Statin use reduces radiation-induced stroke risk in advanced nasopharyngeal carcinoma patients.

OBJECTIVE: This cohort study aimed to evaluate the impact of statin use on ischemic stroke risk in patients with advanced nasopharyngeal carcinoma (NPC) undergoing standard concurrent chemoradiotherapy (CCRT). METHODS: Using data from the Taiwan Cancer Registry Database, we conducted an inverse probability of treatment-weighted Cox regression analysis to examine the association between statin use during CCRT and ischemic stroke risk. RESULTS: The adjusted hazard ratio (aHR) for ischemic stroke in the statin group compared to the non-statin group was 0.70 (95 % CI: 0.54-0.92; P < 0.0107). This protective effect was observed across different statin classes, with hydrophilic statins such as pravastatin showing an aHR of 0.37 (95 % CI: 0.17-0.85) and lipophilic statins including atorvastatin displaying an aHR of 0.32 (95 % CI: 0.21-0.50) compared to non-statin use. Analysis of cumulative defined daily doses (cDDD) revealed a dose-response relationship, with lower stroke risk observed in higher quartiles of cDDD. Additionally, patients with a daily defined dose (DDD) > 1 had a reduced risk of stroke with an aHR of 0.49 (95 % CI: 0.31-0.63), while those with DDD ≤ 1 showed an aHR of 0.59 (95 % CI: 0.40-0.84). CONCLUSIONS: Our study provides evidence supporting the beneficial effects of statin use during the CCRT period in reducing radiation-induced stroke risk among patients with advanced NPC undergoing definitive CCRT. Notably, pravastatin and atorvastatin demonstrated significant reductions in stroke occurrence. Furthermore, the findings suggest a dose-response relationship, where higher cumulative doses and greater daily dose intensity of statin use were associated with a lower risk of stroke.

Comparative Effectiveness of Intensity-Modulated Proton Therapy Versus Intensity-Modulated Radiotherapy for Patients With Inoperable Esophageal Squamous Cell Carcinoma Undergoing Curative-Intent Concurrent Chemoradiotherapy.

INTRODUCTION: This study compared outcomes in patients with inoperable esophageal squamous cell carcinoma (ESCC) undergoing curative-intent concurrent chemoradiotherapy (CCRT) with intensity-modulated radiotherapy (IMRT) versus intensity-modulated proton therapy (IMPT). METHODS: The study encompassed a retrospective cohort analysis of patients with inoperable ESCC who underwent curative-intent CCRT from January 1, 2015, to December 31, 2020, with data sourced from the Taiwan Cancer Registry Database. In this study, both IMRT and IMPT delivered a total equivalent effective dose of approximately 5040 cGy in 28 fractions, accompanied by platinum-based chemotherapy administered as per established protocols. Multivariate Cox regression analyses were performed to assess oncologic outcomes, and statistical analyses were conducted, including inverse probability of treatment-weighted and Fine and Gray method for competing risks. RESULTS: The observed risks of ESCC-specific and all-cause mortality were lower in patients treated with IMPT compared with those treated with IMRT, with adjusted hazard ratios (aHRs) of 0.62 (95% confidence interval [CI]: 0.58-0.70) and 0.72 (95% CI: 0.66-0.80), respectively. IMPT also reduced grade 2 radiation-induced side effects, such as pneumonitis, fatigue, and major adverse cardiovascular events, with aHRs (95% CI) of 0.76 (0.66-0.82), 0.10 (0.07-0.14), and 0.70 (0.67-0.73), respectively. However, IMPT was associated with an increased risk of grade 2 radiation dermatitis, with aHR (95% CI) of 1.48 (1.36-1.60). No substantial differences were found in the incidence of radiation esophagitis between IMPT and IMRT when adjusting for covariates. CONCLUSION: IMPT seems to be associated with superiority over IMRT in managing patients with inoperable ESCC undergoing curative-intent CCRT, suggesting improved survival outcomes and reduced toxicity. These findings have significant implications for the treatment of ESCC, particularly when surgery is not an option.

Antihistamines H1 use on survival outcomes in esophageal squamous cell carcinoma patients undergoing concurrent chemoradiotherapy.

Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related mortality in Taiwan, with poor survival rates despite standard treatment with concurrent chemoradiotherapy (CCRT). Antihistamines H1 (AH1) may have anticancer effects by reducing allergic reactions, activating mitogen-activated protein kinases, and regulating the immune system. However, the impact of AH1 use during CCRT on survival outcomes in patients with ESCC remains uncertain. A propensity score-matched cohort study was conducted using data from the Taiwan Cancer Registry Database and National Health Insurance Research Database. The primary outcome measures were overall survival and ESCC-specific survival. We analyzed the effects of AH1 use during CCRT on these outcomes using multivariable Cox proportional hazards regression models. The current study involved 981 individuals diagnosed with ESCC who underwent standard CCRT. Out of these, 309 were placed in the non-AH1 group and 672 in the AH1 group. AH1 use during CCRT was found to be associated with improved overall survival (adjusted hazard ratio [HR], 0.52; 95% CI, 0.44-0.60; P<0.0001) and ESCC-specific survival (adjusted HR, 0.47; 95% CI, 0.39-0.56; P<0.0001) compared with nonuse. A dose-response relationship was also observed, with higher cumulative defined daily doses of AH1 associated with lower mortality. The optimal daily intensity dose for AH1 use was found to be 0.84 defined daily doses with the lowest mortality. Our study demonstrates that AH1 use during CCRT for ESCC is associated with improved overall survival and ESCC-specific survival.

In silico repurposing of midostaurin as a therapeutic candidate for head and neck cancer via targeting SPARC/MMP9/CD44 Cancer-Associated Fibroblasts (CAFs) oncogenic signature.

Head and neck squamous carcinoma (HNSCC) affects more than half a million individuals and ranks the ninth leading cause of death globally each year. Many patients develop treatment resistance leading to poor clinical outcomes. The poor treatment responses are in part due to the heterogeneity of HNSCC tumor and tumor microenvironment (TME). The interaction of tumor cells with their TME has been studied vigorously in recent years because of their pivotal roles in tumorigenesis and determining the treatment response. Cancer-associated fibroblasts (CAFs) are one of the most abundant tumor-infiltrating cells, which have been shown to associate with the aggressive behavior of HNSCC. Hence, targeting and disrupting the tumor-CAFs interactions represents a rational therapeutic approach. To develop targeted therapeutic drugs against CAFs, the identification of CAF-associated gene signature is essential. Here, we analyzed multiple sequencing databases including microarrays and single-cell RNA-sequencing databases and identified SPARC/MMP9/CD44 as HNSCC targetable gene signatures encompassing cancer-associated fibroblasts (CAFs). We found SPARC/MMP9CD44 signature was highly expressed in HNSC tissues compared to adjacent normal tissues. Increased SPARC/MMP9/CD44 signature levels strongly correlated with tumor-infiltrating CAFs, suggesting the functional importance of this signature for HNSCC-CAFs interaction and progression. Subsequently, we utilized a genomics approach and identified midostaurin as the top-ranking drug candidate for targeting SPARC/MMP9/CD44 signature. For validation, we performed molecular docking of midostaurin in complex with SPARC/MMP9/CD44 and demonstrated midostaurin's high binding affinities compared to their respective standard inhibitors. In summary, our study provided a rapid genomics approach for identifying targetable gene signature and drug candidate for HNSCC.

The association between the severity of periodontitis and osteonecrosis of the jaw in patients with different cancer locations: a nationwide population-based study.

OBJECTIVES: To determine the relation between the severity of periodontitis and osteonecrosis of the jaw (ONJ) occurrence among different cancer locations and estimate the effect of dental care on ONJ prevention in cancer patients. MATERIALS AND METHODS: This population-based cross-sectional study was conducted through the Longitudinal Health Insurance Database, Taiwan. Patients with malignancies were collected and subdivided into groups according to their different cancer locations, the severity of periodontitis, and dental care. Multivariable logistic regression analysis was performed to assess the associations between ONJ and ONJ-related factors. RESULTS: A total of 8,234 ONJ patients and 32,912 control patients were investigated. Lip, oral cavity, and pharynx malignancies had the highest ONJ risk among all cancer locations (OR from 3.07 to 9.56, P < 0.01). There is a linear relationship between different severities of periodontitis and ONJ. Patients with radiotherapy and severe periodontitis had the highest ONJ risk (adjusted OR, 9.56; 95% CI, 5.34-17.1). Patients with good dental care had a lower ONJ risk. CONCLUSIONS: The periodontal condition and cancer location showed a significant impact on the risk of developing ONJ after adjusting for bisphosphonate use. Good dental care could decrease the risk of ONJ in cancer patients. The severity of periodontitis might be a target to predict the potency of ONJ. CLINICAL RELEVANCE: Dentists must be vigilant about the increased risk of ONJ in cancer patients with periodontitis, especially in the head and neck cancer population. Good dental care is advised for cancer patients with severe periodontitis.

