Butyrate inhibits type 2 inflammation in eosinophilic chronic rhinosinusitis.

Butyrate and other Short-chain fatty acids (SCFAs) are microbial metabolites from Bacteroides and Clostridium species that may suppress type 2 inflammation. However, the mechanisms of SCFAs in the nasal sinuses are not fully understood. We aimed to clarify the in vitro and in vivo roles of SCFAs in eosinophilic chronic rhinosinusitis (ECRS) pathophysiology. We investigated whether SCFAs induced changes in type 2 cytokines, IgE, and apoptosis and the roles of GPR41, GPR43, and histone deacetylase. Analysis of the control subjects demonstrated that butyrate of SCFAs effectively inhibited type 2 cytokine production in PBMCs, ILC2s, and CD4+ T cells and IgE production in CD19+ B cells. In annexin V analysis, butyrate also induced late apoptosis of PBMCs. The butyrate-induced inhibition of type 2 cytokines appeared involved in histone deacetylase inhibition but not in GPR41 or GPR43. In an analysis of ECRS in humans, butyrate inhibited type 2 cytokine production in PBMCs and nasal polyp-derived cells. The butyrate concentration in nasal lavage fluid was significantly decreased in ECRS patients compared to controls and non-ECRS patients. Our findings confirm that butyrate can inhibit type 2 inflammation and may be a potential therapeutic target for ECRS.

Raptor and rictor expression in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma.

BACKGROUND: Despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. The aim of the present study was to elucidate the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC). METHODS: The present study involved two strategies. The first was to investigate the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The second was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC. RESULTS: The UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24 h incubation with 6 µM temsirolimus, a rapamycin analog, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene and protein expression of raptor and rictor compared with HPV-unrelated OPSCC. In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression. CONCLUSIONS: These results suggest that raptor and rictor have important roles in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This is the first report to reveal the overexpression of raptor and rictor in HPV-related OPSCC.

ERCC1 C8092A polymorphism predicts fair survival outcome in Japanese patients with pharyngo-laryngeal squamous cell carcinoma.

PURPOSE: To evaluate the prognostic significance of DNA excision repair gene polymorphisms, excision repair cross-complementation group 1 (ERCC1) and X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) polymorphisms were investigated in Japanese patients with head and neck squamous cell carcinoma (HNSCC). METHODS: A total of 225 consecutive patients with HNSCC who underwent surgery or chemoradiotherapy/radiotherapy (CRT/RT) with curative intent as primary treatment from 2006 to 2017 were recruited. ERCC1 C8092A and XRCC1 Arg399Gln polymorphisms in DNA extracted from individual blood samples were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Cumulative survival was estimated by Kaplan-Meier analysis with a log-rank test and Cox proportional hazards model stratified by treatment arm, adjusting for clinical prognostic factors. RESULTS: Multivariate analysis showed that carriers with the ERCC1 8092 (C/A+A/A) genotype (hazard ratio, 3.56; 95% confidence interval, 1.22-7.39; p = 0.02) had significantly worse survival than those with ERCC1 8092 C/C who received CRT/RT. Conversely, the XRCC1 Arg399Gln polymorphism did not influence survival in patients who received CRT/RT as well as surgery. CONCLUSION: The ERCC1 C8092A polymorphism might be an independent predictor of response to CRT and survival outcome in patients with HNSCC. This is the first report to investigate the role of DNA excision repair gene polymorphisms in patients with head and neck cancer in a Japanese population.

Staging and prognosis of oropharyngeal carcinoma according to the 8th Edition of the American Joint Committee on Cancer Staging Manual in human papillomavirus infection.

