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Man-Chen Hung,1 Chuen-Fei Chen,1 Meng-Ting Tsou,2 Hsin-Hui Lin,2 Lee-Ching Hwang,1,2 Ching-Ping Hsu2 1Department of Medicine, Mackay Medical College, New Taipei City, Taiwan; 2Department of Family Medicine, Mackay Memorial Hospital, Taipei, TaiwanCorrespondence: Ching-Ping HsuDepartment of Family Medicine, Mackay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Road, Zhongshan District, Taipei City 104, TaiwanTel +886-2-25433535Fax +886-2-25213847Email drhsuinfo@gmail.comBackground: The prevalence of gallstone disease (GSD) increases with age, and the elderly have a much higher mortality risk and incidence of surgical comorbidities. The aim of this study was to explore the relationship between GSD and cardiometabolic risk factors in elderly people with non-alcoholic fatty liver disease (NAFLD).Methods: In this cross-sectional study, we analyzed the data of elderly people who underwent annual health check-ups at a Northern Taiwan health examination center. These data were collected from physical examination, blood tests, abdominal ultrasonography, and medical histories. We excluded those with hepatitis B or C infections, heavy alcohol consumption, or cholecystectomy.Results: The analysis included 3,037 participants with a mean age of 73.6± 6.0 years. Over 70% were overweight or obese, and the overall prevalence of GSD was 17.7%. In our univariate analysis, GSD was positively correlated with age, body mass index, metabolic syndrome, diabetes mellitus (DM), hypertension (HTN), and various metabolic factors (fasting plasma glucose [FPG], triglyceride, uric acid, and high-density lipoprotein cholesterol [HDL-C] levels). After adjustment for age, gender, and body mass index, metabolic syndrome showed a positive association with GSD (odds ratio [OR] 1.31 [95% confidence interval [CI], 1.05– 1.64]; P=0.020). Specific components of metabolic syndrome that increased the risk for GSD in NAFLD elderly include lower levels of HDL-C (OR 1.35 [95% CI, 1.10– 1.66]; P< 0.001) and elevated FPG (OR 1.36 [95% CI, 1.10– 1.69]; P< 0.001).Conclusion: Our study concluded that GSD is significantly associated with metabolic syndrome in elderly people with NAFLD. Reduced HDL-C and elevated FPG both heighten the risk of developing GSD. Therefore, to lower the risk of GSD in NAFLD patients, their FPG levels and HDL-C levels must be regularly followed-up, and these patients should be educated about the symptoms of GSD if they meet the criteria for metabolic syndrome.Keywords: gallstone disease, cardiometabolic risk factors, metabolic syndrome

Background: Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity.Methods: A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided.Results: Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression.Conclusion: Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. [ABSTRACT FROM AUTHOR]

Trastuzumab is a monoclonal antibody directed against the human EGFR2 (HER2) protein that has been shown to improve survival in patients with HER2-positive breast cancer. Lapatinib is an oral small-molecule tyrosine kinase inhibitor directed against EGFR and HER2. Lapatinib therapy was shown to prolong the time to progression and increase the rate of response to capecitabine in patients who had received anthracycline-based and taxane-based chemotherapy, and whose tumors had progressed on trastuzumab. HER2 status, either gene copy number or the protein expression level, is the best predictive marker available for assessing response to trastuzumab and lapatinib. Whether the power of this predictive marker is the same in advanced and early-stage cancers is unknown. There is great interest in developing diagnostic tests that predict which patients are more likely to benefit from specific HER2-directed therapies. Novel therapeutics that will overcome resistance to trastuzumab and lapatinib are under intense clinical development. In the future, it will be important to characterize mechanisms of resistance in metastatic tumors to determine which novel targeted therapy will be most appropriate for individual patients. [ABSTRACT FROM AUTHOR]

Lecithin cholesterol acyltransferase (LCAT), a crucial enzyme in lipid metabolism, plays important yet poorly understood roles in tumours, especially in hepatocellular carcinoma (HCC). In this study, our investigation revealed that LCAT is a key downregulated metabolic gene and an independent risk factor for poor prognosis in patients with HCC. Functional experiments showed that LCAT inhibited HCC cell proliferation, migration and invasion. Mechanistically, LCAT interacts with caveolin-1 (CAV1) to promote the binding of CAV1 to PRKACA and inhibit its phosphorylation, thereby inhibiting triglyceride (TAG) catabolism. On the other hand, LCAT inhibits fatty acid oxidation (FAO) by interacting with CPT1A to promote its ubiquitination and degradation. These events result in an inadequate supply of raw materials and energy and inhibit the malignant behaviours of HCC cells. In addition, LCAT is a reliable predictive biomarker for the efficacy of lenvatinib treatment in HCC patients, and the inhibition of FAO can increase lenvatinib sensitivity in patients with LCAT low HCC. This study revealed that LCAT plays a critical role in the regulation of lipid metabolic reprogramming and is a reliable predictive biomarker for the efficacy of lenvatinib treatment in HCC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2025. Published by Elsevier B.V.)

Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. In this study, we used next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and angiotensin-converting enzyme 2 (ACE2) expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune-competent mice. Mass cytometry by time of flight revealed that ACE2-deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages, displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor-intrinsic chemokine (C-C motif) ligand 5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1-7)/Mas receptor axis. The lower chemokine (C-C motif) ligand 5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacologic targeting of CCR5 using maraviroc enhanced the tumor-suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade. Significance: ACE2 regulates the immune landscape of hepatocellular carcinoma by abrogating M2-like macrophage polarization and sensitizes tumors to anti-PD-L1, suggesting that harnessing the ACE2 axis could be a promising strategy to improve immunotherapy efficacy., (©2024 American Association for Cancer Research.)

Although breast cancer treatment has evolved significantly in recent years, drug resistance remains a major challenge. To identify new targets for breast cancer, we found that stage-specific embryonic antigen 4 (SSEA-4) is expressed in all subtypes of breast cancer cell lines, and the increased expression of the associated enzymes β3GalT5 and ST3Gal2 correlates with poor recurrence-free survival (RFS) in breast cancer. We also found that SSEA-4 antibodies can be rapidly internalized into breast cancer cells, a property that makes SSEA-4 an attractive target for antibody-drug conjugates (ADCs). Furthermore, the SSEA-4 antibody conjugated to the anticancer agents showed efficacy against SSEA-4-positive breast cancer cells, including those resistant to PARP inhibitor, trastuzumab, and CDK7 inhibitor. In addition, SSEA-4 ADCs showed no efficacy in β3GalT5-knockout MDA-MB-231 cells, highlighting the essential role of SSEA-4 as the target antigen for ADCs activity. Our work shows that SSEA-4-ADCs could be a therapeutic option for breast cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

