Access to Functionalized Cyclohex-2-enones from a Multicomponent Cascade Reaction of Readily Available Alkynes, Ketones, and Ethyl Acetoacetate.

The synthesis of cyclohex-2-enone derivatives is a topic of current interest in organic chemistry. A novel three-component cascade reaction of alkynes with ketones and ethyl acetoacetate has been uncovered. This process provides di- and trisubstituted cyclohex-2-enones in good yields with excellent functional group tolerance. A variety of terminal alkynes and a wide range of aryl, alkyl, and cyclic ketones are viable in this transformation. Successful scale-up preparation and synthetic transformations have demonstrated the potential of this simple operating protocol.

LI-RADS category 3, 4, and M observations: a multiple parameters diagnostic model for hepatocellular carcinoma.

BACKGROUND: Hepatic lesions categorized as LR-3, LR-4, and LR-M are challenging to accurately assess and diagnose. PURPOSE: To combine potential clinical and/or magnetic resonance imaging (MRI) features for a more comprehensive hepatocellular carcinoma (HCC) versus non-HCC diagnosis for patients with LR-3, LR-4, and LR-M graded lesions. METHODS: Data were consecutively retrieved from 82 at-risk patients with LR-3 (n = 43), LR-4 (n = 20), and LR-M (n = 23) lesions. Significant findings for the differentiation of HCC and non-HCC, including MRI features and clinical factors, were identified with univariable and multivariable analyses. The variables for a prediction model were selected through stepwise use of Akaike's Information Criterion (AIC) to build multivariable logistic regression model. RESULTS: Serum alpha-fetoprotein (AFP) >16.2 ng/mL (odds ratio [OR] = 22.4; P = 0.006), septum (OR = 52.1; P = 0.011), and hepatobiliary phase (HBP) hypointensity (OR = 40.2; P = 0.001) were confirmed as independent predictors of HCC. When combining the three predictors and mild-moderate T2 hyperintensity, the model (AIC = 50.91) showed good accuracy with a C-index of 0.948. CONCLUSION: In at-risk patients with LR-3, LR-4, or LR-M lesions, integrating AFP, septum, HBP hypointensity, and mild-moderate T2 hyperintensity achieved high diagnostic performance for the diagnosis of HCC.

Impact of Allergy and Eosinophils on the Morbidity of Chronic Rhinosinusitis with Nasal Polyps in Northwest China.

BACKGROUND: Nasal polyps are a common health problem that can significantly impact the quality of life. OBJECTIVE: To analyze the impact of allergy and peripheral eosinophils (EOS) on the morbidity of chronic rhinosinusitis with nasal polyps (CRSwNP) in Northwest China. METHODS: A retrospective cohort of 323 patients who underwent endoscopic sinus surgery (ESS) for chronic rhinosinusitis without nasal polyps (CRSsNP) and CRSwNP in Xijing Hospital was studied between January 5, 2011, and January 4, 2015. All of the patients underwent an allergen skin prick test and peripheral blood EOS inspection. Detailed information regarding the impact of allergy and EOS on the morbidity of CRSwNP was collected. Potential risk factors associated with nasal polyps were explored using logistic regression analysis. Multivariate logistic regression was performed to identify independent risk factors. RESULTS: The results revealed that EOS is an important risk factor for nasal polyps. In the univariate analysis, the adjusted OR was 2.01 (95% CI 1.08-3.72; p = 0.027). In the multivariate analysis, the adjusted OR was 2.02 (95% CI 1.08-3.76; p = 0.027). Compared to allergic rhinitis and normal EOS levels, nonallergic rhinitis and elevated EOS levels constituted a risk factor for CRSwNP (OR = 2.70; 95% CI 1.32-5.50). Compared to allergen-positive and EOS-normal status, allergen-negative and elevated-EOS status constituted a risk factor for CRSwNP (OR = 2.95; 95% CI 1.38-6.33). CONCLUSION: EOS is a significant factor related to the morbidity of CRSwNP in Northwest China. Elevated EOS levels occurring in the context of nonallergic rhinitis constitute a risk factor for CRSwNP. Similarly, elevated EOS levels occurring in the context of allergen-negative rhinitis are also an important risk factor for morbidity of CRSwNP.

