Overexpression of NUDT16L1 sustains proper function of mitochondria and leads to ferroptosis insensitivity in colorectal cancer.

Cancer research is continuously exploring new avenues to improve treatments, and ferroptosis induction has emerged as a promising approach. However, the lack of comprehensive analysis of the ferroptosis sensitivity in different cancer types has limited its clinical application. Moreover, identifying the key regulator that influences the ferroptosis sensitivity during cancer progression remains a major challenge. In this study, we shed light on the role of ferroptosis in colorectal cancer and identified a novel ferroptosis repressor, NUDT16L1, that contributes to the ferroptosis insensitivity in this cancer type. Mechanistically, NUDT16L1 promotes ferroptosis insensitivity in colon cancer by enhancing the expression of key ferroptosis repressor and mitochondrial genes through direct binding to NAD-capped RNAs and the indirect action of MALAT1. Our findings also reveal that NUDT16L1 localizes to the mitochondria to maintain its proper function by preventing mitochondrial DNA leakage after treatment of ferroptosis inducer in colon cancer cells. Importantly, our orthotopic injection and Nudt16l1 transgenic mouse models of colon cancer demonstrated the critical role of NUDT16L1 in promoting tumor growth. Moreover, clinical specimens revealed that NUDT16L1 was overexpressed in colorectal cancer, indicating its potential as a therapeutic target. Finally, our study shows the therapeutic potential of a NUDT16L1 inhibitor in vitro, in vivo and ex vivo. Taken together, these findings provide new insights into the crucial role of NUDT16L1 in colorectal cancer and highlight its potential as a promising therapeutic target.

Discussion on clinical application and regularity of the theory of "mind-regulating" in clinical acupuncture and moxibustion treatment. / "调神"思想在针灸临床中的运用概况及规律探讨.

The active role of "Shen" (mind) in the process of disease treatment has always been valued by scholars of traditional Chinese medicine (TCM). "Tiaoshen" (mind-regulating) is regarded as the fundamental component of TCM therapy. "Mind-regulating" acupuncture and moxibustion therapy, as a treatment method for both body and mind, is consistent with the present bio-psycho-social medical model. In recent years, a large number of clinical studies have confirmed the exact efficacy of "mind-regulating" acupuncture and moxibustion therapy. This article reviewed the clinical applications of that in psychosomatic diseases, neurological diseases, and digestive diseases over the last decade. This article also summarized the research progress of various "mind-regulating" acupuncture and moxibustion methods, investigated the theoretical connotations of "Tongdu Tiaoshen" (dredging Governor Vessel and regulating mind) acupuncture, "Shugan Tiaoshen" (soothing liver and regulating mind) acupuncture, and the "Tiaoshen needling technique" (mind-regulating needling technique), and generalized the main acupoint selection rules. Lastly, future development directions were provided for the theoretical basis of clinical application of "mind-regulating" acupuncture and moxibustion therapy for further improvement.

Thrombectomy Alone or Alongside Intravenous Thrombolysis in Managing Acute Ischemic Stroke Caused by Basilar Artery Occlusion: A Multicenter Observational Study.

