SLC10A5 deficiency causes hypercholanemia.

BACKGROUND AND AIMS: Solute Carrier Family 10 Member 5 ( SLC10A5 ) is a member of SLC10, comprising transporters of bile acids, steroidal hormones and other substrates, but its function remains unclear. The aim of the current investigation was to clarify its function in the metabolism of bile acid and hypercholanemia. APPROACH: Whole-exome sequencing and Sanger sequencing were used to identify and confirm the variant in the subjects of hypercholanemia. CRISPR/Cas9-mediated genome engineering was used to establish the knockout and point mutation mice. Primary mouse hepatocytes were isolated and cell lines were cultured. SLC10A5 was silenced by siRNA and overexpressed by wild-type and mutant plasmids. The fluorescent bile acid derivative was used for bile acid uptake assay. Bile acids were assessed with ultra-performance liquid chromatography tandem mass spectrometry. RESULTS: A heterozygous variant SLC10A5 : c.994_995del (p.D332X) was identified in subjects with elevated total bile acid or altered bile acid profiles. Bile acids were increased in the serum and liver of knockout and point mutation mice. The expressions of FXR and SHP , regulators involved in the negative feedback of bile acid synthesis, were downregulated, while the bile acid synthesis genes CYP8B1 and CYP7A1 were upregulated in both gene-edited mice. Both the wild and mutant SLC10A5 protein were localized on the plasma membrane. Knockdown, knockout or targeted mutation of SLC10A5 led to the inhibition of bile acid uptake by cell lines and primary mouse hepatocyte. CONCLUSION: SLC10A5 is involved in the uptake of bile acid and its deficiency causes hypercholanemia.

Vimentin and tumor-stroma ratio for neoadjuvant chemoradiotherapy response prediction in locally advanced rectal cancer.

Vimentin expression in tumor tissues and the tumor-stroma ratio (TSR) have been demonstrated as strong prognostic factors for cancer patients, but whether they are predictive markers of neoadjuvant chemoradiotherapy (nCRT) outcome in locally advanced rectal cancer (LARC) patients is poorly understood. This study aimed to explore the predictive significance of vimentin and TSR combined for nCRT response in LARC patients. Imaging mass cytometry (IMC) was performed to determine the association of vimentin and TSR with nCRT response in six LARC patients [three achieved pathological complete response (pCR), three did not]. Immunohistochemistry (IHC) for vimentin and TSR on biopsy tissues before nCRT and logistic regression analysis were performed to further evaluate their predictive value for treatment responses in a larger patient cohort. A trend of decreased vimentin expression and increased TSR in the pCR group was revealed by IMC. In the validation group, vimentin [odds ratio (OR) 0.260, 95% confidence interval (CI) 0.102-0.602, p = 0.002] and TSR (OR 4.971, 95% CI 1.933-15.431, p = 0.002) were associated with pCR by univariate analysis. Patients in the vimentin-low/TSR-low or vimentin-high/TSR-high (OR 5.211, 95% CI 1.248-35.582, p = 0.042) and vimentin-low/TSR-high groups (OR 11.846, 95% CI 3.197-77.079, p = 0.001) had significantly higher odds of pCR. By multivariate analysis, only the combination of vimentin and TSR was an independent predictor for nCRT response (OR 9.324, 95% CI 2.290-63.623, p = 0.006). Our study suggested that the combined assessment of vimentin and TSR can provide additive significance and may be a promising indicator of nCRT response in LARC patients.

Vortex-assisted dispersive liquid-liquid microextraction based on the hydrophobic deep eutectic solvent-based ferrofluid for extraction and detection of myclobutanil.