Histone deacetylase inhibitor sodium butyrate attenuates gentamicin-induced hearing loss in vivo.

OBJECTIVE: Although histone deacetylase (HDAC) inhibition has been shown to protect against gentamicin (GM)-induced hearing loss in vitro, its protective effect has not been proven in vivo. In the present study, the aim was to investigate the protective effect of sodium butyrate (NaB), a specific HDAC inhibitor, on GM-induced ototoxicity in vivo. METHODS: Forty 8-week-old albino guinea pigs were divided into two experimental groups. Group 1 (n=10) underwent bilateral ear surgery to place sponges (0.3mm(3)) permeated with NaB (10µl, 100mg/ml) and physiological saline (10µl; control) in the right and left round window niches, respectively. The sponges were left in place for 15days to evaluate the effects of NaB at the applied concentration. Group 2 (n=30) underwent the same bilateral ear surgery described for Group 1, except three days after surgery, the animals received intramuscular GM injections (200mg/kg/day) for 5 consecutive days. Seven days after the final GM injection, the protective effects of NaB were examined. RESULTS: After 15days of NaB treatment (10µl, 100mg/ml), an increase in histone acetylation was detected in Corti organ samples. Auditory brainstem response (ABR) threshold shifts and hair cell loss were also reduced in NaB-treated ears after GM administration. Furthermore, GM treatment increased HDAC1 expression in outer hair cells (OHCs) in vivo, and NaB blocked this action. CONCLUSION: GM increases HDAC1 expression in OHCs, and NaB is able to block this action. Thus, it appears that the HDAC inhibitor, NaB, attenuates GM-induced hearing loss in guinea pigs.

Single-Molecule Force Spectroscopy of Deoxyribonucleic Acid and Deoxyribonucleic Acid Polymerase Activity Impacted by Alkylating Agents.

DNA alkylating agents are widely used in anticancer pharmacology. Although shown to induce cross-linking and/or methylation of DNA, how they affect the mechanical properties of DNA and activity of DNA enzymes remains to be elucidated. Here, we perform single-molecule optical tweezer experiments on DNA treated with alkylating agents, including melphalan, cisplatin, and dacarbazine. While all three drugs induce a significant increase of overstretching force and a reduction of hysteresis, suggesting stabilization of DNA against shearing forces, their effects on elasticity of DNA were quite different, with the largest change in persistence length induced by cisplatin. Furthermore, we find that these alkylating-agent-induced changes on DNA have different effects on processivity of DNA polymerase, with melphalan and cisplatin showing significantly reduced activity and dacarbazine showing little effect. Overall, our results provide new insights into the effects for these alkylating agents, which could potentially facilitate a better design of related drugs.

Texture Analysis of Three-Dimensional MRI Images May Differentiate Borderline and Malignant Epithelial Ovarian Tumors.

