The diversity of inhibitory receptor co-expression patterns of exhausted CD8+ T cells in oropharyngeal carcinoma.

Exhausted CD8+ T cells (Texs) are characterized by the expression of various inhibitory receptors (IRs), whereas the functional attributes of these co-expressed IRs remain limited. Here, we systematically characterized the diversity of IR co-expression patterns in Texs from both human oropharyngeal squamous cell carcinoma (OPSCC) tissues and syngeneic OPSCC model. Nearly 60% of the Texs population co-expressed two or more IRs, and the number of co-expressed IRs was positively associated with superior exhaustion and cytotoxicity phenotypes. In OPSCC patients, programmed cell death-1 (PD-1) blockade significantly enhanced PDCD1-based co-expression with other IR genes, whereas dual blockades of PD-1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) significantly upregulated CTLA4-based co-expression with other IR genes. Collectively, our findings demonstrate that highly diverse IR co-expression is a leading feature of Texs and represents their functional states, which might provide essential clues for the rational selection of immune checkpoint inhibitors in treating OPSCC.

Lentinan inhibits cell invasion via M2 polarization of tumor-associated macrophages and Wnt/ß-catenin signaling in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is an aggressive and devastating cancer due to its metastasis induced by increased invasion. Lentinan is a polysaccharide exerting antitumor roles in multiple cancers, including lung cancer. However, the influence of lentinan on cell invasion in NSCLC remains unclear. Cell invasion was detected by transwell analysis. Matrix metallopeptidase 9 (MMP9) levels were measured through immunofluorescence staining. The markers arginase-1 (Arg-1), CD206 and interleukin (IL)-10 (IL-10) of M2 macrophages, Wnt3a, and ß-catenin levels were measured by western blot or enzyme linked immunosorbent assay. Lentinan did not affect cell viability and proliferation in NSCLC cells. Lentinan suppressed cell invasion and reduced the expression and secretion of MMP9. Lentinan attenuated also M2 polarization of tumor-associated macrophages. Moreover, lentinan mitigated the M2 macrophage conditioned medium-mediated cell invasion and MMP9 alterations in NSCLC cells. Lentinan inhibited the activation of the Wnt/ß-catenin signaling in NSCLC cells. The activated Wnt/ß-catenin pathway reversed the suppressive effects of lentinan on cell invasion and MMP9 level in NSCLC cells. In conclusion, lentinan reduces cell invasion in NSCLC cells by inhibiting the M2 polarization of tumor-associated macrophages and the Wnt/ß-catenin signaling.

Comparison of Primary B/NKT Non-Hodgkin Lymphomas in Nasopharynx, Nasal Cavity, and Paranasal Sinuses.

OBJECTIVE: We aimed to compare clinical and survival differences between B-cell (B-NHL) and NKT-cell non-Hodgkin lymphomas (NKT-NHL) located in the nasal cavity (NC), nasopharynx, and paranasal sinuses, which are always categorized as one sinonasal type. STUDY DESIGN: Patients diagnosed with primary B-NHL and NKT-NHL in the nasal cavity, nasopharynx, and paranasal sinuses from Surveillance, Epidemiology, and End Results (SEER) database were included (1975-2017). SETTING: Population-based cohort study. METHODS: We conducted univariate and multivariate Cox regressions and Kaplan-Meier analysis to examine survival outcomes of B/NKT-NHL in the nasal cavity, nasopharynx, and paranasal sinuses, respectively. RESULTS: Overall, most B-NHL cases originated from the nasopharynx, while the majority of NKT-NHL cases occurred in the nasal cavity. Notably, the cancer-special survival (CSS) outcomes improved significantly in all sinonasal B-NHL cases over time, whereas no such improvement trend was observed in each sinonasal NKT-NHL type. Additionally, increasing age was linked with an elevated risk of death in B-NHL, particularly in the nasal cavity (Hazard ratio [HR]: 3.37), rather than in NKT-NHL. Compared with B-NHL, the adverse effect of a higher stage on CSS was more evident in NKT-NHL, particularly in its nasopharynx site (HR: 5.12). Furthermore, radiotherapy was beneficial for survival in patients with sinonasal B-NHL and NKT-NHL, except in the nasopharynx NKT-NHL. However, chemotherapy has only been beneficial for CSS in patients with paranasal sinuses B-NHL (HR: 0.42) since 2010, rather than in other types of B/NKT-NHL. CONCLUSION: Although B-NHL and NKT-NHL in the nasal cavity, nasopharynx and paranasal sinuses have similar anatomical locations, their clinicodemographics and prognoses are largely different and should be treated and studied as distinct diseases.

