant splicing event that impacts SHANK2 transcript variants distinctly. Induced pluripotent stem cells (iPSCs) carrying this mutation, from the patient or isogenic editing, fail to differentiate into functional dopamine (DA) neurons, which can be rescued by genetic correction. Available SMART-Seq single-cell data from human midbrain reveals the abundance of SHANK2B transcript in the ALDH1A1 negative DA neurons. We then show that SHANK2BY29X mutation primarily affects SHANK2B expression and ALDH1A1 negative DA neurons in vitro during early neuronal developmental stage. Mice knocked in with the identical mutation exhibit autistic-like behavior, decreased occupancy of ALDH1A1 negative DA neurons and decreased dopamine release in ventral tegmental area (VTA). Our study provides novel insights on a SHANK2 mutation derived from autism patient and highlights SHANK2B significance in ALDH1A1 negative DA neuron.

USP39 Promotes the Viability and Migration of Head and Neck Squamous Cell Carcinoma Cell by Regulating STAT1.

Objective: Ubiquitin-specific peptidase 39 (USP39) plays a carcinogenic role in many cancers, but little research has been conducted examining whether it is involved in head and neck squamous cell carcinoma (HNSCC). Therefore, this study explored the functional role of USP39 in HNSCC. Method: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify differentially expressed proteins (DEPs) between the HNSCC tumor and adjacent healthy tissues. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to assess the functional enrichment of DEPs. Immunohistochemistry was used to detect protein expression. The viability and migration of two HNSCC cell lines, namely CAL27 and SCC25, were detected using the cell counting kit-8 assay and a wound healing assay, respectively. Quantitative real-time PCR was used to detect the expression level of signal transducer and activator of transcription 1 (STAT1) mRNA. Results: LC-MS/MS results identified 590 DEPs between HNSCC and adjacent tissues collected from 4 patients. Through GO and KEGG pathway analyses, 34 different proteins were found to be enriched in the spliceosome pathway. The expression levels of USP39 and STAT1 were significantly higher in HNSCC tumor tissue than in adjacent healthy tissue as assessed by LC-MS/MS analysis, and the increased expression of USP39 and STAT1 protein was confirmed by immunohistochemistry in clinical samples collected from 7 additional patients with HNSCC. Knockdown of USP39 or STAT1 inhibited the viability and migration of CAL27 and SCC25 cells. In addition, USP39 knockdown inhibited the expression of STAT1 mRNA in these cells. Conclusion: Our findings indicated that USP39 knockdown may inhibit HNSCC viability and migration by suppressing STAT1 expression. The results of this study suggest that USP39 may be a potential new target for HNSCC clinical therapy or a new biomarker for HNSCC.

GLP-2 ameliorates D-galactose induced muscle aging by IGF-1/Pi3k/Akt/FoxO3a signaling pathway in C2C12 cells and mice.

BACKGROUND: The study aimed to investigate the effect of Glucagon-like peptide-2 (GLP-2) on muscle aging in vivo and in vitro. METHODS: Six-week-old C57BL/6J mice were administered with D-galactose (200 mg/kg/day, intraperitoneally) for 8weeks, followed by daily subcutaneous injections of GLP-2 (300 or 600 µg/kg/day) for 4weeks. Skeletal muscle function and mass were evaluated using relative grip strength and muscle weight. The sizes and types of muscle fibers and apoptosis were assessed through histological analysis, immunofluorescence staining, and TUNEL staining, respectively. C2C12 myotubes were treated with D-galactose (40 mg/mL) and GLP-2. Protein expression of differentiation-related myogenic differentiation factor D (MyoD), myogenin (MyoG), and myosin heavy chain (Myhc), degradation-related Muscle RING finger 1 (MuRF-1), and muscle atrophy F-box (MAFbx)/Atrogin-1, and apoptosis-related B-cell leukemia/lymphoma 2 (Bcl-2) and Bax, were assessed using western blots. The Pi3k inhibitor LY294002 was applied to investigate whether GLP-2 regulated myogenesis and myotube aging via IGF-1/Pi3k/Akt/FoxO3a signaling pathway. RESULTS: The results demonstrated that GLP-2 significantly reversed the decline in muscles weight, relative grip strength, diameter, and cross-sectional area of muscle fibers induced by D-galactose in mice. Apart from suppressing the expressions of MuRF-1 and Atrogin-1 in the muscles and C2C12 myotubes, GLP-2 significantly increased the expressions of MyoD, MyoG, and Myhc compared to the D-galactose. GLP-2 significantly suppressed cell apoptosis. Western blot analysis indicated that the regulation of GLP-2 may be attributed to the activation of theIGF-1/Pi3k/Akt/FoxO3a phosphorylation pathway. CONCLUSIONS: This study suggested that GLP-2 ameliorated D-galactose induced muscle aging by IGF-1/Pi3k/Akt/FoxO3a pathway.

