Causal associations between serum amino acid levels and osteoarthritis: a Mendelian randomization study.

OBJECTIVE: The association between serum amino acid (AA) levels and osteoarthritis (OA) risk remains unclear. METHOD: We performed a two-sample Mendelian randomization (MR) analysis to analyze the causal effects of serum AA levels on the OA risk by using summary-level genome-wide association study (GWAS) data. Inverse variance weighted (IVW) and Wald ratio were used as the main analysis. We also applied MR-Egger, Weighted median and Robust Adjusted Profile Score (MR.RAPS) methods. Heterogeneity and horizontally pleiotropic outliers were checked. The causal effects of AAs on early-onset all OA were explored. We also performed multivariable MR (MVMR) and conducted the bidirectional MR. RESULTS: The results suggested that genetically predicted alanine (Ala), tyrosine (Tyr) and isoleucine (Ile) levels were significantly associated with OA risk [e.g., association between Ala and hip/knee OA risk: OR = 0.82, 95% confidence interval (CI) = 0.75-0.90, P = 1.54E-05]. The study yielded little evidence of associations between genetically predicted AA levels with early-onset all OA risk. When adjusting the body mass index (BMI) in the MVMR model, suggestive causal effects of Ala and Tyr were also identified, while the effects of Ile substantially attenuated with OA risk. No significant associations between OA and AA levels were observed after testing for bidirectionality. CONCLUSIONS: Some AAs, such as Ala, Tyr and Ile likely affects the OA risk especially at hip or knee joints. The findings highlight the important role that serum AAs might play in the development of OA and provided new treatment approaches to OA.

[The mid-term outcomes of minimally invasive plasty for severe tricuspid regurgitation after cardiac surgery].

Objectives: To evaluate the efficacy of minimally invasive surgery in patients with late severe tricuspid regurgitation after cardiac surgery, and to evaluate the role of leaflets augmentation technique in tricuspid valvuloplasty. Methods: From January 2015 to June 2019, 85 patients undergoing tricuspid valve repair procedure with minimally invasive approach at Department of Cardiovascular Surgery, Guangdong provincial People's Hospital were enrolled. There were 22 males and 63 females, aging of (53.6±12.4) years (range: 15 to 75 years). The interval between the prior and current operations was (16.0±7.3) years (range: 0.2 to 35.0 years). The diameter of right atrium and right ventricle was (77.3±17.2) mm and (61.0±8.4) mm, respectively. Tricuspid regurgitation was severe or extremely severe, the tricuspid regurgitation area was (19.0±10.3) cm(2). All patients underwent minimally invasive tricuspid valvuloplasty or tricuspid valve replacement on beating-heart with totally endoscopic technique and port-access approach through right chest wall. The operations included tricuspid valve replacement and tricuspid valvuloplasty, the technique of tricuspid valvuloplasty including leaflets augmentation with patch, ring implantation, chordae tendineaes reconstruction, release of papillary muscle, edge to edge method, etc. Postoperative hospitalization days, the time of ICU stay, blood transfusion rate, ventilator time and the results of echocardiography were recorded. Follow-up was completed regularly by WeChat, telephone and outpatient visit. Results: Sixty-five patients underwent tricuspid valve repair, and 20 patients underwent tricuspid valve replacement because of prosthetic failure and plasty failure. Five patients died during hospitalization, with mortality rate 5.9%. One patient was transferred to local hospital for anti-infection treatment, the other 79 patients were discharged from hospital in well condition and followed-up. The postoperative hospitalization time was 7.0 (5.5) days (M(Q(R))) days, the mean ventilator time was 18.0 (16.2) hours, and the mean ICU stay time was 68.0 (75.5) hours. There were 35 patients without blood conduction transfusion, the transfusion rate was only 58.9% (50/85). Four cases of severe, 9 cases of moderate and 67 cases of mild to zero tricuspid regurgitation were examined before being discharged, with tricuspid regurgitation area of (2.8±3.5) cm(2) (range: 0 to 19.1 cm(2)). The follow-up time was 1 to 38 months. Two patients died during follow-up, one patient died from infective endocarditis and mitral perivalvular leakage, the other one died of intractable right heart failure. One patient was implanted with permanent pacemaker due to Ⅲ atrioventricular block. Valvular re-replacement was performed in 2 patients who were re-admitted for the artificial valve infection and mechanical valve obstruction. No re-operation of tricuspid valve. Conclusions: Totally endoscopic minimally invasive technique provided satisfactory surgical outcomes for critically sick patients with severe tricuspid regurgitation following cardiac surgery. The application of leaflets augmentation technique achieved ideal repair effect for previously unrepairable lesions.