BACKGROUND AND PURPOSE: It remains unclear whether the combination of endovascular treatment (EVT) with intravenous thrombolysis (IVT) results in a more favorable functional outcome than EVT alone in managing cases of acute ischemic stroke (AIS) caused by basilar artery occlusion (BAO). Thus, this study aimed to compare the outcomes of two approaches-direct EVT (DEVT) and bridging therapy (IVT plus EVT)-in acute BAO patients presenting within 4.5 hours of stroke onset. MATERIALS AND METHODS: This multicenter retrospective cohort study included 153 acute BAO patients presenting within 4.5 hours of stroke onset. Of these patients, 65 (42.5%) and 88 (57.5%) underwent DEVT and bridging therapy, respectively. The primary outcome was defined as good functional outcome (modified Rankin Scale, 0-3) at 90 days. Additionally, pre-operative clinical features, thrombectomy attempts, successful reperfusion rates, incidences of symptomatic intracranial hemorrhage (sICH), and mortality were compared between the two groups. RESULTS: At 90 days, the rate of good functional outcome was comparable between the DEVT (44.6%) and bridging-therapy (39.8%) groups (adjusted odds ratio [aOR], 1.12; 95% confidence interval [CI], 0.55-2.31; p = 0.753). The bridging-therapy group exhibited a lower percentage of patients requiring ≥ 3 attempts of stent retrieval (aOR, 0.39; 95% CI, 0.16-0.93; p = 0.034). Pre-operative clinical features, rate of successful reperfusion, sICH, and mortality were similar between the two groups. CONCLUSIONS: In patients with BAO-induced AIS, DEVT demonstrates a comparable functional outcome to bridging therapy within 4.5 hours of symptom onset, but IVT reduces the number of thrombectomy attempts. ABBREVIATIONS: AIS, acute ischemic stroke; LVO, large-vessel occlusion; EVT, endovascular treatment; IVT, intravenous thrombolysis; BAO, basilar artery occlusion; DEVT, direct endovascular treatment; sICH, symptomatic intracranial hemorrhage; RCT, randomized controlled trial; IRIS, Improving Reperfusion Strategies in Ischemic Stroke; TOAST, Trial of ORG 10172 in Acute Stroke Treatment; mTICI, modified thrombolysis in cerebral infarction; SD, standard deviation; IQR, interquartile range; ICAS, intracranial atherosclerotic stenosis.

The prognostic impact of malnutrition on the outcomes of patients with vertebrobasilar artery occlusion following endovascular treatment.

BACKGROUND AND PURPOSE: Malnutrition is associated with poor outcomes in different diseases. Our aim was to investigate whether measures of malnutrition could be used to predict 90-day outcomes in patients with vertebrobasilar artery occlusion (VBAO) undergoing endovascular treatment (EVT). METHODS: We retrospectively analyzed patients with VBAO who received EVT at three comprehensive stroke centers. Malnutrition was assessed using the controlling nutritional status (CONUT) score, geriatric nutritional risk index (GNRI), and prognostic nutritional index (PNI). Primary outcome was good functional outcome defined as modified Rankin Scale (mRS) 0-3 measured at 90 days. RESULTS: A total of 285 patients were enrolled, of which 260 (91.22 %) met the requirements. According to the CONUT, GNRI, and PNI scores, the proportions of patients classified as moderately or severely malnourished were 7.3 %, 3.08 %, and 35 %, respectively. In the multivariate regression model after adjusting for potential confounders, malnutrition (severe risk versus normal nutritional status) was significantly associated with an increased risk of poor prognosis for CONUT scores (adjusted odds ratio [OR]14.91, 95 %CI, 1.69 - 131.71; P = 0.015), GNRI scores (adjusted [OR] 10.67, 1.17 - 96.93; P = 0.036) and PNI scores (adjusted [OR] 4.61, 2.28 - 9.31; P < 0.001). Similar results were obtained when malnutrition scores were analyzed as continuous variables. Adding the 3 malnutrition measures to the risk reclassification that included traditional risk factors significantly improved the predictive value of 3-month poor prognosis. CONCLUSIONS: Our study showed that malnutrition may be associated with poor prognosis within 3 months of EVT in patients with VBAO.

Comparison of static teeth exposure in different postures and its influencing factors of orthognathic surgery patients.