A vortex-assisted dispersive liquid-liquid microextraction (VA-DLLME) procedure using hydrophobic deep eutectic solvent-based ferrofluid (HDES-FF) as an extractant was established. The developed sample preparation method coupled with high-performance liquid chromatography-diode array detector (HPLC-DAD) was applied to the pretreatment and determination of myclobutanil (MYC) in fruit juice. Hydrophobic deep eutectic solvent, synthesized by n-decanoic acid and DL-menthol, was as a carrier and combined with magnetic nanoparticles (Fe3O4@OA) to form HDES-FF as an extractant with high extraction capacity. The synthesized materials were characterized by Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), and vibrating sample magnetometer (VSM). Parameters affecting extraction efficiency were optimized using single-factor experiments and Box-Behnken design via response surface methodology (BBD-RSM). Parallel tests were performed three times under the optimal conditions predicted by the model, yielding an actual mean recovery of 94.77% with RSD of 2.7% (n = 3) and an enrichment factor of 41.8 ± 0.98 (mean value ± SD, n = 3). Under the optimal conditions, the linear range was 1.0-100.0 µg·mL-1; the limit of detection (LOD) and limit of quantification (LOQ) were 0.25 and 0.80 µg·mL-1, respectively. The average spiked recoveries in the samples ranged from 98.2 to 100.5% with intra-day relative standard deviations (RSDs) of 1.2-3.5% (n = 3) and inter-day RSDs of 1.1-3.8% (n = 3). Finally, the method was successfully applied to the determination of MYC antimicrobial agent in different fruit juice samples. The proposed HDES-FF-VA-DLLME/HPLC-DAD method was verified to widely apply to the extraction of triazole fungicides.

BMP4 Regulates EMT to be Involved in non-Syndromic Cleft lip With or Without Palate.

OBJECTIVE: In the previous study, we identified bone morphogenetic protein 4 (BMP4) responsible for non-syndromic cleft lip with or without cleft palate (NSCL/P). We aimed to elucidate the effects and mechanisms of BMP4 on epithelial-mesenchymal transition (EMT) through Smad1 signaling pathway to be involved in NSCL/P. METHODS: The human oral epidermoid carcinoma cells (KBs) were transfected with plasmids or small interfering RNA (siRNA) to build the models. The migration of the cells was evaluated by transwell assay. Western blotting and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) were used to detect the expressions of BMP4, E-cadherin, N-cadherin, EMT-related transcription factors snal1 and snal2, matrix metalloproteinase 2 (MMP2), MMP9, Smad1, and phosphorylated Smad1. RESULTS: In the overexpression group, the migration number of cells was increased significantly. The protein expression of E-cadherin was decreased significantly, while the protein expression level of the N-cadherin was increased significantly. The protein and mRNA expressions of MMP2, MMP9, snal1, and snal2 were significantly higher. The expression level of Smad1 was not significantly changed, while the phosphorylation of Smad1 was significantly increased. In the BMP4-siRNA group, the migrating number cells was significantly decreased. The protein expression of E-cadherin was increased significantly, while the expression of N-cadherin was significantly decreased. The protein and mRNA expressions of MMP2, MMP9, snal1, and snal2 were significantly lower than that of the control group. The expressions of Smad1 and phosphorylation of Smad1 were not significantly changed. CONCLUSIONS: BMP4 enhances cell migration and promotes cell EMT through Smad1 signaling pathway. Abnormal BMP4 mediates migration and EMT through other relevant signaling pathways resulting in NSCL/P. The study provides new insight into the mechanisms of NSCL/P associated with BMP4.n.

Ionic liquid-based dispersive liquid-liquid microextraction followed by magnetic solid-phase extraction for determination of quinolones.