[Relationship between selenium and the risk for oral cancer: a case-control study].

Objective: To explore the relationship between selenium and the risk for oral cancer. Methods: We performed a case-control study in 325 cases of newly diagnosed primary oral cancer from the First Affiliated Hospital of Fujian Medical University and 650 controls from the same hospital and community. Unconditional logistic regression and stratification analyses were used to explore the association between selenium and oral cancer. Adjusted OR and corresponding 95%CI were calculated. The analyses on multiple interactions between selenium and smoking or drinking status, and fruit or fish intake frequencies were conducted. Results: The level of serum selenium was 112.42 (80.98-145.06) µg/L in the case group, which was lower than 164.85 (144.44-188.53) µg/L in control group, the difference was statistical significant (P<0.01). There was a negative correlation between serum selenium level and the risk for oral cancer regardless of smoking and drinking status, and fruits and fish intake frequencies (P<0.05). There were multiple interactions between serum selenium level and smoking or drinking status, and fruit and fish intakes. Conclusions: The high level of serum selenium is a protective factor for the incidence of oral cancer, and serum selenium has multiple interactions with smoking or drinking status, and fruit and fish intakes. Therefore, reducing tobacco use and alcohol consumption and increasing the intakes of fruit and fish can reduce the risk for oral cancer to some extent.

[Association of single nucleotide polymorphisms of TBX5 gene and environmental exposure index with susceptibility to oral cancer].

Objective: To explore the association of TBX5 polymorphisms and environmental exposure index with susceptibility to oral cancer. Methods: A case-control study was conducted to collect 300 oral cancer patients hospitalized in the Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital of Fujian Medical University from September 2010 to December 2016. A total of 445 non-tumor patients were selected as the control group. Questionnaires were used to collect the information of all subjects and 5 ml peripheral blood was collected to detect single nucleotide polymorphisms (SNPs) of the rs10492336 locus of TBX5 gene. According to the environmental exposure index score, subjects were divided into two groups, low risk group (0-2.31) and high risk group (2.32-11.76). To analyze the association of TBX5 gene rs10492336 SNPs, environmental exposure index and oral cancer and its interactions. Results: The age of all subjects in the case group and control group were (56.19±13.10) years and (54.56±12.48) years old. Compared with CC genotype, the OR (95%CI) values of the co-dominant genetic model AC genotype and the dominant genetic model AC+AA genotype were 0.69 (0.49-0.98) and 0.70 (0.51-0.97), respectively. Compared with the low risk group, the OR (95%CI) risk of oral cancer in the high risk group was 3.72 (2.55-5.43). The results of gene-environment interaction analysis showed that compared with the group with CC genotype and high risk of environmental exposure index, the OR (95%CI) value of oral cancer in the group with AC+AA genotype and low risk of environmental exposure index was 0.18(0.10-0.31). Furthermore there was a multiplicative interaction between rs10492336 SNPs and environmental exposure index (ß=-0.405, P<0.001). Conclusion: This study suggests that the TBX5 gene rs10492336 SNPs and environmental exposure index were associated with oral cancer. And there was a multiplication interaction between rs10492336 SNPs and environmental exposure index.

[A novel prognostic index for oral cancer in Fujian province].