OBJECTIVES: This study aimed to explore the differences and influencing factors of static teeth exposure in different postures of orthognathic surgery patients. METHODS: A total of 148 patients were collected before or after orthognathic surgery. Photographs were taken in the upright and supine positions, and the static teeth exposure values were measured to compare whether the difference among different positions was statistically significant. The patients were classified in accordance with gender, presence or absence of orthodontic brackets, measurement time (preoperative or postoperative), and maxillary movement direction (forward or backward), and the difference of static teeth exposure was compared. The correlation between the difference of static teeth exposure and age was analyzed. RESULTS: The diffe-rence of static teeth exposure between the two positions was 0.99 mm±0.95 mm, which was statistically significant (P=0.000). A statistical difference in the difference of static exposure was observed between female and male (P<0.05). No statistical difference in the difference of static exposure was observed among orthodontic brackets, preoperative or postoperative time points, and maxillary movement direction. In addition, no significant correlation was found between the difference of static teeth exposure and age (r=-0.087, P=0.291). CONCLUSIONS: Compared with the upright position, the static exposure of teeth increased by approximately 0.99 mm in the supine position. The difference of static exposure under different postures was greater in males than in females. Furthermore, orthodontic bracket, maxillary surgery, maxillary movement direction, and age had no effect on the difference of static teeth exposure in different postures.

MXene Based Flame Retardant and Electrically Conductive Polymer Coatings.

Modern polymer coatings possess tremendous multifunctionalities and have attracted immense research interest in recent decades. However, with the expeditious development of technologies and industries, there is a vast demand for the flame retardancy and electrical conductivity of engineered polymer coatings. Traditional functional materials that render the polymer coatings with these properties require a sophisticated fabrication process, and their high mass gains can be a critical issue for weight-sensitive applications. In recent years, massive research has been conducted on a newly emerged two-dimensional (2D) nanosize material family, MXene. Due to the excellent electrical conductivity, flame retardancy, and lightweightness, investigations have been launched to synthesise MXene-based polymer coatings. Consequently, we performed a step-by-step review of MXene-involved polymer coatings, from solely attaching MXene to the substrate surface to the multilayered coating of modified MXene with other components. This review examines the performances of the fire safety enhancement and electrical conductivity as well as the feasibility of the manufacturing procedures of the as-prepared polymer composites. Additionally, the fabricated polymer coatings' dual property mechanisms are well-demonstrated. Finally, the prospect of MXene participating in polymer coatings to render flame retardancy and electrical conductivity is forecasted.

A novel approach to the analysis of Overall Survival (OS) as response with Progression-Free Interval (PFI) as condition based on the RNA-seq expression data in The Cancer Genome Atlas (TCGA).

BACKGROUND: Overall Survival (OS) and Progression-Free Interval (PFI) as survival times have been collected in The Cancer Genome Atlas (TCGA). It is of biomedical interest to consider their dependence in pathway detection and survival prediction. We intend to develop novel methods for integrating PFI as condition based on parametric survival models for identifying pathways associated with OS and predicting OS. RESULTS: Based on the framework of conditional probability, we developed a family of frailty-based parametric-models for this purpose, with exponential or Weibull distribution as baseline. We also considered two classes of existing methods with PFI as a covariate. We evaluated the performance of three approaches by analyzing RNA-seq expression data from TCGA for lung squamous cell carcinoma and lung adenocarcinoma (LUNG), brain lower grade glioma and glioblastoma multiforme (GBMLGG), as well as skin cutaneous melanoma (SKCM). Our focus was on fourteen general cancer-related pathways. The 10-fold cross-validation was employed for the evaluation of predictive accuracy. For LUNG, p53 signaling and cell cycle pathways were detected by all approaches. Furthermore, three approaches with the consideration of PFI demonstrated significantly better predictive performance compared to the approaches without the consideration of PFI. For GBMLGG, ten pathways (e.g., Wnt signaling, JAK-STAT signaling, ECM-receptor interaction, etc.) were detected by all approaches. Furthermore, three approaches with the consideration of PFI demonstrated better predictive performance compared to the approaches without the consideration of PFI. For SKCM, p53 signaling pathway was detected only by our Weibull-baseline-based model. And three approaches with the consideration of PFI demonstrated significantly better predictive performance compared to the approaches without the consideration of PFI. CONCLUSIONS: Based on our study, it is necessary to incorporate PFI into the survival analysis of OS. Furthermore, PFI is a survival-type time, and improved results can be achieved by our conditional-probability-based approach.

