Targeting of FSP1 regulates iron homeostasis in drug-tolerant persister head and neck cancer cells via lipid-metabolism-driven ferroptosis.

BACKGROUND: Research has demonstrated that some tumor cells can transform into drug-tolerant persisters (DTPs), which serve as a reservoir for the recurrence of the disease. The persister state in cancer cells arises due to temporary molecular reprogramming, and exploring the genetic composition and microenvironment during the development of head and neck squamous cell carcinoma (HNSCC) can enhance our comprehension of the types of cell death that HNSCC, thus identifying potential targets for innovative therapies. This project investigated lipid-metabolism-driven ferroptosis and its role in drug resistance and DTP generation in HNSCC. METHODS: High levels of FSP1 were discovered in the tissues of patients who experienced relapse after cisplatin treatment. RNA sequencing indicated that a series of genes related to lipid metabolism were also highly expressed in tissues from these patients. Consistent results were obtained in primary DTP cells isolated from patients who experienced relapse. The Cancer Genome Atlas database confirmed this finding. This revealed that the activation of drug resistance in cancer cells is influenced by FSP1, intracellular iron homeostasis, and lipid metabolism. The regulatory roles of ferroptosis suppressor protein 1 (FSP1) in HNSCC metabolic regulation were investigated. RESULTS: We generated human oral squamous cell carcinoma DTP cells (HNSCC cell line) to cisplatin and observed higher expression of FSP1 and lipid-metabolism-related targets in vitro. The shFSP1 blockade attenuated HNSCC-DTP cell stemness and downregulated tumor invasion and the metastatic rate. We found that cisplatin induced FSP1/ACSL4 axis expression in HNSC-DTPC cells. Finally, we evaluated the HNSCC CSC-inhibitory functions of iFSP1 (a metabolic drug and ferroptosis inducer) used for neo-adjuvant chemotherapy; this was achieved by inducing ferroptosis in a patient-derived xenograft mouse model. CONCLUSIONS: The present findings elucidate the link between iron homeostasis, ferroptosis, and cancer metabolism in HNSCC-DTP generation and acquisition of chemoresistance. The findings may serve as a suitable model for cancer treatment testing and prediction of precision treatment outcomes. In conclusion, this study provides clinically oriented platforms for evaluating metabolism-modulating drugs (FSP1 inhibitors) and new drug candidates of drug resistance and ferroptotic biomarkers.

PAICS/DYRK3 Multienzyme Interactions as Coregulators of Purinosome Formation and Metabolism on Radioresistance in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a prevalent type of oral cancer. While therapeutic innovations have made strides, radioresistance persists as a significant hindrance in OSCC treatment. Despite identifying numerous targets that could potentially suppress the oncogenic attributes of OSCC, the exploration of oncogenic protein kinases for cancer therapy remains limited. Consequently, the functions of many kinase proteins in OSCC continue to be largely undetermined. In this research, we aim to disclose protein kinases that target OSCC and elaborate their roles and molecular mechanisms. Through the examination of the kinome library of radiotherapy-resistant/sensitive OSCC cell lines (HN12 and SAS), we identified a key gene, the tyrosine phosphorylation-regulated kinase 3 (DYRK3), a member of the DYRK family. We developed an in vitro cell model, composed of radiation-resistant OSCC, to scrutinize the clinical implications and contributions of DYRK3 and phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase (PAICS) signaling in OSCC. This investigation involves bioinformatics and human tissue arrays. We seek to comprehend the role of DYRK3 and PAICS signaling in the development of OSCC and its resistance to radiotherapy. Various in vitro assays are utilized to reveal the essential molecular mechanism behind radiotherapy resistance in connection with the DYRK3 and PAICS interaction. In our study, we quantified the concentrations of DYRK3 and PAICS proteins and tracked the expression levels of key pluripotency markers, particularly PPAT. Furthermore, we extended our investigation to include an analysis of Glut-1, a gene recognized for its linkage to radioresistance in oral squamous cell carcinoma (OSCC). Furthermore, we conducted an in vivo study to affirm the impact of DYRK3 and PAICS on tumor growth and radiotherapy resistance, focusing particularly on the role of DYRK3 in the radiotherapy resistance pathway. This focus leads us to identify new therapeutic agents that can combat radiotherapy resistance by inhibiting DYRK3 (GSK-626616). Our in vitro models showed that inhibiting PAICS disrupts purinosome formation and influences the survival rate of radiation-resistant OSCC cell lines. These outcomes underscore the pivotal role of the DYRK3/PAICS axis in directing OSCC radiotherapy resistance pathways and, as a result, influencing OSCC progression or therapy resistance. Our findings also reveal a significant correlation between DYRK3 expression and the PAICS enzyme in OSCC radiotherapy resistance.