PURPOSE: The aim of this study was to evaluate the 8th edition of the American Joint Committee on Cancer Staging Manual: Head and Neck Section on oropharyngeal squamous cell cancer (OPSCC) and to clarify the relationship between p16 overexpression and the presence of human papillomavirus (HPV) DNA using fresh frozen samples. METHODS: Samples from 100 OPSCC patients were analyzed using polymerase chain reaction (PCR) and p16 immunohistochemistry. RESULTS: Five-year overall survival (OS) was 73.0%, 93.9%, and 62.2% in all, p16-positive (n = 34), and p16-negative (n = 66) cases, respectively. OS tended to be better aligned with stage in the 8th edition than in the 7th edition. The 5-year OS was 96.0% in never or light smokers (< 40 pack-years), and 87.5% in heavy smokers (≥ 40 pack-years) in the p16-positive group, respectively (p = 0.027). HPV infection was found in 100% of p16-positive and 21.2% of p16-negative cases. The p16-positive cases had higher viral load and integrated physical status than the p16-negative cases. Although 1 case with p16 overexpression showed no PCR amplification using consensus primers, PCR amplification was detected using HPV 16 E6-specific primers. CONCLUSIONS: The 8th edition predicts OPSCC prognosis more accurately than the 7th edition and p16-overexpression is an excellent surrogate marker for detecting HPV infection. Although high-risk-type HPV infection was observed in p16-negative cases, it showed no significant effect in survival outcome.

Progressive macrothrombocytopenia and hearing loss in a large family with DIAPH1 related disease.

In this study, we describe a Japanese family with progressive hearing loss and macrothrombocytopenia. Using next-generation and Sanger sequencing analyses, we identified a heterozygous variant in exon 27 of the DIAPH1 gene (NM_005219), c.3637C>T, p.R1213X. All patients in the family had sensorineural hearing loss and macrothrombocytopenia. None of the patients exhibited a tendency to bleed. No pathogenic variants were found in the MYH9 gene. Hearing loss began with high-frequency loss during early childhood and progressed to severe hearing loss involving all frequencies. Analyses of the mean platelet volume and platelet distribution width indicated that the macrothrombocytopenia is progressive in patients with DIAPH1 related disease.There are no reports describing progressive macrothrombocytopenia in patients with pathogenic variants of DIAPH1. Thus, progressive macrothrombocytopenia may be a novel feature of deafness patients with pathogenic variants in DIAPH1.

Prognostic importance of pathological response to neoadjuvant chemotherapy followed by definitive surgery in advanced oral squamous cell carcinoma.

OBJECTIVE: The clinical importance of neoadjuvant chemotherapy (NAC) followed by definitive surgery was retrospectively investigated in clinical Stage III/IV oral squamous cell carcinoma (OSCC). METHODS: Surgery was performed for OSCC in 164 patients, including 72 patients who had received NAC (two cycles of cisplatin and fluorouracil) prior to surgery from January 2004 to December 2014. The clinical characteristics and survival parameters of the groups that received and did not receive NAC were evaluated. The pathological response was classified as Grade 0 (no effect), 1a (very slight effect), 1b (slight effect), 2 (moderate effect) or 3 (marked effect), and its correlation with prognosis was investigated. RESULTS: There were no statistical differences in survival indicators between patients who received NAC and those who did not (overall survival, P = 0.75). The proportion of patients who received NAC in the effective NAC group (Grades 1b, 2, and 3) was 52.8%. After a median follow-up of 35 months, overall survival (P = 0.01), disease-free survival (P = 0.002), locoregional disease-free survival (P = 0.003), and distant disease-free survival (P = 0.01) were significantly better in the effective NAC group than in the less effective NAC group (Grades 0 and 1a). CONCLUSION: Although NAC had a limited effect on disease prognosis in OSCC, the pathological response to NAC could be an important prognostic indicator for advanced OSCC.

Is there a higher prevalence of human papillomavirus infection in Chinese laryngeal cancer patients? A systematic review and meta-analysis.

Accumulating evidence suggests that persistent human papillomavirus (HPV) infection is closely related to the risk of certain types of head and neck squamous cell carcinoma types, including laryngeal cancer (LC). Some reports indicated a higher HPV prevalence in Chinese LC patients, which remains to be established due to small study sample sizes. The aim of this study was to estimate the HPV infection rate in Chinese LC patients and assess the LC risk conferred by high-risk subtype HPV infection by meta-analysis. We searched MEDLINE, the Embase Database, Chinese National Knowledge Infrastructure, Wanfang Database, and VIP Database for studies published in either English or Chinese up to October 2013, and systematically reviewed 28 original research articles that met the inclusion criteria. Both the HPV infection rate in the LC group (all 28 studies) and the LC risk from high-risk HPV infection (a subgroup of 12 case-control studies) were analyzed by R 3.0 software. Overall HPV, HPV-16/18, and HPV-6/11 infection rates were 32 % (95 % CI 22-44 %), 30 % (95 % CI 24-37 %), and 12 % (95 % CI 9-17 %), respectively. There was a strong association between high-risk HPV-16/18 infection and LC (P < 0.01; OR = 8.07, 95 % CI 5.67-11.48). Our research indicates that there is a higher HPV prevalence in Chinese LC patients compared to LC patients outside of China and that HPV infection significantly increases LC risk.

