Efficacy, safety and cost of emicizumab prophylaxis in haemophilia A patients with inhibitors: A nationwide observational study in Taiwan.

INTRODUCTION: Emicizumab mimicking the cofactor function of activated factor VIII (FVIII) restores haemostasis. METHODS: This nationwide observational study aimed to retrospectively investigate efficacy, safety, and cost in 1 year before and up to 3 years after emicizumab prophylaxis for haemophilia A (HA) patients with FVIII inhibitors. RESULTS AND DISCUSSION: A total of 39 severe HA patients with a median age of 23.0 years were enrolled. The median historical peak FVIII inhibitor titre was 174.2 BU/mL with an interquartile range of 56.5-578.8 BU/mL. The median annualized bleeding rate reduced from 24 to 0 events in the first year after emicizumab prophylaxis (p < .01) and sustained in the second and third years. The median annualized joint bleeding rate reduced to 0 and maintained up to 3 years (p < .01). Twenty-seven patients (69.2%) had target joints before emicizumab prophylaxis and only seven patients (17.9%) of them had target joints after prophylaxis. Medical costs, including cost of haemostatic therapy, frequency of outpatient department visits, emergency room visits and hospital admission, were significantly reduced after emicizumab prophylaxis (p < .01). FVIII inhibitor titre decreased after emicizumab prophylaxis. Overall, three (7.7%) patients experienced 202 grade 1 drug-related adverse events after emicizumab prophylaxis. No serious adverse events were reported during emicizumab prophylaxis period. The adherence to emicizumab prophylaxis was 100% up to 3 years. CONCLUSIONS: HA patients with FVIII inhibitors treated with emicizumab prophylaxis resulted in a significant reduction in treated bleeds and associated costs. No new safety events were observed.

Cancer-Associated Thrombosis: A Taiwanese Perspective on Therapeutic Options with Focus on Non-Vitamin K Antagonist Oral Anticoagulants.

Cancer-associated thrombosis (CAT) is a common complication of malignancies. Patients with CAT are at risk of venous thromboembolism recurrence, but also at risk of bleeding while anticoagulated. Taiwanese patients are perceived to have a lower incidence of CAT, likely leading to false reassurance for Taiwanese patients with cancer. Because of this, oncologists and cardiologists from multiple medical institutions in Taiwan have set forth to provide clinical consensus guidelines on the management of CAT, based on local clinical practices and guided by predominant international clinical practice guidelines. This paper aims to describe the current disease burden of cancer-associated venous thromboembolism in Taiwanese cancer patients, and discusses the unmet needs and gaps in the management of this medical complication. It also outlines diagnostic and management strategies relevant to the different treatment options available, such as non-vitamin K antagonist oral anticoagulants.

Hesperetin Induces Autophagy and Delayed Apoptosis by Modulating the AMPK/Akt/mTOR Pathway in Human Leukemia Cells In Vitro.

BACKGROUND: Hesperetin has been reported to have anticancer properties. However, the molecular mechanisms underlying its action on leukemia cells remain unclear. This in vitro study evaluated the possible mechanisms of hesperetin in leukemia cells (HL-60 and U937). METHODS: Cell viability was evaluated using a cell counting kit-8 (CCK-8) assay. Apoptosis and autophagy assays were conducted through annexin V/PI staining and acidic vesicular organelle (AVO) staining. Cell cycle analysis was conducted through propidium iodide (PI) and flow cytometry. The expression of proteins related to apoptosis and autophagy, including cleaved-PARP-1, Bcl-2, Bax, LC3-I/II, Beclin-1, Atg5, p62, phospho-AMPK, AMPK, phospho-mTOR, mTOR, phospho-Akt, and Akt, in human leukemia cells were evaluated using Western blotting. RESULTS: Hesperetin dose-dependently inhibited leukemia cell viability. However, we found a low degree of apoptosis and cell cycle arrest induced by hesperetin in U937 cells. These findings imply the presence of additional mechanisms modulating hesperetin-induced cell death. Next, we evaluated autophagy, the possible mechanism modulating cell death or survival, to clarify the underlying mechanism of hesperetin-induced cell death. Hesperetin also dose-dependently increased the ratio of LC3II/I, Atg5, and Beclin 1 and decreased p62. Moreover, 3-methyladenine (3-MA) and bafilomycin A1 (Baf-A1) inhibited hesperetin-induced autophagy. We suggest that hesperetin can protect cancer cells during the transient period and may extend survival. Furthermore, a decrease in p-mTOR and p-Akt expression and an increase in p-AMPK expression were observed. Collectively, these findings suggest that hesperetin induces autophagy by modulating the AMPK/Akt/mTOR pathway. CONCLUSION: Hesperetin promoted cell death in the human leukemic cell line U937 by inducing a low degree of slight apoptosis, cell cycle arrest, and autophagy. It is therefore a potential adjuvant to antileukemia therapy and may be combined with other chemotherapeutic drugs to reduce chemoresistance and side effects.

