Search

Objective: This study involved evaluating the efficacy of the Feijinsheng formula in the therapeutic management of patients with advanced non-small cell lung cancer (NSCLC)., Methods: We extracted the medical records of patients with advanced NSCLC undergoing treatment in the oncology department at the Second Affiliated Hospital of Zhejiang Chinese Medicine University from the medical record system. After applying inclusion and exclusion criteria, clinical data of 150 patients were collected. The patients were stratified into two groups based on their usage of the Feijinsheng formula, comprising 69 cases in the Exposed group and 81 cases in the Control group. A comparative analysis of the survival time difference between the two groups was conducted., Results: The data between the two groups exhibited similarity ( p  > 0.05). Following treatment, the Exposed group demonstrated a notably prolonged overall survival time compared to the Control group ( p  < 0.05). While the Exposed group displayed a higher objective remission rate than the Control group, this disparity did not reach statistical significance ( p  > 0.05)., Conclusion: The Feijinsheng formula extended the duration of survival of patients with advanced NSCLC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Members of the Flaviviridae family, encompassing the Flavivirus and Hepacivirus genera, are implicated in a spectrum of severe human pathologies. These diseases span a diverse spectrum, including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, and adverse fetal outcomes, such as congenital heart defects and increased mortality rates. Notably, infections by Flaviviridae viruses have been associated with substantial cardiovascular compromise, yet the exploration into the attendant cardiovascular sequelae and underlying mechanisms remains relatively underexplored. This review aims to explore the epidemiology of Flaviviridae virus infections and synthesize their cardiovascular morbidities. Leveraging current research trajectories and our investigative contributions, we aspire to construct a cogent theoretical framework elucidating the pathogenesis of Flaviviridae -induced cardiovascular injury and illuminate prospective therapeutic avenues.

The aim of this paper was to reveal the correlation between the expression of ELOVL fatty acid elongase 6 (ELOVL6) gene in lung adenocarcinoma (LUAD) and its clinical significance, immune cell infiltration level and prognosis. Expression profile data of ELOVL6 mRNA were collected from the cancer genome atlas database to analyze the differences in ELOVL6 mRNA expression in LUAD tissues and normal lung tissues, and to analyze the correlation between ELOVL6 and information on clinicopathological features. Based on TIMER database, TISDIB database and GEPIA2 database, the correlation between ELOVL6 expression and tumor immune cell infiltration in LUAD was analyzed. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses of ELOVL6-related co-expressed genes were performed to identify the involved signaling pathways and to construct their co-expressed gene protein interaction networks. Drugs affected by ELOVL6 expression were screened based on the Cell Miner database. These findings suggest that ELOVL6 plays an important role in the course of LUAD, and the expression level of this gene has a close relationship with clinicopathological characteristics and survival prognosis, and has the potential to become a prognostic marker and therapeutic target for LUAD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Herein, inorganic base K 3 PO 4 promoted divergent synthesis of CF 3 -substituted allenes, cyclopentenes, alkynes, and fluorinated enynes via regioselective nucleophilic addition of carbon nucleophiles to 2-trifluoromethyl-1,3-enynes was developed. With the choice of different carbon nucleophiles, various fluorinated compounds could be obtained under K 3 PO 4 /DMF reaction system. When malononitriles were used as nucleophiles, CF 3 -substituted allenes, cyclopentenes, and alkynes could be obtained, respectively. By using 1,3-dicarbonyl compounds as nucleophiles, ring-monofluorinated 4 H -pyrans could be prepared, and 1,1-difluoro-1,3-enynes could be furnished with the participation of diethyl malonate. Moreover, these five kinds of fluorinated allenes, alkenes, and enynes are valuable building blocks.

Symmetrical diaryl sulfides and diaryl disulfides have been efficiently and selectively constructed via the homocoupling of sodium arenesulfinates. The selectivity of products relied on the different reaction systems: symmetrical diaryl sulfides were predominately obtained under the Pd(OAc) 2 catalysis, whereas symmetrical diaryl sulfides were exclusively yielded in the presence of the reductive Fe/HCl system.

High power 1.5 µm band fiber lasers are of great importance for many practical applications. Generally, the technical targets including high average output power, narrow linewidth, temporally suppressed intensity dynamics, high spectral purity, single transverse mode lasing, and excellent robustness are the major concerns when constructing a high-performance laser source. Here, we demonstrate the highest output power of a wavelength tunable 1.5 µm band random fiber laser based on the active fiber gain mechanism to the best of our knowledge. A master oscillator power-amplifier (MOPA) configuration is employed to greatly boost the output power to 20 watt-level with a single transverse mode lasing and the same linewidth as the seed, benefiting from the spectral broadening free feature when employing the random fiber laser as the seed. This work not only enriches the progress of random fiber laser, but also provides an attractive alternative in realizing high performance lasing light source at 1.5 µm band.