OBJECTIVE: To explore the value of magnetic resonance imaging (MRI)-based whole tumor texture analysis in differentiating borderline epithelial ovarian tumors (BEOTs) from FIGO stage I/II malignant epithelial ovarian tumors (MEOTs). MATERIALS AND METHODS: A total of 88 patients with histopathologically confirmed ovarian epithelial tumors after surgical resection, including 30 BEOT and 58 MEOT patients, were divided into a training group (n = 62) and a test group (n = 26). The clinical and conventional MRI features were retrospectively reviewed. The texture features of tumors, based on T2-weighted imaging, diffusion-weighted imaging, and contrast-enhanced T1-weighted imaging, were extracted using MaZda software and the three top weighted texture features were selected by using the Random Forest algorithm. A non-texture logistic regression model in the training group was built to include those clinical and conventional MRI variables with p value < 0.10. Subsequently, a combined model integrating non-texture information and texture features was built for the training group. The model, evaluated using patients in the training group, was then applied to patients in the test group. Finally, receiver operating characteristic (ROC) curves were used to assess the diagnostic performance of the models. RESULTS: The combined model showed superior performance in categorizing BEOTs and MEOTs (sensitivity, 92.5%; specificity, 86.4%; accuracy, 90.3%; area under the ROC curve [AUC], 0.962) than the non-texture model (sensitivity, 78.3%; specificity, 84.6%; accuracy, 82.3%; AUC, 0.818). The AUCs were statistically different (p value = 0.038). In the test group, the AUCs, sensitivity, specificity, and accuracy were 0.840, 73.3%, 90.1%, and 80.8% when the non-texture model was used and 0.896, 75.0%, 94.0%, and 88.5% when the combined model was used. CONCLUSION: MRI-based texture features combined with clinical and conventional MRI features may assist in differentitating between BEOT and FIGO stage I/II MEOT patients.

Influences of S100A8 and S100A9 on Proliferation of Nasopharyngeal Carcinoma Cells through PI3K/Akt Signaling Pathway.

OBJECTIVE: To investigate the effects of S100A8 and S100A9 on proliferation in nasopharyngeal carcinoma cells and the regulatory effects of PI3K/Akt signaling pathway. METHODS: Nasopharyngeal carcinoma cells (CNE1) were cultured and randomly divided into three groups: control group, S100A8/S100A9 overexpression group, and siRNA S100A8/S100A9 group. CCK-8 method was used to detect the effect of S100A8 and S100A9 on the viability of nasopharyngeal carcinoma cells. The effects of S100A8 and S100A9 on the colony forming ability of nasopharyngeal carcinoma cells were detected by colony forming assay. The effects of S100A8 and S100A9 on the proliferation of nasopharyngeal carcinoma cells were detected by EdU staining. The mRNA levels of PI3K and Akt were detected by RT-PCR. The expression levels of PI3K and Akt in NPC cells were detected by Western blot. Wortmannin, an inhibitor of PI3K/Akt pathway, was used to inhibit the activation of PI3K/Akt pathway. RESULTS: Compared with the control group, the cell viability, the number of plate clones, the positive rate of EdU staining, and the mRNA and protein levels of PI3K and Akt were increased in the overexpression group. Compared with the control group, the cell viability, the number of plate clones, the positive rate of EdU staining, and the mRNA and protein levels of PI3K and Akt were decreased in the siRNA group. After inhibiting the activation of PI3K/Akt pathway, the viability of NPC cells in the overexpression group decreased significantly at 48 h and 72 h, while that in the siRNA group increased significantly. CONCLUSION: SiRNA S100A8 and S100A9 could inhibit the proliferation of nasopharyngeal carcinoma cells, and the underlying mechanism may be related to the inhibition of PI3K/Akt signaling pathway.

A Radiomics Nomogram for Preoperative Prediction of Early Recurrence of Small Hepatocellular Carcinoma After Surgical Resection or Radiofrequency Ablation.

BACKGROUND: Patients with small hepatocellular carcinoma (HCC) (3 cm) still have a poor prognosis. The purpose of this study was to develop a radiomics nomogram to preoperatively predict early recurrence (ER) (2 years) of small HCC. METHODS: The study population included 111 patients with small HCC who underwent surgical resection (SR) or radiofrequency ablation (RFA) between September 2015 and September 2018 and were followed for at least 2 years. Radiomic features were extracted from the entire tumor by using the MaZda software. The least absolute shrinkage and selection operator (LASS0) method was applied for feature selection, and radiomics signature construction. A rad-score was then calculated. Multivariable logistic regression analysis was used to establish a prediction model including independent clinical risk factors, radiologic features and rad-score, which was ultimately presented as a radiomics nomogram. The predictive ability of the nomogram was evaluated using the area under the receiver operating characteristic (ROC) curve and internal validation was performed via bootstrap resampling and 5-fold cross-validation method. RESULTS: A total of 53 (53/111, 47.7%) patients had confirmed ER according to the final clinical outcomes. In univariate logistic regression analysis, cirrhosis and hepatitis B infection (P=0.015 and 0.083, respectively), hepatobiliary phase hypointensity (P=0.089), Child-Pugh score (P=0.083), the preoperative platelet count (P=0.003), and rad-score (P<0.001) were correlated with ER. However, after multivariate logistic regression analysis, only the preoperative platelet count and rad-score were included as predictors in the final model. The area under ROC curve (AUC) of the radiomics nomogram to predict ER of small HCC was 0.981 (95% CI: 0.957, 1.00), while the AUC verified by bootstrap is 0.980 (95% CI: 0.962, 1.00), indicating the goodness-of-fit of the final model. CONCLUSIONS: The radiomics nomogram containing the clinical risk factors and rad-score can be used as a quantitative tool to preoperatively predict individual probability of ER of small HCC.

