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Aim: Villoglandular adenocarcinoma (VGA) of the uterine cervix is a variant of endocervical adenocarcinoma. However, the clinicopathologic and immunohistochemical features of VGA are still unclear. The aim of this study was to investigate the clinicopathologic and immunohistochemical features of VGA. Materials and Methods: A total of 20 VGA patients were identified among 852 patients diagnosed with cervical cancer and enrolled in this study. The immunohistochemical levels of Ki-67, P53, P16, progesterone receptor (PR), carcinoembryonic antigen (CEA), vimentin (Vim), and estrogen receptor (ER) were measured by immunohistochemistry. Results: VGA was prevalent in younger women and presented favorable prognosis. Ki-67, P16, and CEA were highly expressed in VGA tissues, while PR expression was hardly to be detected. The positive rates of Ki-67, CEA, and P16 were 90.0%, 90.0%, and 85.0%, respectively, which were significantly higher compared with PR (5.0%, P < 0.001). In addition, the positive rates of P53, Vim, and ER in VGA tissues were 55.0%, 50.0%, and 40.0%, respectively. However, the expression levels of Ki-67, P53, P16, PR, CEA, Vim, and ER were not significantly associated with clinical features (P > 0.05). Conclusion: These data indicate that VGA is a rare cervical adenocarcinoma, which is prevalent in younger women, and presents favorable prognosis. Detection of Ki-67, P53, P16, PR, CEA, Vim, and ER would be beneficial for the diagnosis of VGA.

Objectives: Combination therapy of lenvatinib and immune checkpoint inhibitors (CLICI) has emerged as a promising approach for managing unresectable hepatocellular carcinoma (HCC). However, the response to such treatment is observed in only a subset of patients, underscoring the pressing need for reliable methods to identify potential responders. Materials & methods: This was a retrospective analysis involving 120 patients with unresectable HCC. They were divided into training (n = 72) and validation (n = 48) cohorts. We developed an interpretable deep learning model using multiphase computed tomography (CT) images to predict whether patients will respond or not to CLICI treatment, based on the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). We evaluated the models' performance and analyzed the impact of each CT phase. Critical regions influencing predictions were identified and visualized through heatmaps. Results: The multiphase model outperformed the best biphase and uniphase models, achieving an area under the curve (AUC) of 0.802 (95% CI = 0.780–0.824). The portal phase images were found to significantly enhance the model's predictive accuracy. Heatmaps identified six critical features influencing treatment response, offering valuable insights to clinicians. Additionally, we have made this model accessible via a web server at http://uhccnet.com/ for ease of use. Conclusions: The integration of multiphase CT images with deep learning-generated heatmaps for predicting treatment response provides a robust and practical tool for guiding CLICI therapy in patients with unresectable HCC.

Background/purpose: The incidence of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) is increasing worldwide. HPV vaccines have shown efficacy in preventing diseases in both males and females. Therefore, there is a need to develop cost-effective strategies for HPV vaccines to prevent HPV-related OPC. This meta-analysis aimed to evaluate cost-effectiveness using the global mean of incremental cost-effectiveness ratios compared to the willingness-to-pay threshold and incremental net benefits (INBs) of HPV vaccination strategies between boys’ extension vaccine and girls only. These recommendations will be useful for countries that have not implemented universal HPV vaccines in national programs, such as Taiwan. Materials and methods: Studies evaluating the cost-effectiveness of HPV vaccination strategies in the prevention of OPC that included both sexes versus girls only were identified through the Cochrane Library, EMBASE, PubMed, ScienceDirect, and Web of Science databases on February 05, 2024, and a meta-analysis of pooled INBs was performed using a random-effects model. The outcome was an effective measurement of the OPC burden. The results are represented in USD (2024). Results: Fifteen model analyses were included. All the studies were conducted in high-income countries. The global mean of incremental cost-effectiveness ratio was $39,553 (95% CI, $27,008–66,641) per quality-adjusted life years gained, which was below the global mean of the willingness-to-pay threshold of $65,473 (95% CI, $52,138–83,755). Pooled INBs of $9370 (95% CI, $5046–13,695; P