Background: Targeting glucose uptake by glucose transporter (GLUT) inhibitors is a therapeutic opportunity, but efforts on GLUT inhibitors have not been successful in the clinic and the underlying mechanism remains unclear. We aim to identify the key metabolic changes responsible for cancer cell survival from glucose limitation and elucidate its mechanism., Methods: The level of phosphorylated YAP was analyzed with Western blotting and Phos-tag immunoblotting. Glucose limitation-induced metabolic changes were analyzed using targeted metabolomics (600MRM). The anti-cancer role of metabolite was examined using colony formation assay and APC min/+ mice. Co-immunoprecipitation, LS-MS, qRT-PCR, and immunofluorescence were performed to explore the underlying mechanisms., Results: We found that D-Ribose-5-phosphate (D5P), a product of the pentose phosphate pathway connecting glucose metabolism and nucleotide metabolism, functions as a metabolic checkpoint to activate YAP under glucose limitation to promote cancer cell survival. Mechanistically, in glucose-deprived cancer cells, D5P is decreased, which facilitates the interaction between MYH9 and LATS1, resulting in MYH9-mediated LATS1 aggregation, degradation, and further YAP activation. Interestingly, activated YAP further promotes purine nucleoside phosphorylase (PNP)-mediated breakdown of purine nucleoside to restore D5P in a feedback manner. Importantly, D5P synergistically enhances the tumor-suppressive effect of GLUT inhibitors and inhibits cancer progression in mice., Conclusions: Our study identifies D5P as a metabolic checkpoint linking glucose limitation stress and YAP activation, indicating that D5P may be a potential anti-cancer metabolite by enhancing glucose limitation sensitivity., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were approved by the Institutional Animal Care and Use Committee of the Zhengzhou University. All animal experiments were performed in compliance with the Guide for the Care and Use of Laboratory Animals (National Academies Press, 2011) and according to the institutional ethical guidelines for animal experiments. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Toxic emission from industrial activity is a serious problem, particularly with regard to the quality of water. Thus, the ISO 11348-3 standard for assessing water quality has been established. This method is used to determine solution toxicity from the bioluminescence inhibition of Aliivibrio fischeri. However, the accuracy of measurements is influenced by the selection of individual reaction time points. This study explores the utility of the area under the curve (AUC) method in water quality detection and evaluates how A. fischeri responds to three toxicants, namely ethanol, acetone, and zinc sulfate, over time. The half-maximal effective concentrations of these three substances were found to be 10.13 %, 5.02 %, and 19.49 mg/L, respectively. Compared with the results from individual reaction time point assessments, the results of AUC comprehensively captured the effects of the toxicants, including time-dependent effects and hormetic effects, by capturing dynamic changes under different toxicant concentrations and reaction times. Therefore, AUC analysis mitigates the pitfalls associated with individual reaction times and provides a more accurate and reliable assessment method for water quality detection, contributing to a better understanding of the impact of toxic substances on aquatic environments., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yung-Sheng Lin reports financial support was provided by National Science and Technology Council, Taiwan. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The comorbidity of obesity and depression has major public health impacts, highlighting the need to understand their shared mechanisms. This study explored the connection between obesity and depression through the transient receptor potential V1 (TRPV1) signaling pathway, using obese/depressed murine models and clinical data. Mice fed a high-fat diet showed altered TRPV1 pathway expression in brain regions of the mice: downregulated in the medial prefrontal cortex (mPFC) and hippocampus, and upregulated in the hypothalamus and amygdala, influencing depression-like behaviors and inflammation. Treatments like eicosapentaenoic acid (EPA) and acupoint catgut embedding (ACE) reversed these effects, similar to observations in Trpv1 -/- mice. Furthermore, chemogenetic activation in the ventral mPFC also alleviated depression via TRPV1. In our clinical validation, single nucleotide polymorphisms (SNPs) in TRPV1-related genes (PIK3C2A and PRKCA) were linked to interferon-induced depression. These findings underscore the potential of targeting TRPV1 as a therapeutic approach for obesity-related depression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To compare the intra- and inter-examiner reliability of multidetector computed tomography (MDCT) and cone-beam computed tomography (CBCT) using Amira and Dolphin software analyses for craniofacial/airway measurements by six examiners., Materials and Methods: Five adults and one dry skull with CBCT and MDCT scan files were duplicated and randomly numbered. Six orthodontic residents imported these files into two software programs, oriented the images, set thresholds, and performed 26 measurements. Intra- and inter-examiner reliabilities were determined by using intraclass correlation coefficient (ICC) and presented with scatterplots., Results: Variables including anterior nasal width, posterior nasal width, frontomaxillary suture right-to-left, inner nasal contour point right-to-left, and minimum cross-sectional area in the oropharynx showed "moderate" to "substantial" intra- or inter-examiner agreement. Amira provided relatively reliable airway assessment, while Dolphin showed standard deviations 10 to 30 times larger for volumetric airway measurements. MDCT scans significantly reduced airway volume/area measurements compared to CBCT, except for intraoral airway volume., Conclusions: Unreliable skeletal measurements and low reliability of Dolphin for airway analysis discourage using CT to quantitatively correlate changes in craniofacial structures with airway dimensions., (© 2025 by The EH Angle Education and Research Foundation, Inc.)

Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide. Asiatic acid (AA) is a natural triterpene, which is recognized as effect of antioxidant and antitumor. Sorafenib (Sor), an orally target drug, has been applicate for the HCC therapy. However, the synergistic effect of AA and Sor on human HCC is still unclear. Here, we explore the effect of combined treatment with AA and Sor in the HCC cell line SK-HEP-1 and HepG2. Compared with treating alone, our results demonstrated that AA combined with Sor synergistically inhibited proliferative rates in MTT assay and colony formation assay. We also found that AA combined with Sor in HCC cells strongly caused cell cycle arrest in G0/G1 phase and affected the protein level of cyclin D1 and SKP2. Furthermore, combination treatment strongly enhanced ferroptosis through cellular accumulation of iron ions, lipid peroxidation, and ferroptosis-related proteins (GPX4 and FTH1) in HCC cells. In addition, the combined treatment resulted in higher phosphorylation of JNK1/2 in the promotion of ferroptosis than drug treatment alone. These results indicate that AA combined with Sor synergistically improved ferroptosis in HCC cells through the regulation of JNK1/2 signaling. Taken together, the combinatorial strategy may serve as the potential treatment in HCC., (© 2024 Wiley Periodicals LLC.)