Review-Hysteresis in Carbon Nano-Structure Field Effect Transistor.

In recent decades, the research of nano-structure devices (e.g., carbon nanotube and graphene) has experienced rapid growth. These materials have supreme electronic, thermal, optical and mechanical properties and have received widespread concern in different fields. It is worth noting that gate hysteresis behavior of field effect transistors can always be found in ambient conditions, which may influence the transmission appearance. Many researchers have put forward various views on this question. Here, we summarize and discuss the mechanisms behind hysteresis, different influencing factors and improvement methods which help decrease or eliminate unevenness and asymmetry.

Ex Vivo Expanded Circulating Tumor Cells for Clinical Anti-Cancer Drug Prediction in Patients with Head and Neck Cancer.

The advanced-stage head and neck cancer (HNC) patients respond poorly to platinum-based treatments. Thus, a reliable pretreatment method for evaluating platinum treatment response would improve therapeutic efficiency and outcomes. This study describes a novel strategy to predict clinical drug responses in HNC patients by using eSelect, a lab-developed biomimetic cell culture system, which enables us to perform ex vivo expansion and drug sensitivity profiling of circulating tumor cells (CTCs). Forty liquid biopsies were collected from HNC patients, and the CTCs were expanded ex vivo using the eSelect system within four weeks. Immunofluorescence staining confirmed that the CTC-derived organoids were positive for EpCAM and negative for CD45. Two illustrative cases present the potential of this strategy for evaluating treatment response. The statistical analysis confirmed that drug sensitivity in CTC-derived organoids was associated with a clinical response. The multivariant logistic regression model predicted that the treatment accuracy of chemotherapy responses achieved 93.75%, and the area under the curves (AUCs) of prediction models was 0.8841 in the whole dataset and 0.9167 in cisplatin specific dataset. In summary, cisplatin sensitivity profiles of patient-derived CTCs expanded ex vivo correlate with a clinical response to cisplatin treatment, and this can potentially underpin predictive assays to guide HNC treatments.

MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer types.

MAX dimerization (MXD) protein 3 (MXD3) is a member of the MXD family of basic-helix-loop-helix-leucine-zipper (bHLHZ) transcription factors that plays pivotal roles in cell cycle progression and cell proliferation. However, there is insufficient scientific evidence on the pathogenic roles of MXD3 in various cancers and whether MXD3 plays a role in the immuno-oncology context of the tumor microenvironment, pathogenesis, prognosis, and therapeutic response of different tumors through certain common molecular mechanisms; thus, we saw a need to conduct the present in silico pan-cancer study. Using various computational tools, we interrogated the role of MXD3 in tumor immune infiltration, immune evasion, tumor progression, therapy response, and prognosis of cohorts from various cancer types. Our results indicated that MXD3 was aberrantly expressed in almost all The Cancer Genome Atlas (TCGA) cancer types and subtypes and was associated with the tumor stage, metastasis, and worse prognoses of various cohorts. Our results also suggested that MXD3 is associated with tumor immune evasion via different mechanisms involving T-cell exclusion in different cancer types and by tumor infiltration of immune cells in thymoma (THYM), liver hepatocellular carcinoma (LIHC), and head and neck squamous cell carcinoma (HNSC). Methylation of MXD3 was inversely associated with messenger (m)RNA expression levels and mediated dysfunctional T-cell phenotypes and worse prognoses of cohorts from different cancer types. Finally, we found that genetic alterations and oncogenic features of MXD3 were concomitantly associated with deregulation of the DBN1, RAB24, SLC34A1, PRELID1, LMAN2, F12, GRK6, RGS14, PRR7, and PFN3 genes and were connected to phospholipid transport and ion homeostasis. Our results also suggested that MXD3 expression is associated with immune or chemotherapeutic outcomes in various cancers. In addition, higher MXD3 expression levels were associated with decreased sensitivity of cancer cell lines to several mitogen-activated protein kinase kinase (MEK) inhibitors but led to increased activities of other kinase inhibitors, including Akt inhibitors. Interestingly, MXD3 exhibited higher predictive power for response outcomes and overall survival of immune checkpoint blockade sub-cohorts than three of seven standardized biomarkers. Altogether, our study strongly suggests that MXD3 is an immune-oncogenic molecule and could serve as a biomarker for cancer detection, prognosis, therapeutic design, and follow-up.