Significantly lower mean serum vitamin B12 and folic acid levels and a significantly higher frequency of serum iron deficiency in younger than in older atrophic glossitis patients.

Background/purpose: : Our previous study found that 19.0%, 16.9%, 5.3%, 2.3%, and 11.9% of 1064 atrophic glossitis (AG) patients have anemia, serum iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia, respectively. This study mainly evaluated the anemia, hematinic deficiencies, and hyperhomocysteinemia in 224 younger (≤50 years old) and 840 older (>50 years old) AG patients. Materials and methods: The blood hemoglobin (Hb) and serum iron, vitamin B12, folic acid, and homocysteine levels in 224 younger and 840 older AG patients were measured and compared with the corresponding levels in 112 younger (≤50 years old) and 420 older (>50 years old) healthy control subjects (HCSs), respectively. Results: We found that 224 younger AG patients had significantly lower mean blood Hb and serum iron levels than 112 younger HCSs. Moreover, 840 older AG patients had significantly lower mean blood Hb and serum iron levels and a significantly higher mean serum homocysteine level than 420 older HCSs. In addition, 224 younger AG patients had significantly lower mean serum vitamin B12 and folic acid levels, a lower mean serum homocysteine level (marginal significance, P = 0.056), a significantly higher frequency of serum iron deficiency, and a significantly lower frequency of hyperhomocysteinemia than 840 older AG patients. Conclusion: The younger AG patients do have significantly lower mean serum vitamin B12 and folic acid levels, a significantly higher frequency of serum iron deficiency, and a significantly lower frequency of hyperhomocysteinemia than the older AG patients.

Anemia, hematinic deficiencies, and hyperhomocysteinemia in younger and older burning mouth syndrome patients.

Abstract Background/purpose: Our previous study found that 19.8%, 16.2%, 4.8%, 2.3%, and 19.2% of 884 burning mouth syndrome (BMS) patients have anemia, serum iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia, respectively. This study mainly evaluated the anemia, hematinic deficiencies, and hyperhomocysteinemia in 272 younger (≤50 years old) and 612 older (>50 years old) BMS patients. Materials and methods: The blood hemoglobin (Hb) and serum iron, vitamin B12, folic acid, and homocysteine levels in 272 younger and 612 older BMS patients were measured and compared with the corresponding levels in 136 younger (≤50 years old) and 306 older (>50 years old) healthy control subjects (HCSs), respectively. Results: We found that 272 younger BMS patients had significantly lower mean blood Hb and serum iron, vitamin B12, and folic acid levels than 136 younger HCSs. Moreover, 612 older BMS patients had significantly lower mean blood Hb, and serum iron and vitamin B12 levels and significantly higher mean serum homocysteine level than 306 older HCSs. In addition, 272 younger BMS patients had higher mean blood Hb level (marginal significance, P = 0.056), significantly lower mean serum vitamin B12 and folic acid levels, and significantly higher frequencies of iron and folic acid deficiencies than 612 older BMS patients. Conclusion: The younger BMS patients do have higher mean blood Hb level, significantly lower mean serum vitamin B12 and folic acid levels, and significantly higher frequencies of serum iron and folic acid deficiencies than the older BMS patients.

Significantly higher frequencies of macrocytosis, anemia, serum vitamin B12 and folic acid deficiencies, and hyperhomocysteinemia in male than in female atrophic glossitis patients.