Canonically PD-L1 functions as the inhibitory immune checkpoint on cell surface. Recent studies have observed PD-L1 expression in the nucleus of cancer cells. But the biological function of nuclear PD-L1 (nPD-L1) in tumor growth and antitumor immunity is unclear. Here we enforced nPD-L1 expression and established stable cells. nPD-L1 suppressed tumorigenesis and aggressiveness in vitro and in vivo. Compared with PD-L1 deletion, nPD-L1 expression repressed tumor growth and improved survival more markedly in immunocompetent mice. Phosphorylated AMPKα (p-AMPKα) facilitated nuclear PD-L1 compartmentalization and then cooperated with it to directly phosphorylate S146 of histone variant macroH2A1 (mH2A1) to epigenetically activate expression of genes of cellular senescence, JAK/STAT, and Hippo signaling pathways. Lipoic acid (LA) that induced nuclear PD-L1 translocation suppressed tumorigenesis and boosted antitumor immunity. Importantly, LA treatment synergized with PD-1 antibody and overcame immune checkpoint blockade (ICB) resistance, which likely resulted from nPD-L1-increased MHC-I expression and sensitivity of tumor cells to interferon-γ. These findings offer a conceptual advance for PD-L1 function and suggest LA as a promising therapeutic option for overcoming ICB resistance.

α9-nAChR, a subtype of nicotinic acetylcholine receptor, is significantly overexpressed in female breast cancer tumor tissues compared to normal tissues. Previous studies have proposed that specific single nucleotide polymorphisms (SNPs) in the CHRNA9 (α9-nAChR) gene are associated with an increased risk of breast cancer in interaction with smoking. The study conducted a breast cancer risk assessment of the α9-nAChR SNP rs10009228 (NM&#95;017581.4:c.1325A > G) in the Taiwanese female population, including 308 breast cancer patients and 198 healthy controls revealed that individuals with the heterozygous A/G or A/A wild genotype have an increased susceptibility to developing breast cancer in the presence of smoking compared to carriers of the G/G variant genotype. Our investigation confirmed the presence of this missense variation, resulting in an alteration of the amino acid sequence from asparagine (N442) to serine (S442) to facilitate phosphorylation within the α9-nAchR protein. Additionally, overexpression of N442 (A/A) in breast cancer cells significantly enhanced cell survival, migration, and cancer stemness compared to S442 (G/G). Four-line triple-negative breast cancer patient-derived xenograft (TNBC-PDX) models with distinct α9-nAChR rs10009228 SNP genotypes (A/A, A/G, G/G) further demonstrated that chronic nicotine exposure accelerated tumor growth through sustained activation of the α9-nAChR downstream oncogenic AKT/ERK/STAT3 pathway, particularly in individuals with the A/G or A/A genotype. Collectively, our study established the links between genetic variations in α9-nAChR and smoking exposure in promoting breast tumor development. This emphasizes the need to consider gene-environment interactions carefully while developing effective breast cancer prevention and treatment strategies., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Immune checkpoint inhibitors (ICIs) are therapeutically effective for hepatocellular carcinoma (HCC) but are individually selective. This study examined the role of specific common fragile sites (CFSs) related gene in HCC immunotherapy., Methods: We analyzed HCC tissues using next-generation sequencing and flow cytometry via time-of-flight technology. A humanized orthotopic HCC mouse model, an in vitro co-culture system, untargeted metabolomics and a DNA pulldown assay were used to examine the function and mechanism of WWOX in the tumor immune response., Results: WWOX was the most upregulated CFS-related gene in HCC patients responsive to ICIs. WWOX deficiency renders HCC resistant to PD-1 treatment in humanized orthotopic HCC mouse model. Macrophage infiltration is increased and CD8 T-cell subset infiltration is decreased in WWOX-deficient HCC patients. HCC-derived oleic acid (OA) promotes macrophage conversion to an immunosuppressive phenotype. Mechanistically, WWOX deficiency promoted OA synthesis primarily via competitive binding of NME2 with KAT1, which promoted acetylation of NME2 at site 31 and inhibited NME2 binding to the SCD5 promoter region. Pharmacological blockade of SCD5 enhanced the antitumor effects of anti-PD-1 therapy., Conclusions: WWOX is a key factor for immune escape in HCC patients, which suggests its use as a biomarker for stratified treatment with ICIs in clinical HCC patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A variety of cell death pathways play critical roles in the onset and progression of multiple diseases. Paraptosis, a unique form of programmed cell death, has gained significant attention in recent years. Unlike apoptosis and necrosis, paraptosis is characterized by cytoplasmic vacuolization, swelling of the endoplasmic reticulum and mitochondria, and the absence of caspase activation. Numerous natural products, synthetic compounds, and newly launched nanomedicines have been demonstrated to prime cell death through the paraptotic program and may offer novel therapeutic strategies for cancer treatment. This review summarizes recent findings, delineates the intricate network of signaling pathways underlying paraptosis, and discusses the potential therapeutic implications of targeting paraptosis in cancer treatment. The aim of this review is to expand our understanding of this unique cell death process and explore the potential therapeutic implications of targeting paraptosis in cancer treatment., (© 2024. The Author(s).)

