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The vaginal microbiota plays a crucial role in female reproductive health and is considered a biomarker for predicting disease outcomes and personalized testing. However, its relationship with human papillomavirus (HPV) infection and cervical cancer is not yet clear. Therefore, this article provides a review of the association between the vaginal microbiota, HPV infection, and cervical cancer. We discuss the composition of the vaginal microbiota, its dysbiosis, and its relationship with HPV infection, as well as potential mechanisms in the development of cervical cancer. In addition, we assess the feasibility of treatment strategies such as probiotics and vaginal microbiota transplantation to modulate the vaginal microbiota for the prevention and treatment of diseases related to HPV infection and cervical cancer. In the future, extensive replication studies are still needed to gain a deeper understanding of the complex relationship between the vaginal microbiota, HPV infection, and cervical cancer, and to clarify the role of the vaginal microbiota as a potential biomarker for predicting disease outcomes, thus providing a theoretical basis for personalized testing. [ABSTRACT FROM AUTHOR]

Objective: Non-pharmacological therapies (NPTs) have received increasing attention from researchers as a category of treatment to improve cognitive impairment in patients with dementia because of their fewer side effects. In this study, photobiomodulation (PBM), enriched environment (EE), exercise therapy (ET), computerized cognitive training (CCT), and cognitive stimulation therapy (CST) were selected to compare the effects of NPTs that improve dementia by quantifying information from randomized controlled trials (RCTs). Methods: We did a systematic review and network meta-analysis. We searched PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), China National Knowledge Infrastructure Database, Wan Fang Database, Chinese Biomedical Literature Database, Web of Science, and VIP Database from the time of database creation to 1 August 2022. Two investigators independently screened the literature, extracted information, and assessed the RCTs' quality with the Cochrane Collaboration Network Risk of Bias 2.0. Network meta-analysis was performed using R language (X64 version 4.1.3) and STATA 17.0. Results: We identified 1,268 citations and of these included 38 trials comprising 3,412 participants. For improving dementia, the results of the network metaanalysis showed that compared with the control group (CON), PBM (SMD = 0.90, 95% CI: 0.43-1.37), EE (SMD = 0.71, 95% CI: 0.02-1.41), ET (SMD = 0.42, 95% CI: 0.16-0.68), and CST (SMD = 0.36, 95% CI: 0.11-0.62) were significantly different (P < 0.05); There was no significant difference in CCT (SMD = 0.41, 95% CI: 0.07-0.88) (P > 0.05). The ranked results showed that PBM has more potential to be the best intervention (P = 0.90). In addition, there was a significant difference between PBM and CST in improving cognitive function (SMD = 0.54, 95% CI: 0.00; 1.08, P < 0.05). Conclusion: In this study, NPTs have excellent potential to improve cognition in people with dementia, and PBM may have more significant benefits in improving cognition than the other four NPTs. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Chinese Pharmaceutical Sciences is the property of Journal of Chinese Pharmaceutical Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Saw palmetto extract (SPE) has been widely used as a therapeutic remedy for urinary dysfunction in western countries. Furthermore, as an herb drug, it can be used as an alternative therapy for benign prostatic hyperplasia (BPH) due to its safety and minimum adverse effects. Reportedly, SPE improves the urinary symptoms, which mainly depend on anti-androgenic effects and effects on autonomic receptors in the lower urinary tract. However, the mechanisms of action responsible for the therapeutic roles of SPE have not been fully elucidated. Relevant studies indicate that SPE has some positive effects on the treatment of urological diseases in animals, and clinical trials are ongoing. In this review, we summarize the pharmacological properties and discuss the possible therapeutic mechanisms of SPE in urological diseases, including anti-androgenic effects, effects on autonomic receptors in the lower urinary tract, anti-inflammatory activity, anti-proliferative and pro-apoptotic effects, and highlight a potential therapeutic approach in the clinical treatment of patients with BPH, prostate cancer, chronic prostatitis (CP) and erectile dysfunction (ED). [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical effects of continuous intravenous infusion with high-dose furosemide on early acute kidney injury (AKI) complicated with acute lung edema. Methods: Ninety patients who had been treated by furosemide at routine dose for 12 hour but with unsatisfactory outcomes were selected and subjected to continuous intravenous infusion with high-dose furosemide. The dose was adjusted according to hourly urine output. Serum levels of urea nitrogen, creatinine and potassium, pH, oxygenation index and mechanical ventilation time before and 6, 12, 24, 48 and 72 hour after treatment were compared. Results: The urine outputs before and 6, 12, 24, 48 and 72 hour after treatment were (10.71±1.81), (164.52±21.42), (189.71±29.61), (181.33±23.52), (176.82±24.80) and (164.52±18.91) ml/h respectively. Compared with data before treatment, the serum levels of urea nitrogen, creatinine and potassium significantly decreased while pH and oxygenation index significantly increased after six hour of treatment (P<0.05). After treatment, the kidney functions of 80 patients (88.9%) were completely recovered, without obvious adverse reactions. Conclusion: For patients with early AKI complicated with acute pulmonary edema who cannot be cured by diuretic agent at routine dose, high-dose furosemide increases urine output and improves success rate. [ABSTRACT FROM AUTHOR]

Aim Of Study: This study is to investigate the effects of a novel peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist TZD18 on cell growth, apoptosis, caspase activity, mitochondrial membrane potential, cytochrome c release, and apoptotic-related protein expression in MKN-45 cells.Materials and Methods: 3-(4, 5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide assay against various human cancer cell lines was performed to investigate the whether TZD18 could in reduce the proliferation rates of cancer cells. The percentages of apoptotic cells and mitochondrial membrane potential level were determined by flow cytometry. The subcellular localization of cytochrome c was examined by immunofluorescence microscopy. Western blotting assay was performed to reveal the expression of apoptosis-related proteins.Results: The results showed that the administration of TZD18 could inhibit the growth of MKN-45 cells in a dose- and time-dependent manner. In addition, the apoptotic ratio increased sharply along with a significant increase of caspase activities, mitochondrial membrane potential, and cytochrome c release following TZD18 exposure. The expression of Bax and p27kip1 increased significantly, whereas the expression level of Bcl-2 protein was downregulated.Conclusion: These results indicated that the administration of PPAR α/γ agonist TZD18 may inhibit cell growth by inducing the apoptotic process in MKN-45 cells. [ABSTRACT FROM AUTHOR]

