Genetic polymorphism of WNT9A is functionally associated with thumb osteoarthritis in the Chinese population

Abstract Background In a recent genome-wide association study, novel genetic variations of WNT9A were reported to be involved in the etiopathogenesis of thumb osteoarthritis (TOA) in Caucasians. Our purposes were to replicate the association of WNT9A with the development of TOA in the Chinese population and to further unveil the functional role of the risk variants. Methods SNP rs11588850 of WNT9A were genotyped in 953 TOA patients and 1124 healthy controls. The differences of genotype and allele distributions between the patients and healthy controls were evaluated using the Chi-square test. Luciferase Reporter Assay was performed to investigate the influence of variant on the gene expression. Results There was significantly lower frequency of genotype AA in TOA patients than in the controls 74.9% vs. 81.9%, p < 0.001). The frequency of allele A was remarkably lower in the patients than in the controls (86.3% vs. 90.5%, p < 0.001), with an odds ratio of 0.66 (95% CI = 0.54-0.80). Luciferase Reporter Assay showed that the construct containing mutant allele G of rs11588850 displayed 29.1% higher enhancer activity than the wild allele A construct (p < 0.05). Conclusions Allele G of rs11588850 was associated with the increased risk of TOA possibly via up-regulation of WNT9A expression. Further functional analysis into the regulatory role of rs11588850 in WNT9A expression can shed new light on the genetic architecture of TOA. Key Points Genetic variants of WNT9A were associated with the incidence and severity of TOA. Allele G of rs11588850 was associated with an increased transcriptional activity of WNT9A promoter. Allele G of rs11588850 may add to the risk of TOA possibly via up-regulation of WNT9A expression. Further functional analysis into the regulatory role of rs11588850 in WNT9A expression can shed new light on the genetic architecture of TOA.

Association between duration of smoking abstinence before non-small-cell lung cancer diagnosis and survival: a retrospective, pooled analysis of cohort studies.

BACKGROUND: The association between duration of smoking abstinence before non-small-cell lung cancer (NSCLC) diagnosis and subsequent survival can influence public health messaging delivered in lung-cancer screening. We aimed to assess whether the duration of smoking abstinence before diagnosis of NSCLC is associated with improved survival. METHODS: In this retrospective, pooled analysis of cohort studies, we used 26 cohorts participating in Clinical Outcomes Studies of the International Lung Cancer Consortium (COS-ILCCO) at 23 hospitals. 16 (62%) were from North America, six (23%) were from Europe, three (12%) were from Asia, and one (4%) was from South America. Patients enrolled were diagnosed between June 1, 1983, and Dec 31, 2019. Eligible patients had smoking data before NSCLC diagnosis, epidemiological data at diagnosis (obtained largely from patient questionnaires), and clinical information (retrieved from medical records). Kaplan-Meier curves and multivariable Cox models (ie, adjusted hazard ratios [aHRs]) were generated with individual, harmonised patient data from the consortium database. We estimated overall survival for all causes, measured in years from diagnosis date until the date of the last follow-up or death due to any cause and NSCLC-specific survival. FINDINGS: Of 42 087 patients with NSCLC in the COS-ILCCO database, 21 893 (52·0%) of whom were male and 20 194 (48·0%) of whom were female, we excluded 4474 (10·6%) with missing data. Compared with current smokers (15 036 [40·0%] of 37 613), patients with 1-3 years of smoking abstinence before NSCLC diagnosis (2890 [7·7%]) had an overall survival aHR of 0·92 (95% CI 0·87-0·97), patients with 3-5 years of smoking abstinence (1114 [3·0%]) had an overall survival aHR of 0·90 (0·83-0·97), and patients with more than 5 years of smoking abstinence (10 841 [28·8%]) had an overall survival aHR of 0·90 (0·87-0·93). Improved NSCLC-specific survival was observed in 4301 (44%) of 9727 patients who had quit cigarette smoking and was significant at abstinence durations of more than 5 years (aHR 0·87, 95% CI 0·81-0·93). Results were consistent across age, sex, histology, and disease-stage distributions. INTERPRETATION: In this large, pooled analysis of cohort studies across Asia, Europe, North America, and South America, overall survival was improved in patients with NSCLC whose duration of smoking abstinence before diagnosis was as short as 1 year. These findings suggest that quitting smoking can improve overall survival, even if NSCLC is diagnosed at a later lung-cancer screening visit. These findings also support the implementation of public health smoking cessation strategies at any time. FUNDING: The Alan B Brown Chair, The Posluns Family Fund, The Lusi Wong Fund, and the Princess Margaret Cancer Foundation.