The ongoing COVID-19 pandemic is a persistent challenge, with continued breakthrough infections despite vaccination efforts. This has spurred interest in alternative preventive measures, including dietary and herbal interventions. Previous research has demonstrated that herbal medicines can not only inhibit cancer progression but also combat viral infections, including COVID-19 by targeting SARS-CoV-2, indicating a multifaceted potential to address both viruses and cancer. Here, we found that the Kang Guan Recipe (KGR), a novel herbal medicine formula, associates with potent inhibition activity against the SARS-CoV-2 viral infection. We demonstrate that KGR exhibits inhibitory activity against several SARS-CoV-2 variants of concern (VOCs). Mechanistically, we found that KGR can block the interaction of the viral spike and human angiotensin-converting enzyme 2 (ACE2). Furthermore, we assessed the inhibitory effect of KGR on SARS-CoV-2 viral entry in vivo, observing that serum samples from healthy human subjects having taken KGR exhibited suppressive activity against SARS-CoV-2 variants. Our investigation provides valuable insights into the potential of KGR as a novel herbal-based preventive and therapeutic strategy against COVID-19., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that they have a patent related to the subject matter of this manuscript. Mien-Chie Hung, Sheng-Teng Huang, Wei-Jan Wang and Shi-Chen Ou are co-inventors of a patent entitled “Herbal compositions for treating and preventing SARS-CoV-2 virus infection”., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Impaired tissue regeneration negatively impacts on left ventricular (LV) function and remodeling after acute myocardial infarction (AMI). Little is known about the intrinsic regulatory machinery of ischemia-induced endogenous cardiac stem cells (eCSCs) self-renewing divisions after AMI. The interleukin 22 (IL-22)/IL-22 receptor 1 (IL-22R1) pathway has emerged as an important regulator of several cellular processes, including the self-renewal and proliferation of stem cells. However, whether the hypoxic environment could trigger the self-renewal of eCSCs via IL-22/IL-22R1 activation remains unknown. In this study, the upregulation of IL-22R1 occurred due to activation of hypoxia-inducible factor-1α (HIF-1α) under hypoxic and ischemic conditions. Systemic IL-22 administration not only attenuated cardiac remodeling, inflammatory responses, but also promoted eCSC-mediated cardiac repair after AMI. Unbiased RNA microarray analysis showed that the downstream mediator Bmi1 regulated the activation of CSCs. Therefore, the HIF-1α-induced IL-22/IL-22R1/Bmi1 cascade can modulate the proliferation and activation of eCSCs in vitro and in vivo. Collectively, investigating the HIF-1α-activated IL-22/IL-22R1/Bmi1 signaling pathway might offer a new therapeutic strategy for AMI via eCSC-induced cardiac repair., Competing Interests: Declarations Ethics Approval All animal studies were conducted in accordance with guidelines using protocols approved by the Institutional Animal Care and Use Committees of China Medical University (CMUIACUC-2021-394). Consent to Participate Not applicable: the study did not involve human participants. Consent for Publication Not applicable. Competing Interests The authors declare no conflict of interest., (© 2024. The Author(s).)