Predicting BRCA mutation and stratifying targeted therapy response using multimodal learning: a multicenter study.

BACKGROUND: The status of BRCA1/2 genes plays a crucial role in the treatment decision-making process for multiple cancer types. However, due to high costs and limited resources, a demand for BRCA1/2 genetic testing among patients is currently unmet. Notably, not all patients with BRCA1/2 mutations achieve favorable outcomes with poly (ADP-ribose) polymerase inhibitors (PARPi), indicating the necessity for risk stratification. In this study, we aimed to develop and validate a multimodal model for predicting BRCA1/2 gene status and prognosis with PARPi treatment. METHODS: We included 1695 slides from 1417 patients with ovarian, breast, prostate, and pancreatic cancers across three independent cohorts. Using a self-attention mechanism, we constructed a multi-instance attention model (MIAM) to detect BRCA1/2 gene status from hematoxylin and eosin (H&E) pathological images. We further combined tissue features from the MIAM model, cell features, and clinical factors (the MIAM-C model) to predict BRCA1/2 mutations and progression-free survival (PFS) with PARPi therapy. Model performance was evaluated using area under the curve (AUC) and Kaplan-Meier analysis. Morphological features contributing to MIAM-C were analyzed for interpretability. RESULTS: Across the four cancer types, MIAM-C outperformed the deep learning-based MIAM in identifying the BRCA1/2 genotype. Interpretability analysis revealed that high-attention regions included high-grade tumors and lymphocytic infiltration, which correlated with BRCA1/2 mutations. Notably, high lymphocyte ratios appeared characteristic of BRCA1/2 mutations. Furthermore, MIAM-C predicted PARPi therapy response (log-rank p < 0.05) and served as an independent prognostic factor for patients with BRCA1/2-mutant ovarian cancer (p < 0.05, hazard ratio:0.4, 95% confidence interval: 0.16-0.99). CONCLUSIONS: The MIAM-C model accurately detected BRCA1/2 gene status and effectively stratified prognosis for patients with BRCA1/2 mutations.

Perfusion deficit and vessel wall characteristics to predict recurrent ischemic events in medically treated patients with chronic symptomatic anterior circulation large vessel occlusion.

BACKGROUND: To investigate the association between perfusion deficit, vessel wall characteristics, and risk of recurrent ischemic events in medically treated patients with chronic symptomatic anterior circulation large vessel occlusion. METHODS: We retrospectively reviewed chronic symptomatic patients due to anterior circulation large vessel occlusion in our center. All patients received multiparametric magnetic resonance imaging (including perfusion-weighted imaging and high-resolution vessel wall imaging) within 4 weeks to 3 months after symptom onset. The association between baseline clinical or imaging variables and recurrent ischemic events was assessed in bivariate models and multivariable logistic regression to identify independent predictors of recurrence. RESULTS: Among 71 enrolled patients, 21.1% (15/71) patients had recurrent ischemic events (nine ischemic strokes and six transient ischemic attacks) during a 2-year follow-up. In bivariate models, hypertension, occlusion with hyperintense signals, the presence of intraluminal thrombus, Tmax >4 s volume, Tmax >6 s volume, Tmax >8 s volume, and Tmax >10 s volume were associated with recurrence (all p < 0.05). In multivariate analysis, hypertension (p = 0.039, OR 10.057 (95% CI, 1.123-90.048)), higher deficit volume of Tmax >4 s (p = 0.011, OR 1.012 (95% CI, 1.003-1.021)) and occlusion with hyperintense signal (p = 0.030, OR 6.732 (95% CI, 1.200-37.772)) were still independent predictors of recurrent ischemic events. CONCLUSIONS: Besides hypertension history, higher deficit volume of Tmax >4 s and occlusion with hyperintense signal determined using multiparametric MRI are strongly associated with risk for recurrent ischemic events in medically treated patients with chronic symptomatic anterior circulation large vessel occlusion. Future studies are needed to determine the utility of revascularization strategies in such high-risk patients.