Definitive intensity-modulated radiotherapy or surgery for early oral cavity squamous cell carcinoma: Propensity-score-matched, nationwide, population-based cohort study.

BACKGROUND: No evidence is currently available to estimate the outcomes of intensity-modulated radiation therapy (IMRT) and surgery for patients with early oral cavity squamous cell carcinoma (E-OCSCC). METHODS: We recruited patients from the Taiwan Cancer Registry Database who had received a diagnosis of E-OCSCC. Propensity score matching was performed, and Cox proportional hazards model was used to analyze all-cause mortality. RESULTS: In the multivariate Cox regression analyses, the adjusted hazard ratio (aHR) (95% confidence interval [CI]) for surgery compared with definitive IMRT, T2N0M0 compared with T1N0M0, and male patients compared with female patients were 0.303 (0.245, 0.375), 1.340 (1.077, 1.668), and 2.012 (1.432, 2.826), respectively. The aHRs (95% CIs) for age 61 to 70, 71 to 80, and ≧81 years compared with <40 years were 2.984 (1.43, 4.225), 3.353 (2.578, 4.112), and 4.277 (4.104, 5.679), respectively. CONCLUSIONS: For patients with E-OCSCC, surgery may be considered the first option rather than definitive IMRT.

Definitive radiotherapy or surgery for early oral squamous cell carcinoma in old and very old patients: A propensity-score-matched, nationwide, population-based cohort study.

PURPOSE: Although patients aged >70 years are subject to early oral cavity squamous cell carcinoma (E-OCSCC), evidence is currently lacking regarding the probable outcomes of definitive radiotherapy (RT) compared to surgery in this population. METHODS: We recruited patients aged ≥70 years with a diagnosis of E-OCSCC from the Taiwan Cancer Registry Database. Propensity score matching was performed, and Cox proportional-hazards model curves were used to analyze all-cause mortality of patients at different age intervals undergoing different treatments. RESULTS: The matching process yielded a final cohort of 604 patients in the definitive RT and surgery cohorts who were eligible for further analysis. These patients were classified as old (70-80 years) and very old (>80 years). In the multivariate Cox regression analysis, the adjusted hazard ratio (aHR) (95% confidence interval [CI]) for surgery compared with definitive RT was 0.465 (0.354-0.610, P < 0.001). The aHR (95% CI) for age >80 years compared with age 70-80 years was 2.370 (1.720, 3.265, P < 0.001). The aHR (95% CI) for T2N0M0 compared with T1N0M0 was 1.752 (1.321-2.32, P < 0.001). The aHR (95% CI) for Charlson Comorbidity Index (CCI) ≥ 2 compared with CCI = 0 was 1.264 (1.137-1.738, P = 0.011). After stratified analysis, the aHRs for surgery compared with definitive RT were 0.484 (0.352-0.665, P < 0.001) and 0.411 (0.232-0.728, P = 0.002) among old and very old patients with E-OCSCC, respectively. CONCLUSIONS: Surgery may be more beneficial than definitive RT in selected elderly patients with E-OCSCC.

Assessment of Predictive Scoring System for 90-Day Mortality Among Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma Who Have Completed Concurrent Chemoradiotherapy.