Advanced pancreatic ductal adenocarcinomas (PDACs) respond poorly to all therapies, including the first-line treatment, chemotherapy, the latest immunotherapies, and KRAS-targeting therapies. Despite an enormous effort to improve therapeutic efficacy in late-stage PDAC patients, effective treatment modalities remain an unmet medical challenge. To change the status quo, we explored the key signaling networks underlying the universally poor response of PDAC to therapy. Here, we report a previously unknown chemo-induced symbiotic signaling circuit that adaptively confers chemoresistance in patients and mice with advanced PDAC. By integrating single-cell transcriptomic data from PDAC mouse models and clinical pathological information from PDAC patients, we identified Yap1 in cancer cells and Cox2 in stromal fibroblasts as two key nodes in this signaling circuit. Co-targeting Yap1 in cancer cells and Cox2 in stroma sensitized PDAC to Gemcitabine treatment and dramatically prolonged survival of mice bearing late-stage PDAC, whereas simultaneously inhibiting Yap1 and Cox2 only in cancer cells was ineffective. Mechanistically, chemotherapy triggers non-canonical Yap1 activation by nemo-like kinase in 14-3-3ζ-overexpressing PDAC cells and increases secretion of CXCL2/5, which bind to CXCR2 on fibroblasts to induce Cox2 and PGE2 expression, which reciprocally facilitate PDAC cell survival. Finally, analyses of PDAC patient data revealed that patients who received Statins, which inhibit Yap1 signaling, and Cox2 inhibitors (including Aspirin) while receiving Gemcitabine displayed markedly prolonged survival compared to others. The robust anti-tumor efficacy of Statins and Aspirin, which co-target the chemo-induced adaptive circuit in the tumor cells and stroma, signifies a unique therapeutic strategy for PDAC., (© 2024. The Author(s).)

As a double-stranded RNA-editing enzyme and an interferon-stimulated gene, double-stranded RNA-specific adenosine deaminase (ADAR1) suppresses interferon signaling and contributes to immunotherapy resistance. Suppression of ADAR1 overcomes immunotherapy resistance in preclinical models, but has not yet been translated to clinical settings. By conducting a screening of a subset of the FDA-approved drugs, we found that all-trans retinoic acid (ATRA, also known as tretinoin) caused ADAR1 protein degradation through ubiquitin-proteasome pathways and concomitantly increased PD-L1 expression in pancreatic and breast cancers. In addition, the combination of ATRA and PD-1 blockade reprogrammed the tumor microenvironment and unleashed antitumor immunity and thereby impeded tumor growth in pancreatic cancer mouse models. In a pilot clinical trial, a higher dose of ATRA plus the anti-PD-1 antibody nivolumab prolonged median overall survival in patients with chemotherapy-resistant pancreatic cancer compared to a lower dose of the same regimen. In this study, ATRA was the first drug to be found to cause ADAR1 degradation. We propose translation of a promising 2-pronged antitumor strategy using ATRA and nivolumab to convert immunologically "cold" into "hot" tumors susceptible to immune checkpoint blockade.