[Maxillary Cancer with Metastasis to the Rouviere Nodes -- Complete Response to Chemoradiotherapy Using a Selective Intra-Arterial Infusion Technique].

We report a case of advanced maxillary cancer with multiple lymph node metastases, including metastasis to the Rouviere nodes, which were successfully treated with chemoradiotherapy using a selective intra-arterial infusion technique.A 71-yearold man presented to our hospital with complaints of a staggering gait and epistaxis.He was diagnosed with maxillary cancer (squamous cell carcinoma)classified as T4a disease.Because multiple lymph node metastases were detected, including metastasis to the Rouviere nodes, radical surgical treatment was considered inadequate.Thus, the patient was treated with concurrent chemoradiotherapy with selective intra-arterial infusion of nedaplatin and docetaxel.After chemoradiotherapy, the maxillary cancer and lymph metastasis nearly resolved and the patient achieved a complete response.No additional surgery was needed, and the patient was discharged.We suggest that chemoradiotherapy using a selective intra-arterial infusion technique is a highly effective treatment option for patients with maxillary cancer and metastasis to the Rouviere nodes.

Identification of two novel mutations in the NOG gene associated with congenital stapes ankylosis and symphalangism.

In this study, we describe three unrelated Japanese patients with hearing loss and symphalangism who were diagnosed with proximal symphalangism (SYM1), atypical multiple synostosis syndrome (atypical SYNS1) and stapes ankylosis with broad thumb and toes (SABTT), respectively, based on the clinical features. Surgical findings in the middle ear were similar among the patients. By next-generation and Sanger sequencing analyses, we identified two novel mutations, c.559C>G (p.P178A) and c.682T>A (p.C228S), in the SYM1 and atypical SYNS1 families, respectively. No pathogenic changes were found in the protein-coding regions, exon-intron boundaries or promoter regions of the NOG, GDF5 or FGF9 genes in the SABTT family. Such negative molecular data suggest there may be further genetic heterogeneity underlying SYNS1, with the involvement of at least one additional gene. Stapedotomy resulted in good hearing in all patients over the long term, indicating no correlation between genotype and surgical outcome. Given the overlap of the clinical features of these syndromes in our patients and the molecular findings, the diagnostic term 'NOG-related-symphalangism spectrum disorder (NOG-SSD)' is advocated and an unidentified gene may be responsible for this disorder.

Novel anti-tumor mechanism of galanin receptor type 2 in head and neck squamous cell carcinoma cells.

Galanin and its receptors, GALR1 and GALR2, are known tumor suppressors and potential therapeutic targets in head and neck squamous cell carcinoma (HNSCC). Previously, we demonstrated that, in GALR1-expressing HNSCC cells, the addition of galanin suppressed tumor proliferation via upregulation of ERK1/2 and cyclin-dependent kinase inhibitors, whereas, in GALR2-expressing cells, the addition of galanin not only suppressed proliferation, but also induced apoptosis. In this study, we first transduced HEp-2 and KB cell lines using a recombinant adeno-associated virus (rAAV)-green fluorescent protein (GFP) vector and confirmed a high GFP expression rate (>90%) in both cell lines at the standard vector dose. Next, we demonstrated that GALR2 expression in the presence of galanin suppressed cell viability to 40-60% after 72 h in both cell lines. Additionally, the annexin V-positive rate and sub-G0/G1 phase population were significantly elevated in HEp-2 cells (mock vs GALR2: 12.3 vs 25.0% (P < 0.01) and 9.1 vs 32.0% (P < 0.05), respectively) after 48 h. These changes were also observed in KB cells, although to a lesser extent. Furthermore, in HEp-2 cells, GALR2-mediated apoptosis was caspase-independent, involving downregulation of ERK1/2, followed by induction of the pro-apoptotic Bcl-2 protein, Bim. These results illustrate that transient GALR2 expression in the presence of galanin induces apoptosis via diverse pathways and serves as a platform for suicide gene therapy against HNSCC.

