NAMPT enhances LOX expression and promotes metastasis in human chondrosarcoma cells by inhibiting miR-26b-5p synthesis.

Chondrosarcoma is a malignant bone tumor that emerges from abnormalities in cartilaginous tissue and is related with lung metastases. Nicotinamide phosphoribosyltransferase (NAMPT) is an adipocytokine reported to enhance tumor metastasis. Our results from clinical samples and the Gene Expression Omnibus data set reveal that NAMPT levels are markedly higher in chondrosarcoma patients than in normal individuals. NAMPT stimulation significantly increased lysyl oxidase (LOX) production in chondrosarcoma cells. Additionally, NAMPT increased LOX-dependent cell migration and invasion in chondrosarcoma by suppressing miR-26b-5p generation through the c-Src and Akt signaling pathways. Overexpression of NAMPT promoted chondrosarcoma metastasis to the lung in vivo. Furthermore, knockdown of LOX counteracted NAMPT-facilitated metastasis. Thus, the NAMPT/LOX axis presents a novel target for treating the metastasis of chondrosarcoma.

The effects of job characteristics on physicians' orientation toward lifelong learning.

With the rapidly growing body of medical knowledge, physicians must engage in lifelong learning. Physicians' orientation toward lifelong learning is of crucial importance. This study aimed to explore the effects of job characteristics on physicians' lifelong learning. A multicenter study collecting data from physicians from three medical centers in Taiwan was performed. A total of 321 physicians were surveyed with the Chinese version of the Job Content Questionnaire (C-JCQ) and the revised Jefferson Scale of Physician Lifelong Learning (JeffSPLL) to assess their job characteristics (i.e., job demands, job control, social support) and orientation toward lifelong learning. Exploratory factor analysis was employed to validate both questionnaires. Hierarchical regression was utilized to explore the relationship of job characteristics and predictors with physicians' lifelong learning. The results revealed that job demands (ß = 0.10), job control (ß = 0.19), social support from supervisors (ß = 0.16), the interaction of job demands × job control (ß = - 0.11) and the interaction of job demands × social support from colleagues (ß = 0.13) were significantly (p < .05, p < .001) related to lifelong learning. Moreover, physicians in the active group (high demand, high control) possessed a stronger orientation toward lifelong learning (mean = 3.57) than those in the low-strain group (mean = 3.42), high-strain group (mean = 3.39) and passive group (mean = 3.20). In conclusion, examining physicians' job demands, job control and social support helps us to understand their orientation toward lifelong learning and may provide insight to improve educational strategies.

MnSO4-promoted S-O bond cleavage for synthesizing functionalized sulfonium ylides from activated alkynes and sulfoxides.

A variety of functionalized sulfonium ylides were prepared in good yields through MnSO4-promoted S-O bond cleavage from activated alkynes and sulfoxides. Experimental results showed that the MnSO4 catalyst played important roles in accelerating the reaction and promoting the [1,3]-rearrangement of the S-O bond. Furthermore, the product was easily obtained on a gram scale by simple recrystallization without column chromatography. The obtained product can be converted to new sulfonium ylides and undergo cycloaddition with an alkyne to afford a trisubstituted furan scaffold.

Neurotrophic keratitis in autoimmune polyglandular syndrome type 1: a case report.

BACKGROUND: Autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive disease. In patients with APS-1, the most frequently reported ocular manifestations are keratoconjunctivitis with dry eye and retinal degeneration. However, to our knowledge, no research studies have reported the relationship between APS-1 and neurotrophic keratitis (NK). Possible explanations such as limbus cell deficiency being the primary cause of APS-1 keratopathy are not applicable to our unusual case of the patient with APS-1 presenting as ocular surface disease with NK. Our case findings suggest a new explanation for the observed corneal pathology and a potential treatment for these patients. CASE PRESENTATION: A 27-year-old woman was referred to our hospital because of intermittent blurred vision and recalcitrant ocular surface problems in both eyes for many years. She has a history of autoimmune polyglandular syndrome type 1 (APS-1), which includes hypothyroidism, hypoparathyroidism, hypoadrenalism, and hypogonadotropic hypogonadism. In vivo confocal microscopy clearly demonstrated significant degeneration of the sub-basal nerve plexus and stromal nerve bundles in her corneas bilaterally. She was diagnosed with severe NK and ocular surface disease caused by dry eye. Treatment included the application of therapeutic soft contact lenses and punctual occlusion; however, both treatments had a limited effect. CONCLUSION: Patients with APS-1 may have ocular surface disease and severe damage to corneal nerves. Regular follow-up and treatment focusing on the regeneration of corneal nerves is particularly important in these patients.