Importance: There is currently no system to predict 90-day morality among patients with locally advanced head and neck squamous cell carcinoma (HNSCC) after the completion of concurrent chemoradiotherapy (CCRT). Objective: To validate the accuracy of a predictive scoring system for 90-day mortality among patients with locally advanced HNSCC who have completed CCRT. Design, Setting, and Participants: This prognostic study included 16 029 patients with HNSCC who completed CCRT between January 2006 and December 2015. Data were extracted from the Taiwan Cancer Registry Database. A risk scoring system was developed based on significant risk factors and corresponding risk coefficients. Data analysis was conducted from June 2018 to February 2019. Exposures: Mortality within 90 days of completion of definitive CCRT. Main Outcomes and Measures: The 90-day mortality rate after completion of CCRT and the accuracy of the scoring system, based on a comparison of mortality rates between training and test data sets. Results: Among 16 029 patients with locally advanced HNSCC, 1068 (6.66%; 1016 [95.1%] men; mean [SD] age, 55.11 [11.45] years) died before reaching the 90-day threshold, and 14 961 (93.4%; 14 080 [94.1%] men; mean [SD] age, 52.07 [9.99] years) survived. Multivariable analysis revealed that being aged 50 years or older (adjusted hazard ratio [aHR], 1.263; 95% CI, 1.104-1.445; P < .001), being aged 70 years or older (aHR, 2.183; 95% CI, 1.801-2.645; P < .001), having pneumonia (aHR, 1.946; 95% CI, 1.636-2.314; P < .001), having sepsis (aHR, 3.005; 95% CI, 2.503-3.607; P < .001), having hemiplegia (aHR, 1.430; 95% CI, 1.085-1.884; P = .01), having moderate or severe renal disease (aHR, 2.054; 95% CI, 1.643-2.568; P < .001), having leukemia (aHR, 4.541; 95% CI, 1.132-8.207; P = .03), and having non-HNSCC metastatic solid cancers (aHR, 1.457; 95% CI, 1.292-1.644; P < .001) were significant risk factors for 90-day mortality. Risk scores were categorized as very low risk (score of 0), low risk (score 1-3), moderate risk (score 4-6), and high risk (score ≥7), with 90-day mortality rates of 3.37%, 5.00% to 10.98%, 16.15% to 29.13%, and 33.93% to 37.50%, respectively. Mortality rates for patients with the same risk score in the training and test data sets were similar (score of 0, 3.27% vs 3.66%; score of 6, 27.42% vs 25.00%). Conclusions and Relevance: In this prognostic study, a 90-day mortality scoring system accurately predicted 90-day mortality among patients with locally advanced HNSCC who completed CCRT.

Outcomes for Elderly Patients Aged 70 to 80 Years or Older with Locally Advanced Oral Cavity Squamous Cell Carcinoma: A Propensity Score-Matched, Nationwide, Oldest Old Patient-Based Cohort Study.

Purpose: Although clinicians encounter patients aged ≥70 years with locally advanced oral cavity squamous cell carcinoma (LA-OCSCC), no evidence is available to facilitate decision making regarding treatment for this elderly population. Methods: We selected elderly (≥70 years) patients from the Taiwan Cancer Registry database who had received a diagnosis of LA-OCSCC. Propensity score matching was performed. Cox proportional hazards model curves were used to analyze all-cause mortality in patients in different age groups receiving different treatments. Results: The matching process yielded a final cohort of 976 patients in concurrent chemoradiotherapy (CCRT), non-treatment, radiotherapy (RT) alone, and surgery cohorts who were eligible for further analysis. After stratified analysis, the adjusted hazard ratios (aHRs) (95% confidence intervals [CIs]) derived for surgery, RT alone, and non-treatment compared with CCRT were 0.66 (0.52 to 0.83), 1.02 (0.81 to 1.28), and 1.52 (1.21 to 1.91), respectively, in patients aged 70 to 80 years. In the oldest patients (aged >80 years), multivariate analysis indicated that the results of surgery or RT alone were nonsignificant compared with those of CCRT. The aHR (95% CI) derived for the highest mortality was 1.81 (1.11 to 2.40) for non-treatment compared with CCRT. Conclusions: Surgery for elderly patients with LA-OCSCC is associated with a significant survival benefit, but the association is nonsignificant in the oldest elderly patients. No survival differences were observed between RT alone and CCRT in these elderly patients. Non-treatment should not be an option for these patients.

Age comorbidity scores as risk factors for 90-day mortality in patients with a pancreatic head adenocarcinoma receiving a pancreaticoduodenectomy: A National Population-Based Study.