Objective: To explore the survival factors and construct a prognostic index (PI) for oral squamous cell carcinoma (OSCC). Methods: From January 2004 to June 2016, a total of 634 patients with pathologically confirmed OSCC were recruited in a hospital of Fujian. The clinical and follow-up data of all the patients with pathologically confirmed OSCC were collected to identify the factors influencing the prognosis of OSCC. All the patients were randomly divided into two groups: modeling group (modeling dataset, n=318) and validation group (validation dataset, n=316). Randomization was carried out by using computer-generated random numbers. In the modeling dataset, survival rates were calculated using Kaplan-Meier method and compared using the log-rank test. Cox regression model was used to estimate the hazard ratio (HRs) and 95% confidence intervals (CIs) of prognosis factors. An PI for OSCC patients prognostic prediction model was developed based on ß value of each significant variable obtained from the multivariate Cox regression model. Using the tertile analysis, patients were divided into high-risk group, moderate-risk group, and low-risk group according to the PI, the Akaike information criterion (AIC) and Harrell's c-statistic (C index) were used to evaluated the model's predictability. Results: Results from the multivariate Cox regression model indicated that aged ≥55 years (HR=2.22, 95%CI: 1.45-3.39), poor oral hygiene (HR=2.12, 95%CI: 1.27-3.54), first diagnosis of lymph node metastasis (HR=5.78, 95%CI: 3.60-9.27), TNM stage Ⅲ-Ⅳ (stage Ⅰ as reference) (HR=2.43, 95%CI: 1.10-5.37) and poor differentiation (well differentiation as reference) (HR=2.53, 95%CI: 1.60-4.01) were the risk factors influencing the prognosis of OSCC. The PI model had a high predictability in modeling group and validation group (AIC and C index were 1 205.80, 0.700 2 and 1 150.47, 0.737 3). Conclusion: Age, poor oral hygiene, first diagnosis of lymph node metastasis, TNM stage and histological grade were factors associated with the prognosis of OSCC, and the PI model has a certain significance in the clinical treatment of OSCC.

[A case-control study: association between oral hygiene and oral cancer in non-smoking and non-drinking women].

Objective: To evaluate the influence of oral hygiene on risk of oral cancer in non-smoking and non-drinking women. Methods: From September 2010 to February 2016, 242 non-smoking and non-drinking female patients with pathologically confirmed oral cancer were recruited in a hospital of Fuzhou, and another 856 non-smoking and non-drinking healthy women from health examination center in the same hospital were selected as control group. Five oral hygiene related variables including the frequency of teeth brushing, number of teeth lost, poor prosthesis, regular dental visits and recurrent dental ulceration were used to develop oral hygiene index model. Unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95%CI). The area under the receiver operating characteristic curve (AUROC) was used to evaluate the predictability of the oral hygiene index model. Multivariate logistic regression model was used to analyze the association between oral hygiene index and the incidence of oral cancer. Results: Teeth brushing <2 twice daily, teeth lost ≥5, poor prosthesis, no regular dental visits, recurrent dental ulceration were risk factors for the incidence of oral cancer in non-smoking and non-drinking women, the corresponding OR (95%CI) were 1.50 (1.08-2.09), 1.81 (1.15-2.85), 1.51 (1.03-2.23), 1.73 (1.15-2.59), 7.30 (4.00-13.30), respectively. The AUROC of the oral hygiene index model was 0.705 9, indicating a high predictability. Multivariate logistic regression showed that the oral hygiene index was associated with risk of oral cancer. The higher the score, the higher risk was observed. The corresponding OR (95%CI) of oral hygiene index scores (score 1, score 2, score 3, score 4-5) were 2.51 (0.84-7.53), 4.68 (1.59-13.71), 6.47 (2.18-19.25), 15.29 (5.08-45.99), respectively. Conclusion: Oral hygiene could influence the incidence of oral cancer in non-smoking and non-drinking women, and oral hygiene index has a certain significance in assessing the combined effects of oral hygiene.

