Cobalt-Catalyzed Enantiospecific Dynamic Kinetic Cross-Electrophile Vinylation of Allylic Alcohols with Vinyl Triflates.

Asymmetric cross-electrophile coupling has emerged as a promising tool for producing chiral molecules; however, the potential of this chemistry with metals other than nickel remains unknown. Herein, we report a cobalt-catalyzed enantiospecific vinylation reaction of allylic alcohol with vinyl triflates. This work establishes a new method for the synthesis of enantioenriched 1,4-dienes. The reaction proceeds through a dynamic kinetic coupling approach, which not only allows for direct functionalization of allylic alcohols but also is essential to achieve high chemoselectivity. The use of cobalt enables the reactions to proceed with high enantiospecificity, which have failed to be realized by nickel catalysts.

Clinical and prognostic significance of Krüppel-like transcription factor 6 expression in 67 patients with cutaneous malignant melanoma in China.

Krüppel-like transcription factor 6 (KLF6) is a ubiquitous tumor suppressor gene involved in regulating cell growth, proliferation, differentiation and angiogenesis. The objective of the study was to investigate the clinical and prognostic significance of KLF6 expression in cutaneous malignant melanoma (CMM) patients. A total of CMM 67 patients were enrolled in this study. The specimens were evaluated by immunohistochemistry to detect KLF6. The positive KLF6 expression in CMM tissues was significantly lower than in normal skin tissues (p < 0.01).The presence of KLF6 in CMM was correlated with ulceration (p < 0.01), lymph node metastasis (p < 0.01) and clinical stage (p < 0.01). The overall 5-year survival rate of the 67 patients was 13.4%. The 5-year survival rate of patients with negative KLF6 expression was correlated with KLF6 expression (p < 0.01), ulceration (p < 0.01), lymph node metastasis (p < 0.01), clinical stage (p < 0.01) and operation type (p < 0.01). Ulceration and clinical staging were independent relevant factors. In conclusion, the presence of KLF6 in CMM was correlated with ulceration, lymph node metastasis, clinical stage and poor prognosis.

Author Correction: Immunofluorescence can assess the efficacy of mTOR pathway therapeutic agent Everolimus in breast cancer models.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Immunofluorescence can assess the efficacy of mTOR pathway therapeutic agent Everolimus in breast cancer models.

When breast cancer patients start to exhibit resistance to hormonal therapy or chemotherapy, the mTOR inhibitor everolimus can be considered as an alternative therapeutic agent. Everolimus can deregulate the PI3K/AKT/mTOR pathway and affect a range of cellular functions. In some patients, the agent does not exhibit the desired efficacy and, even worse, not without the associated side effects. This study assessed the use of immunofluorescence (IF) as a modality to fill this unmet need of predicting the efficacy of everolimus prior to administration. Cell viability and MTT assays based on IF intensities of pho-4EBP1 Thr37/46 and pho-S6K1 Ser424 on breast cancer cells (Hs578T, MCF7, BT474, MDA-MB-231) and patient-derived cell culture from metastatic sites (ABC-82T and ABC-16TX1) were interrogated. Results show that independent pho-4EBP1 Thr37/46 and pho-S6K1 Ser424 IF expressions can classify data into different groups: everolimus sensitive and resistant. The combined IF baseline intensity of these proteins is predictive of the efficacy of everolimus, and their intensities change dynamically when cells are resistant to everolimus. Furthermore, mTOR resistance is not only consequence of the AKT/mTOR pathway but also through the LKB1 or MAPK/ERK pathway. The LKB1 and pho-GSK3ß may also be potential predictive markers for everolimus.

Highly Enantioselective Cross-Electrophile Aryl-Alkenylation of Unactivated Alkenes.

Enantioselective cross-electrophile reactions remain a challenging subject in metal catalysis, and with respect to data, studies have mainly focused on stereoconvergent reactions of racemic alkyl electrophiles. Here, we report an enantioselective cross-electrophile aryl-alkenylation reaction of unactivated alkenes. This method provides access to a number of biologically important chiral molecules such as dihydrobenzofurans, indolines, and indanes. The incorporated alkenyl group is suitable for further reactions that can lead to an increase in molecular diversity and complexity. The reaction proceeds under mild conditions at room temperature, and an easily accessible chiral pyrox ligand is used to afford products with high enantioselectivity. The synthetic utility of this method is demonstrated by enabling the modification of complex molecules such as peptides, indometacin, and steroids.