Correction: EGFP-EGF1-Conjugated PLGA Nanoparticles for Targeted Delivery of siRNA into Injured Brain Microvascular Endothelial Cells for Efficient RNA Interference.

[This corrects the article DOI: 10.1371/journal.pone.0060860.].

Signal-averaged electrocardiography as a noninvasive tool for evaluating the ventricular substrate in patients with nonischemic cardiomyopathy: reassessment of an old tool.

Introduction: Signal-averaged electrocardiography (SAECG) provides diagnostic and prognostic information regarding cardiac diseases. However, its value in other nonischemic cardiomyopathies (NICMs) remains unclear. This study aimed to investigate the role of SAECG in patients with NICM. Methods and results: This retrospective study included consecutive patients with NICM who underwent SAECG, biventricular substrate mapping, and ablation for ventricular arrhythmia (VA). Patients with baseline ventricular conduction disturbances were excluded. Patients who fulfilled at least one SAECG criterion were categorized into Group 1, and the other patients were categorized into Group 2. Baseline and ventricular substrate characteristics were compared between the two groups. The study included 58 patients (39 men, mean age 50.4 ± 15.5 years), with 34 and 24 patients in Groups 1 and 2, respectively. Epicardial mapping was performed in eight (23.5%) and six patients (25.0%) in Groups 1 and 2 (p = 0.897), respectively. Patients in Group 1 had a more extensive right ventricular (RV) low-voltage zone (LVZ) and scar area than those in Group 2. Group 1 had a larger epicardial LVZ than Group 2. Epicardial late potentials were more frequent in Group 1 than in Group 2. There were more arrhythmogenic foci within the RV outflow tract in Group 1 than in Group 2. There was no significant difference in long-term VA recurrence. Conclusion: In our NICM population, a positive SAECG was associated with a larger RV endocardial scar, epicardial scar/late potentials, and a higher incidence of arrhythmogenic foci in the RV outflow tract.

Upregulated miR-374a-5p drives psoriasis pathogenesis through WIF1 downregulation and Wnt5a/NF-κB activation.

BACKGROUND: Psoriasis is a chronic, inflammatory skin disease. MicroRNAs (miRNAs) are an abundant class of non-coding RNA molecules. Recent studies have shown that multiple miRNAs are abnormally expressed in patients with psoriasis. The upregulation of miR-374a-5p has been associated with psoriasis severity. However, the specific role of miR-374a-5p in the pathogenesis of psoriasis remain unclear. METHODS: qRT-PCR was employed to validate the expression of miR-374a-5p in psoriatic lesions and in a psoriasis-like cell model constructed using a mixture of M5 (IL-17A, IL-22, OSM, IL-1α, and TNF-α). HaCaT cells were transfected with miR-374a-5p mimic/inhibitor, and assays including EdU, CCK-8, and flow cytometry were conducted to evaluate the effect of miR-374a-5p on cell proliferation. The expression of inflammatory cytokines IL-1ß, IL-6, IL-8, and TNF-α was verified by qRT-PCR. Bioinformatics analysis and dual-luciferase reporter gene assay were performed to detect the downstream target genes and upstream transcription factors of miR-374a-5p, followed by validation of their expression through qRT-PCR and Western blotting. A psoriasis-like mouse model was established using imiquimod cream topical application. The psoriasis area and severity index scoring, hematoxylin-eosin histology staining, and Ki67 immunohistochemistry were employed to validate the effect of miR-374a-5p on the psoriatic inflammation phenotype after intradermal injection of miR-374a-5p agomir/NC. Additionally, the expression of pathway-related molecules and inflammatory factors such as IL-1ß, IL-17a, and TNF-α was verified by immunohistochemistry. RESULTS: Upregulation of miR-374a-5p was observed in psoriatic lesions and the psoriasis-like cell model. In vitro experiments demonstrated that miR-374a-5p not only promoted the proliferation of HaCaT cells but also upregulated the expression of inflammatory cytokines, including IL-1ß, IL-6, IL-8, and TNF-α. Furthermore, miR-374a-5p promoted skin inflammation and epidermal thickening in the Imiquimod-induced psoriasis-like mouse model. Mechanistic studies revealed that miR-374a-5p led to downregulation of WIF1, thereby activating the Wnt5a/NF-κB signaling pathway. The transcription factor p65 encoded by RELA, as a subunit of NF-κB, further upregulated the expression of miR-374a-5p upon activation. This positive feedback loop promoted keratinocyte proliferation and abnormal inflammation, thereby facilitating the development of psoriasis. CONCLUSION: Our findings elucidate the role of miR-374a-5p upregulation in the pathogenesis of psoriasis through inhibition of WIF1 and activation of the Wnt5a/NF-κB pathway, providing new potential therapeutic targets for psoriasis.