A large family of hereditary spherocytosis and a rare case of hereditary elliptocytosis with a novel SPTA1 mutation underdiagnosed in Taiwan: A case report and literature review.

RATIONALE: Hereditary spherocytosis (HS) has a defect in the vertically connected proteins on the cell membrane of red blood cells (RBC). Hereditary elliptocytosis (HE) has a defect in proteins that connect the cell membrane horizontally. We reported two families of RBC membrane disorders in Taiwanese, one was HS and the other was HE. PATIENT CONCERNS: Case 1. A 19-year-old male student with chronic jaundice and splenomegaly. His mother, maternal uncle, grandmother, and many members of older generations also had splenomegaly and underwent splenectomy. Case 2. A 40-year-old man has experienced pallor and jaundice since the age of 20 and was found to have splenomegaly, and gall bladder stones in the older age. His younger sister also had pallor and jaundice for a long time. DIAGNOSES: In case 1, a peripheral blood smear showed 20% spherocytes. Eosin-5-maleimide labeled RBC by flow cytometry showed a result of 30.6 MCF (cutoff value: 45.5 MCF). He was diagnosed with HS. The gene analysis identified a heterozygous mutation with c.166A > G (p.Lys56Glu) in the SLC4A1 gene in this proband, his mother, and maternal uncle. In case 2, more than 40% of ellipsoid RBC present in the peripheral blood smear. He was diagnosed with HE. Genetic analysis of the SPTA1 gene identified a novel heterozygous exon2, c.86A > C, p.Gln29Prol mutation. INTERVENTIONS: The two patients had compensated anemia, clinical follow-up instead of splenectomy was done. OUTCOMES: The two patients had normal daily activities and lives. LESSONS: We reported two Taiwanese families, one was hereditary spherocytosis affected by a heterozygous mutation with c.166A > G (p.Lys56Glu) in SLC4A1, and the other was hereditary elliptocytosis caused by a novel heterozygous SPTA1 gene mutation, c. 86A > C, p.Gln29Prol. These 2 seemingly common hereditary red blood cell membrane protein defects induced by hemolysis are usually underdiagnosed or misdiagnosed.

Deep vein thrombosis after open hepatectomy or other major upper abdominal surgery in Taiwan: A prospective and cross-sectional study relevant to the issue of pharmacological thromboprophylaxis.

BACKGROUD/PURPOSE: Venous thromboembolism, including deep vein thrombosis (DVT) and pulmonary embolism (PE), is an important complication in patients who underwent open hepatic surgery as well as other major upper abdominal surgery. This study aims to investigate the occurrence of postoperative DVT without pharmacological thromboprophylaxis in such cohorts in Taiwan. METHODS: This is a prospective, cross-sectional cohort study conducted from March 2010 to December 2011. Patients who underwent major upper abdominal surgery, including open hepatectomy, were enrolled. Color duplex compression ultrasonography (CUS) was used to detect DVT. Symptomatic PE was excluded if there were no suggestive respiratory symptoms or sudden death. Relevant clinicopathological and surgical information of each patient was collected and analyzed. RESULTS: 195 patients (118 male and 77 female) were enrolled, with a median age of 63.6 years. The majority (169/195, 88.7%) were treated for active malignancy. Totally 147 patients received open hepatectomy. Only one asymptomatic and distal postoperative DVT event was identified by CUS, which occurred on a 73-year-old female patient who received a left lateral segmental hepatectomy for removing the advanced hepatocellular carcinoma (pathologic stage, T3aN0M0). No cases of symptomatic PE or sudden death were observed. No correlation between DVT and precipitating factor was demonstrated in our cohort. CONCLUSION: Without pharmacological thromboprophylaxis, a low rate of postoperative DVT among patients undergoing open hepatectomy (0.7%, 1/147) or major upper abdominal surgery (0.5%, 1/195) in Taiwan was reported. A distinctively regional role of pharmacological thromboprophylaxis for hepatic surgery was also suggested by our data.