The Relationship Between Sleep Traits and Tinnitus in UK Biobank: A Population-Based Cohort Study.

OBJECTIVES: Understanding the association between sleep traits and tinnitus could help prevent and provide appropriate interventions against tinnitus. Therefore, this study aimed to assess the relationship between different sleep patterns and tinnitus. DESIGN: A cross-sectional analysis using baseline data (2006-2010, n = 168,064) by logistic regressions was conducted to evaluate the association between sleep traits (including the overall health sleep score and five sleep behaviors) and the occurrence (yes/no), frequency (constant/transient), and severity (upsetting/not upsetting) of tinnitus. Further, a prospective analysis of participants without tinnitus at baseline (n = 9581) was performed, who had been followed-up for 7 years (2012-2019), to assess the association between new-onset tinnitus and sleep characteristics. Moreover, a subgroup analysis was also carried out to estimate the differences in sex by dividing the participants into male and female groups. A sensitivity analysis was also conducted by excluding ear-related diseases to avoid their confounding effects on tinnitus (n = 102,159). RESULTS: In the cross-sectional analysis, participants with "current tinnitus" (OR: 1.13, 95% CI: 1.04-1.22, p = 0.004) had a higher risk of having a poor overall healthy sleep score and unhealthy sleep behaviors such as short sleep durations (OR: 1.09, 95% CI: 1.04-1.14, p < 0.001), late chronotypes (OR: 1.09, 95% CI: 1.05-1.13, p < 0.001), and sleeplessness (OR: 1.16, 95% CI: 1.11-1.22, p < 0.001) than those participants who "did not have current tinnitus." However, this trend was not obvious between "constant tinnitus" and "transient tinnitus." When considering the severity of tinnitus, the risk of "upsetting tinnitus" was obviously higher if participants had lower overall healthy sleep scores (OR: 1.31, 95% CI: 1.13-1.53, p < 0.001). Additionally, short sleep duration (OR: 1.22, 95% CI: 1.12-1.33, p < 0.001), late chronotypes (OR: 1.13, 95% CI: 1.04-1.22, p = 0.003), and sleeplessness (OR: 1.43, 95% CI: 1.29-1.59, p < 0.001) showed positive correlations with "upsetting tinnitus." In the prospective analysis, sleeplessness presented a consistently significant association with "upsetting tinnitus" (RR: 2.28, p = 0.001). Consistent results were observed in the sex subgroup analysis, where a much more pronounced trend was identified in females compared with the males. The results of the sensitivity analysis were consistent with those of the cross-sectional and prospective analyses. CONCLUSIONS: Different types of sleep disturbance may be associated with the occurrence and severity of tinnitus; therefore, precise interventions for different types of sleep disturbance, particularly sleeplessness, may help in the prevention and treatment of tinnitus.

Natural Antisense Long Noncoding RNA HHIP-AS1 Suppresses Non-Small-Cell Lung Cancer Progression by Increasing HHIP Stability via Interaction with CELF2.

Non-small-cell lung cancer (NSCLC) is a major category of lung cancer, with high incidence and high mortality. Natural antisense long noncoding RNAs (lncRNAs) are involved in the development of NSCLC via their regulation of biological processes. However, the function of the lncRNA Hedgehog-interacting protein antisense RNA 1 (HHIP-AS1) in NSCLC is mostly unknown. In the study discussed here, HHIP-AS1 and HHIP levels were predicted based on the TCGA database, and detected via qRT-PCR or western blotting assays. Cell proliferation, migration, and invasion were measured via CCK-8 and trans-well assays. Related protein levels were measured using western blotting analysis. The results showed that HHIP-AS1 and HHIP levels are downregulated in NSCLC, and that low HHIP-AS1 and HHIP expression is associated with poor outcomes. HHIP-AS1 overexpression represses cell proliferation, migration, and invasion in NSCLC. HHIP-AS1 enhances HHIP expression and stability, and this effect is mediated by CELF2. HHIP silencing attenuates the suppressive roles of HHIP-AS1 in proliferation, migration, and invasion. As a result of these findings, it is concluded that HHIP-AS1 overexpression restrains proliferation, migration, and invasion of NSCLC cells by increasing HHIP stability via its targeting of CELF2.

