Diversity-oriented synthesis of P-stereogenic and axially chiral monodentate biaryl phosphines enabled by C-P bond cleavage.

Chiral monodentate biaryl phosphines (MOPs) have attracted intense attention as chiral ligands over the past decades. However, the creation of structurally diverse chiral MOPs with both P- and axial chirality is still in high demand but challenging. Here, we show a distinct strategy for diversity-oriented synthesis of structurally diverse MOPs containing both P- and axial chirality enabled by enantioselective C-P bond cleavage. The key chiral PdII intermediates, generated through the stereoselective oxidative addition of C-P bond, could be trapped by alkynes, R3Si-Bpin, diboron esters or reduced by H2O/B2pin2, leading to enantioenriched structurally diverse MOPs in excellent diastereo- and enantioselectivities. Based on the outstanding properties of the parent scaffolds, the P- and axially chiral monodentate biaryl phosphines serve as excellent catalysts in asymmetric [3 + 2] annulation of MBH carbonate affording the chiral functionalized bicyclic imide.

Efficiency and safety of microneedling fractional radiofrequency in the treatment of Chinese atrophic acne scars: A retrospective study of 3 consecutive treatments with 1-month intervals.

BACKGROUND: Atrophic acne scars (AAS) impact the aesthetic appearance, inducing social and psychological problems. Effective and safe therapy for AAS is urgently needed now. Microneedling fractional radiofrequency (MFRF) has emerged as a minimal invasive alteration for treating AAS lately, while the existing data on Chinese population was few. AIMS: We aimed to explore the effectivity and safety of MFRF in Chinese patients with facial AAS and analyze the response of different subtypes to MFRF treatment. METHODS: We conducted a retrospective analysis using data from medical records and clinical photographs of 40 Chinese patients with AAS with Fitzpatrick skin type III-IV, all of them had received 3 MFRF treatments with 1-month intervals and were followed up 3 months after the last treatment. The clinical severity was assessed through échelle d'évaluation clinique des cicatrices d'acné (ECCA) score at each visit. Clinical photographs were taken by VISIA. Patients were asked to evaluate their satisfaction of the treatment using a 5-point Likert scale at the last visit. RESULTS: ECCA score decreased more than a half at the last visit based on the baseline. Among the three types of AAS, the M-shaped scars respond most quickly to MFRF and the U-shaped scars improved the most after 3 months follow-up. A significant improvement was seen in clinical appearance, parallel to the change of ECCA, indicating the remarkable improvement of AAS after the MFRF treatment. Concomitant active acne was controlled along with the improvement of AAS. Statistics from VISIA showed excellent improvement in pores and texture as well. Side effects including pain and erythema were transient and mild. The number of MFRF treatment sessions was positively associated with the degree of improvement. Of the total 39 patients who had given a score of satisfaction, more than 89% (35 patients) were very satisfied or satisfied with the outcome. CONCLUSIONS: To sum up, our study reveals that MFRF provides high efficiency in treating Chinese AAS patients with high satisfaction and low risk of adverse effects. M-shaped scars are the most sensitive type to the treatment, but the U-shaped scars improve most at the last visit. The simultaneous minimization of pores and improvement of skin texture imply the increased collagen stimulated by MFRF. Regular MFRF should be considered a good choice in treating AAS.

Multimodal ultrasound for preoperative evaluation of dermatofibrosarcoma protuberans: a series of 40 cases.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare, low to intermediate-grade sarcoma, which needs imaging examination. Small series of ultrasound findings in DFSP have been published; however, the usefulness of elastography and contrast-enhanced ultrasound (CEUS) in DFSP has not been studied. We aim to study multimodal ultrasound findings and report the correlation between imagings and tiny extension in DFSP for preoperative evaluation. METHODS: Two-D ultrasound, 3-D color ultrasound, elastography, and CEUS findings were retrospectively evaluated. Forty histopathologically confirmed DFSPs were studied. RESULTS: On 2-D ultrasound, 26(65%) appeared as mostly hypoechoic lesions with occasional hyperechoic dots within the tumor matrix and lobulated lateral borders. Eight (20%) lesions were multilayered. Ninety-five percent of lesions showed increased vascularity. On 3-D ultrasound, DFSPs showed branch-shaped, striped, and wrapped color patterns. Power Doppler showed mainly artery of a moderate arterial peak systolic blood flow and low resistance index. DFSP is hard on elastography. On CEUS, DFSPs showed a long peak time, low peak and a small amount of perfusion around the tumor, 73.7% (14/19) of lesions showed a heterogeneous contrast enhancement and 89.5% (17/19) of lesions showed hyper-enhancement. CEUS showed better concordance than US with histology on the maximum diameter and depth (P < 0.05). CONCLUSIONS: Multimodal ultrasound showed significant characteristics in DFSP, which would improve diagnostic accuracy. CEUS could be an effective tool to determine tiny tumor extension.

Palladium-Catalyzed Stereoselective Cleavage of C-P Bond: Enantioselective Construction of Atropisomers Containing a P-Stereogenic Center.