Transcriptional profiling of uterine leiomyoma rats treated by a traditional herb pair, Curcumae rhizoma and Sparganii rhizoma.

The aim of this study was to elucidate the concise effects of a traditional herb pair, Curcumae rhizoma-Sparganii rhizoma (CRSR), on uterine leiomyoma (UL) by analyzing transcriptional profiling. The UL rat model was made by intramuscular injection of progesterone and gavage administration of diethylstilbestrol. From 11 weeks of the establishment of the model, rats of the UL+CRSR group were gavaged daily with CRSR (6.67 g/kg). The serum concentrations of progesterone (P) and estradiol (E2) were determined by radioimmunoassay, the uterine index was measured by caliper measurement, and the pathological status was observed by hematoxylin and eosin stain. Gene expression profiling was checked by NimbleGen Rat Gene Expression Microarrays. The results indicated that the uterine mass of UL+CRSR rats was significantly shrunk and serum P and E2 levels significantly reduced compared to UL animals and nearly to the level of normal rats. Results of microarrays displayed the extensive inhibition of CRSR upon the expression of proliferation and deposition of extracellular matrix (ECM)-related genes, and significantly regulated a wide range of metabolism disorders. Furthermore, CRSR extensively regulated key pathways of the UL process, such as MAPK, PPAR, Notch, and TGF-ß/Smad. Regulation of the crucial pathways for the UL process and ECM metabolism may be the underlying mechanisms of CRSR treatment. Further studies will provide clear clues for effectively treating UL with CRSR.

Transcriptional profiling of uterine leiomyoma rats treated by a traditional herb pair, Curcumae rhizoma and Sparganii rhizoma

The aim of this study was to elucidate the concise effects of a traditional herb pair, Curcumae rhizoma-Sparganii rhizoma (CRSR), on uterine leiomyoma (UL) by analyzing transcriptional profiling. The UL rat model was made by intramuscular injection of progesterone and gavage administration of diethylstilbestrol. From 11 weeks of the establishment of the model, rats of the UL+CRSR group were gavaged daily with CRSR (6.67 g/kg). The serum concentrations of progesterone (P) and estradiol (E2) were determined by radioimmunoassay, the uterine index was measured by caliper measurement, and the pathological status was observed by hematoxylin and eosin stain. Gene expression profiling was checked by NimbleGen Rat Gene Expression Microarrays. The results indicated that the uterine mass of UL+CRSR rats was significantly shrunk and serum P and E2 levels significantly reduced compared to UL animals and nearly to the level of normal rats. Results of microarrays displayed the extensive inhibition of CRSR upon the expression of proliferation and deposition of extracellular matrix (ECM)-related genes, and significantly regulated a wide range of metabolism disorders. Furthermore, CRSR extensively regulated key pathways of the UL process, such as MAPK, PPAR, Notch, and TGF-β/Smad. Regulation of the crucial pathways for the UL process and ECM metabolism may be the underlying mechanisms of CRSR treatment. Further studies will provide clear clues for effectively treating UL with CRSR.

Establishment of a rat model for uterine leiomyomas based on Western and traditional Chinese medicine theories.

Uterine leiomyomas (ULs) are benign monoclonal tumors that arise from the underlying myometrial tissue in the uterus. Effective therapies are still lacking because of poor understanding of the pathophysiology and epidemiology. Hence, it is urgent to establish efficient animal models to screen novel anti-UL therapies. In this study, for the first time, traditional Chinese medicine and Western medicine were combined to establish an animal model of ULs in rats. In order to evaluate the function and value of the novel model, it was compared with other models. The long-term and short-term rat models for ULs were established using progesterone and diethylstilbestrol. Rats in Qi stagnation and blood stasis group were injected with epinephrine hydrochloride and received chronic unpredictable stress for two weeks. Rats in combining disease with syndrome group (CDWSG) received not only epinephrine hydrochloride injection and chronic unpredictable stress but also progesterone and diethylstilbestrol treatment. We analyzed differences in organ coefficient, uterus size, uterine pathology, concentrations of progesterone, estradiol, progesterone receptor, estrogen receptor, expression of desmin, α-smooth muscle actin, and vimentin among the five groups. The animal model of ULs was successfully constructed by loading the rats with estrogen and progesterone. The rat model of CDWSG was more stable than other groups and the method was the most efficient.