Background/purpose: Our previous study found that 19.0%, 16.9%, 5.3%, 2.3%, 11.9%, and 26.7% of 1064 atrophic glossitis (AG) patients have anemia, serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody (GPCA) positivity, respectively. This study evaluated the anemia, hematinic deficiencies, and hyperhomocysteinemia in 150 male and 914 female AG patients. Materials and methods: The blood hemoglobin (Hb) and serum iron, vitamin B12, folic acid, homocysteine, GPCA levels in 150 male and 914 female AG patients were measured and compared with the corresponding levels in 75 male and 457 female healthy control subjects (HCSs), respectively. Results: We found that 150 male AG patients had significantly lower mean blood Hb, serum iron, vitamin B12, and folic acid levels, and significantly higher mean serum homocysteine levels than 75 male HCSs. Moreover, 914 female AG patients had significantly lower mean blood Hb and serum iron levels and significantly higher mean serum homocysteine level than 457 female HCSs. In addition, 150 male AG patients had significantly higher mean blood Hb and serum homocysteine levels, significantly lower mean serum vitamin B12 and folic acid levels, and significantly higher frequencies of Hb, vitamin B12, and folic acid deficiency and hyperhomocysteinemia than 914 female AG patients. Conclusion: The male AG patients do have significantly higher mean blood Hb and serum homocysteine levels, significantly lower mean serum vitamin B12 and folic acid levels, and significantly higher frequencies of Hb, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia than the female AG patients.

Anemia, hematinic deficiencies, and hyperhomocysteinemia in male and female burning mouth syndrome patients.

Background/purpose: Our previous study found that 19.8%, 16.2%, 4.8%, 2.3%, 19.2%, and 12.3% of 884 burning mouth syndrome (BMS) patients have anemia, serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody (GPCA) positivity, respectively. This study mainly evaluated the anemia, hematinic deficiencies, and hyperhomocysteinemia in 212 male and 672 female BMS patients. Materials and methods: The blood hemoglobin (Hb) and serum iron, vitamin B12, folic acid, homocysteine, GPCA levels in 212 male and 672 female BMS patients were measured and compared with the corresponding levels in 106 male and 336 female healthy control subjects, respectively. Results: We found that 212 male BMS patients had significantly lower mean blood Hb, serum iron, vitamin B12, and folic acid levels and significantly higher mean serum homocysteine levels than 106 male healthy control subjects. Moreover, 672 female BMS patients had significantly lower mean blood Hb and serum iron levels and significantly higher mean serum homocysteine level than 336 female healthy control subjects. In addition, 212 male BMS patients had significantly higher mean blood Hb and serum homocysteine levels, significantly lower mean serum vitamin B12 and folic acid levels, and significantly higher frequencies of folic acid deficiency and hyperhomocysteinemis than 672 female BMS patients. Conclusion: The male BMS patients do have significantly higher mean blood Hb and serum homocysteine levels, significantly lower mean serum vitamin B12 and folic acid levels, and significantly higher frequencies of folic acid deficiency and hyperhomocysteinemis than the female BMS patients.

Anemia, hematinic deficiencies, hyperhomocysteinemia, and gastric parietal cell antibody positivity in burning mouth syndrome patients with normocytosis.

BACKGROUND/PURPOSE: Normocytosis is defined as having the mean corpuscular volume (MCV) between 80 fL and 99.9 fL. This study evaluated whether 770 burning mouth syndrome (BMS) patients with normocytosis (so-called normocytosis/BMS patients) had significantly higher frequencies of anemia, hematinic deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody (GPCA) positivity than 442 healthy control subjects or 884 BMS patients. MATERIALS AND METHODS: Complete blood count, serum iron, vitamin B12, folic acid, homocysteine, and GPCA levels in 884 BMS patients (including 770 normocytosis/BMS patients) and 442 healthy control subjects were measured and compared. RESULTS: We found that 12.3%, 13.2%, 2.2%, 2.3%, 17.3%, and 10.5% of 770 normocytosis/BMS patients had blood hemoglobin (Hb), iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity, respectively. Furthermore, 770 normocytosis/BMS patients had significantly higher frequencies of blood Hb, iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity than 442 healthy control subjects (all P-values < 0.005). On the contrary, 770 normocytosis/BMS patients had significantly lower frequencies of blood Hb and vitamin B12 deficiencies than overall 884 BMS patients (both P-values < 0.01). CONCLUSION: We conclude that there are significantly higher frequencies of anemia, serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity in normocytosis/BMS patients than in healthy control subjects. On the contrary, normocytosis/BMS patients do have significantly lower frequencies of blood Hb and vitamin B12 deficiencies than overall BMS patients.