An ionic liquid-based dispersive liquid-liquid microextraction (IL-DLLME) combined with magnetic solid-phase extraction (MSPE) was developed for extraction of quinolones (quinolones) from honey and milk prior to high-performance liquid chromatography (HPLC) analysis. 1-Butyl-3-methylimidazolium hexafluorophosphate was used as the extraction solvent and an effective adsorbent based on chitosan modified magnetic core-shell functionalized multi-walled carbon nanotube (MWCNTs-Fe3O4@SiO2-CS) nanoparticles was used to assist IL to adsorb quinolone residues in honey and milk samples. Extraction conditions were optimized through one-factor-at-a-time and response surface methodology using a Box-Behnken design. Under optimum conditions satisfactory linearity (R2 > 0.999) and high sensitivity (method limits of quantification were 4-8 µg kg-1 or µg L-1 in honey or milk samples) was achieved. The recoveries of quinolones in honey and milk ranged from 81.2 to 109%. Based on this study, the proposed method was employed for the determination of antibiotic residues in honey and milk samples.

Selection of treatment for hepatic epithelioid hemangioendothelioma: a single-center experience.

BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare angiogenic tumor with no recognized effective treatment. Treatment options used worldwide include liver transplantation (LT), liver resection (LR), radiofrequency ablation (RFA), chemotherapy, and observation. The aim of this study was to describe the efficacy of different treatment options used for HEHE at our center. METHODS: The medical charts of 12 patients with HEHE (9 women and 3 men) who were diagnosed and treated at the First Affiliated Hospital of Zhejiang University, China, between January 2011 and December 2017 were retrospectively reviewed. RESULTS: The patients were diagnosed by postoperative histopathology or fine needle aspiration biopsy. Two patients with diffuse lesions received LT and were alive without recurrence at the last follow-up. Three patients received LR as the initial treatment, and all of them developed recurrence during the follow-up period. One patient received RFA and remained free of disease, while the remaining six patients opted for simple observation rather than treatment. One of the patients who received LR passed away because of tumor recurrence within 32 months after surgery; the other patients showed no significant disease activity after treatments for their recurrent lesions. As of April 2018, the mean follow-up duration was 39.6 ± 20.1 months (15-82 months). CONCLUSIONS: There are multiple strategies for HEHE. Considering its indolent course, initial observation for assessment of the lesion behavior may aid in the selection of appropriate treatment. Surgery or LT is suitable for patients with disease progression during the observation period. However, our sample size was small, and further studies are required to gather more information that can aid in optimal treatment selection.

The anti-androgenic effects of cypermethrin mediated by non-classical testosterone pathway activation of mitogen-activated protein kinase cascade in mouse Sertoli cells.

Previous studies have demonstrated that the anti-androgenic effects of cypermethrin (CYP) are associated with testosterone (T) - related signaling pathway. This study was to investigate the effects of CYP on mouse Sertoli cells (TM4) and clarify whether the mechanisms were mediated by non-classical T signaling pathway activating mitogen-activated protein kinase (MAPK) cascade. The Cell Counting Kit 8 (CCK8) and Real-Time Cell Analysis iCELLigence (RTCA-iCELLigence) system were performed to detect the effects of 10 µM, 20 µM, 40 µM and 80 µM CYP on the viability and proliferation of TM4. The mammalian two hybrid assay, quantitative Real-Time PCR (qRT-PCR) and western blot were conducted to analyze the key genes and proteins involved in T-mediated MAPK signaling pathway. CYP was found to inhibit the viability and proliferation of TM4. Additionally, CYP disturbed the functions of Sertoli cells by inhibiting inhibin B (INH B) expression and facilitating androgen binding protein (ABP) and transferrin (TF) expression. Moreover, CYP suppressed the interaction of AR and Src kinase and inhibited androgen-mediated phosphorylation of Src, epidermal growth factor receptor (EGFR), extracellular-regulated kinase1/2 (ERK1/2) and transcription factor cAMP response element binding protein (CREB). Furthermore, the androgen-induced mRNA and protein expression of CREB-regulated gene early growth response factor (Egr1) decreased after treated with CYP. It is indicated that CYP inhibits the viability and proliferation of Sertoli cells and non-classical T signaling pathway activation of MAPK cascade is involved in anti-androgenic effect of CYP. This study provides a novel insight into the CYP-induced reproductive toxicity.