Establishment of a rat model for uterine leiomyomas based on Western and traditional Chinese medicine theories

Uterine leiomyomas (ULs) are benign monoclonal tumors that arise from the underlying myometrial tissue in the uterus. Effective therapies are still lacking because of poor understanding of the pathophysiology and epidemiology. Hence, it is urgent to establish efficient animal models to screen novel anti-UL therapies. In this study, for the first time, traditional Chinese medicine and Western medicine were combined to establish an animal model of ULs in rats. In order to evaluate the function and value of the novel model, it was compared with other models. The long-term and short-term rat models for ULs were established using progesterone and diethylstilbestrol. Rats in Qi stagnation and blood stasis group were injected with epinephrine hydrochloride and received chronic unpredictable stress for two weeks. Rats in combining disease with syndrome group (CDWSG) received not only epinephrine hydrochloride injection and chronic unpredictable stress but also progesterone and diethylstilbestrol treatment. We analyzed differences in organ coefficient, uterus size, uterine pathology, concentrations of progesterone, estradiol, progesterone receptor, estrogen receptor, expression of desmin, α-smooth muscle actin, and vimentin among the five groups. The animal model of ULs was successfully constructed by loading the rats with estrogen and progesterone. The rat model of CDWSG was more stable than other groups and the method was the most efficient.

Anti-thyroid drug-induced lupus: a case report and review of the literature

We report a case of drug-induced lupus (DIL) on a Chinese woman caused by methimazole (MMI). This report discusses DIL associated with MMI and briefly reviewed the literature concerning to anti-thyroid DIL.

Anti-thyroid drug-induced lupus: a case report and review of the literature.

We report a case of drug-induced lupus (DIL) on a Chinese woman caused by methimazole (MMI). This report discusses DIL associated with MMI and briefly reviewed the literature concerning to anti-thyroid DIL.

Comparison of wavefront aberrations under cycloplegic, scotopic and photopic conditions using WaveScan.

PURPOSE: To evaluate the differences of wavefront aberrations under cycloplegic, scotopic and photopic conditions. METHODS: A total of 174 eyes of 105 patients were measured using the wavefront sensor (WaveScan® 3.62) under different pupil conditions: cycloplegic 8.58 ± 0.54 mm (6.4 mm - 9.5 mm), scotopic 7.53 ± 0.69 mm (5.7 mm - 9.1 mm) and photopic 6.08 ± 1.14 mm (4.1 mm - 8.8 mm). The pupil diameter, standard Zernike coefficients, root mean square of higher-order aberrations and dominant aberrations were compared between cycloplegic and scotopic conditions, and between scotopic and photopic conditions. RESULTS: The pupil diameter was 7.53 ± 0.69 mm under the scotopic condition, which reached the requirement of about 6.5 mm optical zone design in the wavefront-guided surgery and prevented measurement error due to the pupil centroid shift caused by mydriatics. Pharmacological pupil dilation induced increase of standard Zernike coefficients Z(3)(-3), Z(4)(0) and Z(5)(-5). The higher-order aberrations, third-order aberration, fourth-order aberration, fifth-order aberration, sixth-order aberration, and spherical aberration increased statistically significantly, compared to the scotopic condition (P<0.010). When the scotopic condition shifted to the photopic condition, the standard Zernike coefficients Z(4)(0), Z(4)(2), Z(6)(-4), Z(6)(-2), Z(6)(2) decreased and all the higher-order aberrations decreased statistically significantly (P<0.010), demonstrating that accommodative miosis can significantly improve vision under the photopic condition. Under the three conditions, the vertical coma aberration appears the most frequently within the dominant aberrations without significant effect by pupil size variance, and the proportion of spherical aberrations decreased with the decrease of the pupil size. CONCLUSIONS: The wavefront aberrations are significantly different under cycloplegic, scotopic and photopic conditions. Using the wavefront sensor (VISX WaveScan) to measure scotopic wavefront aberrations is feasible for the wavefront-guided refractive surgery.