Congenital factor V deficiency in Taiwan: identification of a novel variant p.Tyr1813 ∗ and two variants specific to East Asians.

Congenital coagulation factor V deficiency (FVD) is a rare, autosomal recessive bleeding disorder. We characterized the clinical presentations, laboratory features, and genetic alterations of Taiwanese patients with FVD. From 1983 to 2010, five women, one man, and one boy diagnosed with FVD were enrolled in this study. The factor V coagulant activity was determined using a one-stage prothrombin time-based test. The factor V antigen level was measured in an ELISA. Sanger sequencing was performed for genetic analyses of F5 , the gene responsible for the disease. One novel and de novo F5 genetic variant, p.Tyr1813 ∗ , was identified. Based on the presence of a premature termination codon with a resultant truncated factor V-protein lacking an intact light chain fragment, the variant is pathogenic. In addition, we identified seven variants previously found to cause FVD. Among them, p.Gly420Cys and p.Asp96His were repeatedly detected in five and four patients, respectively. Both variants are found to be specific to the East Asian populations. Various FVD-associated bleeding manifestations were observed, predominantly mucocutaneous bleeding and hypermenorrhea. All patients exhibited very low factor V coagulant activity (<1-2.5 IU/dl, reference range: 60-133 IU/dl). The factor V antigen level was less than 2% in six patients (reference range: 75-157%). The novel F5 genetic variant p.Tyr1813 ∗ and two distinct, East Asians-specific, recurrent variants p.Gly420Cys and p.Asp96His were identified among seven index patients with FVD in Taiwan. Our clinical and laboratory findings support the reported features of FVD.

Origin and timing of de novo variants implicated in type 2 von Willebrand disease.

Very few studies have shown the real origin and timing of de novo variants (DNV) implicated in von Willebrand disease (VWD). We investigated four families with type 2 VWD. First, we conducted linkage analysis using single nucleotide variant genotyping to recognize the possible provenance of DNV. Second, we performed amplification refractory mutation system-quantitative polymerase chain reaction to confirm the real origin of variant (~0% mutant cells) or presence of a genetic mosaic variant (0%-50% mutant cells) in three embryonic germ layer-derived tissues and sperm cells. Then, three possible timings of DNV were categorized based on the relative likelihood of occurrence according to the number of cell divisions during embryogenesis. Two each with type 2B VWD (proband 1 p.Arg1308Cys, proband 4 p.Arg1306Trp) and type 2A VWD (proband 2 p.Leu1276Arg, proband 3 p.Ser1506Leu) were identified. Variant origins were identified for families 1, 2 and 3 and confirmed to originate from the mother, father and father, respectively. However, the father of family 4 was confirmed to have isolated germline mosaicism with 2.2% mutant sperm cells. Further investigation confirmed the paternal grandfather to be the origin of variant. Thus, we proposed that DNV originating from the two fathers most likely occurred at the single sperm cell, the one originating from the mother occurred at the zygote during the first few cellular divisions; alternatively, in family 4, the DNV most likely occurred at the early postzygotic development in the father. Our findings are essential for understanding genetic pathogenesis and providing accurate genetic counselling.

Prevalence of non-Alcoholic Fatty Liver Disease and Associated Factors in Patients with Moderate or Severe Hemophilia: A Multicenter-Based Study.

INTRODUCTION: Liver health is essential for persons with hemophilia (PWH) in order to maintain access to new therapies, such as gene therapy. Non-alcoholic fatty liver disease (NAFLD) is seldom reported in the hemophilia population. The study aimed to investigate the prevalence of NAFLD and associated factors in PWH. METHODS: Data of this cross-sectional study were obtained from a multicenter collaborative registry database. RESULTS: A total of 163 moderate or severe PWH with a complete data of liver examination were analyzed. There were 77 (47.2%) PWH diagnosed with NAFLD. The multivariate analysis showed that overweight/obesity was associated with NAFLD (OR, 4.31, P < .001). In comparison with hemophilia B patients, hemophilia A patients showed a weaker correlation with NAFLD, (OR, 0.30, P = .009). A total of 17 (25.8%) PWH with NAFLD had an elevated level of alanine transaminase (ALT). Both overweight/obesity and presence of inhibitor to clotting factor were independently associated with elevated ALT in PWH with NAFLD. CONCLUSIONS: The study indicated that a high prevalence of NAFLD existed in the hemophilia population. Overweight/obesity was an independent factor for NAFLD and elevated ALT.