Environment relevant exposure of perfluorooctanoic acid accelerates the growth of hepatocellular carcinoma cells through mammalian target of rapamycin (mTOR) signal pathway.

Perfluorooctanoic acid (PFOA), a synthetic alkyl chain fluorinated compound, has emerged as a persistent organic pollutant of grave concern, casting a shadow over both ecological integrity and humans. Its insidious presence raises alarms due to its capacity to bioaccumulate within the human liver, potentially paving the treacherous path toward liver cancer. Yet, the intricate mechanisms underpinning PFOA's role in promoting the growth of hepatocellular carcinoma (HCC) remain shrouded in ambiguity. Here, we determined the proliferation and transcription changes of HCC after PFOA exposure through integrated experiments including cell culture, nude mice tests, and colony-forming assays. Based on our findings, PFOA effectively promotes the proliferation of HCC cells within the experimental range of concentrations, both in vivo and in vitro. The proliferation efficiency of HCC cells was observed to increase by approximately 10% due to overexposure to PFOA. Additionally, the cancer weight of tumor-bearing nude mice increased by 87.0% (p < 0.05). We systematically evaluated the effects of PFOA on HCC cells and found that PFOA's exposure can selectively activate the PI3K/AKT/mTOR/4E-BP1 signaling pathway, thereby playing a pro-cancer effect on HCC cells Confirmation echoed through western blot assays and inhibitor combination analyses. These insights summon a response to PFOA's dual nature as both an environmental threat and a promoter of liver cancer. Our work illuminates the obscured domain of PFOA-induced hepatoxicity, shedding light on its ties to hepatocellular carcinoma progression.

6:2 Cl-PFESA, a proposed safe alternative for PFOS, diminishes the gemcitabine effectiveness in the treatment of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC)/pancreatic cancer, is a highly aggressive malignancy with poor prognosis. Gemcitabine-based chemotherapy remains the cornerstone of PDAC treatment. Nonetheless, the development of resistance to gemcitabine among patients is a major factor contributing to unfavorable prognostic outcomes. The resistance exhibited by tumors is modulated by a constellation of factors such as genetic mutations, tumor microenvironment transforms, environmental contaminants exposure. Currently, comprehension of the relationship between environmental pollutants and tumor drug resistance remains inadequate. Our study found that PFOS/6:2 Cl-PFESA exposure increases resistance to gemcitabine in PDAC. Subsequent in vivo trials confirmed that exposure to PFOS/6:2 Cl-PFESA reduces gemcitabine's efficacy in suppressing PDAC, with the inhibition rate decreasing from 79.5 % to 56.7 %/38.7 %, respectively. Integrative multi-omics sequencing and molecular biology analyses have identified the upregulation of ribonucleotide reductase catalytic subunit M1 (RRM1) as a critical factor in gemcitabine resistance. Subsequent research has demonstrated that exposure to PFOS and 6:2 Cl-PFESA results in the upregulation of the RRM1 pathway, consequently enhancing chemotherapy resistance. Remarkably, the influence exerted by 6:2 Cl-PFESA exceeds that of PFOS. Despite 6:2 Cl-PFESA being regarded as a safer substitute for PFOS, its pronounced effect on chemotherapeutic resistance in PDAC necessitates a thorough evaluation of its potential risks related to gastrointestinal toxicity.

Evidence of promoting effects of 6:2 Cl-PFESA on hepatocellular carcinoma proliferation in humans: An ideal alternative for PFOS in terms of environmental health?