Comparison of wavefront aberrations under cycloplegic, scotopic and photopic conditions using WaveScan / Comparação de aberrações de frente de onda sob cicloplegia, condições escotópica e fotópica usando WaveScan

PURPOSE: To evaluate the differences of wavefront aberrations under cycloplegic, scotopic and photopic conditions. METHODS: A total of 174 eyes of 105 patients were measured using the wavefront sensor (WaveScan® 3.62) under different pupil conditions: cycloplegic 8.58 ± 0.54 mm (6.4 mm - 9.5 mm), scotopic 7.53 ± 0.69 mm (5.7 mm - 9.1 mm) and photopic 6.08 ± 1.14 mm (4.1 mm - 8.8 mm). The pupil diameter, standard Zernike coefficients, root mean square of higher-order aberrations and dominant aberrations were compared between cycloplegic and scotopic conditions, and between scotopic and photopic conditions. RESULTS: The pupil diameter was 7.53 ± 0.69 mm under the scotopic condition, which reached the requirement of about 6.5 mm optical zone design in the wavefront-guided surgery and prevented measurement error due to the pupil centroid shift caused by mydriatics. Pharmacological pupil dilation induced increase of standard Zernike coefficients Z3-3, Z4(0) and Z5-5. The higher-order aberrations, third-order aberration, fourth-order aberration, fifth-order aberration, sixth-order aberration, and spherical aberration increased statistically significantly, compared to the scotopic condition (P<0.010). When the scotopic condition shifted to the photopic condition, the standard Zernike coefficients Z4(0), Z4², Z6-4, Z6-2, Z6² decreased and all the higher-order aberrations decreased statistically significantly (P<0.010), demonstrating that accommodative miosis can significantly improve vision under the photopic condition. Under the three conditions, the vertical coma aberration appears the most frequently within the dominant aberrations without significant effect by pupil size variance, and the proportion of spherical aberrations decreased with the decrease of the pupil size. CONCLUSIONS: The wavefront aberrations are significantly different under cycloplegic, scotopic and photopic conditions. Using the wavefront sensor (VISX WaveScan) to measure scotopic wavefront aberrations is feasible for the wavefront-guided refractive surgery.

OBJETIVO: Avaliar as diferenças de aberrações de frente de onda, em diferentes condições pupilares: sob cicloplegia, escotópica e fotópica. MÉTODOS: Um total de 174 olhos de 105 pacientes foram avaliados utilizando o sensor de frente de onda (WaveScan® 3.62) em diferentes condições pupilares: sob cicloplegia 8,58 ± 0,54 mm (6.4 mm-9.5 mm), escotópica 7,53 ± 0,69 mm (5,7 mm - 9,1 mm) e fotópica 6,08 ± 1,14 mm (4,1 mm - 8,8 mm). Diâmetro da pupila, coeficientes de Zernike, RMS ("Root Mean Square") das aberrações de alta ordem e as aberrações dominantes foram comparados entre as condições sob cicloplegia e escotópica, e entre as condições escotópica e fotópica. RESULTADOS: O diâmetro da pupila foi 7,53 ± 0.69 mm sob a condição escotópica e atingiu a exigência de cerca de 6,5 mm de zona óptica na cirurgia baseada em análise de frentes de ondas, evitando erros de medição consequentes à mudança de centroide pupilar provocada por midriáticos. A dilatação farmacológica da pupila induziu aumento dos coeficientes de Zernike Z3-3, Z4(0) e Z5-5. As aberrações de mais alta ordem (terceira, quarta, quinta e sexta ordem) e a aberração esférica aumentaram de forma estatisticamente significativa, em comparação com a condição escotópica (P<0,010). Quando a condição escotópica se mudou para a condição fotópica, os coeficientes de Zernike Z4(0), Z4², Z6-4, Z6-2, Z6² e todas as aberrações de alta ordem diminuíram de forma estatisticamente significativa (P<0,010), demonstrando que a miose acomodativa pode significativamente melhorar a visão sob a condição fotópica. Sob as três condições, a aberração coma vertical apareceu mais frequentemente dentro das aberrações dominantes, sem influência significativa da variação do tamanho da pupila, e a proporção de aberração esférica diminuiu com a diminuição do tamanho da pupila. CONCLUSÕES: As aberrações de frente de onda são significativamente diferentes sob cicloplegia, condições escotópica e fotópica. O uso do sensor de frentes de onda (VISX WaveScan) para medir as aberrações de frente de onda escotópicas é uma opção viável para a cirurgia refrativa baseada em análise de frentes de onda.