Objective: To analyze and compare the efficacy of laparoscopic modified Soave operation and open radical resection in the treatment of Hirschsprung's disease. Methods: Two hundred and sixteen children who suffered from Hirschsprung's disease and were admitted into the hospital from June 2015 to December 2016 were selected as research subjects. They were grouped into an observation group in which patients were treated by laparoscopic modified Soave operation and open radical resection and a control group in which patients were treated by open radical resection. The clinical efficacy and complications of the two groups were observed, and the defecation function was also evaluated. Results: Operation indicators such as the operation time, time to recovery of intestine peristalsis, intraoperative blood loss and pain score of the observation group were superior to those of the control group, and the difference had statistical significance (P<0.05). The mean arterial pressure (MAP) and heart rate (HR) of the observation group were lower than those of the control group at all time points after operation, and the difference suggested statistical significance (P<0.05). The postoperative complications of the observation group were less than those of the control group. The follow-up results demonstrated that the excellent and good rate of Kelly score of the observation group was 81.5%, higher than 61.1% in the control group. Conclusion: Laparoscopic modified Soave operation has definite efficacy in the treatment of Hirschsprung's disease, and the treatment is featured by high safety and few complications, which is beneficial to the recovery of defecation function; hence laparoscopic modified Soave operation is worth clinical promotion. [ABSTRACT FROM AUTHOR]

Background: Renal replacement therapy (RRT) is important to support critically ill patients with acute kidney injury (AKI). This study, a part of a nation-wide survey for AKI conducted by the ISN AKF 0 by 25 China Consortium, aims to study the current RRT practical situation and problems in China.Methods: The current study is a part of a nation-wide survey for AKI conducted by ISN AKF 0 by 25 China Consortium. The survey included 44 sites all over the country, including 22 academic hospitals in big cities and 22 local hospitals in smaller cities or rural areas. Of the 44 sites, all have access to PD and IHD, 93.5% are capable to perform CRRT. Of total 7604 AKI cases, 896 cases (11.8%) had indications for RRT and were included in the current abstract.Results: of the 896 patients that had indications for RRT, only 59.3% received RRT. Patients who were older, male, from lower income areas, in local hospitals, or with severe comorbidities, were less likely to receive RRT. RRT treatment was associated with lower mortality (OR = 0.58, 95%CI 0.38-0.89). The RRT modalities were continuous renal replacement therapy (CRRT) in 53.9%, intermittent hemodialysis (IHD) in 38.0%, CRRT complemented by IHD in 6.2%, CRRT complemented by peritoneal dialysis (PD) in 0.8% and PD in 1.1%. Of the subgroup of patients receiving RRT who did not have an indication for modality of CRRT, 36.8% in fact received CRRT, and their medical cost and mortality rate was higher (7944[4248, 16,055] vs. 5100[2948, 9396] US dollars, p < 0.001 and 10.6% vs. 4.4%, p = 0.047, respectively) compared with those treated with other RRT modalities).Conclusions: Extrapolated to the whole of China our results indicate that an estimated 139,000 patients with an indication of RRT are under treated without RRT over a year. Non-clinical factors influence RRT prescription for severe AKI patients. CRRT may be over-utilized in the treatment of severe AKI and the use of PD is extremely rare. These findings have implications for the effective application of medical resources in the treatment of severe AKI. [ABSTRACT FROM AUTHOR]

This work was conducted to prepare β-caryophyllene-hydroxypropyl-β-cyclodextrin inclusion complex (HPβCD/BCP) and investigate its effects and mechanisms on cognitive deficits in vascular dementia (VD) rats. First, HPβCD/BCP was prepared, optimized, characterized, and evaluated. HPβCD/BCP and AM630 were then administered to VD rats to upregulate and downregulate the cannabinoid receptor type 2 (CB2). Results showed that HPβCD/BCP can significantly increase the bioavailability of BCP. Through the Morris water maze test, HPβCD/BCP can attenuate learning and memory deficits in rats. Cerebral blood flow (CBF) monitoring results indicated that HPβCD/BCP can promote the recovery of CBF. Moreover, molecular biology experiments showed that HPβCD/BCP can increase the expression levels of CB2 in brain tissues, particularly the hippocampus and white matter tissues, as well as the expression levels of PI3K and Akt. Overall, the findings demonstrated the protective effects of HPβCD/BCP against cognitive deficits induced by chronic cerebral ischemia and suggested the potential of HPβCD/BCP in the therapy of vascular dementia in the future. [ABSTRACT FROM AUTHOR]

Background: Many previous studies have shown the potential therapeutic effect of acupuncture for allergic rhinitis. Most of these studies, however, were limited by the short duration of observations and lack of sham acupuncture as the control group. Our preliminary experiments showed that the use of a warm needling achieved a much more persistent effect in the treatment of allergic rhinitis (AR) compared with simple acupuncture therapy. Hence, we have designed a multicenter, randomized controlled trial (RCT) in which the first-line medication loratadine will be used as the control group, and the effect of warm needling therapy will be evaluated through long-term observation.Methods/design: The trial is designed as a multicenter, parallel-group, randomized, single-blinded (outcome assessors), non-inferiority trial. A total of 98 patients with persistent AR will be randomly assigned into two groups. Patients in the treatment group will be treated with warm needling at GV14 and acupuncture at EX-HN3, ST2, LI20, EX-HN8, GV23, LU7, LU5 and LI4 three times a week, for a total of 4 weeks. Patients in the control group will be treated with oral loratadine 10 mg/day for 4 weeks. The primary outcome will be the change in the Total Nasal Symptom Score (TNSS) from baseline to that at 6 months after treatment during the follow-up period. The secondary outcomes will include the Total Non-nasal Symptom Score and the Rhinoconjunctivitis Quality of Life Questionnaire, changes in the TNSS from baseline to that at 2 and 4 weeks during treatment, and 3 months after treatment during the follow-up period. Outcomes will be measured at 2 and 4 weeks, and 3 and 6 months after treatment. Any side effects of treatment will be observed and recorded.Discussion: We expect that the study results will provide evidence to determine the effects of warm needling compared with loratadine. Our final goal of the study is to evaluate the difference in the short-term and long-term effects between the two therapeutic methods, especially the long-term effect of warm needling.Trial Registration: ClinicalTrials.gov NCT02339714 . Registered on 14 January 2015. [ABSTRACT FROM AUTHOR]