Single-cell RNA sequencing (scRNA-seq) is increasingly used in studies on gastrointestinal cancers. This study investigated the prognostic value of epithelial cell-associated biomarkers in colorectal cancer (CRC) using scRNA-seq data. We downloaded and analysed scRNA-seq data from four CRC samples from the Gene Expression Omnibus (GEO), and we identified marker genes of malignant epithelial cells (MECs) using CRC transcriptome and clinical data downloaded from The Cancer Genome Atlas (TCGA) and GEO as training and validation cohorts, respectively. In the TCGA training cohort, weighted gene correlation network analysis, univariate Cox proportional hazard model (Cox) analysis, and least absolute shrinkage and selection operator regression analysis were performed on the marker genes of MEC subsets to identify a signature of nine prognostic MEC-related genes (MECRGs) and calculate a risk score based on the signature. CRC patients were divided into high- and low-risk groups according to the median risk score. We found that the MECRG risk score was significantly correlated with the clinical features and overall survival of CRC patients, and that CRC patients in the high-risk group showed a significantly shorter survival time. The univariate and multivariate Cox regression analyses showed that the MECRG risk score can serve as an independent prognostic factor for CRC patients. Gene set enrichment analysis revealed that the MECRG signature genes are involved in fatty acid metabolism, p53 signalling, and other pathways. To increase the clinical application value, we constructed a MECRG nomogram by combining the MECRG risk score with other independent prognostic factors. The validity of the nomogram is based on receiver operating characteristics and calibration curves. The MECRG signature and nomogram models were well validated in the GEO dataset. In conclusion, we established an epithelial cell marker gene-based risk assessment model based on scRNA-seq analysis of CRC samples for predicting the prognosis of CRC patients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Kai-yu Shen et al.)

Even though polyurethane (PU) has been widely applied, its superhydrophobicity is inadequate for certain applications. As such, the development of superhydrophobic polyurethane (SHPU) has recently attracted significant attention, with numerous motivating reports in recent years. However, a comprehensive review that summarizes these state-of-the-art developments remains lacking. Thus, this review aims to fill up this gap by reviewing the recent preparation methods for SHPU based on superhydrophobic theories and principles. Three main types of methods used in promoting the hydrophobicity of PU are emphasized in this review; (1) incorporation of silicide or fluoride to lower the surface energy, (2) creation of micro/nano-scale rough surfaces by electrospinning or grafting of nanoparticles, and (3) integrating the earlier two methods to develop a synergistic approach. Furthermore, this review also discussed the various applications of SHPU in oil spill treatment, protective coating, self-healing materials and sensors., (Copyright © 2022 Elsevier B.V. All rights reserved.)

3,4-Bisthiolated pyrroles constitute key cores in pyrrole-based semiconductors, and their electronic properties could be improved by the bisthio groups via the S -effect. Herein, a convenient method for the synthesis of 3,4-bisthiolated pyrroles has been developed through the AlCl 3 -catalyzed thiolation/cyclization of homopropargylic azides, and cyclic voltammetry and DFT calculations indicated that the desired 3,4-bisthiolated pyrroles had higher HOMO orbital energies and lower band gaps than the parent unsubstituted 2,5-diphenylpyrrole.