The transition-metal-catalyzed C-P bond cleavage has emerged as a powerful tool for the formation of both C-C and C-P bond. However, the transition-metal-catalyzed stereoselective cleavage of C-P bond is still undeveloped. Herein, we report a palladium-catalyzed stereoselective cleavage of C-P bond for the construction of P-stereogenic phosphines and stereogenic axis. This protocol enables the quick synthesis of atropisomers bearing a P-stereogenic center in high yields, diastereo- and enantioselectivities of up to 98 % ee, >25 : 1 dr. The product is able to serve as chiral catalyst in phosphine catalyzed [3+2] cycloaddition of allenoates to imines, showing the great potential of the present methodology.

Skin Lesion Classification Using Additional Patient Information.

In this paper, we describe our method for skin lesion classification. The goal is to classify skin lesions based on dermoscopic images to several diagnoses' classes presented in the HAM (Human Against Machine) dataset: melanoma (MEL), melanocytic nevus (NV), basal cell carcinoma (BCC), actinic keratosis (AK), benign keratosis (BKL), dermatofibroma (DF), and vascular lesion (VASC). We propose a simplified solution which has a better accuracy than previous methods, but only predicted on a single model that is practical for a real-world scenario. Our results show that using a network with additional metadata as input achieves a better classification performance. This metadata includes both the patient information and the extra information during the data augmentation process. On the international skin imaging collaboration (ISIC) 2018 skin lesion classification challenge test set, our algorithm yields a balanced multiclass accuracy of 88.7% on a single model and 89.5% for the embedding solution, which makes it the currently first ranked algorithm on the live leaderboard. To improve the inference accuracy. Test time augmentation (TTA) is applied. We also demonstrate how Grad-CAM is applied in TTA. Therefore, TTA and Grad-CAM can be integrated in heat map generation, which can be very helpful to assist the clinician for diagnosis.

Circ-GLI1 promotes metastasis in melanoma through interacting with p70S6K2 to activate Hedgehog/GLI1 and Wnt/ß-catenin pathways and upregulate Cyr61.

Circular RNAs (circRNAs) are emerging regulators in the development of human cancers. However, the role of circRNAs in melanoma is poorly understood. Microarray analysis and qRT-PCR was applied to screen out circRNAs that were differentially expressed in melanoma cells compared to normal cells. Currently, we first proved that inhibition of CYR61, an angiogenesis factor with controversial functions in melanoma, restrained cell migration, invasion and angiogenesis in melanoma. Thereafter, a novel circRNA hsa_circ_0027247 derived from GLI1 (circ-GLI1) was identified to positively modulate CYR61 expression in melanoma cell lines. Besides, silencing circ-GLI1 hindered melanoma cell metastasis as well. Interestingly, we unveiled that circ-GLI1 enhanced CYR61 transcription by an indirect manner. Meanwhile, circ-GLI1 activated Hedgehog/GLI1 and Wnt/ß-catenin pathways by affecting the degradation of GLI1 and ß-catenin. Moreover, we found that circ-GLI1 interacted with p70S6K2 to induce GSK3ß phosphorylation at Ser9, and therefore blocked the binding of GSK3ß with GLI1 and ß-catenin so as to elevate their protein expression. Of note, CYR61 was transcriptionally activated by MYC, a well-recognized downstream target of both GLI1 and ß-catenin. In conclusion, circ-GLI1 exacerbates the metastasis and angiogenesis of melanoma by upregulating Cyr61 via p70S6K2-dependent activation of Hedgehog/GLI1 and Wnt/ß-catenin pathways.

MiR-4458/human antigen R (HuR) modulates PBX3 mRNA stability in melanoma tumorigenesis.

Melanoma, a malignancy of the melanocyte, is characterized as the most fatal skin cancer with an increasing incidence. Of note, in spite of great attempts made for better treatment, the therapeutic outcome is barely satisfactory. Abnormal expression of microRNAs (miRNAs) acting as oncogenes or tumor suppressor genes, is frequently implicated in multiple human cancers, including melanoma. Here, we found that miRNA-4458, a reportedly tumor-suppressive miRNA in several cancers, was downregulated in melanoma cells. Besides, our findings indicated that microRNA-4458 (miR-4458) hindered cell proliferation and migration, yet induced apoptosis in melanoma. Mechanical interaction of miR-4458 and PBX3 mRNA, thereby inhibiting PBX3 expression in melanoma cells, was also presented in this work. Human antigen R (HuR) was reported to be greatly upregulated in diverse cancers and HuR-dependent stabilization of target gene contributed a lot to tumor progression. In this study, it revealed the stabilization of PBX3 mRNA by HuR, thereby boosting PBX3 expression. Lastly, we concluded that miR-4458 and HuR modulated the expression of PBX3 in a competitive manner in melanoma tumorigenesis, which might yield a novel insight into the molecular pathogenesis of melanoma.

Dermatofibrosarcoma protuberans: our 10-year experience on 80 patients.