Hepatobiliary phase hypointensity on gadobenate dimeglumine-enhanced magnetic resonance imaging may improve the diagnosis of hepatocellular carcinoma.

BACKGROUND: To determine the clinical value of hepatobiliary phase (HBP) hypointensity for noninvasive diagnosis of hepatocellular carcinoma (HCC). METHODS: A total of 246 high-risk patients with 263 selected nodules (126 HCCs, 137 non-HCCs) undergoing gadobenate dimeglumine (Gd-BOPTA)-enhanced magnetic resonance imaging (MRI) were included in the study. Imaging-based diagnoses of small (≤3 cm) and large (>3 cm) HCCs were made using the following 4 criteria: (I) non-rim arterial phase hyper-enhancement (APHE) plus hypointensity on the portal venous phase (PVP); (II) non-rim APHE plus hypointensity on the PVP and/or transitional phase (TP); (III) non-rim APHE plus hypointensity on the PVP and/or TP and/or HBP; (IV) criterion 3 plus non-LR-1/2/M. Based on typical imaging features, LR-1, LR-2, or LR-M (if definitely benign, probably benign, malignant but not HCC specific, respectively) were defined according to the Liver Imaging Reporting and Data System (LI-RADS). Sensitivities and specificities of imaging criteria were calculated and compared using McNemar's test. RESULTS: Among the diagnostic criteria for small HCCs, criterion 3 and 4, which included HBP hypointensity, showed significantly higher sensitivities (96.4% and 94.6%, respectively) than criterion 1 (58.9%, P<0.001 for both). Moreover, criterion 4, which included HBP hypointensity and ancillary features, showed significantly higher specificity (94.7%) than criterion 3 (66.7%, P<0.001) and comparable specificity to criterion 1 (97.4%, P=0.375), achieving the highest accuracies (94.7%). The diagnostic performance of criterion 4 for large HCCs was similar to that for small HCCs. CONCLUSIONS: HBP hypointensity acquired from Gd-BOPTA-MRI can improve sensitivity and maintain high specificity in the diagnosis of both small and large HCCs after excluding benignities or non-HCC malignancies according to characteristic imaging features.

A radiomics nomogram based on contrast-enhanced MRI for preoperative prediction of macrotrabecular-massive hepatocellular carcinoma.