Pathological cardiac hypertrophy is commonly associated with an upregulation of fetal genes, fibrosis, cardiac dysfunction, and heart failure. Previous studies have demonstrated that gastrodin (GAS) exerts cardioprotective action in the treatment of cardiac hypertrophy. However, the mechanism by which GAS protects against cardiac hypertrophy is yet to be elucidated. A mouse model of myocardial hypertrophy was established using an angiotensin II (Ang II) induction. GAS (5 or 50 mg/kg/d) was orally administered every day starting 7 days prior to the Ang II infusion combined with sham-operated controls. Heart samples from each group were collected for RNA sequencing. Using bioinformatics analysis, the key differentially expressed genes (DEGs) that are involved in reversing cardiac function were identified. Through bioinformatics analysis, the key DEGs that are involved in GAS's inhibition of Ang II-induced abnormal gene expression within the heart were identified. This was further validated using quantitative real-time PCR and Western blotting in neonatal rat cardiomyocytes (NRCMs). Oral administration of GAS significantly suppressed the Ang II-induced increase in heart size and heart weight to body weight. Furthermore, pretreatment of the NRCMs with GAS led to a dose-dependent inhibition of Ang II-induced increases in Nppb mRNA expression. We identified 620 upregulated and 87 downregulated Ang II-induced DEGs II, among which the expression patterns of 58 and 146 genes were inverted by low-dose and high-dose GAS, respectively. These inverted DEGs were found to be mainly enriched in the biological processes of regulation of Ras protein signal transduction, heart contraction, covalent chromatin modification, glucose metabolism, and positive regulation of cell cycle. Among them, the insulin-like growth factor type 2 ( Igf2 ) gene, which was found to be highly reversed and downregulated by GAS, served as a core gene linking energy metabolism, immune regulation, and systemic development. Subsequent functional verification demonstrated that IGF2, and its receptor IGF2R, is one of the targets of GAS that helps protect against cardiac hypertrophy. Taken together, we have identified, for the first time, IGF2/IGF2R as a potential target influenced by GAS in the prevention of cardiac hypertrophy., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

The pathophysiology of cardiac hypertrophy is complex and multifactorial. Both the store-operated Ca 2+ entry (SOCE) and excessive autophagy are the major causative factors for pathological cardiac hypertrophy. However, it is unclear whether these two causative factors are interdependent. In this study, we examined the functional role of SOCE and Orai1 in angiotensin II (Ang II)-induced autophagy and hypertrophy using in vitro neonatal rat cardiomyocytes (NRCMs) and in vivo mouse model, respectively. We show that YM-58483 or SKF-96365 mediated pharmacological inhibition of SOCE, or silencing of Orai1 with Orail-siRNA inhibited Ang II-induced cardiomyocyte autophagy both in vitro and in vivo . Also, the knockdown of Orai1 attenuated Ang II-induced pathological cardiac hypertrophy. Together, these data suggest that Ang II promotes excessive cardiomyocyte autophagy through SOCE/Orai1 which can be the prime contributing factors in cardiac hypertrophy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zheng, Gao, Xie, Li, Ma, Song, Luo, Huang, Yang, Zhang, Huang, Yang and Yao.)

Spectral similarity indices were used to select similar soil samples from a spectral library and improve the predictive accuracy of target samples. There are many similarity indices available, and precisely how to select the optimum index has become a critical question. Five similarity indices were evaluated: Spectral angle mapper (SAM), Euclidean distance (ED), Mahalanobis distance (MD), SAM&#95;pca and ED&#95;pca in the space of principal components applied to a global soil spectral library. The accordance between spectral and compositional similarity was used to select the optimum index. Then the optimum index was evaluated if it can maintain the greatest predictive accuracy when selecting similar samples from a spectral library for the prediction of a target sample using a partial least squares regression (PLSR) model. The evaluated physiochemical properties were: soil organic carbon, pH, cation exchange capacity (CEC), clay, silt, and sand content. SAM and SAM&#95;pca selected samples were closer in composition compared to the target samples. Based on similar samples selected using these two indices, PLSR models achieved the highest predictive accuracy for all soil properties, save for CEC. This validates the hypothesis that the accordance information between spectral and compositional similarity can help select the appropriate similarity index when selecting similar samples from a spectral library for prediction., Competing Interests: The authors have declared that no competing interests exist.