Clinical features and outcomes of Acanthamoeba keratitis in a tertiary hospital over 20- year period.

PURPOSE: To analyze the outcomes of Acanthamoeba keratitis (AK) in terms of different clinical presentations in a tertiary hospital in Taiwan over a 20- year period. METHODS: This is a retrospective case series. Patients with AK diagnosed at the National Taiwan University Hospital between January 1996 and December 2015 were identified. A diagnosis of AK was made on the basis of positive Acanthamoeba smear/cultures or pathological identification of Acanthamoeba cysts on keratoplasty specimens. Patient demographics, clinical presentations, treatment courses, and final visual outcomes were collected and analyzed. Visual acuity, postoperative complications and graft survivals were measured as outcomes. RESULTS: Of the 62 patients with AK in our study, 64.5% were medically treated while 35.5% underwent surgical treatment. In those with ring infiltrate, 52.4% patients could be successfully treated with medications. In eyes receiving penetrating keratoplasty, postoperative complications were more common in therapeutic penetrating keratoplasty (TPK) than those in optical penetrating keratoplasty (OPK) group (82.4% versus 40%, p = 0.04). The graft size was larger in TPK than that in OPK group (8.56 versus 7.83 mm, p = 0.002). Furthermore, post-operative glaucoma, which was the major complication, was found to be associated with larger graft size (p = 0.02) and dilated pupil/iris atrophy (p = 0.01). CONCLUSION: Even in advanced cases with ring infiltrate, eradication of infection with anti-amoebic drugs is possible. In those requiring keratoplasty, the surgical timing should be made meticulously considering graft size and signs of dilated pupil/iris atrophy in terms of post-operative glaucoma.

Therapeutic penetrating keratoplasty for microbial keratitis in Taiwan from 2001 to 2014.

PURPOSE: To study the surgical outcome of therapeutic penetrating keratoplasty (TPK) for medically uncontrolled microbial keratitis at a tertiary hospital in Taiwan over a 14-year period. METHODS: This is a retrospective case series study. Patients who underwent TPK at National Taiwan University Hospital in 2001-2014 were included. Patients were divided into 3 diagnostic groups: bacterial keratitis, fungal keratitis, and acanthamoeba keratitis. Each of the following criteria was evaluated: graft clarity at 1 month and 1 year postoperatively, cure of the disease, and anatomical success rate. RESULTS: A total of 107 TPKs were included. TPK eradicated the infection in 57/62 (91.9%) of bacterial keratitis, 33/41 (80.5%) of fungal keratitis, and 9/10 (90.0%) of acanthamoeba keratitis. 22/57 grafts (38.6%) of bacterial keratitis, 22/38 grafts (57.9%) of fungal keratitis, and 5/10 grafts (50.0%) of acanthamoeba keratitis remained clear at 1 year postoperatively. The 1-year graft survival rate did not significantly differ among these 3 groups. The leading causes of graft failure were late endothelial decompensation and graft reinfection. A higher percentage of graft clarity was achieved in grafts <8.5 mm in diameter than in larger grafts (55.4% vs. 31.4%, P = 0.027). Of the 14 patients with endophthalmitis at the time of TPK, the infection was successfully treated in 13 patients except 1 patient required evisceration. CONCLUSION: TPK is valuable in the management of medically uncontrolled microbial keratitis, although the 1-year graft survival rate is unsatisfactory. TPK combined with intravitreal antibiotics and vitrectomy is also a beneficial treatment strategy for patients with endophthalmitis secondary to microbial keratitis.