A comparative study for the short-term effects of targeted high-intensity UVB and narrow-band UVB in the treatment of vitiligo.

Vitiligo is a common acquired depigmentation disorder for which many treatments have previously been used with varying effects. The aim of the present study was to evaluate the efficacy and safety of targeted high-intensity (TH) and narrow band (NB) ultraviolet B light (UVB) for vitiligo treatment. A total of 33 patients with vitiligo were enrolled in the present study. Patients with a symmetrical or near-symmetrical distribution of lesions on their bodies were selected for the present study. For each patient, half of the body was treated with TH-UVB and the other with NB-UVB twice weekly over a period of 12 weeks (24 times total). The patients were assessed each week for repigmentation of lesions. All data were analyzed using SPSS software, and a total of 30 patients were evaluated. The effective rate was significantly higher in the TH-UVB group (56.7%) compared with the NB-UVB group (20.0%; P<0.05). Additionally, the mean number of radiations necessary for initial repigmentation was significantly lower in the TH-UVB group (7.95±3.43) compared with the NB-UVB group (15.36±3.43; P<0.05). No correlation was found between the clinical features of patients and the efficacy of treatment. In summary, the results of the present study suggest that TH-UVB is a more effective treatment for vitiligo than NB-UVB.

IL-17 promotes keratinocyte proliferation via the downregulation of C/EBPα.

Psoriasis vulgaris is a common chronic inflammatory skin disease characterized by the hyperproliferation and abnormal differentiation of keratinocytes. CCATT/enhancer binding protein α (C/EBPα) is abundant in the epidermis and is associated with the proliferation of keratinocytes. However, the role of C/EBPα in the proliferation of keratinocytes and the pathogenesis of psoriasis vulgaris are yet to be elucidated. In the present study, using two-step immunohistochemistry, the expression levels of C/EBPα and Ki-67 were examined in skin biopsies harvested from 30 patients with psoriasis vulgaris and 30 healthy control subjects. The proliferation index (PI) was calculated and the correlation between C/EBPα expression levels and the PI was assessed using Pearson's correlation coefficient. In addition, the effect on HaCaT immortalized human keratinocytic cells of treatment with various concentrations of interleukin (IL)-17 was investigated. Subsequently, cell proliferation rates were examined using a Cell Counting kit-8 assay and the mRNA and protein expression levels of C/EBPα were analyzed using semiquantitative reverse transcription-polymerase chain reaction and western blotting, respectively, in order to analyze the effects of IL-17 stimulation on C/EBPα expression levels. C/EBPα expression was predominantly detected in the cytoplasm of the keratinocytes and C/EBPα expression levels were significantly lower in the psoriatic lesions (P<0.05), as compared with the control group. An inverse correlation was detected between the expression levels of C/EBPα and the PI in the psoriatic lesions. Furthermore, a significant increase in the cell proliferation rate and significant reductions in the mRNA and protein expression levels of C/EBPα were detected in HaCaT cells following treatment with IL-17. These results demonstrated that C/EBPα may act as a downstream target of IL-17 and may be associated with the pathogenesis of psoriasis.

A novel 96well-formatted micro-gap plate enabling drug response profiling on primary tumour samples.

Drug-based treatments are the most widely used interventions for cancer management. Personalized drug response profiling remains inherently challenging with low cell count harvested from tumour sample. We present a 96well-formatted microfluidic plate with built-in micro-gap that preserves up to 99.2% of cells during multiple assay/wash operation and only 9,000 cells needed for a single reagent test (i.e. 1,000 cells per test spot x 3 selected concentration x triplication), enabling drug screening and compatibility with conventional automated workstations. Results with MCF7 and MDA-MB-231 cell lines showed that no statistical significance was found in dose-response between the device and conventional 96-well plate control. Primary tumour samples from breast cancer patients tested in the device also showed good IC50 prediction. With drug screening of primary cancer cells must consider a wide range of scenarios, e.g. suspended/attached cell types and rare/abundant cell availability, the device enables high throughput screening even for suspended cells with low cell count since the signature microfluidic cell-trapping feature ensures cell preservation in a multiple solution exchange protocol.