Background: Multiple-ligament injured knee (MLIK) is a rare but severe injury. Although the principles of MLIK management have progressed over the past 40 years, there is a paucity of high-quality evidence upon which to base the management of MLIK. Treatment strategies for MLIK are challenging for most orthopedic surgeons, and the optimal treatment remains controversial, especially with regard to repair vs. reconstruction of the ligaments. The aim of the present study was to observe clinical outcomes of single-stage in situ suture repair of knee dislocation with multiple-ligament injury using nonabsorbable suture material.Methods: Consecutive patients with MLIK between 2002 and 2010 were included, for a total of 25 patients with knee dislocation. 17 patients (18 knees) with closed knee dislocation with a mean follow-up of 4.8 ± 1.3 years were retrospective analyzed. All patients were treated surgically with single-stage in situ suture repair for all injured ligaments and followed a standardized postoperative rehabilitation protocol. The VAS score, satisfactory score, total SF-36 score, Lysholm score, Tegner score, the Meyers functional rating and the ranges of motion and knee stability were used to evaluate outcomes.Results: At final follow-up, mean visual analog scale score was 2.4 ± 0.9, patient satisfaction score was 8.0 ± 1.1, 36-item Short-Form Health Survey total score was 85.5 ± 10.4, and mean Lysholm score was 87.5 ± 7.7. There were significant differences between mean preinjury and postoperative Tegner activity scores (5.6 ± 1.4 and 3.4 ± 1.7, respectively; P < 0.01) and in mean range of motion between the injured and contralateral knees (112.5 ± 8.4° and 129.6 ± 10.3°, respectively; P < 0.01). At final follow-up, no patient demonstrated obvious ligamentous laxity, and only one patient was unable to return to work. Three patients had knee joint stiffness, two had wound problems (infection or fat liquefaction), and two had heterotopic bone formation.Conclusions: Single-stage in situ suture repair of injured ligaments confers advantages of reliable fixation and early exercise. It could be considered as an alternate and effective option in the dislocation knee with multiple-ligament injury. [ABSTRACT FROM AUTHOR]

Background: The objective of the current meta.analysis was to assess the arterial spin labeling. (ASL) perfusion imaging measurement of cerebral blood flow. (CBF) in patients with brain tumors, and assessing preoperative tumor grade in brain. Materials and Methods: PubMed, Web of Science, Embase, China BioMedicine (CBM), CINAHL, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were chosen to evaluate the associations between ASL and brain cancer. Two reviewers separately evaluated the quality of the included trials. Standardized mean difference (SMD) at 95% confidence interval (95% CI) was also calculated. Results: Finally, 475 patients were enrolled into this meta-analysis from 12 eligible studies and were selected for statistical analysis. Results showed that relative tumor blood flow (rTBF) and relative cerebral blood flow (rCBF) in high-grade brain cancer patients were faster than those in low-grade brain cancer patients. Subgroup analysis stratified by country implied that ASL may be the main prediction of increased rTBF in high-grade brain cancer patients among USA, Korea and China; and rCBF was faster in high-grade brain cancer using ASL in USA and China. Further reference by tissue-stratified analysis revealed a positive association of rTBF with high-grade brain cancer by utilization of ASL in all the experimental subgroups, while rCBF was only correlated in white subgroups. Conclusion: These results showed that rTBF and rCBF were faster in high-grade brain cancer patients, suggesting that ASL may provide suitable measurement for the differential diagnosis of tumor grade in brain. [ABSTRACT FROM AUTHOR]

Copyright of Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas is the property of Universidad de Santiago de Chile and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose. Radiotherapy is an effective treatment modality in the clinical treatment of breast cancer. The present work investigated the effect of 3,3'-diindolylmethane (DIM) on γ-irradiation sensitizing human breast carcinoma. Methods. Cell survival, intracellular ROS levels, cell cycle distribution, cell apoptosis, and expression of proteins related to apoptosis were measured with MTT assays, flow cytometry, and Western blot analysis, respectively. Results. In vitro DIM plus γ-irradiation arrested the activity of G2/M phase cell cycle, increased intracellular ROS level, significantly suppressed PARP (poly ADP-ribose polymerase), and enhanced γ-irradiation-induced apoptosis, thereby inhibiting the proliferation of MCF-7 cells. Conclusion. These data provide a rationale for the use of DIM as a promising sensitizer of γ-irradiation. [ABSTRACT FROM AUTHOR]