Brexpiprazole: A new option in treating agitation in Alzheimer's dementia-Insights from transgenic mouse models.

AIM: Brexpiprazole is the first FDA-approved treatment for agitation associated with dementia due to Alzheimer's disease. Agitation in Alzheimer's dementia (AAD) occurs in high prevalence and is a great burden for patients and caregivers. Efficacy, safety, and tolerability of brexpiprazole were demonstrated in the AAD clinical trials. To demonstrate the agitation-ameliorating effect of brexpiprazole in animals, we evaluated brexpiprazole in two AAD mouse models. METHODS: The resident-intruder test was conducted in 5- to 6-month-old Tg2576 mice, given vehicle or brexpiprazole (0.01 or 0.03 mg/kg) orally 1 h before the test. Locomotor activity was measured in 6-month-old APPSL-Tg mice given vehicle or brexpiprazole (0.01 or 0.03 mg/kg) orally the evening before the start of locomotor measurement for 3 days. RESULTS: In the resident-intruder test, Tg2576 mice showed significantly higher attack number and shorter latency to first attack compared to non-Tg mice. In the Tg mice, brexpiprazole treatment (0.03 mg/kg) significantly delayed the latency to first attack and showed a trend toward a decrease in attack number. APPSL-Tg mice (≧6 months old) showed significantly higher locomotion during dark period Phase II (Zeitgeber time [ZT] 16-20) and Phase III (ZT20-24) compared to non-Tg mice, correlating with the clinical observations of late afternoon agitation in Alzheimer's disease. Brexpiprazole treatment (0.01 and 0.03 mg/kg) significantly decreased hyperlocomotion during the Phase III in APPSL-Tg mice. CONCLUSION: The suppression of attack behavior and the reduction of nocturnal hyperlocomotion in these Tg mice may be indicative of the therapeutic effect of brexpiprazole on AAD, as demonstrated in the clinical trials.

Analysis of reconstructed oropharynx shape after total glossolaryngectomy reconstruction using a free rectus abdominis musculocutaneous flap.

Introduction: Restoring oral intake through oropharyngeal reconstruction is vital for patients undergoing total glossolaryngectomy. Despite its importance, research in this area is limited, leaving clinicians with few guidelines. The debate regarding the optimal shape of the reconstructed oropharynx highlights the need for further research. Methods: This retrospective study analysed data from 16 consecutive patients who underwent primary reconstruction with a free rectus abdominis musculocutaneous flap after total glossolaryngectomy at the University of the Ryukyus Hospital between April 2015 and March 2022. Parameters assessed included reconstructed oropharynx shape (flat or funnel-shaped), demographics, flap characteristics, post-operative course and oral intake outcomes. Results: Among the 16 patients, 10 had flat oropharynx, whereas 6 had a funnel-shaped oropharynx. At 6 months post-surgery, 13 patients resumed oral feeding, whereas 3 did not. Significant differences were observed between the groups in preoperative body mass index (21.1 kg/m² vs 17.8 kg/m², Welch's t-test, p=0.035) and days until the first oral intake (34.2 days vs 19.2 days, Welch's t-test, p=0.01). However, no significant differences were found in the form of oral intake at 6 months after surgery (Fisher's exact test, p=0.518). Conclusion: This study suggests that the shape of the reconstructed oropharynx (flat or funnel-shaped) does not significantly impact long-term post-operative oral intake. These findings provide valuable insights into oropharyngeal reconstruction outcomes after total glossolaryngectomy and offer guidance for future research in this area. Nevertheless, further studies are warranted to elucidate the clinical implications of these findings and address any limitations of this study, particularly those regarding sample size constraints.

Prospective Analysis of Squamous Cell Carcinoma Antigen-1 and -2 for Diagnosing Sinonasal Inverted Papilloma.