Overexpression of long noncoding RNA DUXAP8 inhibits ER-phagy through activating AKT/mTOR signaling and contributes to preeclampsia.

Preeclampsia (PE) is a life-threatening pregnancy-specific complication with controversial mechanisms and no effective treatment except delivery is available. Currently, increasing researchers suggested that PE shares pathophysiologic features with protein misfolding/aggregation disorders, such as Alzheimer disease (AD). Evidences have proposed defective autophagy as a potential source of protein aggregation in PE. Endoplasmic reticulum-selective autophagy (ER-phagy) plays a critical role in clearing misfolded proteins and maintaining ER homeostasis. However, its roles in the molecular pathology of PE remain unclear. We found that lncRNA DUXAP8 was upregulated in preeclamptic placentae and significantly correlated with clinical indicators. DUXAP8 specifically binds to PCBP2 and inhibits its ubiquitination-mediated degradation, and decreased levels of PCBP2 reversed the activation effect of DUXAP8 overexpression on AKT/mTOR signaling pathway. Function experiments showed that DUXAP8 overexpression inhibited trophoblastic proliferation, migration, and invasion of HTR-8/SVneo and JAR cells. Moreover, pathological accumulation of swollen and lytic ER (endoplasmic reticulum) was observed in DUXAP8-overexpressed HTR8/SVneo cells and PE placental villus trophoblast cells, which suggesting that ER clearance ability is impaired. Further studies found that DUXAP8 overexpression impaired ER-phagy and caused protein aggregation medicated by reduced FAM134B and LC3II expression (key proteins involved in ER-phagy) via activating AKT/mTOR signaling pathway. The increased level of FAM134B significantly reversed the inhibitory effect of DUXAP8 overexpression on the proliferation, migration, and invasion of trophoblasts. In vivo, DUXAP8 overexpression through tail vein injection of adenovirus induced PE-like phenotypes in pregnant rats accompanied with activated AKT/mTOR signaling, decreased expression of FAM134B and LC3-II proteins and increased protein aggregation in placental tissues. Our study reveals the important role of lncRNA DUXAP8 in regulating trophoblast biological behaviors through FAM134B-mediated ER-phagy, providing a new theoretical basis for understanding the pathogenesis of PE.

Strong effect-correlated electrochemical CO2 reduction.

Electrochemical CO2 reduction (ECR) holds great potential to alleviate the greenhouse effect and our dependence on fossil fuels by integrating renewable energy for the electrosynthesis of high-value fuels from CO2. However, the high thermodynamic energy barrier, sluggish reaction kinetics, inadequate CO2 conversion rate, poor selectivity for the target product, and rapid electrocatalyst degradation severely limit its further industrial-scale application. Although numerous strategies have been proposed to enhance ECR performances from various perspectives, scattered studies fail to comprehensively elucidate the underlying effect-performance relationships toward ECR. Thus, this review presents a comparative summary and a deep discussion with respect to the effects strongly-correlated with ECR, including intrinsic effects of materials caused by various sizes, shapes, compositions, defects, interfaces, and ligands; structure-induced effects derived from diverse confinements, strains, and fields; electrolyte effects introduced by different solutes, solvents, cations, and anions; and environment effects induced by distinct ionomers, pressures, temperatures, gas impurities, and flow rates, with an emphasis on elaborating how these effects shape ECR electrocatalytic activities and selectivity and the underlying mechanisms. In addition, the challenges and prospects behind different effects resulting from various factors are suggested to inspire more attention towards high-throughput theoretical calculations and in situ/operando techniques to unlock the essence of enhanced ECR performance and realize its ultimate application.