Background: SKF83959 stimulates the phospholipase Cp/inositol phosphate 3 pathway, resulting in the activation of Ca2+/ calmodulin-dependent kinase lia, which affects the synthesis of brain-derived neurotrophic factor, a neurotrophic factor critical for the pathophysiology of depression. Previous reports showed that SKF83959 elicited antidepressant activity in the forced swim test and tail suspension test as a novel triple reuptake inhibitor. However, there are no studies showing the effects of SKF83959 in a chronic stress model of depression and the role of phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway in SKF83959-mediated antidepressant effects. Methods: In this study, SKF83959 was firstly investigated in the chronic social defeat stress model of depression. The changes in hippocampal neurogenesis, dendrite spine density, and brain-derived neurotrophic factor signaling pathway after chronic social defeat stress and SKF83959 treatment were then investigated. Pharmacological inhibitors and small interfering RNA/ short hairpin RNA methods were further used to explore the antidepressive mechanisms of SKF83959. Results: We found that SKF83959 produced antidepressant effects in the chronic social defeat stress model and also restored the chronic social defeat stress-induced decrease in hippocampal brain-derived neurotrophic factor signaling pathway, dendritic spine density, and neurogenesis. By using various inhibitors and siRNA/shRNA methods, we further demonstrated that the hippocampal dopamine Ds receptor, phospholipase C/inositol phosphate 3/ calmodulin-dependent kinase lia pathway, and brain-derived neurotrophic factor system are all necessary for the SKF83959 effects. Conclusion: These results suggest that SKF83959 can be developed as a novel antidepressant and produces antidepressant effects via the hippocampal Ds/ phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is one of the most common types of cancer in China. Artesunate (ART) is used clinically as an anti-malarial agent and exhibits potent antiproliferative activity. In addition, ART has demonstrated remarkable antitumor activity, presenting a novel candidate for cancer chemotherapy. However, its effect on ESCC remains unknown. The present study analyzed the antitumor effects of ART in the KYSE-150 ESCC line by assessing cell proliferation, cell death, cell migration/invasion and the biomechanical properties of ART-treated KYSE-150 cells. ART treatment significantly suppressed the proliferation of KYSE-150 cells in a dose- and time-dependent manner, as assessed by MTT assay. Following treatment with 30 mg/l ART, the cell population in the G0/G1 phase and the level of cell apoptosis significantly increased from 54±1.5 to 68.1±0.3%, and from 4.53±0.58 to 12.45±0.62%, respectively. Furthermore, the cell migration and invasion of KYSE-150 cells treated with 30 mg/l ART was markedly inhibited. The cell membrane and biomechanical properties were investigated using atomic force microscopy, as targets of ART action. ESCC cells treated with 30 mg/l ART exhibited increased adhesive force, increased cytomembrane roughness and reduced elasticity compared with the control group (KYSE-150 cells without ART treatment). The biomechanical properties of KYSE-150 cells treated with 30 mg/l ART were similar to those of the SHEE normal human esophageal epithelial cell line. In conclusion, the present study demonstrated that ART may inhibit cell proliferation and migration in ESCC through changes in the biomechanical properties of the ESCC cells. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate the therapeutic effect of intra-articular hyaluronic acid (HA) in comparison to corticosteroids (CS) for knee osteoarthritis (OA). The data sources included PubMed, EMBASE, The Cochrane Central Register of Controlled Trials and hand searched reviews. Randomized controlled trials that reported the effects of intra-articular HA and CS in the treatment of knee OA were selected based on specific inclusion criteria. A meta-analysis was performed for the visual analog scale (VAS), Lequesne index, Knee Society Clinical Rating System (KSS), maximum flexion and adverse events of knee OA. Sensitivity analysis was also conducted to avoid bias. The seven eligible trials included 583 participants and the majority of the trials were of high quality. After one month, the mean difference in the VAS was 1.66 [95% confidence interval (CI); -0.90, 4.23), indicating equal efficacy for HA and CS. However, after three months, the mean difference was -12.58 (95% CI; -17.76, -7.40), while after six months, the difference was -9.01 (95% CI; -12.62, -5.40), favoring HA. For the additional indicators, including the Lequesne index, the KSS, maximum flexion and adverse events, no statistically significant differences were observed between the two treatment approaches for knee OA. Therefore, the results of the meta-analysis highlight a therapeutic trajectory for intra-articular HA in knee OA pain, as compared with CS, over six months post-intervention. After one month, the two approaches exhibited equal efficacy; however, in the long term, HA was found to have an enhanced effect. No statistically significant difference was observed in the adverse events caused by the two interventions. Further investigation and understanding into the trend observed in the present study may aid clinicians in the treatment of knee OA. [ABSTRACT FROM AUTHOR]

The fungal polysaccharides have been revealed to exhibit a variety of biological activities, including antitumor, immune-stimulation and antioxidation activities. In the present study, the immune and anticancer activities of a novel polysaccharide, BSF-A, isolated from Boletus speciosus Frost was investigated. The inhibitory rate of S180 tumors in mice treated with 40 mg/kg BSF-A reached 62.449%, which was the highest rate from the three doses administered; this may be comparable to mannatide. The antitumor activity of BSF-A is commonly considered to be a consequence of the stimulation of the cell-mediated immune response, as it may significantly promote the macrophage cells in the dose range of 100-400Μg/ ml in vitro. The levels of the cytokines, IL-6, IL-lβ and TNF-α, and nitric oxide, induced by BSF-A treatment at varying concentrations in the macrophage cells were similar to the levels in the cells treated with lipopolysaccharide. There was weak expression of the TNF-α, IL-6, IL-lβ and inducible nitric oxide synthase mRNA in the untreated macrophages, but this increased significantly in a dose-dependent manner in the BSF-A-treated cells. BSF-A also had a time- and dose-dependent effect on the growth inhibition of the Hep-2 cells, with the concentration of 400 Μg/ml having the highest inhibitory rate. A quantitative PCR array analysis of the gene expression profiles indicated that BSF-A had anticancer activities that affected cell apoptosis in the Hep-2 cells. The results obtained in the present study indicated that the purified polysaccharide of Boletus speciosus Frost is a potential source of natural anticancer substances. [ABSTRACT FROM AUTHOR]