The overexpression of epithelial cell adhesion molecule (EpCAM) in glioma.

Epithelial cell adhesion molecule (EpCAM) is overexpressed in various neoplasms as a tumor-associated antigen and absent in natural brain. However, little is known about EpCAM's expression in gliomas. To investigate the expression of EpCAM in gliomas and understand the correlation of EpCAM expression with malignancy, proliferation, angiogenesis, and prognosis, we studied the expression of EpCAM in 98 glioma samples by immunohistochemistry and by western blotting (N = 12). Correlative analysis of EpCAM overexpression with microvessel density (MVD), Ki-67 expression, age, and gender were made. Survival data was analyzed with Kaplan-Meier method and Cox Proportional Hazard Model. Immunohistochemistry results showed EpCAM was widely expressed in glioma (90.8 %). The overexpression rate of WHO grade IV gliomas was significantly higher EpCAM overexpression correlated significantly with Ki-67 expression and MVD. Western blot analysis also revealed a stepwise increase in EpCAM expression from WHO II to IV glioma. The overall survival of WHO III and IV glioma patients with EpCAM overexpression was obviously lower than that without EpCAM overexpression. EpCAM overexpression was an independent prognostic factor for overall survival in glioma patients. This study firstly shows that EpCAM overexpression correlates significantly with malignancy (WHO grades), proliferation (Ki67), angiogenesis (MVD), and prognosis in gliomas. EpCAM may participate in tumorgenesis of gliomas.

[Analysis of the endoplasmic reticulum stress in non-ablative skin rejuvenation using Q-switched 1064nm Nd:YAG laser].

OBJECTIVE: To study the effect of Q-switched 1 064 nm Nd:YAG laser treatment on the proliferation of dermal collagen and expression of immunoglobulin binding protein/glucose related protein 78 (BiP/GRP78) in rats' skin and the mechanism of endoplasmic reticulum stress. METHODS: Dorsal skin of 25 Wistar rats was divided into two parts equally after hair removal. Q-switched 1 064nm Nd:YAG laser was applied to treat rats' dorsal skin for 4 times at an interval of 2 days in the experiment part. The control part received no laser treatments. The rats' dorsal skin samples were taken on the 14th and 30th day after laser treatment to measure the dermis thickness and collagen bundles under HE stain and to measure the hydroxyproline content by alkaline hydrolysis method after laser treatment. The expression of BiP/GRP78 was also detected by immunohistochemical method. Statistics was used to analyze the data. RESULTS: The dermis thickness increased by 29. 6% on the 14th day and 16.7% on the 30th day after laser treatment. The collagen bundles became thicker and denser. The hydroxyproline in the skin was also raised after laser treatment (P < 0.05). The immunohistochemical result showed the expression of BiP/GRP78 increased to 100% after laser treatment, showing a significant difference from the control group(X2 = 28.76, P < 0.01). CONCLUSIONS: The Q-switched 1064 nm Nd:YAG laser treatment can induce endoplasmic reticulum stress, so as to enhance the protein folding and synthesizing precisely. The proliferation of dermis collagen is the base of effect of non-ablative skin rejuvenation.

Expression of dendritic cell lysosome-associated membrane protein and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin in condyloma acuminatum lesions.

OBJECTIVE: Retrospective, observational study to explore the role of dendritic cells (DCs) in condyloma acuminatum lesions (genital warts) and their relationship with duration of the disease. METHODS: Condyloma acuminatum lesion samples were collected from male patients with the condition and compared with normal foreskin samples from male volunteers. Cellular locations of dendritic cell lysosome-associated membrane protein (DC-LAMP) and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) were detected using immunohistochemistry. Levels of both proteins were determined using Western blot analysis; levels of their corresponding mRNAs were measured using reverse transcription-polymerase chain reaction. RESULTS: The mRNA and protein levels of DC-LAMP and DC-SIGN were both significantly higher in condyloma acuminatum lesions (n = 30 samples) compared with normal skin samples (n = 13). Levels of DC-LAMP and DC-SIGN protein and duration of disease were inversely correlated. CONCLUSIONS: DC-LAMP and DC-SIGN may be involved in the pathogenesis of condyloma acuminatum. Their levels were inversely correlated with the duration of disease, suggesting that DCs might be involved in human papillomavirus clearance.