Background/purpose: Clear aligners are popular orthodontic tools because of their relatively aesthetic appearance and convenience of use. Nevertheless, bodily tooth movements still present challenges. This study evaluated various configurations of attachments placed on the mandibular canine in terms of the efficiency of canine bodily movement and correction of tipping. Materials and methods: A finite element model of the mandible was constructed to investigate the effects of various attachment configurations on the overall bodily movement and undesirable tipping of a mandibular canine. Canine movements were categorized into four types, namely tipping and bodily movements in the mesial and distal directions. The size and shape of the attachments were fixed, but their placement and orientation were varied. Five and seven attachment configurations were evaluated for their influence on tipping and bodily movements, respectively. Results: Attachment configuration significantly influenced mandibular canine tipping. The mesial occlusal–distal cervical and mesial occlusal–mesial cervical configurations had notable effects on mesial tipping, and the mesial occlusal–mesial cervical configuration excelled in distal tipping by increasing strain by 33.1%. The mesial occlusal–mesial cervical attachment configuration consistently had superior efficiency in facilitating both mesial and distal bodily movements of the canine. Conclusion: The mesial occlusal–mesial cervical attachment configuration excelled in all four types of canine movement. Irrespective of the attachment configuration, canines tend to move overall with slight tipping due to skeletal resistance and their center of rotation. The attachment configuration is crucial to the success of clear aligner treatment and must be carefully considered in clinical practice.

Nonalcoholic steatohepatitis (NASH) may soon become the leading cause of end-stage liver disease worldwide with limited treatment options. Liver fibrosis, which is driven by chronic inflammation and hepatic stellate cell (HSC) activation, critically determines morbidity and mortality in patients with NASH. Pyruvate kinase M2 (PKM2) is involved in immune activation and inflammatory liver diseases; however, its role and therapeutic potential in NASH-related fibrosis remain largely unexplored. Bioinformatics screening and analysis of human and murine NASH livers indicated that PKM2 was upregulated in nonparenchymal cells (NPCs), especially macrophages, in the livers of patients with fibrotic NASH. Macrophage-specific PKM2 knockout (PKM2FL/FLLysM-Cre) significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by a methionine- and choline-deficient (MCD) diet, a high-fat high-cholesterol (HFHC) diet, and a western diet plus weekly carbon tetrachloride injection (WD/CCl4). Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophages reduced profibrotic Ly6Chigh macrophage infiltration. Mechanistically, PKM2-dependent glycolysis promoted NLR family pyrin domain containing 3 (NLRP3) activation in proinflammatory macrophages, which induced HSC activation and fibrogenesis. A pharmacological PKM2 agonist efficiently attenuated the profibrotic crosstalk between macrophages and HSCs in vitro and in vivo. Translationally, ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides, a novel oligonucleotide drug that preferentially accumulates in the liver, dose-dependently reversed NASH-related fibrosis without causing observable hepatotoxicity. The present study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis. Thus, therapeutic modulation of PKM2 in a macrophage-specific or liver-specific manner may serve as a novel strategy to combat NASH-related fibrosis.