[Pickled food, fish, seafood intakes and oral squamous cell carcinoma: a case-control study].

Objective: To investigate the effects between fish, seafood and pickled food intakes on oral squamous cell carcinoma (OSCC). Methods: A case-control study was carried out in Fujian area during September 2010 to December 2016, in which 604 newly diagnosed primary OSCC cases confirmed by pathological diagnosis were collected from hospital and 1 343 control subjects were enrolled from community and healthy hospital population. Demographic data, history of smoking drinking and tea drinking, oral hygiene status and dietary behaviors (fish, seafood and pickled food intakes) were collected by in-person interviews using a standard questionnaire.Using unconditional logistic regression to estimate adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to assess the effects of fish, seafood and pickled food intakes on OSCC. Analysis stratified by smoking, alcohol drinking and bad prosthesis to explore the possible difference in association between subgroups. Multiplicative interactions and additive interactions between fish and bad prosthesis, seafood and alcohol drinking, pickled food and bad prosthesis were assessed by unconditional logistic regression, relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (S). Results: The average age of case group and control group were separately (58.69±13.92) years old and (59.27±11.37) years old (χ(2)=4.75, P=0.191). The people whose fish and seafood intakes ≥3 times/week had the lower risk of OSCC, the adjusted OR (95%CI) values were 0.63 (0.52-0.77) and 0.51 (0.41-0.64); The stratified analysis indicated that the people having bad prosthesis had the lower risk of OSCC if they eating fish ≥3 times/week, and the adjusted OR (95%CI) values was 0.53 (0.39-0.71); the people having bad prosthesis had the higher risk of OSCC if they eating pickled food ≥3 times/week, the adjusted OR (95%CI) values was 1.37 (1.02-1.88). Regularly eating seafood can decrease the risk of OSCC for non-smokers, smokers, non-drinkers, drinkers, people without bad prosthesis and had bad prosthesis, the adjusted OR (95%CI) values were 0.49 (0.36-0.68), 0.52 (0.37-0.73), 0.41 (0.31-0.55), 0.77 (0.51-0.96), 0.49 (0.36-0.67), 0.59 (0.42-0.83). Crossover analysis showed fish and bad prosthesis exist multiplication interaction relationship (adjusted OR=0.66, 95%CI: 0.44-0.97) and additional interaction relationship (RERI=-0.81, 95%CI:-1.43--0.19; AP=-0.76, 95%CI:-1.35--0.17; S=0.08, 95%CI: 0.01-0.98); pickled food and bad prosthesis exist multiplication interaction relationship (adjusted OR=1.63, 95%CI: 1.06-2.51) and addition interaction relationship (RERI=0.65, 95%CI:0.08-1.22; AP=0.36, 95%CI:0.10-0.62; S=5.19, 95%CI:1.32-54.49). Conclusion: Reducing the consumption of pickled food, quitting smoking and limiting alcohol consumption, and regularly eating fish and seafood can prevent the occurrence of OSCC.

Tea consumption and its interactions with tobacco smoking and alcohol drinking on oral cancer in southeast China.