Higher gastric parietal cell antibody titer significantly increases the frequencies of macrocytosis, serum vitamin B12 deficiency, and hyperhomocysteinemia in patients with burning mouth syndrome.

BACKGROUND/PURPOSE: Our previous study found 109 gastric parietal cell antibody (GPCA)-positive burning mouth syndrome (BMS) patients (so-called GPCA+BMS patients in this study) in a group of 884 BMS patients. This study evaluated whether high-titer (GPCA titer ≥ 160) GPCA+BMS patients had greater frequencies of macrocytosis, anemia, serum iron and vitamin B12 deficiencies, and hyperhomocysteinemia than low-titer (GPCA titer < 160) GPCA+BMS patients or 442 healthy control subjects. MATERIALS AND METHODS: Complete blood count, serum iron, vitamin B12, folic acid, homocysteine, and GPCA levels in 42 high-titer GPCA+BMS patients, 67 low-titer GPCA+BMS patients, and 442 healthy control subjects were measured and compared. RESULTS: We found that 33.3%, 38.1%, 19.0%, 33.3%, 2.4%, and 57.1% of 42 high-titer GPCA+BMS patients and 10.4%, 25.4%, 14.9%, 6.0%, 1.5%, and 11.9% of 67 low-titer GPCA+BMS patients were diagnosed as having macrocytosis, blood hemoglobin, iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia, respectively. Moreover, both 42 high-titer and 67 low-titer GPCA+BMS patients had significantly greater frequencies of macrocytosis, blood hemoglobin, serum iron and vitamin B12 deficiencies, and hyperhomocysteinemia than 442 healthy control subjects (all P-values < 0.001). In addition, 42 high-titer GPCA+BMS patients also had greater frequencies of macrocytosis, serum vitamin B12 deficiency, and hyperhomocysteinemia than 67 low-titer GPCA+BMS patients (all P-values < 0.01). CONCLUSION: The high-titer GPCA+BMS patients have significantly greater frequencies of macrocytosis, anemia, serum iron and vitamin B12 deficiencies, and hyperhomocysteinemia than healthy control subjects and significantly greater frequencies of macrocytosis, serum vitamin B12 deficiency, and hyperhomocysteinemia than low-titer GPCA+BMS patients.

Anemia, hematinic deficiencies, and hyperhomocysteinemia in burning mouth syndrome patients with thyroglobulin antibody/thyroid microsomal antibody positivity but without gastric parietal cell antibody positivity.

BACKGROUND/PURPOSE: Our previous study found that 222 of 884 burning mouth syndrome (BMS) patients have thyroglobulin antibody (TGA) positivity and/or thyroid microsomal antibody (TMA) positivity but without gastric parietal cell antibody positivity (GPCA-TGA+/TMA+BMS patients). This study mainly assessed whether the serum TGA/TMA positivity was significantly associated with anemia, hematinic deficiencies, and hyperhomocysteinemia in GPCA-TGA+/TMA+BMS patients. MATERIALS AND METHODS: The complete blood count, iron, vitamin B12, folic acid, and homocysteine levels were measured and compared between 222 GPCA-TGA+/TMA+BMS patients and 553 GPCA-negative, TGA-negative, and TMA-negative BMS patients (GPCA-TGA-TMA-BMS patients) or 442 healthy control subjects. RESULTS: We found that 222 GPCA-TGA+/TMA+BMS patients had significantly lower mean corpuscular volume (MCV) and lower blood Hb and serum iron levels than 442 healthy control subjects and significantly lower MCV and lower serum homocysteine levels than 553 GPCA-TGA-TMA-BMS patients. Moreover, 222 GPCA-TGA+/TMA+BMS patients had significantly greater frequencies of microcytosis, macrocytosis, blood Hb and serum iron deficiencies, and hyperhomocysteinemia than 442 healthy control subjects and significantly higher frequency of microcytosis but significantly lower frequency of hyperhomocysteinemia than 553 GPCA-TGA-TMA-BMS patients. However, no significant differences in the frequencies of macrocytosis, blood Hb, serum iron, vitamin B12, and folic acid deficiencies were discovered between 222 GPCA-TGA+/TMA+BMS patients and 553 GPCA-TGA-TMA-BMS patients. CONCLUSION: We conclude that the disease of BMS itself does play a significant role in causing macrocytosis, anemia, hematinic deficiencies, and hyperhomocysteinemia in GPCA-TGA+/TMA+BMS patients. However, the serum TGA/TMA-positivity is not significantly associated with anemia and serum iron, vitamin B12, and folic acid deficiencies in GPCA-TGA+/TMA+BMS patients.