BACKGROUND: Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) represents an aggressive form of hepatocellular carcinoma and is associated with poor survival outcomes. AIMS: This study aimed to develop a radiomics nomogram based on contrast-enhanced MRI for preoperative prediction of MTM-HCC. METHODS: This study enrolled 88 patients with histologically confirmed HCC, including 32 MTM-HCCs and 56 Non-MTM-HCCs. The clinical and gadobenate dimeglumine (Gd)-enhanced MRI features were retrospectively reviewed by two abdominal radiologists. The regions of interest (ROIs) on the largest cross-sectional image and two adjacent images of the tumor, from which radiomics features were extracted via MaZda software and a radiomics score (Rad-score) was calculated via Python software. Combined with the Rad-score and independent imaging factors, a radiomics nomogram was constructed using R software. Nomogram performance was estimated with calibration curve. RESULTS: A total of eleven top weighted radiomics features were selected among five sequences of MR images. There was a significant difference in Rad-score between MTM-HCC and non-MTM-HCC patients (P < 0.001), where patients with MTM-HCC generally had higher Rad-scores (absolute value). After multivariate analysis, radiomics score (OR = 7.794, P < 0.001) and intratumor fat (OR = 9.963, P = 0.014) were determined as independent predictors associated with MTM-HCC. The area under the receiver operating characteristic (ROC) curve of the selected model was 0.813 (95% CI 0.714-0.912) and the optimal cutoff value was 0.60. The nomogram showed overall satisfactory prediction performance (AUC = 0.785 [95% CI 0.684-0.886]). CONCLUSIONS: A contrast-enhanced MRI-based radiomics nomogram may be useful for preoperative prediction of MTM-HCC in primary HCC patients, allowing opportunity to improve the treatment course and patient outcomes.

[Analysis of comorbid psychiatric disorders in patients with chronic otitis media associated tinnitus].

Objective:To analyze the distribution of comorbid psychiatric disorders in patients with chronic otitis media associated tinnitus. Method:The data of patients with chronic otitis media associated tinnitus who accepted surgical treatments from July 2017 to September 2018 were retrospectively analyzed. All patients accepted pure tone audiometry and acoustic conductance examination and were requested to fill the tinnitus history questionnaire, THI, TEQ, SAS, SDS and PSQI scales before operation. When the SAS or/and SDS score ≥50 the patient was judged as having comorbid psychiatric disorders. When the PSQI score>6 the patient was judged as having comorbid sleep disorder, and then all the results were analyzed. Result:Sixty-two patients were included in the study, 43 cases were diagnosed as chronic suppurative otitis media, and 19 cases were diagnosed as middle ear cholesteatoma. The average course of chronic otitis media or middle ear cholesteatoma was（14.38±14.06） years, while the average course of tinnitus was（8.39±11.69） years. There were 32 cases with mild to moderate tinnitus（gradeⅠ-Ⅱ）（51.61%） and 30 cases with moderate to severe tinnitus（grade Ⅲ-Ⅴ）（48.39%）. Before operation, there were 4 cases（6.45%） with normal hearing, 38 cases（61.29%） with conductive hearing loss, and 20 cases（32.36%） with mixed hearing loss. There was no significant difference in tinnitus severity between different hearing loss degrees and types（P>0.05）. The average SAS score was 45.10±11.61, and the average SDS score was 43.48±14.67, both higher than the normal modulus（30 points）, among which 27 cases（44.00%） comorbid psychiatric disorders. The THI score in patients with comorbid psychiatric disorders（57.85±21.1） was significantly higher than that in patients without comorbid psychiatric disorders（29.2±17.39）（P<0.05）. The PSQI score in patients with comorbid psychiatric disorders（8.86±3.47） was significantly higher than that of those without comorbid psychiatric disorders（6.24±2.54）（P<0.05）. Fifty-three patients were followed up for 0.5 to 1.8 years after operation, and in 43 cases the tinnitus was reduced or disappeared after operation（the effective rate was 81.13%）. There were no significant difference between patients in tinnitus relief group and those in tinnitus without relief group in age, sex, course of the disease, type of the disease, with or without comorbid psychiatric disorders and/or sleep disorder, postoperative hearing improvement. Conclusion:Comorbid psychiatric disorders are common in patients with chronic otitis media associated tinnitus and the tinnitus in patients with comorbid psychiatric disorders is significantly more serious than that those without. For the treatment of chronic otitis media associated tinnitus, besides surgery, the complications such as psychiatric and sleep disorders and so on should be evaluated and treated accordingly.

Quantitative analysis of multiphase magnetic resonance images may assist prediction of histopathological grade of small hepatocellular carcinoma.