Characterization of congenital factor XII deficiency in Taiwanese patients: identification of one novel and one common mutation.

BACKGROUND: Factor XII (FXII) deficiency is an interesting condition that causes prolonged activated partial thromboplastin time without bleeding diathesis. FXII may be not important in hemostasis, but still plays roles in thrombosis and inflammation. In order to raise clinical awareness about this condition, we studied patients with severe FXII deficiency and their relatives. METHODS: Consecutive severely FXII deficient patients presenting from 1995 to 2020 were recruited from two medical centers in Taiwan. Index patients and their families were tested for FXII function, antigen and F12 gene. F12 variants were constructed into the pIRES-hrGFP vector and expressed on human embryonic kidney cells (HEK293T). FXII antigen and activity were analyzed. RESULTS: We found five severely FXII deficient patients, three women and two men, aged 44-71 years. FXII antigen results ranged from undetectable to 43.7%. Three different mutations were identified: c.1681C>A (p.Gly542Ser), c.1561G>A (p.Glu502Lys), and a novel mutation c.1556T>A (p.Leu500Gln). HEK293T cells expressed consistently low FXII activity with all mutations. FXII antigen expression was similar to the wild type in c.1681C>A (p.Gly542Ser), but reduced in c.1556T>A (p.Leu500Gln) and c.1561G>A (p.Glu502Lys). CONCLUSIONS: We report five unrelated patients with severe FXII deficiency, one of whom carried a novel, cross-reacting material negative mutation c.1556T>A (p.Leu500Gln).

Deep vein thrombosis after major orthopedic surgery in Taiwan: A prospective cross-sectional study and literature review.

BACKGROUND/PURPOSE: Postoperative venous thromboembolism is an important complication in Taiwan. We prospectively investigated the occurrence of deep vein thrombosis (DVT) after major orthopedic surgery without pharmacologic thromboprophylaxis in a cohort of 120 patients (46 males, 74 females, median age 71 years) at our institute. METHODS: Color duplex compression ultrasonography (CUS) was used to detect DVT before and after the operation, while contrast venography was performed postoperatively for comparison and validation. RESULTS: Total knee arthroplasty (TKA, 57 cases) and total hip arthroplasty (23 cases) were the most commonly performed operations. The rate of postoperative DVT was 7.5% (9/120), including five with proximal DVT and four with distal DVT. All were detected in the limbs on the operated side. Four of them were symptomatic DVT cases. Venography was performed in 19 patients and confirmed most findings of CUS, indicating the effectiveness of CUS for detecting DVT. The type of surgery (TKA) was significantly correlated with postoperative DVT. No clinically symptomatic pulmonary embolism or sudden death events were noted. CONCLUSION: Nine out of 120 (7.5%) orthopedic patients without pharmacologic thromboprophylaxis developed postoperative sonographic DVT in our study. The DVT rate is consistent with other reports from various Asian countries and evidence from meta-analyses.

Clinical features and genetic defect in six index patients with congenital fibrinogen disorders: Three novel mutations with one common mutation in Taiwan's population.

INTRODUCTION: Congenital fibrinogen disorders (CFDs) are caused by mutations in fibrinogen-encoding genes, FGA, FGB, and FGG, which lead to quantitative or qualitative abnormalities of fibrinogen. Although the diagnosis of CFDs is based on antigenic and functional level of fibrinogen, few genotypes are clearly correlated with phenotype. METHODS: In this study, we investigated all of the referred patients diagnosed as CFDs in Taiwan's population between 1995 and 2020. Clinical features, laboratory data and genetic defects were analysed. Functional fibrinogen level was determined by the Clauss method. Antigenic fibrinogen was measured by an enzyme-linked immunosorbent assay. Fibrinogen genes were assessed for mutations by polymerase chain reaction and sequencing. RESULTS: A total of 18 patients from six unrelated families with CFDs were identified. One patient from a consanguineous family was diagnosed as afibrinogenemia type 1A with a novel homozygous frameshift mutation in FGB exon 4. The other five (83.3 %) index patients were all diagnosed as dysfibrinogenemia type 3A caused by two novel and one known mutation. Six (33.3 %) patients from three families had a novel mutation in FGB exon 8. The clinical features and laboratory data were highly variable among these patients with the same mutation. CONCLUSIONS: Three novel mutations of CFDs causing afibrinogenemia and dysfibrinogenemia were identified. The point mutation in FGB exon 8 is also a common mutation in Taiwan's population. Considerable phenotypic variability among the patients with an identical mutation was observed.