Deep Learning-Based Fish Detection Using Above-Water Infrared Camera for Deep-Sea Aquaculture: A Comparison Study.

Long-term, automated fish detection provides invaluable data for deep-sea aquaculture, which is crucial for safe and efficient seawater aquafarming. In this paper, we used an infrared camera installed on a deep-sea truss-structure net cage to collect fish images, which were subsequently labeled to establish a fish dataset. Comparison experiments with our dataset based on Faster R-CNN as the basic objection detection framework were conducted to explore how different backbone networks and network improvement modules influenced fish detection performances. Furthermore, we also experimented with the effects of different learning rates, feature extraction layers, and data augmentation strategies. Our results showed that Faster R-CNN with the EfficientNetB0 backbone and FPN module was the most competitive fish detection network for our dataset, since it took a significantly shorter detection time while maintaining a high AP50 value of 0.85, compared to the best AP50 value of 0.86 being achieved by the combination of VGG16 with all improvement modules plus data augmentation. Overall, this work has verified the effectiveness of deep learning-based object detection methods and provided insights into subsequent network improvements.

Paradoxical herniation associated with hyperbaric oxygen therapy after decompressive craniectomy: A case report.

BACKGROUND: Whether hyperbaric oxygen therapy (HBOT) can cause paradoxical herniation is still unclear. CASE SUMMARY: A 65-year-old patient who was comatose due to brain trauma underwent decompressive craniotomy and gradually regained consciousness after surgery. HBOT was administered 22 d after surgery due to speech impairment. Paradoxical herniation appeared on the second day after treatment, and the patient's condition worsened after receiving mannitol treatment at the rehabilitation hospital. After timely skull repair, the paradoxical herniation was resolved, and the patient regained consciousness and had a good recovery as observed at the follow-up visit. CONCLUSION: Paradoxical herniation is rare and may be caused by HBOT. However, the underlying mechanism is unknown, and the understanding of this phenomenon is insufficient. The use of mannitol may worsen this condition. Timely skull repair can treat paradoxical herniation and prevent serious complications.

Gene expression prognostic of early relapse risk in low-risk B-cell acute lymphoblastic leukaemia in children.

ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukaemia (ALL) and is associated with favorable outcomes, especially in low-risk children. However, as many as 10% of children relapse within 3 years, and such early relapses have poor survival. Identifying children at risk for early relapse is an important challenge. We interrogated data from 87 children with low-risk ETV6::RUNX1-positive B-cell ALL and with available preserved bone marrow samples (discovery cohort). We profiled somatic point mutations in a panel of 559 genes and genome-wide transcriptome and single-nucleotide variants. We found high TIMD4 expression (> 85th-percentile value) at diagnosis was the most important independent prognostic factor of early relapse (hazard ratio [HR] = 5.07 [1.76, 14.62]; p = 0.03). In an independent validation cohort of low-risk ETV6::RUNX1-positive B-cell ALL (N = 68) high TIMD4 expression at diagnosis had an HR = 4.78 [1.07, 21.36] (p = 0.04) for early relapse. In another validation cohort including 78 children with low-risk ETV6::RUNX1-negative B-cell ALL, high TIMD4 expression at diagnosis had an HR = 3.93 [1.31, 11.79] (p = 0.01). Our results suggest high TIMD4 expression at diagnosis in low-risk B-cell ALL in children might be associated with high risk for early relapse.

Association between the oxidative balance score and low muscle mass in middle-aged US adults.

Background: Oxidative Balance Score (OBS) is a tool for assessing the oxidative stress-related exposures of diet and lifestyle. The study aimed to investigate the association between OBS and low muscle mass. Methods: Overall, 6,307 individuals over the age of 18 were assessed using data from the 2011 to 2018 National Health and Nutrition Examination Survey (NHANES). Weighted logistic regression and models were used, together with adjusted models. Results: There was a negative relationship between OBS and low muscle mass [odds ratio (OR): 0.96, 95% confidence interval (CI): 0.94-0.97, p< 0.0001] using the first OBS level as reference. The values (all 95% CI) were 0.745 (0.527-1.054) for the second level, 0.650 (0.456-0.927) for the third level, and 0.326 (0.206-0.514) for the fourth level (P for trend <0.0001). Independent links with low muscle mass were found for diet and lifestyle factors. A restricted cubic spline model indicated a non-linear association between OBS and low muscle mass risk (P for non-linearity<0.05). In addition, the inflection points of the nonlinear curves for the relationship between OBS and risk of low muscle mass were 20. Conclusion: OBS and low muscle mass were found to be significantly negatively correlated. By modulating oxidative balance, a healthy lifestyle and antioxidant rich diet could be a preventive strategy for low muscle mass.