Dermatologic tacrolimus ointment on the eyelids for steroid-refractory vernal keratoconjunctivitis.

PURPOSE: The study aims to evaluate the therapeutic effects of dermatologic tacrolimus ointment on eyelids to treat refractory vernal keratoconjunctivitis (VKC). METHOD: This institutional study examined the effects of steroid treatment for 10 patients diagnosed with severe VKC refractory to steroid treatment. Patients received 0.1% dermatologic topical tacrolimus treatment on their eyelids once or twice daily for concomitant atopic dermatitis. The therapeutic outcomes were evaluated according to change in severity of clinical findings recorded with serial external ocular photography and change in requirement for steroid treatment. RESULTS: Clinical signs and symptoms improved substantially after tacrolimus treatment. Significant reduction in size of papillae, decrease of discharge, improvement in hyperemia, and shield ulcer healing with re-epithelization were observed in all patients. Six out of 10 (60%) patients did not receive steroid treatment. Long-term maintenance of tacrolimus was required to prevent episodic exacerbation. Patients' only treatment-related complaints were of mild burning sensations during medication application to eyelids, and this sensation disappeared a few days after treatment. CONCLUSIONS: Application of 0.1% dermatologic tacrolimus ointment to eyelids is effective and safe in the treatment of refractory VKC in patients with concomitant atopic dermatitis. This treatment may serve as a substitute for or decrease the requirement of steroid treatment.

Clinicopathologic correlation of ocular surface squamous neoplasia from a university hospital in North Taiwan 1994 to 2014.

BACKGROUND/PURPOSE: To describe the clinical and histologic characteristics of ocular surface squamous neoplasia (OSSN) and evaluate factors significant in recurrence at a university hospital in North Taiwan. METHODS: Patient charts, clinical features, and pathology records were retrospectively reviewed in patients with pathology-proved OSSN from January, 1994 to December, 2014. Clinicopathologic correlation was analyzed. RESULTS: Thirty-six patients were recruited. Mean age was 63.4 ± 13.0 (ranging from 23 to 87) years old. OSSN was predominant in men (21/36). Clinical appearances included papilliform in 17 eyes, gelatinous in 11 eyes, leukoplakic in 3 eyes, and 5 eyes in corneal intraepithelial neoplasia (CIN). Of 31 conjunctival OSSN, there were 4 in CIN I, 11 in CIN II, 13 in CIN III, and 3 in squamous cell carcinoma. Superior location was associated with higher-grade OSSN. Although statistical analysis was not significant, papilliform and multifocal lesions showed a trend of high-grade OSSN. The stages of tumor were 4, 5, 26, and 1 eye(s) in T1 to T4, respectively. Recurrence of disease occurred in 9 cases (25%) with mean recurrence time of 20.6 (range: 4 to 65) months. Multifocal lesion has a higher tendency for recurrence. CONCLUSION: Superior location was associated with high-grade OSSN, and papilliform OSSN might have a tendency of severe and invasive lesions. Multifocal lesions might be associated with higher-grade OSSN and higher recurrence rates.

Anti-Diabetic Effect of a Shihunine-Rich Extract of Dendrobium loddigesii on 3T3-L1 Cells and db/db Mice by Up-Regulating AMPK-GLUT4-PPARα.