Review article inferior vena cava thrombosis: a case series of patients observed in Taiwan and literature review.

Inferior vena cava thrombosis (IVCT) is rare and can be under-recognized. However, the associated complications and mortality may be severe. We report the first case series of IVCT observed in Taiwan with a brief literature review. Eight Taiwanese patients with IVCT between May 2012 and December 2019 were enrolled in this study. Deep venous thrombosis (DVT, 8/8) and pulmonary embolism (5/8) were reported. Various risk factors were identified, including an unretrieved inferior vena cava (IVC) filter, pregnancy, surgery, presence of lupus of anticoagulants, essential thrombocythemia, antithrombin deficiency, and hemoglobin H disease. Of note, four of our patients experienced complete IVC thrombosis with bilateral lower extremity swelling (due to DVT) and abdominal wall superficial venous dilatation, while four other patients presented with partial IVCT and unilateral DVT. The etiology, clinical characteristics, presentations, diagnosis, and treatment of IVCT were reviewed.

First reported case of congenital thrombotic thrombocytopenic purpura in Taiwan with novel mutation of ADAMTS13 gene.

Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare disease that is defined as biallelic mutations of ADAMTS13 causing persistent absence of ADAMTS13 activity. The confirmed diagnosis requires a genetic study, and cTTP has never been previously reported in Taiwan. Our patient was a 29-year-old Taiwanese woman who presented with severe hyperbilirubinemia at birth. She had severe thrombocytopenia and hemolytic anemia at the age of 1, and another acute TTP event at the age of 7 triggered by an upper airway infection. Regular plasma replacement was started at age 12 based on a presumptive diagnosis of cTTP. Clinical diagnosis of cTTP, with undetectable ADAMTS13 activity and absence of ADAMTS13 inhibitor, was confirmed at age 27. A genetic study showed a previously reported mutation c.1921G to A, inherited from her father, and a maternally inherited, novel mutation at exon 12, c.1435+1dupG, which results in a splicing site change and frame shift. Reports of cTTP from East Asia, except Japan, are scarce. Some prevalent ADAMTS13 mutations are also race or region specific. With this report, we hope to raise awareness among physicians in Taiwan, promote early, proper diagnosis of cTTP, and reveal the true prevalence of cTTP in the Taiwanese population.

Acquired FXIII inhibitor: Patient characteristics and treatment outcome, a case series in Taiwan.

INTRODUCTION: Acquired factor XIII (FXIII) inhibitor is a rare but possibly underdiagnosed bleeding disorder. To date, less than one hundred cases have been reported, but the number has increased rapidly in recent years, especially in Japan. Because of the rarity of this disorder, no treatment guidelines are available. In some reports, physicians treated the bleeding with cryoprecipitate or factor XIII concentrate and eradicated the inhibitor with various immune suppressants. METHODS: From January 2015 to December 2018, we collected consecutive patients diagnosed as having acquired FXIII inhibitor. FXIII activity and inhibitor were measured by a fluorescent factor XIII assay using isopeptidase reaction catalyzed by activated factor XIII and the Bethesda method, respectively. Factor XIII antigen was measured by latex-enhanced immunoassay. RESULTS: We found five adult patients with detectable FXIII inhibitor. Four of them were older than 70. Two had systemic lupus erythematosus. All the patients presented with ecchymosis and intramuscular hematoma. No life-threatening bleeding was observed. Delayed diagnosis was common with varied time periods needed to achieve a correct diagnosis. All bleedings were treated and improved by cryoprecipitate. Steroids were given to all patients and cyclophosphamide, rituximab, and other immune suppressants were also used. FXIII inhibitor was totally resolved in three, partially resolved in one, and persisted in one patient. CONCLUSION: We documented five patients with acquired FXIII inhibitor, found over 4 years. The most common presentations were ecchymosis and intramuscular hematomas. Cryoprecipitate was effective in controlling most bleeds. Steroid, cyclophosphamide and rituximab were effective in eradicating inhibitor in some patients.