Brain metastases (BrMs) evade the immune response to develop in the brain, yet the mechanisms of BrM immune evasion remains unclear. This study shows that brain astrocytes induce the overexpression of neuronal-specific cyclin-dependent kinase 5 (Cdk5) in breast cancer-derived BrMs, which facilitates BrM outgrowth in mice. Cdk5-overexpressing BrMs exhibit reduced expression and function of the class I major histocompatibility complex (MHC-I) and antigen-presentation pathway, which are restored by inhibiting Cdk5 genetically or pharmacologically, as evidenced by single-cell RNA sequencing and functional studies. Mechanistically, Cdk5 suppresses MHC-I expression on the cancer cell membrane through the Irf2bp1-Stat1-importin α-Nlrc5 pathway, enabling BrMs to avoid recognition by T cells. Treatment with roscovitine-a clinically applicable Cdk5 inhibitor-alone or combined with immune checkpoint inhibitors, significantly reduces BrM burden and increases tumour-infiltrating functional CD8 + lymphocytes in mice. Thus, astrocyte-induced Cdk5 overexpression endorses BrM immune evasion, whereas therapeutically targeting Cdk5 markedly improves the efficacy of immune checkpoint inhibitors and inhibits BrM growth., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background/purpose: The use of computed tomography (CT) for craniofacial measurements is common in medical imaging, but concerns about accuracy and reliability persist, especially with different CT technologies. This study assessed the accuracy of twenty-six common measurements on consecutive CT images from the same patients, using multidetector CT (MDCT) and cone-beam CT (CBCT) with two software programs (Amira and Dolphin)., Materials and Methods: Ten adult subjects with consecutive CBCT scans within one year were randomly selected. Another ten subjects with consecutive MDCT scans were paired with the CBCT group based on age, gender, race, occlusion, and craniofacial pattern. All digital imaging and communications in medicine (DICOM) files were randomly coded and analyzed using the two software programs. Intra-examiner reliability was assessed using the intraclass correlation coefficient. Successive measurement errors from consecutive scans for both imaging modalities and software programs were compared., Results: For most skeletal linear and angular measurements, Dolphin showed greater successive measurement errors compared to Amira. Eight of the 26 common measurements had errors greater than one unit (millimeter or degree). Despite almost perfect intra-examiner reliability for upper airway analysis, average successive measurement errors were notably high, particularly for intraoral and oropharyngeal airway volumes. The successive Dolphin measurement error for oropharyngeal airway volume on CBCT images was over three times that on MDCT images., Conclusion: Given the substantial successive measurement errors observed during consecutive CT scanning for the upper airway, this study does not support the quantitative use of CT for analyzing changes in airway dimensions for research purposes., Competing Interests: The authors declare no conflict of interest., (© 2024 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Herpes zoster (HZ) is a painful, vesicular, cutaneous eruption from reactivation of varicella zoster virus (VZV), which can lead to potentially debilitating complications. The lifetime risk of HZ is estimated to be 20%-30% in the general population, with an increased risk in the elderly and immunocompromised populations. The most effective strategy to prevent HZ and its complications is by vaccination. Two types of HZ vaccines, zoster vaccine live and recombinant zoster vaccine, have been approved for use. This guidance offers recommendations and suggestions for HZ vaccination in adults, aiming to reduce the disease burden of HZ and its complications. It is intended as a guide to first-line healthcare providers, but does not supersede clinical judgement when assessing risk and providing recommendations to individuals. The Working Group on Adult Immunization Practice was appointed by the Infectious Diseases Society of Taiwan (IDST) and recommendations were drafted after a full literature review, using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. The recommendations were reviewed and revised by expert review panels during a series of consensus meetings and endorsed by the IDST, Taiwan Association of Family Medicine, the Taiwanese Dermatological Association, the Taiwan Oncology Society, the Taiwan Society of Blood and Marrow Transplantation, the Transplantation Society of Taiwan, the Taiwan AIDS Society, and the Taiwan College of Rheumatology. This guidance describes the epidemiology of HZ and provides recommendations for HZ vaccination in adults with varying levels of risk, differing history of previous VZV infection and past varicella or zoster vaccinations., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with regards to the research, authorship, or publication of this article., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: To investigate the effectiveness of different adjunctive local treatments combined with non-surgical periodontal therapy (NSPT) to reduce pocket depth (PD), gain clinical attachment level (CAL), and/or reduce glycated hemoglobin (HbA1c) in individuals with both type 2 diabetes mellitus (T2DM) and periodontitis in a systematic review and network meta-analysis., Data Sources: Publications were searched in Cochrane databases, EMBASE, Google Scholar, MEDLINE, PubMed, opengrey.eu, and www., Clinicaltrials: gov up to May 29, 2024 with no language restriction., Study Selection: Only randomized controlled trials (RCTs) were included. Network meta-analysis utilized frequentist models., Data: The network meta-analysis of 30 RCTs involving 1224 patients revealed that, in short-term (2-3 months) and medium-term (4-6 months), adjunctive local treatment involving statins or metformin significantly outperformed scaling and root planning (SRP) with/without additional interventions such as photodynamic and laser therapies (PDT/LT), phytotherapy, doxycycline, bisphosphonates, antibiotics, antiseptics, or placebo for reducing PD and/or gaining CAL. In the long-term (>6 months), statins yielded the most significant additional PD reduction and CAL gain, followed by antibiotics, compared to SRP with antiseptics or placebo. Only PDT/LT demonstrated significantly greater HbA1c reduction in the short term compared to SRP with/without statins, antiseptics, or placebo., Conclusion: This study moderately supports that adding metformin or statins locally to NSPT may enhance PD reduction and CAL gain compared to SRP with/without placebo., Clinical Significance: Clinicians are guided to optimize adjunctive therapies, enhancing the health of patients with type 2 diabetes and periodontitis. A strategic approach is proposed to tackle systemic and oral health challenges simultaneously., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