Gender-specific association between obstructive sleep apnea and cognitive impairment among adults.

OBJECTIVES: This study aims to explore the gender-specific association between obstructive sleep apnea (OSA) and cognitive impairment. METHODS: Participants from UK biobank who have completed at least one of the five baseline cognitive tests (visuospatial memory, prospective memory, fluid intelligence, short numeric memory and reaction time) were included, which were initially divided into two groups based on gender and were further categorized into three subgroups: (1) OSA, (2) self-reported snoring but without OSA, and (3) healthy controls (without OSA or snoring). Multivariable regression analysis was performed to examine the associations among snoring, OSA and performance of each of the five cognitive domains. RESULTS: A total of 267,889 participants (47% male, mean age: 57 years old) were included in our study. In the multivariable regression analysis, female participants in the OSA group had a higher risk of having poor prospective memory (OR: 1.24, 95% CI: 1.02～1.50, p = 0.03). Meanwhile, among female participants, OSA were inversely associated with the performances of fluid intelligence (ß: 0.29, 95% CI: 0.46～-0.13, p < 0.001) and short-numeric memory (ß: 0.14, 95% CI: 0.35～0.08, p = 0.02). Besides, age-related subgroup analyses showed that these associations were largely reserved in younger (＜65 years old) female participants rather than older (≥65 years old) female participants. In contrast, among male participants, no significant association was observed between OSA and impairment of the five cognitive domains. CONCLUSIONS: OSA was significantly associated with cognitive impairment at certain dimensions in female participants rather than in male participants, indicating that more special attention and timely interventions should be given to younger female OSA patients to prevent further cognitive impairment.

Successful cervicothoracic esophageal stricture treatment with partial sternectomy and a pedicled TAAP flap: A case report.

Postoperative benign esophageal anastomotic leakage and stenosis are common complications after esophagectomy. Treatment options for anastomosis stenosis include endoscopic mechanical dilation, dilation-combined steroid injection, incisional therapy, stent placement, and self-bougienage. However, long-segmental cervicothoracic esophageal stenosis and cutaneous fistula are always refractory to conservative treatments and are clinically challenging. When lesions extend well below the thoracic inlet, transthoracic esophagectomy and alimentary canal reconstruction seem to be the common choice but are susceptible to perioperative mortality and donor-site sequelae, especially for patients with poor health conditions. In this report, we present a novel surgical approach for cervicothoracic esophageal stenosis and fistula via partial sternectomy and reconstruction with a pedicled thoracoacromial artery perforator flap. No recurrence or complications occurred throughout 3 months of follow-up. This case study adds new perspectives to the treatment of anastomotic stenosis.

Evaluating the prognostic contributions of TNM classifications and building novel staging schemes for middle ear squamous cell carcinoma.

BACKGROUND: A universally acknowledged cancer staging system considering all aspects of the T-, N-, and M-classifications for middle ear squamous cell carcinoma (MESCC) remains absent, limiting the clinical management of MESCC patients. MATERIALS AND METHODS: A total of 214 MESCC patients were extracted from the SEER (the Surveillance, Epidemiology, and End Results) database between 1973 and 2016. The relationships between patient's characteristics and prognoses were analyzed by Kaplan-Meier and Cox proportional hazards regression models. Novel staging schemes for MESCC were designed by adjusted hazard ratio (AHR) modeling method according to the combinations of Stell's T-classification and the eighth AJCC N- and M-classifications, of which performances were evaluated based on five criteria: hazard consistency, hazard discrimination, explained variation, likelihood difference, and balance. RESULTS: T-classification was the most significant prognostic factor for MESCC patients in multivariable analysis (p = 0.021). The N- and M-classifications also had obvious prognostic effect but were not statistically significant by multivariate analysis due to the limited metastasis events. Three novel staging schemes (AHR-Ⅰ-Ⅲ models, different combination of T- and N-classifications) and ST (solely derived from Stell's T-classification) were developed, among which the AHR-Ⅰ staging scheme performed best. CONCLUSIONS: Tumor extension, quantified by Stell's T-classification, is the most significant prognostic factor for MESCC patients. However, our AHR-Ⅰ staging scheme, a comprehensive staging scheme that integrating T-, N-, and M-classifications, might be an optimal option for clinical practitioners to predict MESCC patients' prognosis and make proper clinical decisions.