Abstract Background Cholangiocarcinoma (CCA), a malignancy that arises from biliary epithelial cells, has a dismal prognosis, and few targeted therapies are available. Aurora B, a key mitotic regulator, has been reported to be involved in the progression of various tumors, yet its role in CCA is still unclarified. Methods Human CCA tissues and murine spontaneous CCA models were used to assess Aurora B expression in CCA. A loss‐of‐function model was constructed in CCA cells to determine the role of Aurora B in CCA progression. Subcutaneous and liver orthotopic xenograft models were used to assess the therapeutic potential of Aurora B inhibitors in CCA. Results In murine spontaneous CCA models, Aurora B was significantly upregulated. Elevated Aurora B expression was also observed in 62.3% of human specimens in our validation cohort (143 CCA specimens), and high Aurora B expression was positively correlated with pathological parameters of tumors and poor survival. Knockdown of Aurora B by siRNA and heteroduplex oligonucleotide (HDO) or an Aurora B kinase inhibitor (AZD1152) significantly suppressed CCA progression via G2/M arrest induction. An interaction between Aurora B and c‐Myc was found in CCA cells. Targeting Aurora B significantly reduced this interaction and accelerated the proteasomal degradation of c‐Myc, suggesting that Aurora B promoted the malignant properties of CCA by stabilizing c‐Myc. Furthermore, sequential application of AZD1152 or Aurora B HDO drastically improved the efficacy of gemcitabine in CCA. Conclusions Aurora B plays an essential role in CCA progression by modulating c‐Myc stability and represents a new target for treatment and chemosensitization in CCA.

Background and aims: Liver cirrhosis is a complex disease that may result in increased morbidity and mortality following bariatric surgery (BS). This study aimed to explore the outcome of BS in patients with unexpected cirrhosis, focusing on postoperative complications and the progression of liver disease. Methods: A retrospective study of bariatric patients with cirrhosis from four centers in China between 2016 and 2023 was conducted, with follow-up for one year after BS. The primary outcome was the safety of BS in patients with unexpected cirrhosis, while the secondary outcome was the metabolic efficacy of BS in this group postoperatively. Results: A total of 47 patients met the study criteria, including 46 cases of Child-Pugh class A cirrhosis and 1 case of Child-Pugh B. Pathological examination confirmed nodular cirrhosis in 21 patients (44.68%), pseudolobule formation in 1 patient (2.13%), lipedema degeneration with inflammatory cell infiltration in 3 patients (6.38%), and chronic hepatitis in 1 patient (2.13%). The average percentage of total weight loss was 29.73 ± 6.53% at one year postoperatively. During the 30-day postoperative period, the complication rate was 6.38%, which included portal vein thrombosis, gastrointestinal bleeding, and intra-abdominal infection. Moreover, no cases of liver decompensation or mortality were reported during the follow-up period. The remission rates of comorbidities among 41 patients one year after surgery were as follows: dyslipidemia 100%, type 2 diabetes 82.61%, hypertension 84.62%, and obstructive sleep apnea syndrome 85.71%. Conclusions: BS can be safely performed in patients with unexpected cirrhosis in the compensated stage of liver disease, with low postoperative morbidity and no mortality observed during one-year follow-up.

Attentional control theory indicates that concentration is considered an important variable that contributes to learning. There are some devices for players to practice their concentration, but there are few virtual reality (VR) designs which can increase the level of difficulty for students to discipline their mental concentration with incongruent hands-on movement. To address this gap, a VR system named Tracking Fun was designed, which requires hand-eye coordination to move a ball to a target hole. To explore the effect of playing Tracking-fun on players' concentration performance, the study explored the relationship among entity beliefs of concentration ability (EBCA), intrinsic cognitive load (ICL), failure attribution of VR operation (FAVRO), flow experience, and gameplay performance. Students from a skills-based senior high school took part in this experimental research, and 259 valid questionnaires were returned. The research results showed that: EBCA can positively predict cognitive load; EBCA can positively predict FAVRO; ICL and flow have a negative correlation; FAVRO can negatively predict flow experience when interacting with VR; and flow can negatively predict gameplay performance. Based on the results, enriching the opportunity and difficulty level of Tracking-fun can enhance players' concentration. Follow-up research suggestions are proposed.