A family with an MYH9-related disorder with different phenotypes masquerading as immune thrombocytopaenia: an underreported disorder in Taiwan.

A 66-year-old woman had experienced abnormal bleeding since the age of 7. Thrombocytopenia was not detected until she was 48, and immune thrombocytopenia was diagnosed at age 66. She also reported experiencing hearing disturbance since the age of 30 and acute renal failure since the age of 61 but reported no visual disturbance. Her younger son, who was 40 years old, also experienced abnormal bleeding since the age of 6, but immune thrombocytopenia was diagnosed as late as age 35. He had no other associated disorders. Laboratory examinations of both mother and son revealed a low platelet count (8000 and 29,000 µL, respectively), giant platelets and Döhle body-like granulocyte inclusion bodies. The mother had a high creatinine level (15.4 mg/dL) and normal liver enzyme levels. MYH9 genetic analysis identified a heterozygous mutation, c.101T>A, p.Val34Glu at exon 2 in both patients. These clinical and laboratory findings were consistent with a diagnosis of an MYH9-related disorder with different phenotypes observed in the same family. MYH9-related disorders were recognised in 2003, but were often misdiagnosed as immune thrombocytopenia, and hence, they have rarely been reported in Taiwan.

Characterization of hereditary factor XI deficiency in Taiwanese patients: identification of three novel and two common mutations.

Hereditary coagulation factor XI (FXI) deficiency is a rare bleeding disorder, but information on FXI deficiency in Taiwanese patients remains scarce. We evaluated clinical and genetic features of severe FXI deficiency patients in Taiwan. We collected clinical information and performed coagulation laboratory tests and genetic studies in ten unrelated Taiwanese families with severe FXI deficiency. FXI coagulation activity was assayed using a one-stage method. FXI antigen was determined using enzyme-linked immunosorbent assay. Underlying genetic mutations were evaluated using direct sequencing methods. Ten unrelated Taiwanese patients with hereditary FXI deficiency and variable bleeding tendencies were analyzed. Half of the patients were male. The most common bleeding manifestations were easy bruising (40%), bleeding after dental procedures (40%), and postoperative bleeding (33%). Two patients (20%) were asymptomatic. No correlation was found between bleeding manifestations and baseline FXI levels. Three novel mutations were identified: c.1322delT p.Lys442Cysfs*8, c.599G > C p.Cys200Ser, and IVS4 c.325 + 2del124. Two common mutations, c.1107C > T p.Tyr369* (40%) and c.841C > T p.Gln281* (30%), were also found. No correlation existed between bleeding and FXI activity, highlighting the difficulty in predicting FXI deficiency-related bleeding. Three novel FXI genetic mutations and two common mutations were identified, contributing to the known spectrum of FXI deficiency-related mutations.

Arctigenin Reduces Myofibroblast Activities in Oral Submucous Fibrosis by LINC00974 Inhibition.

Oral submucous fibrosis (OSF) is an oral precancerous condition associated with the habit of areca nut chewing and the TGF-ß pathway. Currently, there is no curative treatment to completely heal OSF, and it is imperative to alleviate patients' symptoms and prevent it from undergoing malignant transformation. Arctigenin, a lignan extracted from Arctium lappa, has been reported to have a variety of pharmacological activities, including anti-fibrosis. In the present study, we examined the effect of arctigenin on the cell proliferation of buccal mucosal fibroblasts (BMFs) and fibrotic BMFs (fBMFs), followed by assessment of myofibroblast activities. We found that arctigenin was able to abolish the arecoline-induced collagen gel contractility, migration, invasion, and wound healing capacities of BMFs and downregulate the myofibroblast characteristics of fBMFs in a dose-dependent manner. Most importantly, the production of TGF-ß in fBMFs was reduced after exposure to arctigenin, along with the suppression of p-Smad2, α-smooth muscle actin, and type I collagen A1. In addition, arctigenin was shown to diminish the expression of LINC00974, which has been proven to activate TGF-ß/Smad signaling for oral fibrogenesis. Taken together, we demonstrated that arctigenin may act as a suitable adjunct therapy for OSF.