Background: Acute pharyngitis is frequently seen in primary care. Acute viral pharyngitis may be easily misdiagnosed as acute bacterial pharyngitis. Laboratory-confirmed diagnosis of respiratory viruses is recommended. The purpose of this study was to compare the sensitivities among oropharyngeal swab (OPS), nasopharyngeal swab (NPS), and nasal wash (NW) in adults with acute pharyngitis. Methods: OPS, NPS, and NW were obtained from each participant with acute pharyngitis. The specimens were tested for 15 respiratory viruses by TaqMan real-time polymerase chain reaction. A sample was considered to be a true positive if any of the specimens was positive. The sensitivities among samples were compared by chi-square test or Fisher's exact test, as appropriate. Results: One hundred three triple samples collected consecutively by OPS, NPS, and NW were obtained. In 73 patients, one or more viruses were detected by any of the three methods. Among all viruses, the sensitivity of NPS was significantly higher than that of NW (74% vs. 49%, respectively; p < 0.01) and OPS (74% vs. 49%, respectively; p < 0.01). Conclusions: Flocked NPS collection may be the most effective alternative to NW and OPS for detection of respiratory viruses in adults with acute pharyngitis using TaqMan real-time polymerase chain reaction. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to evaluate the efficacy and safety of combination therapy of Endostar (recombinant human endostatin) and S-1 combined with oxaliplatin (SOX) in patients with advanced gastric cancer. Methods: In this randomized, controlled trial, 165 late-stage gastric cancer patients were assigned to the experimental arm with Endostar in combination with SOX (80 patients) and the control arm with SOX alone (85 patients). The end points of this study included progression-free survival, response rate, and disease-control rate. Results: There was no statistically significant difference in response rate between the experimental arm and the control arm (53.8% vs 42.4%, P=0.188). The difference in disease-control rate was also statistically insignificant between the two arms (85.0% vs 72.9%, P=0.188). Progression-free survival in the experimental arm was significantly higher than that in the control arm (15.0 months vs 12.0 months, P=0.0001). Common adverse events included immunosuppression, gastrointestinal distress, and neuropathy. There was no statistical difference in the incidences of adverse events. Conclusion: Combination therapy of Endostar and SOX provides therapeutic benefits to advanced gastric cancer patients, with tolerable adverse effects. [ABSTRACT FROM AUTHOR]

Background: This study was designed to determine whether advanced non-small-cell lung cancer (NSCLC) patients with high copy number of epidermal growth factor receptor (EGFR) can benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Methods: EGFR gene copy number was assessed by fluorescence in situ hybridization (FISH) and EGFR mutations was tested using Luminex xTAG technology in 502 TKI-treated NSCLC patients. The association between both biomarkers and clinical benefit from EGFR-TKI were analyzed. Results: EGFR FISH + and EGFR mutations were significantly associated with higher response rates (37.2% and 43.7%, respectively), superior progression-free survival (PFS) (FISH+, 11.2 months; hazard ratio [HR], 0.51; 95% CI, 0.42 to 0.62; p < 0.001; mutation+, 11.7 months; HR, 0.37; 95% CI, 0.31 to 0.45; p < 0.001) and overall survival (OS) (FISH+, 30.2 months; HR, 0.51; 95% CI, 0.40 to 0.65; p < 0.001; mutation+, 30.2 months; HR, 0.45; 95% CI, 0.36 to 0.58; p < 0.001). In patients with wild-type EGFR, EGFR FISH + correlated with longer PFS than EGFR FISH- status (4.4 months vs. 2.0 months; HR, 0.56; 95% CI, 0.41 to 0.75; p < 0.001), so did amplification (5.0 months vs. 2.0 months; HR, 0.43; 95% CI, 0.24 to 0.76; p = 0.003). However, FISH + had no association with improved PFS in EGFR-mutated patients (HR, 0.77; 95% CI, 0.57 to 1.03; p = 0.076). Conclusions: A combined analysis of EGFR FISH and mutation is an effective predictor of EGFR-TKI therapy. Specifically, a high EGFR copy number may predict benefit from TKIs treatment for NSCLC patients with wild-type EGFR. [ABSTRACT FROM AUTHOR]

Objective: To analyze our experiences in patients with traumatic retroperitoneal hematoma, and highlight the problems in diagnosis and treatment to facilitate the surgeons to make decision. Methodology: One hundred and eight patients of traumatic retroperitoneal hematoma treated in our institution from May 2008 to Jun 2012 were reviewed retrospectively. The data including patient's age, type of injury, hospital stays, type of treatment, injured organs and mortality rate were collected. Results: In 108 patients, seventy-seven patients were male and 31 were female with a mean age of 36.5 years; eighty-seven patients sustained blunt trauma and 21 penetrating injury. Centro-medial hematoma was found in 31 patients, lateral hematoma in 36 patients, pelvic hematoma in 35 and pelvic-central hematoma in six patients. Eighty-three patients were treated surgically and 25 patients were treated conservatively. Six patients died and the mortality rate is 6.5%. Wound infection occurred in five patients, deep vein thrombosis in one patient, gastric fistula in two patients and duodenal fistula in one patient. Conclusion: Traumatic retroperitoneal hematoma is life-threatening condition, early diagnosis and correct treatment is of upmost importance. Mandatory exploration should be performed in cases of retroperitoneal hematomas resulting from penetrating injury, but the selection of treatment mode in blunt injury depends on the anatomical position of hematoma, visceral injury and the hemodynamic status of the patients. [ABSTRACT FROM AUTHOR]

Introduction. The effect of Qigong on psychological well-being is relatively unknown. This study systematically reviewed the effects of Qigong on anxiety, depression, and psychological well-being. Methods. Using fifteen studies published between 2001 and 2011, a systematic review was carried out and meta-analyses were performed on studies with appropriate homogeneity. The quality of the outcome measures was also assessed. Results. We categorized these studies into three groups based on the type of subjects involved as follows: (1) healthy subjects, (2) subjects with chronic illnesses, and (3) subjects with depression. Based on the heterogeneity assessment of available studies, meta-analyses were conducted in three studies of patients with type II diabetes in the second group, which suggested that Qigong was effective in reducing depression (ES = -0.29; 95% CI, -0.58-0.00) and anxiety (ES = -0.37; 95% CI, -0.66-0.08), as measured by Symptom Checklist 90, and in improving psychological well-being (ES = -0.58; 95% CI, -0.91-0.25) as measured by Diabetes Specific Quality of Life Scale. Overall, the quality of research methodology of existing studies was poor. Conclusions. Preliminary evidence suggests that Gigong may have positive effects on psychological well-being among patients with chronic illnesses. However the published studies generally had significant methodological limitations. More high-quality studies are needed. [ABSTRACT FROM AUTHOR]