BACKGROUND/OBJECTIVES: Epidemiological results on the association between tea consumption and oral cancer remain controversial. We aimed to evaluate the exact relationship between tea consumption and oral cancer in Chinese population. SUBJECTS/METHODS: A large-scale case-control study was conducted on 586 oral cancer patients and 1024 controls frequency-matched by age and gender. Epidemiological data were collected through face-to-face interviews with a structure questionnaire. Unconditional logistic regression model was used to assess the effect of tea consumption on oral cancer stratified by smoking, alcohol drinking and demographics. Quantity of tea consumed (ml/day) was categorized into five subgroups based on quartiles and then its interactions was evaluated with tobacco smoking and alcohol drinking at each subgroup. RESULTS: Tea consumption showed an inverse association with oral cancer for non-smokers or non-alcohol drinkers (the odds ratios (ORs) were 0.610 (95% confidence interval (CI): 0.425-0.876) and 0.686 (95% CI: 0.503-0.934), respectively). For smokers or alcohol drinkers, decreased risk was only observed in those who consumed >800 ml/day. Furthermore, oolong tea consumption was associated with decreased risk of oral cancer in smokers or alcohol drinkers but not in non-smokers or non-alcohol drinkers. Tea consumption combined with smoking or/and alcohol drinking had a greater risk than tea consumption alone, but the risk was roughly reduced from zero to Q4 (>800 ml/day). Additionally, when stratified by demographics, the protective effect of tea was especially evident in females, urban residents, normal body mass index population (18.5-23.9), farmers, office workers and those aged <60 years. CONCLUSIONS: Tea consumption protects against oral cancer in non-smokers or non-alcohol drinkers, but this effect may be obscured in smokers or alcohol drinkers. Additionally, demographics may modify the association between tea consumption and oral cancer.

Influence of oral hygiene and its interaction with standard of education on the risk of oral cancer in women who neither smoked nor drank alcohol: a hospital-based, case-control study.

We know of only limited data about the role of oral hygiene and the risk of oral cancer with different standards of education. The aim of this study was to assess the association between oral hygiene and risk of oral cancer, with stratification by standard of education, in Chinese women. We organised a case-control study with 250 women with oral cancer and 996 age-matched controls in Fujian, China. Data were collected by personal interview using a structured questionnaire. We used unconditional logistic regression with stratification by educational standard to estimate the odds ratios (OR) and 95% CI. Tooth-brushing twice a day or more was inversely related to the risk of oral cancer in women with high school education or above (OR 0.50; 95% CI 0.25 to 0.98), but not in those who were illiterate or had primary-middle school education. Wearing dentures showed an increased risk only in less well-educated women: the OR were 2.23 (95% CI 1.14 to 4.34) for the illiterate and 1.68 (95% CI 1.08 to 2.62) for the primary-middle school group. The loss of more than five teeth and oral ulceration were associated with increased risks of oral cancer in all three groups. There was also a multiplicative interaction between oral hygiene and standard of education for risk of oral cancer (p=0.001). Our results suggest that oral hygiene seems to have a critical role in the risk of oral cancer in Chinese women, but this effect may be modified by their educational standard.

[Study of survival factors of oral squamous cell carcinoma].

Objective: To explore the survival factors for oral squamous cell carcinoma(OSCC). Methods: A total of 492 patients with OSCC were recruited from the First Affiliated Hospital of Fujian Medical University from June 2003 to December 2014. Then, 456 cases were included in the present study according to inclusion and exclusion criteria. Clinical and follow-up data were collected to evaluate survival factors of OSCC. Survival rates were calculated using the Kaplan-Meier method and compared using the Log-rank test. The Cox proportional hazards regression model was used to estimate the hazard ratio(HR)and 95% confidence intervals(CI)of survival factors. We also stratified by TNM Classification of Malignant Tumours stage and BMI to assess the association between treatments and OSCC outcomes. Results: The age of the recruited patients was(57.89±11.61)years, and the proportions in TNM stages Ⅰ, Ⅱ, Ⅲ, and Ⅳ were 14.0%(64), 23.7%(108), 16.1%(73)and 42.5%(194), respectively. The multivariate Cox regression indicated that the HR(95% CI)of the increase to mortality risk associated with stage T2-T3, T4(T1 as reference), stage N2-N3(N0 as reference), poormoderate differentiation, BMI<18.5 kg/m2(compared with BMI 18.5-23.9 kg/m2), alcohol consumption ≥20 g/d(compared with no alcohol)before treatment were 2.69(1.21-5.95), 3.40(1.54-7.53), 2.65(1.17-6.00), 2.56(1.39-4.71), 2.00(1.15-3.50), 2.09(1.11-3.93), and 1.68(1.03-2.73), respectively. The stratification analysis demonstrated that, compared with surgery alone, surgery combined with radiotherapy reduced the mortality risk of stage Ⅲ-Ⅳ, HR(95% CI)0.33(0.12-0.93). Surgery combined with chemoradiotherapy reduced the mortality risk of OSCC with normal BMI, HR(95% CI)were 0.39(0.17-0.87). Conclusions: Clinical stage and histological grade are survival factors for patients with OSCC.