BACKGROUND: To estimate easily assessed preoperative factors for predicting 90-day mortality in patients with a pancreatic head adenocarcinoma (PHA) receiving a pancreaticoduodenectomy. METHODS: We analyzed data from the Taiwan Cancer Registry Database of patients with a PHA who received a pancreaticoduodenectomy. Basic demographic characteristics, including gender and age, were categorized. The selection of preoperative comorbidities was based on the preoperative American Society of Anesthesiologists score and Charlson comorbidity index. RESULTS: We enrolled 8490 patients with a PHA who received a pancreaticoduodenectomy without distant metastasis. Currently, a pancreaticoduodenectomy for a PHA achieves an overall 90-day mortality rate of 8.39%. Univariate and multivariate Cox regression analyses indicated that an older age (65-74 and ≥75 years) and specific comorbidities (chronic obstructive pulmonary disease, chronic kidney disease, dementia, and sepsis) were significant independent prognostic factors for predicting 90-day mortality after a pancreaticoduodenectomy. After adjustment, the adjusted hazard ratios (aHRs) (95% confidence intervals [CIs]) of subjects with middle and high comorbidity scores for 90-day mortality in 65 to 74-year-old patients were 1.36 (1.05-1.75) and 2.25 (1.03-4.90), respectively, compared to subjects with low comorbidity scores. The aHRs (95% CIs) of subjects with middle and high comorbidity scores for 90-day mortality in ≥75-year-old patients were 1.35 (1.07-1.78) and 2.07 (1.19-3.62), respectively, compared to those with low comorbidity scores. CONCLUSIONS: Elderly patients with a PHA and moderate or high comorbidity scores have an increased risk of 90-day mortality after a pancreaticoduodenectomy.

Slug mediates myofibroblastic differentiation to promote fibrogenesis in buccal mucosa.

Epithelial-mesenchymal transition (EMT) has been implicated in fibrogenesis and carcinogenesis; however, the exact role of EMT-inducer Slug in the progression of precancerous oral submucous fibrosis (OSF) has not been investigated. In the current study, we showed that the expression of Slug was upregulated in OSF tissues and associated with various myofibroblast markers. After silence of Slug in fibrotic buccal mucosal fibroblasts (fBMFs), the elevated myofibroblast activities and fibrosis markers were all downregulated. Our data revealed that arecoline, an areca nut alkaloid, increased the expression of Slug in normal BMFs, and inhibition of Slug successfully prevented the arecoline-induced myofibroblast activation. Additionally, overexpression of Slug in BMFs stimulated the activities of myofibroblasts, indicating that upregulation of Slug by arecoline contributes to the myofibroblast transdifferentiation. Most importantly, Slug was able to bind to the E-box of type I collagen, leading to increased expression of type I collagen. Altogether, this study demonstrated the abnormal elevation of Slug in OSF and its significance in arecoline-induced fibrogenesis. Moreover, downregulation of Slug could be a potential target for OSF remedy via suppression of myofibroblast activities and type I collagen.

LncRNA LINC00974 activates TGF-ß/Smad signaling to promote oral fibrogenesis.

BACKGROUND: Oral submucous fibrosis (OSF) is a progressive scarring disease and has been considered as a premalignant condition of the oral cavity. However, the detailed molecular mechanisms underlying the pathogenesis of OSF are still unclear. METHOD: Here, we examined the expression of a novel long non-coding RNA LINC00974 in OSF and investigated its function role in myofibroblast transdifferentiation. Phenotypic analyses, including collagen gel contraction, migration, invasion and wound healing assays, were used to assess the myofibroblast activities following overexpression or inhibition of LINC00974. RESULTS: We found that the expression of LINC00974 in OSF tissues or myofibroblasts was aberrantly upregulated, and there was a positive correlation between LINC00974 and myofibroblast markers. Our results showed that inhibition of LINC00974 suppressed the myofibroblast activities, while overexpression of LINC00974 increased the activation. We demonstrated that the expression levels of α-SMA, α-1 type I collagen, fibronectin were downregulated in the LINC00974-inhibited myofibroblasts. Additionally, the TGF-ß secretion and phosphorylated Smad2 expression were also repressed in the LINC00974-inhibited myofibroblasts. We further demonstrated that silence of LINC00974 prevented the arecoline-induced myofibroblast activation, and LINC00974-increased myofibroblast activities were via TGF-ß pathway. CONCLUSION: Altogether, these findings suggested that arecoline-increased myofibroblast transdifferentiation was via LINC00974-mediated activation of TGF-ß signaling.