BACKGROUND: The aim of the study was to investigate whether preoperative quantitative analysis of multiphase magnetic resonance images may assist in predicting the pathological grade of small hepatocellular carcinoma (HCC). METHODS: A total of 49 patients with small HCCs (≤3 cm) underwent multiphase magnetic resonance imaging (MRI) and were retrospectively reviewed. Routine unenhanced and post gadobenate dimeglumine (Gd-BOPTA)-enhanced MRI were preoperatively performed. Signal intensity (SI) was measured within the designated region of interest (ROI) including those of the lesion and paraspinous muscles. The lesion-to-paraspinous muscle relative contrast ratio (RCR) on T2-weighted (T2W) imaging, diffusion-weighted (DW) imaging, and dynamic phase Gd-BOPTA-enhanced T1W (T1-weighted) imaging were calculated, and statistical analysis was performed to determine the predictive power for the histological grade. RESULTS: In all, 49 cases were included comprising 3 well-differentiated (WD) HCCs, 36 moderately differentiated (MD) HCCs, and 10 poorly differentiated (PD) HCCs. There was a negative correlation between the RCR and pathological grade of small HCC in the arterial phase [correlation coefficient (ρ)=-0.305, P<0.05]. However, there was no correlation between RCR in other phases and pathological grade (P>0.05 for all). There was also no correlation between tumor margin, tumor location, cystic/necrotic change, intratumoral fat, enhancement pattern, tumor capsule, tumor boundary or tumor size, and any of the differentiation categories (P>0.05 for all). CONCLUSIONS: The lesion-to-paraspinous muscle RCR on arterial phase Gd-BOPTA-enhanced T1W imaging may be useful for the prediction of the histological characteristics of small HCC.

[The effect of one-stage tympanoplasty for stapes fixation with tympanosclerosis].

Objective:To evaluate hearing outcome and complications of one-stage tympanoplasty in patients with stapes fixation due to tympanosclerosis. Method:59 patients（sixty-one ears） underwent one-stage tympanoplasty for stapes fixation due to tympanosclerosis were retrospectively analyzed. Stapes fixation due to tympanosclerosis were proved during the surgery in these patients diagnosed with chronic otitis media. For all the patients, tympanosclerotic plaques around stapes were removed for stapes mobilization. Then the ossicular chain was rebuilt by autogenous incus or PORP. The pre-and post-operative audiometric results（500 Hz, 1 kHz, 2 kHz and 4 kHz） were evaluated for each patient. Improvement of pure-tone average more than 10 dB postoperatively were accepted as success criteria. Result:Complications included temporary facial paralysis（1/61）, temporary vertigo（2/61）, mild elevation in bone conduction thresholds（2/61） and delayed healing of tympanic membrane（1/61）. Postoperative（1 and 3 months） bone conduction thresholds improved at frequencies of 1 and 2 kHz（P<0.01）. Postoperative（1 and 2 years） air conduction thresholds improved at all frequencies（P<0.01 or P<0.05）. A gain ≥10 dB in pure-tone average was found in 44（72.13%） patients at 1 year after surgery. The air conduction levels were significantly improved in both autogenous incus and PORP groups（P<0.01）. There was no difference about success rate between these two groups（P>0.05）. Conclusion:For patients with stapes fixation due to tympanosclerosis, one-stage tympanoplasty can improve hearing threshold though ossicular chain reconstruction and stapes release. The major complications such as facial paralysis and sensorineural hearing loss should be avoided by delicate surgical operation.

[Analysis of surgical effect on middle ear cholesterol granuloma].