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are synthetic chemicals, encompassing compounds like perfluorooctane sulfonate (PFOS), which have widespread applications across various industries, including food packaging and firefighting. In recent years, China has increasingly employed 6:2 Cl-PFESA as an alternative to PFOS. Although the association between PFAS exposure and hepatocellular carcinoma (HCC) has been demonstrated, the underlying mechanisms that promote HCC proliferation are uncleared. Therefore, we aimed to investigate the effects and differences of PFOS and 6:2 Cl-PFESA on HCC proliferation through in vivo and in vitro tumor models. Our results reveal that both PFOS and 6:2 Cl-PFESA significantly contribute to HCC proliferation in vitro and in vivo. Exposure led to reduced population doubling times, enlarged cell colony sizes, enhanced DNA synthesis efficiency, and a higher proportion of cells undergoing mitosis. Furthermore, both PFOS and 6:2 Cl-PFES) have been shown to activate the PI3K/AKT/mTOR signaling pathway and inhibit necroptosis. This action consequently enhances the proliferation of HCC cells. Our phenotypic assay findings suggest that the tumorigenic potential of 6:2 Cl-PFESA surpasses that of PFOS; in a subcutaneous tumor model using nude mice, the mean tumor weight for the 6:2 Cl-PFESA-treated cohort was 2.33 times that observed in the PFOS cohort (p < 0.01). Despite 6:2 Cl-PFESA being considered a safer substitute for PFOS, the pronounced effects of this chemical on HCC cell growth warrant a thorough assessment of hepatotoxicity risks linked to its usage.

Performance of noninvasive prenatal screening for fetal sex chromosome aneuploidies in a cohort of 116,862 pregnancies.

BACKGROUND: Noninvasive prenatal screening (NIPS) has shown good performance in screening common aneuploidies. However, its performance in detecting fetal sex chromosome aneuploidies (SCAs) needs to be evaluated in a large cohort. RESEARCH DESIGN AND METHODS: In this retrospective observation, a total of 116,862 women underwent NIPS based on DNA nanoball sequencing from 2015 to 2022. SCAs were diagnosed based on karyotyping or chromosomal microarray analysis (CMA). Among them, 2,084 singleton pregnancies received karyotyping and/or CMA. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of NIPS for fetal SCAs were evaluated. RESULTS: The sensitivity was 97.7% (95%CI, 87.7-99.9), 87.3% (95% CI, 76.5-94.4), 96.1% (95%CI, 86.5-99.5), and 95.7% (95% CI, 78.1-99.9), the PPV was 25.8% (95%CI, 19.2-33.2), 80.9% (95%CI, 69.5-89.4), 79.0% (95%CI, 66.8-88.3), and 53.7% (95%CI, 37.4-69.3) for 45,X, 47,XXY, 47,XXX, and 47,XYY, respectively. The specificity was 94.1% (95%CI, 93.0-95.1) for 45,X, and more than 99.0% for sex chromosome trisomy (SCT). The NPV was over 99.0% for all. CONCLUSIONS: NIPS screening for fetal SCAs has high sensitivity, specificity and NPV. The PPV of SCAs was moderate, but that of 45,X was lower than that of SCTs. Invasive prenatal diagnosis should be recommended for high-risk patients.

Chinese surgical robot-assisted surgery for parotid tumor: a case report.

Robotic surgery is known as the "third technological revolution" in the field of surgery, and is an important milestone in the development of modern surgery. However, our country's innovative surgical robot industry is still in its early stages, and it is only being utilized in certain surgical fields. To explore the effectiveness of the application of domestic surgical robot in oral and maxillofacial surgery, the author successfully completed a case of benign parotid tumor resection with the assistance of a domestic autonomous robot. The operation was successful, facial nerve function was preserved, and postoperative wound healing was good.

Deep learning nomogram for preoperative distinction between Xanthogranulomatous cholecystitis and gallbladder carcinoma: A novel approach for surgical decision.