RNA-binding proteins (RBPs) play a crucial role in the biological processes of liver hepatocellular carcinoma (LIHC). Peptidyl-prolyl cis-trans isomerase H (PPIH), an RBP, possesses prolyl isomerase activity and functions as a protein chaperone. The relationship between PPIH and LIHC has not yet been fully elucidated. This study elucidated potential mechanisms through which PPIH affects the prognosis of LIHC. Bioinformatics analysis and in vitro experiments revealed that PPIH expression was higher in LIHC tissues than in normal tissues. PPIH was identified as an independent prognostic factor, with high PPIH expression being associated with worse prognoses. Moreover, PPIH increased the m6A RNA methylation level and promoted cell proliferation by modulating DNA replication and the expression of cell cycle-related genes in LIHC cells. Bioinformatics analysis also revealed that PPIH expression increased immune cell infiltration and the expression of immune checkpoint proteins. Collectively, these findings indicate that PPIH might promote LIHC progression by enhancing the m6A RNA methylation level, increasing cell proliferation, and altering the tumor immune microenvironment. Our study demonstrates that PPIH, as a poor prognostic factor, may lead to LIHC malignancy through multiple pathways. Further in-depth research on this topic is warranted., Competing Interests: None., (AJCR Copyright © 2024.)

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i co-treatment. Finally, we show that xenograft tumors derived from patients with BRCA1-mutant breast cancer with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers. Significance: BRCA1 deficiency promotes resistance to erastin-induced ferroptosis via blocking VDAC3 yet renders cancer cells vulnerable to GPX4i-induced ferroptosis via inhibiting GPX4. NCOA4 induction and defective GPX4 further synergizes GPX4i with PARPi to induce ferroptosis in BRCA1-deficient cancers and targeting GPX4 mitigates PARPi resistance in those cancers. See related commentary by Alborzinia and Friedmann Angeli, p. 1372., (©2024 American Association for Cancer Research.)

Protein lipoylation, a crucial post-translational modification (PTM), plays a pivotal role in mitochondrial function and emerges as a key player in cell death through cuproptosis. This novel copper-driven cell death pathway is activated by excessive copper ions binding to lipoylated mitochondrial proteins, disrupting energy production and causing lethal protein aggregation and cell death. The intricate relationship among protein lipoylation, cellular energy metabolism, and cuproptosis offers a promising avenue for regulating essential cellular functions. This review focuses on the mechanisms of lipoylation and its significant impact on cell metabolism and cuproptosis, emphasizing the key genes involved and their implications for human diseases. It offers valuable insights into targeting dysregulated cellular metabolism for therapeutic purposes., Competing Interests: Declaration of interests The authors have no competing interests to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Under nitrogen deficient conditions, the Aurantiochytrium limacinum strain BL10 greatly increases the production of docosahexaenoic acid (DHA) and n-6 docosapentaenoic acid. Researchers have yet to elucidate the mechanism by which BL10 promotes the activity of polyunsaturated fatty acid synthase (Pfa), which plays a key role in the synthesis of polyunsaturated fatty acid (PUFA). Analysis in the current study revealed that in nitrogen-depleted environments, BL10 boosts the transcription and synthesis of proteins by facilitating the expression of pfa genes via transcriptional regulation. It was also determined that BL10 adjusts the lengths of the 5'- and 3'-untranslated regions (suggesting post-transcriptional regulation) and modifies the ratio of two Pfa1 isoforms to favor PUFA production via post-translational regulation (ubiquitination). These findings clarify the exceptional DHA production of BL10 and provide additional insights into the regulatory mechanisms of PUFA biosynthesis in Aurantiochytrium., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitors (ICIs) activate anti-cancer immunity by blocking T cell checkpoint molecules such as programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Although ICIs induce some durable responses in various cancer patients, they also have disadvantages, including low response rates, the potential for severe side effects, and high treatment costs. Therefore, selection of patients who can benefit from ICI treatment is critical, and identification of biomarkers is essential to improve the efficiency of ICIs. In this review, we provide updated information on established predictive biomarkers (tumor programmed death-ligand 1 [PD-L1] expression, DNA mismatch repair deficiency, microsatellite instability high, and tumor mutational burden) and potential biomarkers currently under investigation such as tumor-infiltrated and peripheral lymphocytes, gut microbiome, and signaling pathways related to DNA damage and antigen presentation. In particular, this review aims to summarize the current knowledge of biomarkers, discuss issues, and further explore future biomarkers., Competing Interests: Declaration of interests M.-C.H. is a co-inventor on the methodology for de-glycosylation staining., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)