Objective:To evaluate surgical effects on middle ear cholesterol granuloma（CG）. Method:The patients receiving surgery due to middle ear CG were retrospectively analyzed. The choice of operative methods was made according to medical history, endotoscope, pure-tone audiometry and temporal bone CT. Tympanostomy tube（TT） insertion was performed on 12 patients; canal wall up（CWU） tympanoplasty combined with tympanostomy tube was performed on 40 patients, and canal wall down（CWD） tympanoplasty combined with TT on 14 cases. The pre-and postoperative audiometric results（500, 1000, 2000 and 4000 Hz） were evaluated for each patient. Then the average air-bone gap（ABG） was analyzed. Result:One patient had postoperative tube obstruction. One patient who performed only TT insertion recurred. Secretory otitis media occurred in one case undergoing CWU tympanoplasty after removal of the ventilation tube. For TT insertion group, pre-and postoperative ABG levels were （21.25±5.96） dB and （8.85±6.49） dB, respectively（P<0.01）. For CWU+TT group, pre-and postoperative ABG levels were （34.19±10.43） dB and （23.55±12.48） dB, respectively（P<0.01）. For CWD+TT group, pre-and postoperative ABG levels were （36.43±12.11） dB and （25.71±13.50） dB, respectively（P<0.01）. Conclusion:The aim of surgical treatment for middle ear CG includes thorough removal of lesions, improvement of ventilation and drainage of middle ear. Individualized surgical strategy should be adopted according to the patients' conditions. And long-term follow-up should be done after operation.

miR-195 inhibits the proliferation and migration of chondrocytes by targeting GIT1.

Previous studies have demonstrated that G-protein coupled receptor kinase interacting protein-1 (GIT1) and microRNAs (miRNAs) serve an important role in chondrocyte proliferation and migration. However, a limited number of studies conducted thus far have investigated the association between GIT1 and miRNAs. In the present study, putative miR­195 binding sites in the GIT1 3'­untranslated region were identified using common bioinformatic algorithms (miRanda, TargetScan, miRBase and miRWalk), and it was demonstrated that they may be involved in regulating GIT1 expression. Following transfection of miR­195 mimics in chondrocytes, the expression of GIT1 was significantly reduced, whereas the expression was significantly increased following transfection with miR­195 inhibitors. In addition, the results of the current study demonstrated that increased miR­195 expression may downregulate chondrocyte proliferation and reduce cell migration. However, chondrocyte proliferation and migration was enhanced following suppression of miR­195 expression. Furthermore, upon co­transfection of miR­195 and GIT1 expression vectors, the inhibitory effect of miR­195 on chondrocyte proliferation and migration was attenuated. Therefore, miR­195 may affect chondrocyte proliferation and migration via targeted regulation of GIT1 expression. The results of the current study provide novel evidence for the regulatory mechanisms of miRNAs in bone and cartilage tissues, which may facilitate further research and provide a greater understanding of different osteoarticular diseases.

Computational exploration of the activated pathways associated with DNA damage response in breast cancer.

Molecular signaling events regulate cellular activity. Cancer stimulating signals trigger cellular responses that evade the regulatory control of cell development. To understand the mechanism of signaling regulation in cancer, it is necessary to identify the activated pathways in cancer. We have developed RepairPATH, a computational algorithm that explores the activated signaling pathways in cancer. The RepairPATH integrates RepairNET, an assembled protein interaction network associated with DNA damage response, with the gene expression profiles derived from the microarray data. Based on the observation that cofunctional proteins often exhibit correlated gene expression profiles, it identifies the activated signaling pathways in cancer by systematically searching the RepairNET for proteins with significantly correlated gene expression profiles. Analyzing the gene expression profiles of breast cancer, we found distinct similarities and differences in the activated signaling pathways between the samples from the patients who developed metastases and the samples from the patients who were disease free within 5 years. The cellular pathways associated with the various DNA repair mechanisms and the cell-cycle checkpoint controls are found to be activated in both sample groups. One of the most intriguing findings is that the pathways associated with different cellular processes are functionally coordinated through BRCA1 in the disease-free sample group, whereas such functional coordination is absent in the samples from patients who developed metastases. Our analysis revealed the potential cellular pathways that regulate the signaling events in breast cancer.

Sulforaphane activates the cerebral vascular Nrf2-ARE pathway and suppresses inflammation to attenuate cerebral vasospasm in rat with subarachnoid hemorrhage.