Long non-coding RNA LINC00511 promotes proliferation, invasion, and migration of non-small cell lung cancer cells by targeting miR-625-5p/GSPT1.

BACKGROUND: Lung cancer is a malignant tumor with a high rate of mortality and metastasis. Recently, extensive research has shown that long non-coding RNAs (lncRNAs) play a crucial role in the development and progression of non-small cell lung cancer (NSCLC). In this paper, we aimed to explore the impact of long intergenic non-coding RNA 00511 (LINC00511) on the development and metastasis of NSCLC. METHODS: A dataset containing 501 lung squamous cell carcinoma (LUSC) samples and 49 normal samples was downloaded from The Cancer Genome Atlas (TCGA). The differential gene expression and prognostic potential of LINC00511 in LUSC were analyzed by "limma" in R software. Samples of tumor tissues and normal tissues from 67 patients with NSCLC were obtained, along with clinical features. NSCLC cell proliferation, cell cycle, migration, and invasion were detected by LINC00511 knockdown with Cell Counting Kit-8 (CCK-8), flow cytometry, wound-healing assay, and Transwell experiment. The regulatory relationship between LINC00511 and microRNA (miR)-625-5p, or between miR-625-5p and G1 to S phase transition 1 (GSPT1), was detected by luciferase reporter gene assay. LINC00511, miR-625-5p, and GSPT1 expression in tumor and normal tissues and cells was determined by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot. A xenograft experiment in nude mice was performed. Ki67 and GSPT1 expression in the tumor tissues of the nude mice was assessed by immunohistochemistry. RESULTS: LINC00511 expression was clearly higher in the tumor tissues of the NSCLC patients than in normal tissues (P<0.001). High LINC00511 expression was related to larger tumor size, positive lymph node metastasis, advanced TNM stage, and a lower 5-year survival rate. Compared with those of the shNC group, the NSCLC cells of the shLINC00511 group had a prominently lower optical density (OD) 450 value at 72 h, a lower percentage of cells in S phase, a higher relative wound width, and a lower invasive cell number (P<0.01 or P<0.001). LINC00511 promoted GSPT1 expression via suppressing miR-625-5p. Compared with those of the shNC group, the nude mice of the shLINC00511 group had a much lower subcutaneous tumor volume and weight (P<0.05 or P<0.001). CONCLUSIONS: lncRNA LINC00511 promotes proliferation, invasion, and migration of NSCLC cells by targeting miR-625-5p/GSPT. LINC00511 may be a potential diagnostic marker and therapeutic target for NSCLC.

miR-937 regulates the proliferation and apoptosis via targeting APAF1 in breast cancer.

Background: Previous research had shown that an imbalance in cell proliferation and apoptosis is a vital mechanism for tumorigenesis and cancer progression that may directly influence biological behaviors of cancer. microRNAs are associated with the occurrence and development of tumors. This study aimed to explore the influence of miR-937 on breast cancer regulation of APAF1 expression. Methods: Cancer Genome Altas microarray analysis (fold change > 2, p<0.05) was used to verify differentially expressed microRNAs and RT-qPCR was used to detect miR-937 mRNA level in breast cancer. Cell viability and proliferation were measured using CCK8 and colony formation assays, respectively, after the miR-937 mimics/inhibitors and their negative control were transfected into MCF7 cells. The variations in cell cycle and apoptosis were examined using flow cytometry. DAVID database was used to perform GO enrichment analysis. We use dual luciferase report system to detect the effect of miR-937 on the transcriptional activity of APAF1. APAF1 protein level was determined by Western blot assay. Results: miR-937 was up-regulated in breast cancer cell lines and high miR-937 expression is associated with a poorer survival rate in cancer patients. miR-937 overexpression promoted the viability, down-regulated the G1 phase ratios and increased the ability of colony formation in breast cancer cells. miR-937 inhibition inhibited the viability and the ability of colony formation, promoted the apoptosis and up-regulated the G1 phase ratios. Our results showed that miR-937 targeted bind to the APAF1-3'UTR. APAF1 overexpression inhibited the viability and the ability of colony formation, promoted the apoptosis and up-regulated the G1 phase ratios. After cells were co-transfection miR-937 mimics and APAF1, cell apoptosis level was increased. Conclusion: APAF1 up-regulation or APAF1 down-regulation in breast cancer may regulate cell proliferation and apoptosis.

KIF26B promotes cell proliferation and migration through the FGF2/ERK signaling pathway in breast cancer.