The stems of Dendrobium loddigesii, a Chinese herb, are often used to treat diabetes and its polar extract is rich in shihunine, a water-soluble Orchidaceae alkaloid, but little is known about the anti-diabetes effects and mechanism of shihunine. This study investigated the anti-diabetic effect of a shihunine-rich extract of D. loddigesii (DLS) based on 3T3-L1 cells and db/db mice. The underlying mechanisms were primarily explored using Western blot analysis and immunohistochemical staining. The 3T3-L1 cell experiments showed that DLS can reduce the intracellular accumulation of oil droplets as well as triglycerides (p < 0.001) and promote the 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2deoxyglucose (2-NBDG) uptake of 3T3-L1 cells (p < 0.001). The animal experiments confirmed that after 8 weeks of DLS treatment, the body weight, fasting blood sugar, and serum lipid levels of mice were significantly lowered, and the oral glucose tolerance test and serum insulin level were significantly improved compared to the no-treatment diabetes mellitus group. Further histomorphology observation led to the conclusion that the quantities of islet cells were significantly increased and the increase in adipose cell size was significantly suppressed. The immunohistochemical test of pancreatic tissue revealed that DLS inhibited the expression of cleaved cysteine aspartic acid-specific protease 3 (cleaved caspase-3). Western blot experiments showed that DLS had agonistic effects on adenosine monophosphate (AMP)-activated protein kinase phosphorylation (p-AMPK) and increased the expression levels of peroxisome proliferator-activated receptor α (PPARα) and glucose transporter 4 (GLUT4) in liver or adipose tissues. These data suggest that the shihunine-rich extract of D. loddigesii is an anti-diabetic fraction of D. loddigesii. Under our experimental condition, DLS at a dose of 50 mg/kg has good anti-diabetic efficacy.

Oil supplementation improved growth and diet digestibility in goats and sheep fed fattening diet.

OBJECTIVE: This study evaluated the growth, digestibility and rumen fermentation between goats and sheep fed a fattening diet fortified with linseed oil. METHODS: Twelve 3 to 4 months old male goats and sheep were randomly allocated into two dietary treatment groups in a 2 (species)×2 (oil levels) factorial experiment. The treatments were: i) goats fed basal diet, ii) goats fed oil-supplemented diet, iii) sheep fed basal diet, and iv) sheep fed oil-supplemented diet. Each treatment group consisted of six animals. Animals in the basal diet group were fed with 30% alfalfa hay and 70% concentrates at a rate equivalent to 4% of their body weight. For the oil treatment group, linseed oil was added at 4% level (w:w) to the concentrate portion of the basal diet. Growth performance of the animals was determined fortnightly. Digestibility study was conducted during the final week of the feeding trial before the animals were slaughtered to obtain rumen fluid for rumen fermentation characteristics study. RESULTS: Sheep had higher (p<0.01) average daily weight gain (ADG) and better feed conversion ratio (FCR) than goats. Oil supplementation did not affect rumen fermentation in both species and improved ADG by about 29% and FCR by about 18% in both goats and sheep. The above enhancement is consistent with the higher dry matter and energy digestibility (p<0.05), as well as organic matter and neutral detergent fiber digestibility (p<0.01) in animals fed oil- supplemented diet. Sheep had higher total volatile fatty acid production and acetic acid proportion compared to goat. CONCLUSION: The findings of this study suggested that sheep performed better than goats when fed a fattening diet and oil supplementation at the inclusion rate of 4% provides a viable option to significantly enhance growth performance and FCR in fattening sheep and goats.

In Vivo Confocal Microscopic Study of Hard Contact Lens-Induced Lipid Keratopathy Secondary to Corneal Neovascularization in a Rabbit Hypercholesterolemic Model.