Anemia, hematinic deficiencies, and hyperhomocysteinemia in serum gastric parietal cell antibody-positive burning mouth syndrome patients without serum thyroid autoantibodies.

BACKGROUND/PURPOSE: Our previous study found that 70 of 884 burning mouth syndrome (BMS) patients have serum gastric parietal cell antibody (GPCA) positivity but without thyroglobulin antibody (TGA) and thyroid microsomal antibody (TMA) (so-called GPCA+TGA-TMA-BMS patients). This study assessed whether these 70 GPCA+TGA-TMA-BMS patients had significantly higher frequencies of macrocytosis, anemia, hematinic deficiencies, and hyperhomocysteinemia than 553 GPCA-negative, TGA-negative, and TMA-negative BMS (GPCA-TGA-TMA-BMS) patients or 442 healthy control subjects. MATERIALS AND METHODS: Complete blood count, serum iron, vitamin B12, folic acid, homocysteine, GPCA, TGA, and TMA levels in 70 GPCA+TGA-TMA-BMS patients, 553 GPCA-TGA-TMA-BMS patients, and 442 healthy control subjects were measured and compared. RESULTS: We found that 15.7%, 28.6%, 20.0%, 11.4%, 2.9%, and 25.7% of 70 GPCA+TGA-TMA-BMS patients and 3.8%, 17.7%, 15.9%, 3.8%, 2.7%, and 20.1% of 553 GPCA-TGA-TMA-BMS patients had macrocytosis, blood hemoglobin, iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia, respectively. Moreover, both 70 GPCA+TGA-TMA-BMS patients and 553 GPCA-TGA-TMA-BMS patients had significantly greater frequencies of macrocytosis, blood hemoglobin, serum iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia than 442 healthy control subjects (all P-values < 0.05). In addition, 70 GPCA+TGA-TMA-BMS patients also had greater frequencies of macrocytosis, anemia, serum vitamin B12 deficiency, and hyperhomocysteinemia than 553 GPCA-TGA-TMA-BMS patients (all P-values < 0.05). CONCLUSION: The GPCA + TGA-TMA-BMS patients have significantly greater frequencies of macrocytosis, anemia, serum iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia than healthy control subjects and significantly greater frequencies of macrocytosis, anemia, serum vitamin B12 deficiency, and hyperhomocysteinemia than GPCA-TGA-TMA-BMS patients.

Anemia, hematinic deficiencies, hyperhomocysteinemia, and gastric parietal cell antibody positivity in burning mouth syndrome patients with macrocytosis.

BACKGROUND/PURPOSE: Macrocytosis is defined as having the mean corpuscular volume (MCV) ≥ 100 fL. This study evaluated whether 46 burning mouth syndrome (BMS) patients with macrocytosis had significantly higher frequencies of anemia, hematinic deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody (GPCA) positivity than 442 healthy control subjects or 884 BMS patients. MATERIALS AND METHODS: Complete blood count, serum iron, vitamin B12, folic acid, homocysteine, and GPCA levels in 46 BMS patients with macrocytosis, 884 BMS patients, and 442 healthy control subjects were measured and compared. RESULTS: We found that 65.2%, 23.9%, 47.8%, 0.0%, 60.9%, and 45.7% of 46 BMS patients with macrocytosis were diagnosed as having blood hemoglobin, iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity, respectively. Moreover, 46 BMS patients with macrocytosis had significantly higher frequencies of blood hemoglobin and serum vitamin B12 deficiencies, hyperhomocysteinemia, and serum GPCA positivity than 442 healthy control subjects or 884 BMS patients (all P-values < 0.001). In addition, 46 BMS patients with macrocytosis also had a significantly higher frequency of serum iron deficiency than 442 healthy control subjects (P < 0.001). Pernicious anemia was found in 15 BMS patients with macrocytosis. CONCLUSION: There are significantly higher frequencies of anemia and serum iron and vitamin B12 deficiencies, hyperhomocysteinemia, and serum GPCA positivity in BMS patients with macrocytosis than in healthy control subjects. BMS patients with macrocytosis also have significantly higher frequencies of anemia, serum vitamin B12 deficiency, hyperhomocysteinemia, and serum GPCA positivity than BMS patients.