Pseudoginsenoside-F11 (PF11), a component of Panax quinquefolism (American ginseng), plays a lot of beneficial effects on disorders of central nervous system. In this paper, the neuroprotective effect of PF11 on Parkinson's disease (PD) and the possible mechanism were investigated in a rat PD model. PF11 was orally administered at 3, 6, and 12mg/kg once daily for a period of 2 weeks before and 1 week after the unilateral lesion of left medial forebrain bundle (MFB) induced by 6-hydroxydopamine (6-OHDA). The results showed that PF11 markedly improved the locomotor, motor balance, coordination, and apomorphine-induced rotations in 6-OHDA-lesioned rats. The expression of tyrosine hydroxylase (TH) in substantia nigra (SN) and the content of extracellular dopamine (DA) in striatum were also significantly increased after PF11 treatment. Moreover, significant reduction in the levels of striatal extracellular hydroxyl radical ('OH), detected as 2,3- and 2,5-dihydroxy benzoic acid (2,3- and 2,5-DHBA), and increase in the level of striatal extracellular ascorbic acid (AA) were observed in the PF11-treated groups compared with 6-OHDA-lesioned rats. Taken together, we propose that PF11 has potent anti-Parkinson property possibly through inhibiting free radical formation and stimulating endogenous antioxidant release. [ABSTRACT FROM AUTHOR]

The circulatory inflammatory cytokine tumor necrosis factor alpha (TNF-α) is increased in pathologic conditions that initiate or exacerbate vascular endothelial injury, such as diabetes. Protein kinase C (PKC) has been shown to play a critical role in TNF-α-induced human endothelial cell apoptosis. However, the relative roles played by specific isoforms of PKC in TNF-α-induced human endothelial cell apoptosis have not been addressed. We investigated the effects of a selective PKCβ2 inhibitor (CGP53353) on TNF-α-induced apoptosis in human vascular endothelial cells (cell line ECV304) and on the production of reactive oxygen species and nitric oxide, and compared its effects with rottlerin, a reagent that has been shown to reduce PKCδ protein levels. Cultured human vascular endothelial cells (ECV304) were treated for 24 h with one of 4 regimes: 40 ng/mL TNF-α alone (TNF-α), TNF-α with 10 µmol/L rottlerin (T+rottlerin), TNF-α with 1 µmol/L CGP53353 (T+CGP), or untreated (control). Cell viability was measured by MTT assay, and cell apoptosis was assessed by flow cytometry. TNF-α-induced endothelial cell apoptosis was associated with dramatic increases in production of intracellular hydrogen peroxide (approximately 20 times greater than control) and superoxide (approximately 16 times greater than control), as measured by dichlorofluorescein and dihydroethidium fluorescent staining, respectively. This increase was accompanied by reduced activity of superoxide dismutase and glutathione peroxidase and, subsequently, an increase in the lipid peroxidation product malondialdehyde. CGP53353, but not rottlerin, abolished or attenuated all these changes. We conclude that PKCβ2 plays a major role in TNF-α-induced human vascular endothelial cell apoptosis. [ABSTRACT FROM AUTHOR]

Purpose: We longitudinally investigated macular function by multifocal electroretinography (mfERG) in a cohort of patients with Vogt-Koyanagi-Harada (VKH) syndrome. Design: Prospective study. Methods: VKH syndrome was diagnosed in 11 patients (22 eyes) according to history and ocular examinations. They were treated with immunosuppressive agents and the macular function was evaluated using best-corrected visual acuity (BCVA) and mfERG before treatment and one, three, six, and 12 months after treatment. Results: All investigated patients with VKH syndrome showed active intraocular inflammation at their first visit. A decreased visual acuity (VA) and abnormalities of mfERG were observed in all these patients. VA rapidly improved at one and three months and gradually improved thereafter. All but one eye achieved a BCVA of ≥20/25 at 12 months following treatment. The N1 amplitude and latency were significantly improved at three and six months and continuously improved thereafter. The P1 amplitude and latency were significantly improved at one and three months and progressively improved thereafter. However, the amplitude of N1 and P1 waves was still significantly decreased at 12 months. Conclusion: Macular function revealed by Snellen chart and mfERG is severely impaired in VKH patients with active uveitis. Treatment with immunosuppressive agents leads to an earlier, faster, and better recovery of VA, and a delayed but limited recovery of macular function as indicated by mfERG at 12 months. MfERG could be an ancillary test that may be useful in guiding therapy of patients with VKH syndrome. [Copyright &y& Elsevier]

To explore the therapeutic effects of adenovirus vector mediated transfer of the ICOSIg gene on immuno-inflammation-mediated cardiac remodeling in an experimental autoimmune myocarditis (EAM) model, pAdeno-ICOSIg was constructed and transfected into HEK 293 cells to produce the ICOSIg adenovirus. Ad-CMV-GFP was used as a control. EAM was induced in Lewis rats by injection of porcine cardiac myosin. The immunized rats were divided into two groups. The inducible co-stimulatory molecule (ICOS) group received the adenovirus containing ICOSIg on day 14; the green fluorescent protein (GFP) group received the adenovirus containing GFP as the control adenovirus and 15 normal rats (Control group) consisted of the normal controls that were not immunized. On day 28, all rats were euthanized after echocardiography and histopathologically examined for cardiac fibrosis. Western blotting was performed to detect ICOS, ICOS ligand (ICOSL), matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 and real-time RT-PCR was performed to detect B7-1, B7-2 and interleukin (IL)-17 expression. ELISPOT was applied to detect Th1 and Th2 cytokine production. Collagen concentration and collagen cross-linking were determined as markers of cardiac fibrosis. It was found that blockade with ICOSIg exerted antifibrotic effects on cardiac remodeling in EAM. On day 28, cardiac function and inflammatory myocardial fibrosis improved significantly in the ICOS group compared to the GFP group. The expression of ICOS, the ICOSL, B7-1 and IL-17 was statistically significantly lower in the ICOS and Control groups compared to the GFP group. ICOSIg significantly augmented Th2 cytokine production and diminished Th1 and Th17 cytokine production. This blockade of the ICOS co-stimulatory pathway with ICOSIg alleviated autoimmune inflammation-mediated cardiac remodeling and improved cardiac function. Regulation of the Th1/Th2/Th17 balance may be one of the underlying mechanisms responsible for this effect.Immunology and Cell Biology (2008) 86, 659–665; doi:10.1038/icb.2008.45; published online 1 July 2008 [ABSTRACT FROM AUTHOR]