OBJECTIVES: In vivo confocal microscopy was used to observe the morphological presentations and anatomical correlations between corneal neovascularization (NV) and intracorneal lipid deposition in a rabbit model of contact lens (CL)-induced lipid keratopathy secondary to corneal NV. METHODS: Rabbits were divided into 3 groups: (1) 8-week normal diet, (2) 8-week high-cholesterol diet, and (3) 4-week normal diet followed by 4-week high-cholesterol diet. Corneal NV was induced by closed-eye CL. The formation and maturation of corneal NV were shown by immunohistochemical staining against CD31 and high-molecular-weight melanoma-associated antigen. In vivo confocal microscopy identified corneal NV and lipid deposition. Acquired images for each eye were arranged and mapped into subconfluent montages. RESULTS: In group 1, corneal NV sprouting formed from the peripheral to the central cornea by the end of week 4. Pericytes around vessels were shown after 2 weeks of CL wear. In group 2, lipid deposition started from the peripheral cornea and progressively covered the whole cornea. In group 3, lipid deposition was found first in the central cornea after 2 weeks of high-cholesterol diet and progressed to cover the peripheral cornea. In vivo confocal microscopy demonstrated four different patterns of intracorneal lipid deposition: spindle shapes arranged randomly or in parallel, amorphous shapes, multiangular shapes, and mixed types. Intracorneal lipid deposition was distributed from basal corneal epithelium to deep stroma. CONCLUSIONS: Intracorneal lipids tend to accumulate around newly formed corneal NV but can extend to the area covered with mature NV. In vivo confocal microscopy can demonstrate various shapes and depths of intracorneal lipid deposition.

Mini-Scleral Lenses for Correction of Refractive Errors After Radial Keratotomy.

OBJECTIVE: To evaluate the factors affecting clinical outcomes of correcting cumulative refractive errors or irregular astigmatism after radial keratotomy (RK) using mini-scleral lenses. METHODS: We retrospectively analyzed 36 eyes receiving mini-scleral lenses after RK from July 2011 to June 2016. Analyses included age, refractive errors, best spectacle-corrected visual acuity (BSCVA), best contact lens-corrected visual acuity (BCLCVA), topographic indices, RK treatment zone diameter (TZD), power difference (PrD) within the RK treatment zone, and decentration distance (DD) of the RK treatment zone center. An increase of three lines or more of Snellen visual acuity was considered a successful fitting. RESULTS: Of the eyes fitted with mini-scleral lenses, the BCLCVA (logarithm of the minimum angle of resolution [logMAR] 0.19±0.22) was significantly better than the BSCVA (logMAR 0.47±0.30). Twenty-three patients (64%) had a successful fitting. There was no statistically significant difference between successful and unsuccessful fittings with regard to age, prefitting refractive error, BSCVA, corneal astigmatism, simulated steep/flat K values, surface regularity index, TZD, or PrD. However, successful fittings had better centration of treatment zones with an average DD of 0.54±0.44 mm compared with a DD of 0.92±0.53 mm in the unsuccessfully fitted eyes. In addition, our case series showed that there was a negative impact on fitting outcomes in the presence of small central clear zones resulting from central incisions or scars. CONCLUSIONS: Although decentration of the RK treatment zone and small central clear zones were related to less optimal fitting results, mini-scleral lenses are a feasible option to correct cumulative refractive errors and irregular astigmatism in post-RK patients.

Analysis of SmartPlug Insertion-Related Complications.

PURPOSE: To evaluate the complications and the treatment results of SmartPlug-related complications. METHODS: Retrospective review of all patients from a single medical hospital who received SmartPlug (Medennium, Inc., Irvine, CA) insertions from October 2007 to February 2014. All patients who developed SmartPlug-related canaliculitis and pyogenic granuloma were analyzed. Lacrimal irrigation with antibiotics was performed in most patients. RESULTS: Six hundred thirty-one eyes received SmartPlug insertion and 18 eyes developed SmartPlug-related complications (14 canaliculitis and 4 pyogenic granuloma). The mean time interval from insertion to development of the complications is 3.0 (0.5-6.9) years. Sixteen eyes received lacrimal irrigation with antibiotics, and all the eyes showed improvement without recurrence. The other two eyes had recurrence of granuloma pyogenica only after surgical excision. CONCLUSIONS: SmartPlug-related complications, including canaliculitis and granuloma pyogenica, required long-term follow-up. Most of the complications can be cured by lacrimal irrigation of antibiotics.

Effects of Rich-Polyphenols Extract of Dendrobium loddigesii on Anti-Diabetic, Anti-Inflammatory, Anti-Oxidant, and Gut Microbiota Modulation in db/db Mice.