The distinction between Xanthogranulomatous Cholecystitis (XGC) and Gallbladder Carcinoma (GBC) is challenging due to their similar imaging features. This study aimed to differentiate between XGC and GBC using a deep learning nomogram model built from contrast enhanced computed tomography (CT) scans. 297 patients were included with confirmed XGC (94) and GBC (203) as the training and internal validation cohort from 2017 to 2021. The deep learning model Resnet-18 with Fourier transformation named FCovResnet18, shows most impressive potential in distinguishing XGC from GBC using 3-phase merged images. The accuracy, precision and area under the curve (AUC) of the model were then calculated. An additional cohort of 74 patients consisting of 22 XGC and 52 GBC patients was enrolled from two subsidiary hospitals as the external validation cohort. The accuracy, precision and AUC achieve 0.98, 0.99, 1.00 in the internal validation cohort and 0.89, 0.92, 0.92 in external validation cohort. A nomogram model combining clinical characteristics and deep learning prediction score showed improved predicting value. Altogether, FCovResnet18 nomogram has demonstrated its ability to effectively differentiate XGC from GBC preoperatively, which significantly aid surgeons in making informed and accurate surgical decisions for XGC and GBC patients.

Evaluation of a newly developed oral and maxillofacial surgical robotic platform (KD-SR-01) in head and neck surgery: a preclinical trial in porcine models.

Traditional open head and neck surgery often leaves permanent scars, significantly affecting appearance. The emergence of surgical robots has introduced a new era for minimally invasive surgery. However, the complex anatomy of the head and neck region, particularly the oral and maxillofacial areas, combined with the high costs associated with established systems such as the da Vinci, has limited the widespread adoption of surgical robots in this field. Recently, surgical robotic platform in China has developed rapidly, exemplified by the promise shown by the KangDuo Surgical Robot (KD-SR). Although the KD-SR has achieved some results comparable to the da Vinci surgical robot in urology and colorectal surgery, its performance in complex head and neck regions remains untested. This study evaluated the feasibility, effectiveness, and safety of the newly developed KD-SR-01, comparing it with standard endoscopic systems in head and neck procedures on porcine models. We performed parotidectomy, submandibular gland resection, and neck dissection, collected baseline characteristics, perioperative data, and specifically assessed cognitive workload using the NASA-TLX. None of the robotic procedures were converted to endoscopic or open surgery. The results showed no significant difference in operation time between the two groups (P = 0.126), better intraoperative bleeding control (P = 0.001), and a significant reduction in cognitive workload (P < 0.001) in the robotic group. In conclusion, the KD-SR-01 is feasible, effective, and safe for head and neck surgery. Further investigation through well-designed clinical trials with long-term follow-up is necessary to establish the full potential of this emerging robotic platform.

Bright and Stable Red Perovskite LEDs under High Current Densities.

Perovskite LEDs (PeLEDs) have emerged as a next-generation light-emitting technology. Recent breakthroughs were made in achieving highly stable near-infrared and green PeLEDs. However, the operational lifetimes (T50) of visible PeLEDs under high current densities (>10 mA cm-2) remain unsatisfactory (normally <100 h), limiting the possibilities in solid-state lighting and AR/VR applications. This problem becomes more pronounced for mixed-halide (e.g., red and blue) perovskite emitters in which critical challenges such as halide segregation and spectral instability are present. Here, we demonstrate bright and stable red PeLEDs based on mixed-halide perovskites, showing measured T50 lifetimes of up to ∼357 h at currents of ≥25 mA cm-2, a record for the operational stability of visible PeLEDs under high current densities. The devices produce intense and stable emission with a maximum luminance of 28,870 cd m-2 (radiance: 1584 W sr-1 m-2), which is record-high for red PeLEDs. Key to this demonstration is the introduction of sulfonamide, a dipolar molecular stabilizer that effectively interacts with the ionic species in the perovskite emitters. It suppresses halide segregation and migration into the charge-transport layers, resulting in enhanced stability and brightness of the mixed-halide PeLEDs. These results represent a substantial step toward bright and stable PeLEDs for emerging applications.

Comprehensive Comparison of Effects of Antioxidant (Astaxanthin) Supplementation from Different Sources in Haliotis discus hannai Diet.