Background: Hepatocellular carcinoma (HCC) with tumor thrombus in the bile duct (BDTT) is easily misdiagnosed or mistreated due to the clinicopathological diversity of the thrombus and its relationship with primary lesions., Aim: To propose a new classification for HCC with BDTT in order to guide its diagnosis and treatment., Methods: A retrospective review of the diagnosis and treatment experience regarding seven typical HCC patients with BDTT between January 2010 and December 2019 was conducted., Results: BDTT was preoperatively confirmed by computed tomography/magnetic resonance imaging in only four patients. Three patients with recurrent HCC and one patient with first-occurring HCC had no visible intrahepatic tumors; of these, misdiagnosis occurred in two patients, and three patients died. One patient was mistreated as having common bile duct stones, and another patient with a history of multiple recurrent HCC was misdiagnosed until obvious biliary dilation could be detected. Only one patient who received hepatectomy accompanied by BDTT extraction exhibited disease-free survival during the follow-up period. A new classification was proposed for HCC with BDTT as follows: HCC with microscopic BDTT (Type I); resectable primary or recurrent HCC mass in the liver with BDTT (Type II); BDTT without an obvious HCC mass in the liver (Type III) and BDTT accompanied with unresectable intra- or extrahepatic HCC lesions (Type IV)., Conclusion: We herein propose a new classification system for HCC with BDTT to reflect its pathological characteristics and emphasize the significance of primary tumor resectability in its treatment., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Primitive neuroectodermal tumours (PNETs) are rare malignant small round cell tumours. Notably, despite widespread reports of PNET in multiple parts of the body, it is extremely rare in the pelvis. Here, a rare case of giant PNET of the pelvis, that was treated with surgical intervention comprising hemipelvectomy and amputation, is reported. A 42-year-old female patient presented with an enlarged mass on the left hip and severe pain in the left lower extremity for the previous 6 months. Preoperative imaging examinations indicated an irregular soft tissue-like signal shadow sized 19 × 15 × 12 cm at the left ilium and sacrum. After surgical intervention involving left hemipelvectomy and amputation, the tumour was diagnosed by pathology as PNET. During the courses of postoperative radiotherapy and chemotherapy, local recurrence and distant metastasis occurred, and the patient died 9 months following surgical treatment. To the best of the authors' knowledge, the current case is the largest pelvic PNET resection reported to date. Pelvic PNET is extremely malignant and has a high mortality rate regardless of surgical treatment, however, surgical resection of the lesion may relieve the symptoms, extend life, and improve quality of life to a certain extent.

Disulfide bonds are a significant motif in life and drug-delivery systems. In particular, steric hindrance and stereoscopic disulfide linkers are closely associated with the stability of antibody-drug conjugates, which affects the potency, selectivity, and pharmacokinetics of drugs. However, limited availability and diversity of tertiary thiols impede the construction of steric and stereoscopic disulfides for cross-linkage in biochemistry and pharmaceuticals. Through modulating the mask effect of disulfurating reagents, we develop a facile and robust strategy for construction of diverse steric and stereoscopic disulfides via N -dithiophthalimides. The practical cross-linkage of biomolecules including amino acids, saccharides, and nucleosides with different drugs and fluorescent molecules is successfully established through hindered disulfide linkers., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: This present study is aimed to retrospectively assess the efficacy of three-dimensional (3D) printing assisted osteotomy guide plate in accurate osteotomy of adolescent cubitus varus deformity., Material and Methods: Twenty-five patients (15 males and 10 females) with the cubitus varus deformity from June 2014 to December 2017 were included in this study and were enrolled into the conventional group (n = 11) and 3D printing group (n = 14) according to the different surgical approaches. The operation time, intraoperative blood loss, osteotomy degrees, osteotomy end union time, and postoperative complications between the two groups were observed and recorded., Results: Compared with the conventional group, the 3D printing group has the advantages of shorter operation time, less intraoperative blood loss, higher rate of excellent correction, and higher rate of the parents' excellent satisfaction with appearance after deformity correction (P < 0.001, P < 0.001, P = 0.019, P = 0.023). Nevertheless, no significant difference was presented in postoperative carrying angle of the deformed side and total complication rate between the two groups (P = 0.626, P = 0.371)., Conclusions: The operation assisted by 3D printing osteotomy guide plate to correct the adolescent cubitus varus deformity is feasible and effective, which might be an optional approach to promote the accurate osteotomy and optimize the efficacy.

The anterior transpedicular screws (ATPS) fixation is a valuable discovery in the field of lower cervical spine (LCS) reconstruction, as it has the advantages of both anterior and posterior approaches. In recent years, with in-depth research on ATPS fixation related to anatomy, biomechanical tests, and clinical applications, its firm stability and excellent biomechanical properties have been recognized by more and more surgeons. Although ATPS fixation has been gradually applied in clinic settings under the promotion of emerging distinctive instruments, its long-term efficacy still needs to be further clarified due to the lack of large sample size studies and long-term follow-up. Nevertheless, it is believed that with the maturity of digital devices and the development of precision medicine, ATPS fixation has a promising prospect.

An efficient method for the synthesis of 4-sulfenyl isoxazoles has been developed via AlCl 3 -mediated electrophilic cyclization/sulfenylation of 2-alkyn-1-one O-methyloximes. Remarkably, N-arylsulfanylsuccinimides are employed as electrophiles for the construction of 4-arylsulfanyl isoxazoles, and 4-alkylsulfanyl isoxazoles are accessed with dialkyl disulfides as electrophiles.