Background: Since the 1980s, many studies have indicated there are hypodermic migration channels of radiotracer along meridians independent of lymphatic and blood vessels in vivo. However, the radioactive trajectories were not clear enough to identify the anatomic structures in the living body. Objectives: To establish an alternative method to image the specific fluid pathways, we hypothesized that a minimal amount of low molecular weight tracer could enter the specific channels and by magnetic resonance imaging technique, we could image the regional channels originating from the acupoints on 6 yin meridians of forearm and lower leg. Design and results: Seven (7) healthy volunteers were injected hypodermically with a minimal amount of tracer into 6 acupoints on 6 yin meridians of the hand and foot. We found a total of 6 regional specific channels in one forearm and one lower leg of each subject, respectively, but no specific channels were visualized following injection of the tracer into the sites of nonacupoints. Magnetic resonance angiography confirmed the specific channels were not the superficial veins in the subcutis. Subsequent acupuncture needling studies revealed that migration of tracer along each of the specific channels could not be interrupted by acupuncture needling and remained intact, which was different from the nature of either lymphatics or blood vessels. Conclusions: We imaged 6 regional migration channels originating from 6 acupoints on 6 yin meridians of hand and foot by injecting a minimal amount of tracer into acupoints directly in humans. The responses of the subcutaneous specific channels to acupuncture needling are different from those of lymphatic or blood vessels and coincide partially with the characteristics of acupuncture therapeutics, suggesting the existence of meridian-like channels in humans. These findings may contribute to further research on the specific interstitial fluid drainage. [ABSTRACT FROM AUTHOR]

Objective: To compare the ocular hypotensive effect of the commercially available preparations of bimatoprost or travoprost added to latanoprost in monkey eyes with laser-induced unilateral glaucoma. Methods: Four monkeys with unilateral laser-induced glaucoma were used in each treatment group and received drops in the glaucomatous eye only. Intraocular pressure (IOP) was measured hourly for 6 hours, beginning at 9:30 AM on day 1 (untreated baseline), days 6 and 7 (single-agent therapy), and days 13 and 14 (2-drug combination therapy). On days 2 through 7, 1 drop of the scheduled single agent was given immediately after the 9:30 AM IOP measurement, and on days 8 through 14, the second scheduled drug was given 5 minutes after the first. The following 5 different dosing protocols were studied: latanoprost with bimatoprost added, bimatoprost with latanoprost added, latanoprost with travoprost added, travoprost with latanoprost added, and latanoprost with a second dose of latanoprost added. Results: There were no statistically significant (P=.95) differences among the mean baseline IOPs in any of the 5 treatment groups. When applied as single agents, latanoprost, bimatoprost, and travoprost all produced significant (P<.05) and equivalent (P=.98) reductions in IOP. The mean ±SEM maximum reduction (P<.05) from baseline IOP was 7.0±0.4 mm Hg (20% reduction) with travoprost alone, 6.5±1.6 mm Hg (18%) with bimatoprost alone, and 7.5±1.0mmHg (22%) with latanoprost alone. The mean±SEMmaximumadditive reductions in IOP were 3.0±0.6 mm Hg (P<.05) for travoprost added to latanoprost; 2.0±0.4 mm Hg (P<.05) for latanoprost added to travoprost; 4.8±1.3mmHg (P<.05) for bimatoprost added to latanoprost; 4.3±0.6 mm Hg (P<.05) for latanoprost added to bimatoprost; and 0.3±0.5 mm Hg (P<.60) for latanoprost added to itself. The combination of bimatoprost and latanoprost produced a greater (P<.05) lowering of IOP at trough and peak than the combination of travoprost and latanoprost. Conclusions: Latanoprost, bimatoprost, and travoprost used as monotherapy produced significant and equivalent reductions in IOP in glaucomatous monkey eyes. The IOP effects of the commercial concentrations of bimatoprost or travoprost were additive to that of latanoprost, with bimatoprost showing a greater additive response than travoprost. Clinical Relevance: Because treatment with multiple medications is common among patients with glaucoma, determining which glaucoma medications produce an additive ocular hypotensive response when used in combination has practical implications for clinicians. [ABSTRACT FROM AUTHOR]

Objective To test the accuracy of real-time three-dimensional echocardiography (RT3DE) imaging system for evaluating left ventricular mass (LVM) in phantom and excised canine heart. Methods Ten left ventricular (LV) wall phantoms made of two rubber-bursas, ten excised canine hearts underwent RT3DE and two-dimensional echocardiography (2DE). In RT3DE "full volume" imaging, the myocardial volume was measured using 2,4,8, and 16-plane method with the analysis software of RT3DE. Mass was then calculated by multiplying the resulting myocardial volume by specific density of myocardial tissue. In 2DE the masses were measured by area-length method. The true LV wall phantom mass was measured by water displacement and the canine LVM was weighed by anatomy, which served as a reference standard. We compared RT3DE or 2DE with true mass. Results In LV wall phantoms, RT3DE correlated with true masses strongly (r = 0.8 13-0.994) and weakly correlated between 2DE and true masses (r = 0.62 8). In excised canine hearts, there is an excellent correlation between RT3DE and true masses (r=0.764-0.99l), while 2DE value showed a lesser correlation (r= 0.514). There are no difference between RT-3DE and true masses (P > 0.05) but different between 2DE and true masses (P < 0.05). In different planes, there was no difference between 8-plane and 16-plane (P > 0.05) but different between 8-plane and 2,4-plane (P < 0.05). Conclusion RT3DE can accurately quantify LVM and provide a new tool to evaluate LVM function. For LVM by RT3DE, 8-plane measurement method is the best choice for accuracy and convenience. [ABSTRACT FROM AUTHOR]