Nrf2-ARE pathway reportedly plays a protective role in several central nervous system diseases. No study has explored the role of the Nrf2-ARE pathway in cerebral vasospasm(CVS) after subarachnoid hemorrhage(SAH). The purpose of the present study was to investigate the activation of the cerebral vascular Nrf2-ARE pathway and to determine the potential role of this pathway in the development of CVS following SAH. We investigated whether the administration of sulforaphane (SFN, a specific Nrf2 activator) modulated vascular caliber, Nrf2-ARE pathway activity, proinflammatory cytokine expression, and clinical behavior in a rat model of SAH. A two-hemorrhage protocol was used to generate an animal model of SAH in male Sprague-Dawley rats. Administration of SFN to these rats following SAH enhanced the activity of the Nrf2-ARE pathway and suppressed the release of proinflammatory cytokines. Vasospasm was markedly attenuated in the basilar arteries after SFN therapy. Additionally, SFN administration significantly ameliorated two behavioral functions disrupted by SAH. These results suggest that SFN has a therapeutic benefit in post-SAH, and this may be due to elevated Nrf2-ARE pathway activity and inhibition of cerebral vascular proinflammatory cytokine expression.

Therapeutic Effect of Histone Deacetylase Inhibitor, Sodium Butyrate, on Allergic Rhinitis In Vivo.

Despite the well-documented therapeutic effects of histone deacetylase inhibitor (HDACi) on various diseases, including arthritis and asthma, the therapeutic effect of HDACi on allergic rhinitis remains unmentioned in the literature. This study investigated the therapeutic effect of sodium butyrate (SoB), a form of HDACi, on mice with allergic rhinitis. The results showed that the expression levels of histone deacetylase 1 (HDAC1), histone deacetylase 3 (HDAC3), and thymic stromal lymphopoietin (TSLP) were significantly upregulated in mice with allergic rhinitis, whereas H3 acetylation at lysine 9 (H3AcK9) was decreased. The intranasal application of SoB inhibited the expression levels of TSLP levels and upregulated the expression of H3AcK9 in a mouse model of allergic rhinitis. Furthermore, SoB treatment significantly decreased the increased levels of ovalbumin-specific IgE and improved clinical symptoms and nasal mucosa epithelial morphology in the mouse model of allergic rhinitis. In addition, we further demonstrated that SoB treatment significantly increased the serum levels of IL-2 and IFN-γ and decreased the serum levels of IL-4 and IL-10, correcting the Th1/Th2 imbalance in the mouse model of allergic rhinitis. Taken together, our study suggests that SoB has the potential to treat allergic rhinitis.

MiR-4638-5p inhibits castration resistance of prostate cancer through repressing Kidins220 expression and PI3K/AKT pathway activity.

MicroRNAs (miRNAs) are short, conserved segments of non-coding RNA which play a significant role in prostate cancer development and progression. To identify miRNAs associated with castration resistance, we performed miRNA microarray analysis comparing castration resistant prostate cancer (CRPC) with androgen dependent prostate cancer (ADPC). We identified common underexpression of miR-4638-5p in CRPC compared to ADPC samples, which were further confirmed by quantitative PCR analysis. The role of miR-4638-5p in prostate cancer androgen-independent growth has been demonstrated both in vitro and in vivo. We also identified Kidins220 as a target gene directly regulated by miR-4638-5p and shRNA-mediated knockdown of Kidins220 phenocopied miR-4638-5p restoration. Subsequently, we revealed that Kidins220 activates PI3K/AKT pathway, which plays a key role in CRPC. Loss of miR- 4638-5p may lead to CRPC through the activity of Kidins220 and PI3K/AKT pathway. Furthermore, we found that miR-4638-5p, through regulating Kidins220 and the downstream activity of VEGF and PI3K/AKT pathway, influences prostate cancer progression via angiogenesis. The identification of miR-4638-5p down-regulation in CRPC and the understanding of the functional role of miR-4638-5p and its downstream genes/pathways have the potential to develop biomarkers for CRPC onset and to identify novel targets for novel forms of treatments of this lethal form of PCa.