The asymmetric aza-Henry reaction of N-Boc imines and nitroalkanes was realized in the presence of 10 mol % dinuclear zinc-AzePhenol catalysts under ambient conditions. A variety of nitroamines were obtained in good yields (up to 97%) with excellent enantioselectivities (up to 99% ee) and high diasteroselectivity (up to 14:1 dr). Our protocol combined the operational simplicity and mild reaction conditions, thus making the process amenable for technical applications.

A new and convenient method for one-pot synthesis of α-arylhydrazo-β-keto sulfones is developed via Cu (II)-catalyzed oxysulfonylation/diazenylation of alkenes. This four-component cascade reaction enables a series of α-arylhydrazo-β-keto sulfone derivatives accessed from readily available alkenes, sulfinates, and diazonium salts under aerobic conditions. Furthermore, the 3-sulfonyl cinnolin-4(1 H)-one skeleton is successfully constructed from the corresponding α-arylhydrazo-β-keto sulfone product under basic conditions.

Herein, we report a chemoselective P(NMe 2 ) 3 -mediated reductive epoxidation of α-dicarbonyl compounds such as isatins, α-keto esters, and α-diketones with aldehydes and ketones, leading to an efficient synthesis of a wide range of highly functionalized unsymmetrical epoxides in moderate to excellent yields and diastereoselectivities. The Kukhtin-Ramirez adduct, which is exclusively generated in situ from an α-dicarbonyl compound and P(NMe 2 ) 3 , plays a key role in governing the chemoselectivity. It represents the first practical synthesis of unsymmetrical epoxides via direct reductive epoxidation of two different carbonyl electrophiles and also complements the existing methods of generating epoxides.

Objectives: To investigate the efficiency of a new cascade biocatalysis system for the conversion of R, S-β-amino alcohols to enantiopure vicinal diol and β-amino alcohol., Results: An efficient cascade biocatalysis was achieved by combination of a transaminase, a carbonyl reductase and a cofactor regeneration system. An ee value of > 99% for 2-amino-2-phenylethanol and 1-phenyl-1, 2-ethanediol were simultaneously obtained with 50% conversion from R, S-2-amino-2-phenylethanol. The generality of the cascade biocatalysis was further demonstrated with the whole-cell approaches to convert 10-60 mM R, S-β-amino alcohol to (R)- and (S)-diol and (R)- and (S)-β-amino alcohol in 90-99% ee with 50-52% conversion. Preparative biotransformation was demonstrated at a 50 ml scale with mixed recombinant cells to give both (R)- and (S)-2-amino-2-phenylethanol and (R)- and (S)-1-phenyl-1, 2-ethanediol in > 99% ee and 40-42% isolated yield from racemic 2-amino-2-phenylethanol., Conclusions: This cascade biocatalysis system provides a new practical method for the simultaneous synthesis of optically pure vicinal diol and an β-amino alcohol.

Switchable ortho/ipso-cyclization of N-arylpropynamides induced with N-sulfanylsuccinimides as general sulfur reagents is reported. In the presence of MeOH, para-fluoro N-arylpropynamides exclusively undergo the ipso-cyclization to give 3-sulfenyl azaspiro[4,5]trienones. Two kinds of bioactive heterocycles, benzothieno-[3,2-b]quinoline and -[2,3-c]quinolone, have been directly and efficiently prepared from the corresponding sulfenylated products.

Objective: To define the survival effect of surgery of primary adrenal malignant lesions in metastatic adrenocortical carcinoma (ACC) patients., Patients and Methods: We used the Surveillance, Epidemiology and End Results (SEER) database (1973-2014) to identify metastatic ACC patients (stage IV by using European Network for the Study of Adrenal Tumors stage classification). Correlated variables, including age, sex, race, tumor laterality, treatment modality, lymph node dissection, surgery of metastatic site, tumor size, and tumor stage, were extracted. Univariate and multivariate Cox regression analyses were used to define the efficacy of surgery on survival outcomes, including overall survival and cancer-specific survival of ACC., Results: There were 290 metastatic ACC patients identified from the database. The overall median survival time was 7 (95% CI, 6-8) months. Among these patients, 118 patients received primary site surgery and 172 patients did not. In both univariate and multivariate analyses, primary site surgery significantly improved both overall (hazard ratio 0.413, 95% CI, 0.299-0.571, P <0.01) and cancer-specific survival (hazard ratio 0.408, 95% CI, 0.290-0.574, P <0.01) for metastatic ACC patients., Conclusion: Our study suggests that primary site surgery in metastatic ACC patients significantly improved overall and cancer-specific survival. Further multicenter prospective studies are still needed to validate these outcomes., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: To define the prognostic factors associated with overall survival (OS) and cancer-specific survival (CSS) for adrenocortical carcinoma (ACC). Patients and Methods: We used the Surveillance, Epidemiology and End Results (SEER) database (1973-2014) to identify ACC patients. Correlated variables, including age, sex, race, tumor laterality, marital status at diagnosis, treatment of primary site, lymph node dissection, radiation therapy, chemotherapy, tumor size and tumor stage, were extracted. Univariate and multivariate Cox regression were used to define the prognostic factors. Harrell’s concordance index (C index) was calculated to evaluate the discrimination ability for the prognostic predictive models. Results: There were 749 ACC patients identified from the database. The overall median survival time was 22 (95%CI, 18-25) months. In multivariate analysis, age, treatment, chemotherapy and tumor stage were independent risk factors for both overall and cancer-specific survival. Tumor stage had a dominant effect on the cancer prognosis. Additionally, the ENSAT stage had better discrimination than the AJCC stage group in different predictive models. Conclusion: Our study shows that age, treatment of primary site, chemotherapy and tumor stage were prognostic factors for overall and cancer-specific mortality in ACC patients. Among these factors, tumor stage had a dominant effect. The ENSAT stage was more discriminative than the 7th AJCC stage group. Further multi-center prospective validation is still needed to confirm these outcomes., (Creative Commons Attribution License)