[Objectives ] To establish a method for the determination of tannin in Sanguisorba officinalis L., and provide guarantee for further control over quality of semi-finished tannin products from Sanguisorba officinalis L. [Methods] With gallic acid as reference substance, the UV method was used to determine the content of tannin in Sanguisorba offcinalis L., and the methodological examination was done. [ Results] With gallic acid as standard, when the concentration of tannin in Sanguisorba ojfcinalls L. was 1.02 - 10.14 μg · mL-1, there was a good linear relationship with absorbance, the precision, reproducibility and recovery were in line with the requirements, and the absorbance value was stable within 40 min after coloration. [Conclusions] The method was simple, rapid and accurate in determining the content of tannin in Sanguisorba ooficinalls L. [ABSTRACT FROM AUTHOR]

The article discusses the case of a 76-year-old man who presented with multiple vesicles and erosions and who was diagnosed with pemphigus vulgaris. Initial treatment was made with oral prednisolone and topical clobetasol propionate. A skin biopsy was conducted from the patient's lesions, which showed focal suprabasal acantholysis, epidermal ulceration, and upper dermal necrosis. The addition of valacyclovir to the treatment regimen is also mentioned.

The article discusses real-time three-dimensional echocardiography (RT3DE), which is a new ultrasound technique that enables dynamic three-dimensional visualization and quantification of the heart in real time. Investigation of feasibility and methodology of RT3DE in determining left ventricular (LV) and right ventricular (RV) volumes, RT3DE was performed in 35 normal adults using Philips SONOS 7500 system with a 2-4 MHz matrix array transducer. The 60 into 60 degrees "pyramid" volume database was obtained and analyzed on a TomTec echo workstation.

Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of α-tubulin in vitro. 23bb has a good pharmacokinetic profile with oral bioavailability of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116, acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, 23bb more effectively inhibited the tumor growth than SAHA even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results indicated that 23bb is a potent oral anticancer candidate for selective HDAC6 inhibitor and deserves further investigation. [ABSTRACT FROM AUTHOR]

In the present study, a series of novel histone deacetylase (HDAC) inhibitors using the morpholinopurine as the capping group were designed and synthesized. Several compounds demonstrated significant HDAC inhibitory activities and antiproliferative effects against diverse human tumor cell lines. Among them, compound 10o was identified as a potent class I and class IIb HDAC inhibitor with good pharmaceutical profile and druglike properties. Western blot analysis further confirmed that 10o more effectively increased acetylated histone H3 than panobinostat (LBH-589) and vorinostat (SAHA) at the same concentration in vitro. In in vivo efficacy evaluations of HCT116, MV4-11, Ramos, and MM1S xenograft models, 10o showed higher efficacy than SAHA or LBH-589 without causing significant loss of body weight and toxicity. All the results indicated that 10o could be a suitable candidate for treatment of both solid and hematological cancer. [ABSTRACT FROM AUTHOR]

Structure-based design, synthesis, and biological evaluation of a series of very potent HIV-1 protease inhibitors are described. In an effort to improve backbone ligand-binding site interactions, we have incorporated basic-amines at the C4 position of the bis-tetrahydrofuran (bis-THF) ring. We speculated that these substituents would make hydrogen bonding interactions in the flap region of HIV-1 protease. Synthesis of these inhibitors was performed diastereoselectively. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 25f, 25i, and 25j were evaluated against a number of highly-PI-resistant HIV-1 strains, and they exhibited improved antiviral activity over darunavir. Two high resolution X-ray structures of 25f- and 25g-bound HIV-1 protease revealed unique hydrogen bonding interactions with the backbone carbonyl group of Gly48 as well as with the backbone NH of Gly48 in the flap region of the enzyme active site. These ligand-binding site interactions are possibly responsible for their potent activity. [ABSTRACT FROM AUTHOR]

Uridine, a potential endogenous neuromodulator, has been demonstrated to interact with the dopaminergic system and to regulate dopamine-related behaviors. The present study investigated the effects of uridine on morphine-induced hyperactivity and behavioral sensitization and on modulating dopaminergic neurotransmission in mice, which may help to understand how uridine and its metabolites act as modulators of the GABAA receptors. The results showed that either systemic (30 or 100 mg/kg) or central (30, 100 or 300 nM) uridine administration significantly attenuated the hyperactivity induced by acute morphine treatment in mice. Intracerebroventricular administration of uracil and β-alanine also inhibited morphine-induced hyperactivity. Uridine, a known modulator of the GABA receptors, increased the extracellular levels of GABA in the brain. In addition, the GABAA receptors antagonist bicuculline significantly attenuated the effects of uridine on morphine-induced hyperactivity, suggesting that the GABAA receptors potentially mediate the effects of uridine and its metabolites on morphine-related activity. It was also observed that morphine-induced locomotor sensitization was abolished after chronic uridine treatment. In vivo microdialysis demonstrated that uridine reversed morphine-induced dopamine release in the dorsal striatum of morphine-sensitized mice. In conclusion, these data suggest that the therapeutic effects of uridine and its metabolites on morphine-induced hyperactivity and established behavioral sensitization may be mediated in part by interfering with the dopaminergic system possibly via agonistic effects at GABAA receptors. [ABSTRACT FROM AUTHOR]

The structure-based design, synthesis, and biological evaluationof a series of nonpeptidic macrocyclic HIV protease inhibitors aredescribed. The inhibitors are designed to effectively fill in thehydrophobic pocket in the S1′−S2′ subsites andretain all major hydrogen bonding interactions with the protein backbonesimilar to darunavir (1)or inhibitor 2.The ring size, the effect of methyl substitution, and unsaturationwithin the macrocyclic ring structure were assessed. In general, cyclicinhibitors were significantly more potent than their acyclic homologues,saturated rings were less active than their unsaturated analoguesand a preference for 10- and 13-membered macrocylic rings was revealed.The addition of methyl substituents resulted in a reduction of potency.Both inhibitors 14band 14cexhibited markedenzyme inhibitory and antiviral activity, and they exerted potentactivity against multidrug-resistant HIV-1 variants. Protein−ligandX-ray structures of inhibitors 2and 14cprovided critical molecular insights into the ligand-binding siteinteractions. [ABSTRACT FROM AUTHOR]