Dendrobium is a traditional Chinese herb with anti-diabetic effects and has diverse bibenzyls as well as phenanthrenes. Little is known about Dendrobium polyphenols anti-diabetic activities, so, a rich-polyphenols extract of D. loddigesii (DJP) was used for treatment of diabetic db/db mice; the serum biochemical index and tissue appearance were evaluated. In order to gain an insight into the anti-diabetic mechanism, the oxidative stress index, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and gut microbiota modulation were determined by ELISA, immunohistochemistry or high throughput sequencing 16S rRNA gene. The results revealed that DJP had the effects to decrease the blood glucose, body weight, low density lipoprotein cholesterol (LDL-C) levels and increase insulin (INS) level in the mice. DJP improved the mice fatty liver and diabetic nephropathy. DJP showed the anti-oxidative abilities to reduce the malondialdehyde (MDA) level and increase the contents of superoxide dismutase (SOD), catalase (CAT) as well as glutathione (GSH). DJP exerted the anti-inflammatory effects of decreasing expression of IL-6 and TNF-α. After treatment of DJP, the intestinal flora balance of the mice was ameliorated, increasing Bacteroidetes to Firmicutes ratios as well as the relative abundance of Prevotella/Akkermansia and reducing the relative abundance of S24-7/Rikenella/Escherichia coli. The function's prediction of gut microbiota indicated that the microbial compositions involved carbohydrate metabolism or lipid metabolism were changed. This study revealed for the first time that DJP improves the mice symptoms of diabetes and complications, which might be due to the effects that DJP induced the decrease of inflammation as well as oxidative stress and improvement of intestinal flora balance.

Surgical result of pterygium extended removal followed by fibrin glue-assisted amniotic membrane transplantation.

BACKGROUND/PURPOSE: To report the recurrence rate and cosmetic results of conjunctival wound edge and caruncle, and complications after pterygium extended removal followed by fibrin glue-assisted amniotic membrane transplantation. METHODS: A prospective interventional cohort study enrolled 57 (58 eyes) patients undergoing pterygium extended removal followed by fibrin glue-assisted amniotic membrane transplantation. All patients received postoperative follow-up for at least 12 months. Recurrence rate was graded from 1 to 4, and cosmetic results of conjunctival edge and caruncle were graded from 1 to 5. RESULTS: The cohort included 48 eyes with nasal pterygium, 5 eyes with temporal pterygium, and 5 eyes with double pterygium. There were 81.0% (n=47), 0% (n=0), 12% (n=7), and 7% (n=4) of eyes with Grades 1-4 recurrence, respectively. The cosmetic results of conjunctival wound edge and caruncle in cases with nasal pterygium showed 59.3% (n=32), 14.8% (n=8), 9.3% (n=5), 16.6% (n=9), and 0% (n=0) of eyes with Grades 1-5 morphology, respectively. Overall, 5.1% (n=3), 3.4% (n=2), 3.4% (n=2), 3.4% (n=2), 1.7% (n=1), 6.9% (n=4), and 1.7% (n=1) of patients suffered from postoperative pyogenic granuloma, transient diplopia, permanent motility restriction, steroid glaucoma, fat prolapse, subamniotic membrane hemorrhage, and early detachment of amniotic membrane, respectively. CONCLUSION: Pterygium extended removal followed by fibrin glue-assisted amniotic membrane transplantation results in low recurrence, satisfactory cosmetic results and a low incidence of additional complications.

Influence Analysis of Target Surface Emissivity on Infrared Radiation Polarization Characteristics.