A simple and efficient metal-free sulfenylation/cyclization of aryl alkynoates has been developed, obtaining various 3-sulfenylated coumarins in moderate to excellent yields. In the presence of BF 3 ·Et 2 O, the stable and readily accessible N-sulfanylsuccinimides were employed as electrophiles to induce the 6-endo-dig electrophilic cyclization of alkynoates. The reaction using substrates bearing a methoxy group on the phenoxy ring proceeded in an exclusively distinct pathway via either ipso sulfenylcyclization or sulfenylation of the phenoxy ring depending on the different locations of the methoxy substituent. The resulting 3-sulfenylated coumarins can be readily transformed to 3-sulfinylated or 3-sulfonylated coumarins under different oxidation conditions.

Previously we have found vicagrel, a new acetate derivative of clopidogrel, underwent hydrolysis to 2-oxo-clopidogrel and subsequent conversions to its pharmacological active metabolite (AM) and inactive carboxylic acid metabolite (CAM). This study demonstrated the interspecies differences of the vicagrel bioactivation by comparing the critical vicagrel metabolites formation in rats, dogs and human. The pharmacokinetic studies with rats and dogs were conducted after intragastric administration of vicagrel, followed by in vitro metabolism investigation in venous system, intestinal/hepatic microsomes from rats, dogs and human. An obvious disparity was observed in system exposure to AM (99.0 vs. 635.1 μg⋅h/L, p < 0.05) and CAM (10119 vs. 2634 μg⋅h/L, p < 0.05) in rats and dogs. It was shown that the cleavage of vicagrel was almost completed in intestine with great different clearance (53.28 vs. 3.643 L⋅h -1 ⋅kg -1 , p < 0.05) in rats and dogs. With no further hydrolysis to CAM, the greatest clearance of AM (3.26 mL⋅h -1 ⋅kg -1 ) was found in dog intestine. In rat plasma, 2-oxo-clopidogrel was much more extensively hydrolyzed to CAM than in dog and human. Albeit similar hydrolysis clearance and AM production was observed among hepatic microsomes of the three species, the production velocity of CAM ranked highest in dogs (7.55 pmol/min/mg protein). Therefore, the unconformity of AM and CAM exposure cross species mainly came from the metabolism of 2-oxo-clopidogrel associated largely with tissue specificity and interspecies differences of esterases. In human, the pharmacokinetics of vicagrel might be more optimistic due to less inactivation hydrolysis before reaching liver.

Aim: To analyze RASSF6 expression in pancreatic ductal adenocarcinoma (PDAC) and to determine whether RASSF6 has an independent prognostic value in PDAC., Methods: We studied RASSF6 expression in 96 histologically confirmed PDAC samples and 20 chronic pancreatitis specimens using immunohistochemistry and real-time quantitative reverse transcription-PCR. PDAC issues were then classified as RASSF6 strongly positive, weakly positive or negative. RASSF6 mRNA and protein expression in PDAC samples with strong positive staining was further evaluated using real-time PCR and Western blot analysis. Lastly, correlations between RASSF6 staining and patients' clinicopathological variables and outcomes were assessed., Results: RASSF6 was negatively expressed in 51 (53.1%) PDAC samples, weakly positively expressed in 29 (30.2%) and strongly positively expressed in 16 (16.7%), while its expression was much higher in para-tumor tissues and chronic pancreatitis tissues. Positive relationships between RASSF6 expression and T-stage (P = 0.047) and perineural invasion (P = 0.026) were observed. The median survival time of strongly and weakly positive and negative RASSF6 staining groups was 33 mo, 15 mo and 11 mo, respectively. Cox multivariate analysis indicated that RASSF6 was an independent prognostic indicator of overall survival in patients with PDAC. A survival curve analysis revealed that increased RASSF6 expression was correlated with better overall survival (P = 0.009)., Conclusion: RASSF6 expression is an independent biomarker of an unfavorable prognosis in patients with PDAC.