Anaplastic lymphoma kinase (ALK) is an attractive therapeutic target for the treatment of anaplastic large cell lymphoma (ALCL). We identified novel deuterated 2,4-diarylamino pyrimidine compounds as potent ALK inhibitors. The compound 9 (AMX6001) showed better in vitro activity against ALK and NPM-ALK kinase and significantly inhibited proliferation of Karpas299 and SU-DHL-1 cell lines. In vivo efficacy of compound 9 was better than reference standard ceritinib in ALCL Karpas299 mice models. Daily oral treatment of compound 9 (25 mg/kg) induced tumor suppression TGI up to 95.8 % in ALCL models.

Background/purpose: Osteoclast differentiation is crucial for orchestrating both tooth movement and the maintenance of bone density. Therefore, the current study sought to explore the impact of low-level laser therapy (LLLT) on osteoclast differentiation, functional gene expression, molecular signaling pathways, and orthodontic tooth movement in clinical settings. Materials and methods: The RAW 264.7 cell line served as the precursor for osteoclasts, and these cells underwent irradiation using a 808-nm LLLT. Osteoclast differentiation was assessed through tartrate-resistant acid phosphatase (TRAP) staining. Functional gene expression levels were evaluated using real-time quantitative polymerase chain reaction (RT-qPCR) while signaling molecules were examined through Western blot analysis. In the clinical study, 12 participants were enrolled. Their tooth movement was monitored using a TRIOS desktop scanner. Bone density measurements were conducted using Mimics software, which processed cone-beam computed tomography (CBCT) images exported in Digital Imaging and Communications in Medicine (DICOM) format. Results: We found that LLLT effectively promoted receptor activator of nuclear factor-κB ligand (RANKL)-dependent osteoclast differentiation and the expression of osteoclast functional genes, including matrix metallopeptidase 9 (MMP9), nuclear factor of activated T-cells cytoplasmic 1(NFATc1), tartrate-resistant acid phosphatase (TRAP) and cathepsin K (CTSK) in RAW264.7 cells. Clinically, the cumulative tooth movement over 90 days was significantly higher in the laser group than in the control group. Conclusion: Our research demonstrates that LLLT not only significantly promotes osteoclast differentiation but is also a valuable adjunct in orthodontic therapy.

Background/Aims The global proportion of hepatocellular carcinoma (HCC) attributable to metabolic dysfunction-associated fatty liver disease (MAFLD) is unclear. The MAFLD diagnostic criteria allows objective diagnosis in the presence of steatosis plus defined markers of metabolic dysfunction, irrespective of concurrent liver disease. We aimed to determine the total global prevalence of MAFLD in HCC cohorts (total-MAFLD), including the proportion with MAFLD as their sole liver disease (single-MAFLD), and the proportion of those with concurrent liver disease where MAFLD was a contributary factor (mixed-MAFLD). Methods This systematic review and meta-analysis included studies systematically ascertaining MAFLD in HCC cohorts, defined using international expert panel criteria including ethnicity-specific BMI cut-offs. A comparison of clinical and tumour characteristics was performed between single-MAFLD, mixed-MAFLD, and non-MAFLD HCC. Results 22 studies (56,565 individuals with HCC) were included. Total and single-MAFLD HCC prevalence was 48.7% (95% confidence interval [CI] 34.5–63.0%) and 12.4% (95% CI 8.3–17.3%), respectively. In HCC due to chronic hepatitis B, C, and alcohol-related liver disease, mixed-MAFLD prevalence was 40.0% (95% CI 30.2–50.3%), 54.1% (95% CI 40.4–67.6%) and 64.3% (95% CI 52.7–75.0%), respectively. Mixed-MAFLD HCC had significantly higher likelihood of cirrhosis and lower likelihood of metastatic spread compared to single-MAFLD HCC, and a higher platelet count and lower likelihood of macrovascular invasion compared to non-MAFLD HCC. Conclusions MAFLD is common as a sole aetiology, but more so as a co-factor in mixed-aetiology HCC, supporting the use of positive diagnostic criteria.