Polarization imaging contains rich target parameters including spectrum, radiant intensity, polarization state, space geometry, etc. Polarization imaging can improve the target detection and recognition ability. The infrared polarization imaging is a new infrared detect technology in recent years. Infrared polarization imaging mainly aims to detect and identify the target with the difference of infrared radiation polarization characteristic between target and scene. But the state of polarization is affected by transmission medium in the transmission process of infrared radiation polarization information while the common method is to analyze the infrared radiation polarization characteristics of target that is not able to describe effects of all interrelated parameters and is difficult to estimate influence factors in the process of transmission. The equation of infrared polarized radiation is established through bidirectional reflectance distribution function based on micro-facet theory. And the mathematical model of the relationship between infrared radiation polarization degree and emissivity is derived in this paper. Result shows that the influence of target surface emissivity on the infrared degree can be ignored. On the basis of theoretical analysis, the infrared spectrum polarization imaging tests are unfolded, and the analysis of test data is consistent with the theoretical analysis. It is concluded that the correlation between the polarization degree of infrared and the emissivity of target surface can be neglected. The research production of this paper is conductive to increase of target detect efficiency, and it will provide new ways and means for camouflage target detect and identify. Therefore, the research production can be applied to detect and identify the camouflage target that is accomplished camouflage through change emissivity of camouflage target surface.

Evaluation of the in vitro and in vivo metabolic pathway and cytochrome P450 inhibition/induction profile of Huperzine A.

Huperzine A (HupA), one of the reversible and selective acetylcholinesterase inhibitors derived from Chinese herb Huperzia Serrata, possesses affirmative action of ameliorating cognitive dysfunction of Alzheimer's disease. Up to now, the effects of HupA on human cytochrome P450s (CYPs) have not been fully elucidated. The purpose of the present study was to clarify the metabolic pathway of HupA in vitro and in vivo, and to evaluate the CYPs inhibition/induction profile of HupA in vitro. The catalytic activity of CYP enzymes (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4) was measured by the quantification of specific enzyme substrates using validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods. The in vivo metabolic pathway evaluation was performed in an open, single-dose pharmacokinetic study of HupA in fourteen elderly subjects, with urine collecting at certain intervals. In human liver microsomes, HupA (10 ng/mL) was not metabolized within 90 min, and it showed negligible inhibition against these CYP isoforms within 0.2-100 ng/mL. In human liver hepatocytes, the activities of CYP1A2 and CYP3A4 were not significantly altered when incubated at 2 or 20 ng/mL of HupA. After oral administration of 0.1 mg HupA, the total proportion of HupA excreted through urine was relatively high, accounting to 35± 9% at the limited time period of 48 h. These results suggest that HupA is substantially excreted by kidney unchanged rather than metabolized by human liver, and is unlikely to cause clinically relevant drug-drug interaction (DDI) when co-administrated with drugs that are metabolized by CYP isoenzyme system.

Polymorphisms in the MTHFR gene are associated with breast cancer risk and prognosis in a Chinese population.

Breast cancer is the most common cancer affecting women in China and the world. Folate supplementation is proven to be effective in reducing the risk of breast cancer or improving its prognosis. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. This study aims to examine whether single nucleotide polymorphisms (SNP) in the MTHFR gene are associated with risk and survival of breast cancer and serum folate levels in healthy controls. We genotyped nine tagging SNPs in the MTHFR gene in a case-control study, including 560 breast cancer cases and 560 healthy controls in China. We found that TT genotype of rs1801133 had significant increased risk of breast cancer [adjusted odds ratio (OR) = 1.60, 95 % confidence interval (CI) 1.12-2.28] compared with CC genotype, and CC genotype of rs9651118 conferred significant reduced risk of breast cancer (adjusted OR = 0.65, 95 % CI 0.45-0.95) compared to TT genotype. Haplotype analysis also showed that MTHFR CACCAA and AGTCAC haplotypes (rs12121543-rs13306553-rs9651118-rs1801133-rs4846048-rs1801131) had significant reduced risk of breast cancer (adjusted OR = 0.70, 95 % CI 0.58-0.86; adjusted OR = 0.57, 95 % CI 0.40-0.80) compared with CATTAA haplotype. Besides, MTHFR rs9651118 CC genotype was significantly associated with survival in breast cancer cases (adjusted hazard ratio (HR) = 0.63, 95 % CI 0.40-0.99). But none of the SNPs in the MTHFR gene was associated with serum folate level in healthy controls. These findings suggest that variants in the MTHFR gene may influence the risk and prognosis of breast cancer.