[Tea, coffee intakes and risk of oral squamous cell carcinoma: a case-control study].

Objective: To evaluate the effects of tea and coffee intakes on oral squamous cell carcinoma (OSCC) stratified by milk intake. Methods: A case-control study involving 593 OSCC patients confirmed by pathological diagnoses and 1 128 gender-age frequency matched controls was conducted in Fujian province during September 2010-March 2016. Unconditional logistic regression was used to calculate adjusted odds ratios (aORs) and corresponding 95% confidence intervals (CIs) to assess the effects of coffee, tea intakes and related variables on OSCC. Additive interaction was estimated by relative excess risk interaction (RERI), attributable proportions interaction (API) and synergy index (SI). Results: Tea intake was significantly associated with decreased risk of OSCC: the adjusted ORs were 0.54 for all subjects (95%CI: 0.41-0.71), 0.47 for milk consumers (95%CI: 0.31-0.71) and 0.57 for non-milk consumers (95%CI: 0.40-0.81). Moreover, starting tea drinking at age ≥25 years, moderate tea concentration and water temperature, drinking green tea and oolong tea showed effects to decrease the risk for OSCC in three groups. Additionally, there was a tendency of a reduced risk with increased daily tea drinking and longer tea-drinking period (all trend P<0.05). No significant association was observed between coffee intake and OSCC. A multiplicative but not additive interactions was found between tea drinking and milk intake. Additionally, we did not observe multiplicative and additive interaction between coffee drinking and milk intake. Conclusion: Tea drinking is a protective factor for OSCC, and there is a multiplicative interaction between tea drinking and milk intake. Therefore, tea drinking and increasing intake of milk can reduce the risk of OSCC at certain extent.

Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma.

Osteosarcoma (OS) is the most common primary malignancy of bone. There is a critical need to identify the events that lead to the poorly understood mechanism of OS development and metastasis. The goal of this investigation is to identify and characterize a novel marker of OS progression. We have established and characterized a highly metastatic OS subline that is derived from the less metastatic human MG63 line through serial passages in nude mice via intratibial injections. Microarray analysis of the parental MG63, the highly metastatic MG63.2 subline, as well as the corresponding primary tumors and pulmonary metastases revealed insulin-like growth factor binding protein 5 (IGFBP5) to be one of the significantly downregulated genes in the metastatic subline. Confirmatory quantitative RT-PCR on 20 genes of interest demonstrated IGFBP5 to be the most differentially expressed and was therefore chosen to be one of the genes for further investigation. Adenoviral mediated overexpression and knockdown of IGFBP5 in the MG63 and MG63.2 cell lines, as well as other OS lines (143B and MNNG/HOS) that are independent of our MG63 lines, were employed to examine the role of IGFBP5. We found that overexpression of IGFBP5 inhibited in vitro cell proliferation, migration and invasion of OS cells. Additionally, IGFBP5 overexpression promoted apoptosis and cell cycle arrest in the G1 phase. In an orthotopic xenograft animal model, overexpression of IGFBP5 inhibited OS tumor growth and pulmonary metastases. Conversely, siRNA-mediated knockdown of IGFBP5 promoted OS tumor growth and pulmonary metastases in vivo. Immunohistochemical staining of patient-matched primary and metastatic OS samples demonstrated decreased IGFBP5 expression in the metastases. These results suggest 1) a role for IGFBP5 as a novel marker that has an important role in the pathogenesis of OS, and 2) that the loss of IGFBP5 function may contribute to more metastatic phenotypes in OS.