Dietary antioxidant supplementation, especially astaxanthin, has shown great results on reproductive aspects, egg quality, growth, survival, immunity, stress tolerance, and disease resistance in aquatic animals. However, the effects of dietary astaxanthin supplementation from different sources are still unknown. A comprehensive comparison of survival, growth, immune response, antioxidant activity, thermal resistance, disease resistance, and intestinal microbial structure was conducted in dietary antioxidant supplementation from the sources of Gracilaria lemaneiformis (GL), industrial synthetic astaxanthin (80 mg/kg astaxanthin actual weight, named as group 'SA80'), Phaffia rhodozyma (80 mg/kg astaxanthin actual weight, named as group 'PR80') and Haematococcus pluvialis (120 mg/kg astaxanthin actual weight, named as group 'HP120') at their optimal supplementation amounts. Furthermore, the SA80, PR80, and HP120 groups performed better in all aspects, including survival, growth, immune response, antioxidant activity, thermal resistance, and disease resistance, compared with the GL group. The PR80 and HP120 group also had a better growth performance than the SA80 group. In terms of heat stress and bacterial challenge, abalone in the PR80 group showed the strongest resistance. Overall, 80 mg/kg astaxanthin supplementation from Phaffia rhodozyma was recommended to obtain a more effective and comprehensive outcome. This study contributes to the discovery of the optimum dietary astaxanthin supplementation source for abalone, which is helpful to improve the production efficiency and economic benefits of abalone. Future research can further explore the action mechanism and the method of application of astaxanthin to better exploit its antioxidant role.

DBF4 Dependent Kinase Inhibition Suppresses Hepatocellular Carcinoma Progression and Potentiates Anti-Programmed Cell Death-1 Therapy.

The progression of hepatocellular carcinoma (HCC) remains a huge clinical challenge, and elucidation of the underlying molecular mechanisms is critical to develop effective therapeutic strategy. Dumbbell former 4 (DBF4) complexes with cell division cycle 7 (CDC7) to form DBF4-dependent kinase (DDK), playing instrumental roles in tumor cell survival, whereas its roles in HCC remain elusive. This study revealed that DBF4 expression was upregulated in HCC and constituted an independent prognostic factor of patient survival. We identified p65 as an upstream inducer which increased DBF4 expression by directly binding to its promoter. DBF4 accelerated HCC cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, DBF4 complexed with CDC7 to bind to the coiled coil domain of STAT3 and activate STAT3 signaling through XPO1-mediated nuclear exportation. Notably, p65 enhanced the nuclear transport of DDK and DDK-STAT3 interaction by transcriptionally upregulating XPO1. DBF4 expression positively correlated with activated STAT3 and XPO1 in HCC tissues. Furthermore, combining DDK inhibitor XL413 with anti-PD-1 immunotherapy dramatically suppressed HCC growth and prolonged the survival of HCC-bearing mouse. Our findings reveal that DDK activates STAT3 pathway and facilitates HCC progression, and demonstrate the proof of the concept of targeting DDK to improve the efficacy of HCC immunotherapy.

Prognosis prediction and risk factors for triple-negative breast cancer patients with brain metastasis: A population-based study.

BACKGROUND: Brain metastasis (BM) in triple-negative breast cancer (TNBC) patients is associated with significant morbidity and mortality. In this research we aimed to develop a nomogram to predict the prognosis of TNBC patients with BMs (TNBC-BM) and explore the potential risk factors. METHODS: We used data from the Surveillance, Epidemiology, and End Results (SEER) database. A prognostic nomogram was built and validated based on patients with BM at newly diagnosed TNBC (nTNBC-BM). Its effect on TNBC patients with BM was also validated in an extended group. The prognostic effect of treatment and risk factors for nTNBC-BM were further tested. RESULTS: A nomogram was constructed and validated to predict overall survival (OS) in TNBC-BM patients. For patients with BM diagnosed at the initial treatment or later course, the C-index (0.707, 0.801, and 0.685 in the training, validation, and extended groups, respectively) and calibration plots showed the acceptable prognostic accuracy and clinical applicability of the model. Surgery on the primary tumor and chemotherapy were found to confer significantly better OS (11 months vs. 4 months; 5 months vs. 3 months, respectively). In addition, advanced tumor/nodal stage and bilateral cancer were associated with a higher risk of nTNBC-BM. CONCLUSION: We developed a sensitive and discriminative nomogram to predict OS in TNBC-BM patients, both at initial diagnosis and the latter course. nTNBC-BM patients may benefit more from surgery and chemotherapy than from radiotherapy. In addition, in the predictive model, TNBC patients harboring advanced tumor/nodal stages and bilateral tumors were more likely to have BM at initial diagnosis.