The role of ascorbate redox turnover in iron toxicity tolerance.

Iron (Fe) toxicity is a major abiotic stress in lowland rice production. Breeding tolerant varieties has proven challenging due to the complex genetic architecture of Fe toxicity tolerance and the strong genotype-by-environment interactions. Additionally, conventional methods for phenotyping visible stress symptoms are often inaccurate, inconsistent, and lack reproducibility. In our previous work, we identified that ascorbate redox regulation, mediated by the activities of dehydroascorbate reductase (DHAR) and ascorbate oxidase (AO), contributed to high tolerance in an indica rice genotype across various environments. To explore whether this mechanism is common among other rice genotypes, we selected ten genotypes with contrasting stress symptoms under Fe-toxic conditions to examine the roles of DHAR and AO in regulating Fe toxicity tolerance. Additionally, we aimed to develop objective and accurate image-based phenotyping methods to replace the traditional leaf bronzing scoring method. Among the ten genotypes we tested, we found significant positive correlations between DHAR activity and stress symptoms in plants grown under both Fe toxicity and control conditions, suggesting a general link between ascorbate redox regulation and Fe toxicity tolerance. Using RGB signals from leaf images of plants exposed to 1000 mg/L Fe2+, we evaluated 36 different color indices to quantify stress symptoms. We identified the normalized green‒red difference index as most significant in quantifying stress symptoms under Fe toxicity conditions. Our findings suggest that DHAR activity could be potentially employed as a biomarker in the screening of rice germplasms and breeding tolerant cultivars to Fe toxicity.

Association of peripheral eosinophil count with chronic kidney disease progression risk: a retrospective cohort study in Chinese population.

BACKGROUND: The role of peripheral eosinophils in chronic kidney disease (CKD) requires further evaluation. We aimed to determine whether an eosinophil count increase is related to the occurrence of end-stage renal disease (ESRD). METHODS: This single-center, observational, retrospective cohort study was conducted between January 2016 and December 2018 in Hangzhou, China, and included 3163 patients, categorized into four groups according to peripheral eosinophil count (PEC) quartile values. The main outcome was ESRD development during follow-up. We evaluated the relationship between the serum eosinophil count, demographic and clinical information, and ESRD incidence. Cox proportional hazards models and Kaplan-Meier survival curves were used. RESULTS: A total of 3163 patients with CKD were included in this cohort, of whom 1254 (39.6%) were females. The median (interquartile range [IQR]) age was 75 [64, 85] years, and the median (IQR) estimated glomerular filtration rate was 55.16 [45.19, 61.19] mL/min/1.73 m2. The median PEC was 0.1224 × 109/L (IQR, 0.0625-0.212). Among the 3163 patients with CKD, 273 (8.6%) developed ESRD during a median follow-up time of 443.8 [238.8, 764.9] days. Individuals in the highest PEC quartile had a 66.2% higher ESRD risk than those in the lowest quartile (hazard ratio, 1.662; 95% confidence interval, 1.165-2.372). The results from the Kaplan-Meier survival curves confirmed the conclusion. CONCLUSIONS: Alongside traditional risk factors, patients with CKD and an elevated PEC are more likely to develop ESRD. Therefore, more attention should be paid to those patients with CKD who have a high PEC.

Vertically Fluorinated Graphene Encapsulated SiOx Anode for Enhanced Li+ Transport and Interfacial Stability in High-Energy-Density Lithium Batteries.