BACKGROUND: Many studies have suggested that high KIF26B expression is directly linked to poor prognostic outcomes in breast cancer. However, the exact role of KIF26B in breast cancer progression is not fully understood. In this study, we aimed to explore the function and mechanism of KIF26B in breast cancer progression. METHODS: Quantitative real-time PCR and immunohistochemistry analysis were used to detect KIF26B expression in breast cancer cell lines and patient samples. Cell proliferation was assessed by CCK-8 assay, and cell migration and invasion were evaluated by wound healing assay and transwell assay. Western blot analysis was carried out to assess the underlying molecular mechanisms. Tumor formation and metastasis were determined by in vivo mouse experiments. RESULTS: KIF26B levels were significantly increased in breast cancer cells and patient samples. KIF26B level correlated with tumor size, TNM grade, and differentiation in patients with breast cancer. Overexpressing KIF26B in vitro promoted breast cancer cell proliferation and migration by activating FGF2/ERK signaling, while silencing KIF26B had the opposite effects. Similarly, KIF26B knockdown repressed tumor formation and metastasis in nude mice. CONCLUSION: KIF26B promoted the development and progression of breast cancer and might act as a potential therapeutic target for treating breast cancer.

Agomelatine versus fluoxetine in glycemic control and treating depressive and anxiety symptoms in type 2 diabetes mellitus subjects: a single-blind randomized controlled trial.

BACKGROUND: Depressive and anxiety symptoms could seriously affect the quality of life of type 2 diabetes mellitus (T2DM) subjects. Currently, little is known about the efficacy and acceptability of agomelatine versus fluoxetine in treating these symptoms in T2DM subjects. Therefore, this study was performed to find out which one was better in treating these symptoms in T2DM subjects. MATERIALS AND METHODS: T2DM subjects with depressive and anxiety symptoms were randomly assigned to receive either fluoxetine (30-40 mg/day) or agomelatine (25-50 mg/day). The treatment was continued for 12 weeks. The data of the Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) were collected (at baseline and also at weeks 4, 8 and 12) to assess the depressive and anxiety symptoms, respectively. The metabolic parameters, including body mass index (BMI), fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c), were assessed at baseline and after 12 weeks of treatment. The treatment-related adverse events during the scheduled treatment period were recorded to compare the acceptability of these two drugs. RESULTS: After 12 weeks of treatment, the average HDRS and HARS scores were significantly decreased in both groups. The average HDRS scores were not significantly different between the two groups, although the agomelatine group had a lower average HDRS score. The response and remission rates were similar between the two groups, and these two drugs had no significant effects on BMI and FPG. However, compared with the fluoxetine group, the agomelatine group had the significantly lower average HARS score (p=0.0017) and lower average HbA1c level (p<0.00001). Moreover, the incidence of adverse events was significantly lower in the agomelatine group than in the fluoxetine group (p=0.032). CONCLUSION: Both fluoxetine and agomelatine could effectively reduce depressive and anxiety symptoms in T2DM subjects, but agomelatine might be more effective and acceptable. Future studies with more subjects are needed to support and validate our conclusion.

Association between Body Mass Index and Migraine: A Survey of Adult Population in China.

Both migraine and obesity are prevalent disorders in the general population, which are characterized by disability and impaired quality of life. Although so many researches had studied the association between migraine and obesity, there are still no full knowledge of the relationship between body mass index (BMI) and migraine, especially chronic migraine (CM). In this study, we analyzed a previous epidemiological survey data of primary headache patients in Chongqing, which surveyed consecutive neurological outpatients through face-to-face interview with physicians using a headache questionnaire. 166 episodic migraine (EM) patients and 134 chronic migraine (CM) patients were included in the study out of 1327 primary headache patients. And 200 healthy adults from the physical examination center were included as a control group. Finally, we found that the patients with migraine (EM and CM) were more likely to be overweight, obese, or morbidly obese compared to those in the healthy group. Significant difference was found between BMI and frequency of migraine attacks but not severity or duration of headache onset. And no significant difference was found in severity and duration of headache onset between episodic and chronic migraine among different BMI classifications. Such may update our knowledge about the clinical features of migraine and BMI, revealing that the frequency of attacks may be associated with being overweight, obese, or morbidly obese in patients with migraine and that the extent of being overweight, obese, or morbidly obese in CM patients was lower than that in EM patients.