Background: The goal of this research was to confirm whether preoperative serum squamous cell carcinoma antigen (SCCA)-1 and -2 levels are useful diagnostic markers for sinonasal inverted papilloma (IP) in a prospective study. Methods: Participants were 102 patients who underwent consecutive endoscopic sinus surgery: 18 with IP, two with other types of papilloma, 77 with chronic rhinosinusitis, four with sinonasal cancer, and one with hemangioma. SCCA-1 and SCCA-2 were measured preoperatively by an automatic chemiluminescence immunoassay and an enzyme-linked immunosorbent assay, respectively. Results: SCCA-1 and SCCA-2 values were significantly correlated (r = 0.603, p < 0.001). Receiver operating characteristic analysis for differentiating papilloma (IP and other types of papilloma) from other diseases yielded an area under the curve of 0.860, with a Youden index of 1.75. Combined with SCCA-2 analysis, the detection system had a sensitivity and specificity of 0.65 and 0.98, respectively. While our study did not find a strong link between SCCA levels and skin or lung diseases, smoking status may influence SCCA levels in IP patients (p = 0.035). We recommend a cutoff value of 1.8 ng/mL for SCCA-1 in IP diagnosis. Conclusions: SCCA-1 and SCCA-2 when combined with imaging and pathology hold promise for enhancing the preoperative detection of IP, which would be a valuable contribution to clinical practice.

Utility of Ultrahigh-Resolution Computed Tomography for Laryngeal Reconstructive Surgery.

OBJECTIVE: Unilateral vocal fold paralysis (UVFP) presents as incomplete glottal closure and leads to breathy hoarseness. Various treatments, including laryngeal framework surgery (type 1 thyroplasty [TP1] and arytenoid adduction [AA]), have been devised to correct this condition. Ultrahigh-resolution computed tomography (U-HRCT) allows detailed three-dimensional imaging of the larynx, which aids our understanding of vocal fold motion disorders. This study assessed whether U-HRCT is beneficial for correct diagnosis and surgical planning. METHODS: The participants were 26 UVFP patients who underwent laryngeal framework surgery (TP1 and/or AA). U-HRCT was used to measure the vocal fold volume (VFV) and level difference (LD). The need to combine AA with TP1 to obtain satisfactory surgical outcomes was evaluated by U-HRCT and various voice function tests. RESULTS: VFV was smaller in paralyzed folds than in unaffected folds. LD correlated strongly with voice parameters and showed high intra-rater and inter-rater reliability. The surgical outcome of the laryngeal framework surgery performed was judged to be excellent for improving voice function. Comparison of LD between the TP1 group and TP1 + AA group indicated that LD is an excellent parameter to determine the need to combine AA with TP1. CONCLUSION: These findings underscore the value of preoperative U-HRCT, especially LD, in surgical decision-making and afford insights for optimal phonosurgery and individualized intervention. Patients with LD >1.0 mm may benefit from thyroplasty with AA. LEVEL OF EVIDENCE: Level 3 (case-control study) Laryngoscope, 2024.

Pathogenic substitution of IVS15 + 5G > A in SLC26A4 in patients of Okinawa Islands with enlarged vestibular aqueduct syndrome or Pendred syndrome.