Achieving high energy density has always been the goal of lithium-ion batteries (LIBs). SiOx has emerged as a compelling candidate for use as a negative electrode material due to its remarkable capacity. However, the huge volume expansion and the unstable electrode interface during (de)lithiation, hinder its further development. Herein, we report a facile strategy for the synthesis of surface fluorinated SiOx (SiOx@vG-F), and investigate their influences on battery performance. Systematic experiments investigations indicate that the reaction between Li+ and fluorine groups promotes the in-situ formation of stable LiF-rich solid electrolyte interface (SEI) on the surface of SiOx@vG-F anode, which effectively suppresses the pulverization of microsized SiOx particles during the charge and discharge cycle. As a result, the SiOx@vG-F enabled a higher capacity retention of 86.4% over 200 cycles at 1.0 C in the SiOx@vG-F||LiNi0.8Co0.1Mn0.1O2 full cell. This approach will provide insights for the advancement of alternative electrode materials in diverse energy conversion and storage systems.

Local hydroxide ion enrichment at the inner surface of lacunaris perovskite nanotubes facilitates the oxygen evolution reaction.

Numerous strategies have been devised to optimize the intrinsic activity of perovskite oxides for the oxygen evolution reaction (OER). However, conventional synthetic routes typically yield limited numbers of active sites and low mass activities. More critically, the sluggish mass transfer poses a huge challenge, particularly under high polarization conditions, which impedes the overall reaction kinetics. Herein, lacunaris La0.5Pr0.25Ba0.25Co0.8Ni0.2O3-δ nanotubes (LPBCN-NTs) were prepared via electrospinning and post-annealing, which exhibited a small overpotential of 358.8 mV at 10 mA cm-2 and a lower Tafel slope of 71.46 mV dec-1, superior to the values for the same stoichiometric LPBCN nanoparticles and solid nanofibers, state-of-the-art counterparts and commercial IrO2. Density functional theory calculations revealed that the surface oxygen vacancies in LPBCN-NTs significantly lowered the OH- adsorption energy, while finite element analysis indicated that the precisely constructed lacunaris NT structure enriched the OH- concentration at its inner surface by an order of magnitude, both of which collectively resulted in accelerated OER kinetics. This study clarifies the underlying mechanism of how the lacunaris nanotubular architecture and the surface oxygen vacancies of perovskite oxides affect heterocatalysis, which undoubtedly paves the way to handling the long-standing issues of sluggish mass transfer rates and poor intrinsic catalytic activity.

IL-6/STAT3 signaling pathway induces prostate apoptosis response protein-4(PAR-4) to stimulate malignant behaviors of hepatocellular carcinoma cells.

INTRODUCTION AND OBJECTIVES: Prostate apoptosis response protein-4 (PAR-4) is considered a tumor suppressor. However, the role of PAR-4 in hepatocellular carcinoma (HCC) has rarely been reported. The study explores the role of PAR-4 in the malignant behaviors of HCC cells. MATERIALS AND METHODS: TCGA database was applied to analyze the expression of PAR-4 in HCC. Evaluated PAR-4 relationship with clinical parameters and prognosis by tissue microarray; expression of STAT3, p-STAT3, Src and Ras was detected by Western blotting or laser confocal microscopy. Cell scratch and flow cytometry assays were used to observe IL-6 regulation of the malignant behaviors of HCC cells. The tumorigenic potential of HCC cells in vivo was evaluated in a nude mouse tumor model. RESULTS: Analysis indicated that the expression of PAR-4 in HCC tissues was significantly higher than that in normal liver tissues; and PAR-4 interacted with STAT3. KEGG analysis showed that PAR-4 plays a role in the Janus kinase (JAK)/STAT signaling pathway. The positive expression rate of PAR-4 in HCC tissues was significantly higher than that in adjacent tissues. Positive correlation between IL-6 and PAR-4 expression in the HCC tissues. Exogenous IL-6 significantly promoted the proliferation and migration of HCC cells and up-regulated the expression of PAR-4 and p-STAT3 in HCC cells. Interference of the expression of PAR-4 could reduce the malignant behaviors of HCC cells and inhibit tumorigenesis in a nude mouse tumor model. CONCLUSIONS: PAR-4 expression is positively correlated with HCC; PAR-4 promotes malignant behavior of HCC cells mediated by the IL-6/STAT3 signaling pathway.