MVI-TR: A Transformer-Based Deep Learning Model with Contrast-Enhanced CT for Preoperative Prediction of Microvascular Invasion in Hepatocellular Carcinoma.

In this study, we considered preoperative prediction of microvascular invasion (MVI) status with deep learning (DL) models for patients with early-stage hepatocellular carcinoma (HCC) (tumor size ≤ 5 cm). Two types of DL models based only on venous phase (VP) of contrast-enhanced computed tomography (CECT) were constructed and validated. From our hospital (First Affiliated Hospital of Zhejiang University, Zhejiang, P.R. China), 559 patients, who had histopathological confirmed MVI status, participated in this study. All preoperative CECT were collected, and the patients were randomly divided into training and validation cohorts at a ratio of 4:1. We proposed a novel transformer-based end-to-end DL model, named MVI-TR, which is a supervised learning method. MVI-TR can capture features automatically from radiomics and perform MVI preoperative assessments. In addition, a popular self-supervised learning method, the contrastive learning model, and the widely used residual networks (ResNets family) were constructed for fair comparisons. With an accuracy of 99.1%, a precision of 99.3%, an area under the curve (AUC) of 0.98, a recalling rate of 98.8%, and an F1-score of 99.1% in the training cohort, MVI-TR achieved superior outcomes. Additionally, the validation cohort's MVI status prediction had the best accuracy (97.2%), precision (97.3%), AUC (0.935), recalling rate (93.1%), and F1-score (95.2%). MVI-TR outperformed other models for predicting MVI status, and showed great preoperative predictive value for early-stage HCC patients.

Per-/polyfluoroalkyl substance concentrations in human serum and their associations with liver cancer.

Per-/polyfluoroalkyl substances (PFASs) are widespread in global human blood, and have some toxic effects on liver. However, effects of PFAS exposure on human liver cancer (LC) risk are still not known. In this study, 203 LC patients and 203 controls were recruited, and their serum samples were collected between 2019 and 2021. We determined the residues of 12 PFASs in serum from all participants and quantified their association with LC incidence and tumor markers. PFOS (9.8 ng/mL) had the highest mean concentration in human serum, followed by PFOA (8.3 ng/mL) and 6:2 Cl-PFESA (3.9 ng/mL). We found that concentrations of PFOS and 6:2 Cl-PFESA in human serum were significantly correlated with the levels of alpha fetoprotein (AFP) (ßPFOS = 0.13, 95% confidence interval (CIPFOS): 0.088, 0.17; ß6:2 Cl-PFESA = 0.070, CI6:2 Cl-PFESA: 0.036, 0.10). A positive association of PFOS and 6:2 Cl-PFESA with odds ratios (OR) of LC (ORPFOS = 0.609, CIPFOS: 1.179, 4.029, P = 0.001; OR6:2 Cl-PFESA = 1.844, CI6:2 Cl-PFESA: 1.176, 2.512, P = 0.02) were found, after adjusting for different covariates. Moreover, serum PFOA concentrations were associated with carcinoembryonic antigen (CEA), but their correlation with the LC incidence was not statistically significant. This new finding supports the evidence for the positive associations among PFAS exposure, change of specific tumor marker, and LC risks.