Clinicopathological study of periapical scars.

BACKGROUND/PURPOSE: Periapical scar (PS) is an alternative healing process with the formation of scar tissue after appropriate endodontic treatments/retreatments with or without periapical surgeries. This retrospective study evaluated the clinical, radiographic, and histopathological features of 7 PSs. MATERIALS AND METHODS: The clinical, radiographic, and histopathological data of 7 PSs were collected and analyzed. RESULTS: The 7 PSs were taken from the maxilla (3 cases) and mandible (4 cases) of 3 men and 4 women. The most frequently involved teeth were maxillary or mandibular incisors (4 cases) and first or second molars (3 cases). Of 7 PS patients, 6 had none of symptoms, 5 had previous nonsurgical endodontic treatments/retreatments, and 2 had previous endodontic treatments/retreatments plus periapical surgery. Radiographically, all 7 PS cases presented as a persistent and well-defined periapical radiolucent lesion for a long period of time. Microscopically, all 7 surgical specimens of PS showed dense fibrous collagenous tissues with one having amalgam particles in the scar tissue. CONCLUSION: PSs do have their common clinical and radiographic features. When the periapical radiolucent lesion is well-defined, persistent without a significant change of its size, and free from symptoms and signs after a long-term follow-up; the involved tooth has no evidence of root fracture and healthy periodontium except the periapical radiolucency; and the previous endodontic treatment/retreatment or periapical surgery is well performed with an adequate root canal or retrograde filling, then the PS may be a possible diagnosis and a close follow-up may be a more conservative treatment strategy for this condition.

Pandemic Risk Management for Public Health Care Schemes.

The coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2, has caused a large death, a range of serious health problems, and significant economic costs in many countries around the world. This study analyzes statistical characteristics of pandemic disasters using historical records since the Middle Ages. Compared to literature which studies the effect of the COVID- 19 pandemic on the financial market, this paper attempts to find two financial instruments in the financial market to hedge pandemic risks. Two instruments could be useful for public health care schemes to increase their assets or decrease their liabilities during the pandemic period, namely, assets in the form of a biotechnology investment portfolio and liabilities in the form of pandemic bonds. Empirical results show the feasibility of such instruments and the informational efficiency of the U.S. stock market.

Review of oral ulcerative lesions in COVID-19 patients: A comprehensive study of 51 cases.

Numerous oral manifestations of COVID-19 have been reported in the literatures. Common oral lesions in COVID-19 patients included ulcerations, xerostomia, dysgeusia, gingival inflammation, and erythema. Among them, oral ulceration is the most frequent finding and is present as various but distinct patterns. Thus, we conducted a comprehensive review of 51 COVID-19 patients with oral ulcerative lesions to further analyze the various oral ulcerative lesions in COVID-19 patients. There were a median age of 41.4 years and a slight female predilection in these patients. Most oral lesions manifested as an aphtha-like ulceration but lack of an evidence of recurrent aphthous stomatitis. Some of them were present as herpetiform ulcerations without HSV infection. Widespread ulcerations accompanied with necrosis were observed in the more severe and immunosuppressed older patients. Although some reported patients were asymptomatic, most of them had systemic symptoms concurring or slightly preceding the oral ulcerative lesions and the latency from the onset of systemic symptoms to oral ulcerative lesions were under 10 days, suggesting that oral ulceration was one of the early symptoms of COVID-19. Therefore, the oral ulcerative lesions may be considered as oral markers for early diagnosis of the underlying COVID-19 infection in the asymptomatic patients.