Promising response of proliferative glomerulonephritis with monoclonal IgG deposits to low-dose daratumumab: a case report.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a rare disease without standardized treatment modalities. Daratumumab is a human IgG monoclonal anti-CD38 antibody that has been demonstrated to be highly effective and safe in the treatment of PGNMID. This article reports a 66-year-old female who suffered from edema in both lower limbs and face for 6 years with mild proteinuria and hypoproteinemia. Renal biopsy displayed eight glomeruli, among which two presented with glomerulosclerosis, and the remaining six exhibited moderate diffuse hyperplasia of glomerular mesangial cells and stroma with endothelial cell proliferation. Immunofluorescence microscopy revealed lumpy and diffuse deposits of C3, C1q, IgG, and κ light chain in the glomerular mesangium, with strongly positive staining for IgG3 and varying degrees of weak to negative staining for IgG1, IgG2, IgG4, and λ light chain. Additionally, ultrastructural analysis unveiled that the glomerular basement membrane was segmentally thickened, accompanied by diffuse pedicle fusion, segmental tethered insertion, subendothelial deposits, and electron-dense material in tethered areas. The patient received a total dose of 800 mg of daratumumab (400 mg daily for two consecutive days), as well as daily prednisone (25 mg) and valsartan (80 mg), for treatment and achieved complete remission after three-month follow-up. This case represents an early attempt to treat PGNMID with low-dose daratumumab but requires long-term follow-up.

Multiplex cerebrospinal fluid proteomics identifies biomarkers for diagnosis and prediction of Alzheimer's disease.

Recent expansion of proteomic coverage opens unparalleled avenues to unveil new biomarkers of Alzheimer's disease (AD). Among 6,361 cerebrospinal fluid (CSF) proteins analysed from the ADNI database, YWHAG performed best in diagnosing both biologically (AUC = 0.969) and clinically (AUC = 0.857) defined AD. Four- (YWHAG, SMOC1, PIGR and TMOD2) and five- (ACHE, YWHAG, PCSK1, MMP10 and IRF1) protein panels greatly improved the accuracy to 0.987 and 0.975, respectively. Their superior performance was validated in an independent external cohort and in discriminating autopsy-confirmed AD versus non-AD, rivalling even canonical CSF ATN biomarkers. Moreover, they effectively predicted the clinical progression to AD dementia and were strongly associated with AD core biomarkers and cognitive decline. Synaptic, neurogenic and infectious pathways were enriched in distinct AD stages. Mendelian randomization did not support the significant genetic link between CSF proteins and AD. Our findings revealed promising high-performance biomarkers for AD diagnosis and prediction, with implications for clinical trials targeting different pathomechanisms.

The neurotransmitter calcitonin gene-related peptide shapes an immunosuppressive microenvironment in medullary thyroid cancer.

Neurotransmitters are key modulators in neuro-immune circuits and have been linked to tumor progression. Medullary thyroid cancer (MTC), an aggressive neuroendocrine tumor, expresses neurotransmitter calcitonin gene-related peptide (CGRP), is insensitive to chemo- and radiotherapies, and the effectiveness of immunotherapies remains unknown. Thus, a comprehensive analysis of the tumor microenvironment would facilitate effective therapies and provide evidence on CGRP's function outside the nervous system. Here, we compare the single-cell landscape of MTC and papillary thyroid cancer (PTC) and find that expression of CGRP in MTC is associated with dendritic cell (DC) abnormal development characterized by activation of cAMP related pathways and high levels of Kruppel Like Factor 2 (KLF2), correlated with an impaired activity of tumor infiltrating T cells. A CGRP receptor antagonist could offset CGRP detrimental impact on DC development in vitro. Our study provides insights of the MTC immunosuppressive microenvironment, and proposes CGRP receptor as a potential therapeutic target.