Cancer stem cells (CSCs) are believed to have a crucial role in triple-negative breast cancer (TNBC) recurrence. However, the exact mechanisms that are functionally critical in CSCs-mediated recurrence remain unclear. Here, we showed that CSCs derived from recurrent TNBCs are endowed with increased self-renewal capacity as compared with those from the matched primary lesions. Using patient-derived specimens, we demonstrated the existence of paracrine brain-derived neurotrophic factor (BDNF) signaling between differentiated recurrent TNBC cells and CSCs characterized by the expression of TrkB, the receptor of BDNF. We showed that paclitaxel induced BDNF expression and apoptosis simultaneously in a cell cycle-dependent manner. BDNF promotes the self-renewal potential of the TrkB+CSCs through induction of KLF4. The TrkB+CSCs represent a particular subset indispensable for TNBC relapse. In line with this, TrkB is proved to be a superior predictor for TNBC recurrence. Using a genetically engineered mouse model of TNBC, we observed that ablation of the TrkB+CSCs potentially prevents relapse of malignant tumors. Further preclinical investigation of this promising approach may lead to development of a novel therapeutic strategy to improve the devastating prognosis of TNBC patients.

Cellular prion protein (PrPc) is a glycosylphosphatidylinositol-anchored membrane protein that has various physical functions, including protection against apoptotic and oxidative stress, cellular uptake of copper ions, transmembrane signaling, and adhesion to the extracellular matrix. In this study, we show that PrPc is highly expressed in colorectal adenocarcinomas. Transcriptome profiling of PrPc-depleted DLD-1 cells revealed downregulation of glucose transporter 1 (Glut1). PrPc is shown to be involved in regulating Glut1 expression through the Fyn-HIF-2α pathway. As Glut1 is the natural transporter of glucose and is required for the high glycolytic rate seen in colorectal tumors, silencing of PrPc reduced the proliferation and survival rate of colorectal cancer cells in vitro. In vivo, knockdown of PrPc by hydrodynamic injection with a cocktail of PrPc-shRNA-encoding plasmids also inhibited tumorigenicity in a xenograft model in nude mice. In summary, our data characterize a novel molecular mechanism that links PrPc expression to the regulation of glycolysis. Targeting PrPc will therefore be a promising strategy to overcome the growth and survival advantage in colorectal tumors., (© 2010 Japanese Cancer Association.)

The activation of K-ras gene and expression of annexin A1 play an important role in colorectal tumorigenesis. We initiated this study to analyze the possible relationship between the annexin A1 expression and the K-ras mutation status in colorectal cancer. K-ras mutations are present in one fourth to one half of colorectal cancers. Annexin A1, a 37-kDa calcium- and phospholipid-binding protein, is over-expressed in colorectal cancers and may be involved in invasive tumor growth and metastasis. Here, we examined twenty paired specimens of colorectal cancer and adjacent normal tissues for K-ras mutations and annexin A1 expression. Sequencing analysis of codons 12 and 13 of K-ras revealed the presence of K-ras mutations in six colorectal cancer tissue specimens (30%). RT-PCR and immunoblotting studies further found that the expression levels of annexin A1 mRNA and protein were increased (2.9-fold and 1.7-fold, respectively) in colorectal cancers harboring K-ras codon 12 or codon 13 mutation compared with adjacent normal tissues (P < 0.05). In colorectal cancer tissues with wild-type K-ras, 12 (85.7%) specimens showed reduced expression of annexin A1 (0.48-fold and 0.81-fold, respectively). No significant association was found between K-ras mutations or annexin A1 over-expression and demographic or other clinicopathological parameters such as gender, differentiation or metastasis. However, a significant and positive correlation was identified between K-ras mutations and annexin A1 over-expression. Our findings indicate that annexin A1 could be implicated in colorectal cancer development and progression and could be of potential use as a predictive marker for guiding targeted therapy for colorectal cancer.