BACKGROUND: Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA) are caused by SLC26A4 mutations. The Okinawa Islands are the southwestern-most islands of the Japanese archipelago. And ancestral differences have been reported between people from Okinawa Island and those from the main islands of Japan. To confirm the ethnic variation of the spectrum of SLC26A4 mutations, we investigated the frequencies of SLC26A4 mutations and clinical manifestations of patients with EVA or PS living in the Okinawa Islands. METHODS: We examined 22 patients with EVA or PS from 21 unrelated families in Okinawa Islands. The patient's clinical history, findings of physical and otoscopic examinations, hearing test, and computed tomography (CT) scan of the temporal bones were recorded. To detect mutations, all 21 exons and the exon-intron junctions of SLC26A4 were sequenced for all subjects. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) for SLC26A4 and calculations using the comparative CT (2(-ΔΔCT)) method were used to determine the pathogenicity associated with gene substitutions. RESULTS: SLC26A4 mutations were identified in 21 of the 22 patients. We found a compound heterozygous mutation for IVS15 + 5G > A/H723R in nine patients (41%), a homozygous substitution of IVS15 + 5G > A in six patients (27%), and homozygous mutation for H723R in five patients (23%). The most prevalent types of SLC26A4 alleles were IVS15 + 5G > A and H723R, which both accounted for 15/22 (68%) of the patients. There were no significant correlations between the types of SLC26A4 mutation and clinical manifestations. Based on qRT-PCR results, expression of SLC26A4 was not identified in patients with the homozygous substitution of IVS15 + 5G > A. CONCLUSIONS: The substitution of IVS15 + 5G > A in SLC26A4 was the most common mutation in uniquely found in patients with PS and EVA in Okinawa Islands. This suggested that the spectrum of SLC26A4 mutation differed from main islands of Japan and other East Asian countries. The substitution of IVS15 + 5G > A leads to a loss of SLC26A expression and results in a phenotype of PS and EVA.

Surgical site infection in clean-contaminated head and neck cancer surgery: risk factors and prognosis.

Since new treatment strategies, such as chemoradiotherapy, have been introduced for head and neck cancer, a higher number of unknown factors may be involved in surgical site infection in clean-contaminated head and neck cancer surgery. The aim of the present study was to clarify the risk factors of surgical site infection in clean-contaminated surgery for head and neck cancer and the prognosis of patients with surgical site infection. Participants were 277 consecutive patients with head and neck cancer who underwent clean-contaminated surgery for primary lesions at the Aichi Cancer Center over a 60-month period. A total of 22 putative risk factors were recorded in each patient and statistically analyzed to elucidate surgical site infection related factors. Surgical site infection was observed in 92 (32.1 %) of 277 cases. Univariate analysis indicated that alcohol consumption, T classification, neck dissection, reconstructive procedure, and chemoradiotherapy were significantly associated with surgical site infection. Multiple logistic regression analysis identified two independent risk factors for surgical site infection: reconstructive surgery (p = 0.04; odds ratio (OR) 1.77) and chemoradiotherapy (p = 0.01; OR 1.93). In spite of surgical site infection, the five-year overall survival rate of patients with surgical site infection was not significantly different from those without surgical site infection. Although surgical site infection did not impact the overall survival of patients with surgical procedures, head and neck surgeons should pay attention to patients with previous chemoradiotherapy as well as to those with a high risk of surgical site infection requiring reconstructive surgery.

[Three cases of external auditory exostoses in a habitual sauna user].

Exostoses are benign bony excrescences of the external auditory canal, commonly encountered in people who avidly engage in aquatic activities, hence the name "surfer's ear". Exostoses are more prevalent in cold water surfers, and additional years of surfing increase one's risk not only for developing an exostosis but also for developing more severe lesions. Exostoses remain clinically silent until they become large enough to impair the egress of epithelial debris and water from the canal, in which case there may be an associated external otitis and fluctuating hearing loss. Histologically, they demonstrate a laminated structure consistent with a periodic growth pattern. They may also cause a hearing loss by impinging upon the tympanic membrane and manubrium. Symptomatic relief is attained by surgical removal and skin grafting of the epithelially denuded areas of the bony walls of the external auditory canal. We report herein on 3 cases of exostoses which developed in patients who had a habit of taking a cold water bath after a hot sauna for more than 15 years: in spite of the limited time of exposure to cold water stimulation, alternating exposure to the hot environment of the sauna and cold water baths seemed to have acceralated the formation of the exostoses.

Synergistic anti-depressive effect of combination treatment of Brexpiprazole and selective serotonin reuptake inhibitors on forced swimming test in mice.