Tanshinone IIA destabilizes SLC7A11 by regulating PIAS4-mediated SUMOylation of SLC7A11 through KDM1A, and promotes ferroptosis in breast cancer.

INTRODUCTION: Breast cancer (BC) is the most common malignancy in women with unfavorite prognosis. OBJECTIVES: Tanshinone IIA (Tan IIA) inhibits BC progression, however, the underlying mechanism remains largely undefined. METHODS: The cytotoxicity of Tan IIA was assessed by CCK-8 and LDH assays. Ferroptosis was monitored by the level of MDA, Fe2+, lipid ROS and GSH. IHC and western blot were employed to detect the localization and expression of SLC7A11, PIAS4, KDM1A and other key molecules. The SUMOylation of SLC7A11 was detected by Ni-beads pull-down assay and Co-IP. Luciferase and ChIP assays were employed to detect the direct association between KDM1A and PIAS4 promoter. The proliferative and metastatic properties of BC cells were assessed by colony formation, CCK-8 and Transwell assays, respectively. The in vitro findings were verified in xenograft and lung metastasis models. RESULTS: Tan IIA promoted ferroptosis by suppressing SLC7A11 in BC cells. Silencing of PIAS4 or KDM1A inhibited cell growth and metastasis in BC. Mechanistically, PIAS4 facilitated the SUMOylation of SLC7A11 via direct binding to SLC7A11, and KDM1A acted as a transcriptional activator of PIAS4. Functional studies further revealed that Tan IIA decreased KDM1A expression, thus suppressing PIAS4 expression transcriptionally. The inhibition of PIAS4-dependent SUMOylation of SLC7A11 further induced ferroptosis, thereby inhibiting proliferation and metastasis in BC. CONCLUSION: Tan IIA promoted ferroptosis and inhibited tumor growth and metastasis via suppressing KDM1A/PIAS4/SLC7A11 axis.

Circulating plasma cells as a predictive biomarker in Multiple myeloma: an updated systematic review and meta-analysis.

BACKGROUND: Circulating plasma cells (CPCs) are defined by the presence of peripheral blood clonal plasma cells, which would contribute to the progression and dissemination of multiple myeloma (MM). An increasing number of studies have demonstrated the predictive potential of CPCs in the past few years. Therefore, there is a growing need for an updated meta-analysis to identify the specific relationship between CPCs and the prognosis of MM based on the current research status. METHODS: The PubMed, Embase, and Cochrane Library databases were screened to determine eligible studies from inception to November 5, 2023. Publications that reported the prognostic value of CPCs in MM patients were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) and progression-free survival (PFS) were extracted to pool the results. Subgroup analyses were performed based on region, sample size, cut-off value, detection time, initial treatment, and data type. The association between CPCs level and clinicopathological characteristics, including the International Staging System (ISS), Revised-ISS (R-ISS), and cytogenetic abnormalities were also evaluated. Statistical analyses were conducted using STATA 17.0 software. RESULTS: Twenty-two studies with a total of 5637 myeloma patients were enrolled in the current meta-analysis. The results indicated that myeloma patients with elevated CPCs were expected to have a poor OS (HR = 2.19, 95% CI: 1.81-2.66, p < 0.001) and PFS (HR = 2.45, 95% CI: 1.93-3.12, p < 0.001). Subgroup analyses did not alter the prognostic role of CPCs, regardless of region, sample size, cut-off value, detection time, initial treatment, or data type. Moreover, the increased CPCs were significantly related to advanced tumour stage (ISS III vs. ISS I-II: pooled OR = 2.89, 95% CI: 2.41-3.46, p < 0.001; R-ISS III vs. R-ISS I-II: pooled OR = 3.65, 95% CI: 2.43-5.50, p < 0.001) and high-risk cytogenetics (high-risk vs. standard-risk: OR = 2.22, 95% CI: 1.60-3.08, p < 0.001). CONCLUSION: Our meta-analysis confirmed that the increased number of CPCs had a negative impact on the PFS and OS of MM patients. Therefore, CPCs could be a promising prognostic biomarker that helps with risk stratification and disease monitoring.

There is a growing need for an updated meta-analysis to identify the specific relationship between CPCs and the prognosis of MM based on the current research status.Our meta-analysis revealed that a high CPCs level was significantly associated with worse OS and PFS in MM patients.CPCs could be a promising predictive biomarker that helps with risk stratification and disease monitoring.