Objective: To investigate the clinical usefulness of diffusion tensor imaging (DTI) in demonstrating between gliomas and surrounding fibers., Methods: 24 patients of glioma (WHO grade: grade I - II 16 cases; grade III - IV 8 cases) were examined using DTI and conventional contrast-enhanced MRI of 3.0 T MRI scanner (GE company, America). After the initial data acquisition introduced into workstation, image analysis was performed with the use of functool software. Mean diffusivity (MD) and fractional anisotropy (FA) values were measured in regions of solid tumor, surrounding edema and normal white matter of the high grade cerebral gliomas. Differences in these values among the tissues were assessed on the high grade cerebral gliomas. Anatomic relationship between intracranial tumors and surrounding fibers was analysed on fractional anisotropic (FA) map, color-coded directional map, three-dimensional white matter tractography. All patients' symptoms were evaluated preoperative and postoperative respectively., Results: The DTI patterns altered by the tumor were categorized as follows: displacement, infiltration and destruction. The tractography showed that the main influence in 16 cases of grade I - II glioma on adjacent white matter tracts was displacement, but infiltration and destruction were also revealed. The patients have definite improvement in symptoms. The destruction and infiltration of fiber tracts could be seen in all edema regions around grade III - IV gliomas in 8 cases. The patients have not definite improvement in symptoms. Apparently significant differences of MD were found in solid tumor, surrounding edema, compared with normal white matter regions (P < 0.05). But there was no significant difference among solid tumor and surrounding edema region (P > 0.05). There were significant differences of FA between solid tumor, surrounding edema and normal white matter region (P < 0.05)., Conclusions: The DTI offered the optimal visualization of white matter tracts. DTI plays an important role in demonstrating relationship between gliomas and neighboring fibers. MD and FA values could be used to distinguish normal white matter from solid tumor and surrounding edema region of high grade glioma. The application of DTI in preoperation plays an guidance role in making microsurgery plans and the evaluation of brain functional recovery in postoperation. DTI should be of great value in the microsurgical planning as well as estimation and reduction of potential postoperative neurological deficits for the cerebral gliomas resection.

Objective: To study the expression of the mRNAs of transient receptor potential (TRP) gene subfamily TRPV and TRPM in rat testes., Methods: Normal SD rat testes were collected and the expression of TRPV and TRPM mRNAs were detected by routine RT-PCR., Results: The TRPV4, TRPV5, TRPV6, TRPM3, TRPM4 and TRPM8 mRNAs were detected in the rat testes, but the other members of TRPV and TRPM family were not detected., Conclusions: TRPV4, TRPV5, TRPV6, TRPM3, TRPM4 and TRPM8 are expressed in rat testes. This finding provides the basis for exploring the functions of TRPV and TRPM in the testes and the relation between testis diseases and the TRP family.

Objective: To investigate the expression of transient receptor potential melastatin (TRPM) and transient receptor potential vanilloid (TRPV) channel family genes in rat spermatogenic cells., Methods: Rat spermatogenic cells were isolated by a mechanical procedure and the total RNA was extracted using TRIzol reagent. TRPM and TRPV channel family genes were amplified by RT-PCR and the presence of the target genes was detected by agarose gel electrophoresis. The relative gene expression levels were measured by real-time quantitative RT-PCR., Results: TRPV5, TRPM3, TRPM4 and TRPM7 mRNAs were expressed in rat spermatogenic cells, but TRPV1, TRPV2, TRPV3, TRPV4, TRPV6, TRPM1, TRPM2, TRPM5, TRPM6, TRPM7 and TRPM8 mRNAs were not detected. The relative expressions of TRPM and TRPV mRNA were determined by quantitative real-time RT-PCR. TRPM7 expression was the highest among all the TRPM subtypes in rat spermatogenic cells, at a level equivalent to (0.0430-/+0.0034)% of beta-actin expression. TRPM3 and TRPM4 were also highly expressed, but their expression levels were only approximately 56% and 63% of that of TRPM7, respectively. For the TRPV subfamily, only TRPV5 mRNA was abundantly expressed at the level of (0.0157-/+0.0029)% relative to that of beta-actin., Conclusion: TRPV5, TRPM3, TRPM4 and TRPM7 mRNAs were coexpressed in spermatogenic cells in rats, among which TRPM4 and TRPM7 mRNA were expressed at high levels. TRPM4 and TRPM7 channels may be involved in the regulation of growth, differentiation and maturation of rat spermatogenic cells and are associated with the generation of the sperms.