AIM: Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). In MDD treatment, SSRIs do not show remission in approximately 30% of patients, indicating a need for a better treatment option. Forced swimming test (FST) is a behavioral assay to evaluate depression-like behavior and antidepressant efficacy in rodents. In the present study, we evaluated the combination effect of brexpiprazole with SSRIs on FST in mice, in order to investigate their synergistic effect. METHODS: Brexpiprazole (0.003 mg/kg) was intraperitoneally injected to mice 15 min before testing. Escitalopram (10 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), or sertraline (15 mg/kg) were orally administered to mice 60 min before testing. Then, the mice were placed in water and immobility time was measured. Data from animals treated with escitalopram, fluoxetine, paroxetine, and sertraline were pooled as SSRI-treated group data. RESULTS: Combination treatment of brexpiprazole with SSRIs reduced immobility time in FST more than vehicle or each single treatment. A significant interaction effect was confirmed in the combination of brexpiprazole and SSRIs (p = 0.0411). CONCLUSION: Efficacy of adjunctive brexpiprazole has already been demonstrated in clinical trials in MDD patients not adequately responding to antidepressants including escitalopram, fluoxetine, paroxetine, and sertraline. The synergistic antidepressant-like effect of brexpiprazole with SSRIs found in this study supports the already known clinical findings.

Human Papillomavirus Infection and EGFR Exon 20 Insertions in Sinonasal Inverted Papilloma and Squamous Cell Carcinoma.

This study aimed to clarify the roles of high-risk human papillomavirus (HR-HPV) infection and epidermal growth factor receptor (EGFR) exon 20 mutations in sinonasal inverted papilloma (IP) and sinonasal squamous cell carcinoma (SNSCC). Samples were collected from 20 cases with IP, 7 with IP and squamous cell carcinoma (IP-SCC), and 20 with SNSCC and examined for HPV infection and EGFR exon 20 mutations. Low- or high-risk HPV DNA was observed in 25% of IP, 57.1% of IP-SCC, and 35% of SNSCC cases. Transcriptionally active HR-HPV infections in IP-SCC and SNSCC, accompanied by p16 overexpression, were observed in 28.5% and 25% of cases, respectively. Heterozygous EGFR exon 20 amino acid insertions (ex20ins), located between amino acids 768-774, were observed in 45% of IP, 28.5% of IP-SCC, and 0% of SNSCC and chronic sinusitis cases. EGFR phosphorylation sites were located at tyrosine (Y) 845, Y1068, Y1086, and Y1197 and induced PI3K/AKT/mTOR activation. The phosphorylation pattern of EGFR with ex20ins resembled that of HPV-related SNSCC and oropharyngeal cancer. The transcriptionally active HR-HPV infection and ex20ins might be responsible for the pathogenesis of IP-SCC cases with different fashions. Since IP-SCC might be a multifactorial disease, further investigation is needed to understand IP-SCC etiology.

Exploring stage­specific embryonic antigen 3 involvement in oral cancer progression and as a potential target for taxane­based chemotherapy.

Despite significant advancements in therapeutic approaches, oral neoplasms remain formidable and life­threatening conditions that affect a substantial number of individuals worldwide. Within oral malignancies, a subset of cancer stem cells (CSCs) represent a crucial population responsible for tumor initiation and progression. The identification of reliable markers for the detection and characterization of CSCs in solid tumors, particularly in the context of oral cancers, remains an ongoing challenge. Stage­specific embryonic antigen 3 (SSEA3), previously associated with mesenchymal stem cells and linked to the progression of breast neoplasms and poor prognosis, has yet to be comprehensively elucidated in the context of oral malignancies. The present study aimed to investigate the expression and properties of SSEA3 in 16 distinct subsets of human oral neoplastic cell lines, classified as either CD44 positive (+) or CD44 negative (­). For the first time, SSEA3 was examined as an indicator of tumorigenicity and resistance to taxane­derived chemotherapeutic agents. In the majority of oral neoplastic cell lines analyzed, SSEA3 was expressed in a small population of CD44(+) cells. Significantly, SSEA3(+) cells exhibited heightened proliferative activity and upregulated expression of genes associated with stem cells compared with SSEA3(­) cells. The aforementioned findings suggested that SSEA3 may contribute to the evolution and progression of oral malignancies by fostering tumor growth. Furthermore, SSEA3(+) cells displayed increased sensitivity to taxane­based pharmaceuticals, indicating the potential for SSEA3 to be a viable target in the treatment schema for oral cavity neoplasms. In conclusion, the present study provides novel insight into the role of SSEA3 in the progression and management of oral neoplasms, potentially paving the way for more effective therapeutic approaches.