Background: Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma. Its high recurrence rate is a clinical challenge.Objective: To analyze DFSP clinicopathologic factors and review our experience of treatments.Materials and methods: A total of 80 patients who were treated between 2007 and 2017 in Shanghai Ninth People's Hospital were evaluated. Outcomes were compared focusing on recurrence following different treatment methods. Classical DFSP and transformed DFSP were classified as the two subtypes.Results: The recurrence rate after local excision was significantly higher than that after wide margin excision. Patients undergoing wide margin excision (margins over 3 cm) were found to have lower recurrence rate compared with those margins less than 3 cm, while 10 underwent Mohs surgery were not found recurrence. Transformed DFSP had a greater tendency to recur.Conclusions: Clean margin of excision should be achieved to prevent recurrence of DFSP. Slow Mohs surgery is recommended to treat DFSP.

Protective Effects Of Astragalus Polysaccharides On Oxidative Stress In High Glucose-Induced Or SOD2-Silenced H9C2 Cells Based On PCR Array Analysis.

BACKGROUND: Oxidative stress in cardiac myocytes is an important pathogenesis of diabetic cardiomyopathy (DCM). Previously, we reported that astragalus polysaccharide (APS) has protective effects against the oxidative stress of DCM. This study aimed to determine the effect of APS on the oxidative stress induced by hyperglycemia in H9C2 cells. METHODS: Rat H9C2 cells were cultured in vitro and randomly divided into the control group, HG group, APS-HG group, siRNASOD2 group, and APS-siRNASOD2 group. The cellular ultrastructure was measured by transmission electron microscopy. Cell apoptosis was examined by TUNEL staining. Levels of reactive oxygen species (ROS) were detected by a quantitative fluorescence assay (DHE). 8-OH-dG and nitrotyrosine, the indicators of oxidative stress injury, were detected by immunohistochemistry. A PCR array was used to evaluate the expression levels of 84 oxidative stress genes in cultured cells, and the PCR array results were partially verified by Western blot. RESULTS: APS treatment protected the H9C2 cell ultrastructure, reduced the level of cell apoptosis, inhibited cellular ROS production, and reduced the levels of oxidative stress injury indicators 8-OH-dG and nitrotyrosine in high glucose-induced or SOD2-silenced H9C2 cells. It also altered oxidative stress-related genes at the mRNA and protein levels. CONCLUSION: APS may improve antioxidant capacity and inhibit oxidative stress injury in high glucose induced H9C2 cells.

Long noncoding RNA CPS1-IT1 suppresses melanoma cell metastasis through inhibiting Cyr61 via competitively binding to BRG1.

Long noncoding RNA CPS1-IT1 is recently recognized as a tumor suppressor in several cancers. Here, we investigate the role of CPS1-IT1 in human melanoma. Presently, our study reveals the low expression of CPS1-IT1 in human melanoma tissues and cell lines, which is significantly associated with metastasis and tumor stage. Besides, the potential of CPS1-IT1 as a prognosis-predictor is strongly indicated. Functionally, CPS1-IT1 overexpression inhibits cell migration, invasion, epithelial-mesenchymal transition, and angiogenesis in melanoma cells. CYR61, an angiogenic factor that participates in tumor metastasis as well as a recognized oncogene in melanoma, is shown to be confined under CPS1-IT1 overexpression in melanoma cells. Furthermore, enforced expression of Cyr61 in CPS1-IT1-silenced melanoma cells dramatically normalized the protein level of Cyr61 and that of its downstream targets vascular endothelial growth factor and matrix metalloproteinase-9, as well as the repressive effect of CPS1-IT1 overexpression on melanoma cell metastasis. BRG1, a core component of SWI/SNF complex, is implied to interact with both CPS1-IT1 and Cyr61 in melanoma cells. Moreover, CPS1-IT1 negatively regulates Cyr61 expression by blocking the binding of BRG1 to Cyr61 promoter. Jointly, CPS1-IT1 controls melanoma metastasis through impairing Cyr61 expression via competitively binding with BRG1, uncovering a novel potential therapeutic and prognostic biomarker for patients with melanoma.

Effect of Astragalus Polysaccharides on Cardiac Dysfunction in db/db Mice with Respect to Oxidant Stress.

OBJECTIVE: Oxidant stress plays an important role in the development of diabetic cardiomyopathy. Previously we reported that Astragalus polysaccharides (APS) rescued heart dysfunction and cardinal pathological abnormalities in diabetic mice. In the current study, we determined whether the effect of APS on diabetic cardiomyopathy was associated with its impact on oxidant stress. METHODS: Db/db diabetic mice were employed and administered with APS. The hematodynamics, cardiac ultra-structure, apoptosis, and ROS formation of myocardium were assessed. The cardiac protein expression of apoptosis target genes (Bax, Bcl-2, and caspase-3) and oxidation target genes (Gpx, SOD2, t/p-JNK, catalase, t/p-p38 MAPK, and t/p-ERK) were evaluated, respectively. RESULTS: APS therapy improved hematodynamics and cardinal ultra-structure with reduced apoptosis and ROS formation in db/db hearts. In addition, APS therapy inhibited the protein expression of apoptosis target genes (Bax, Bcl-2, and caspase-3) and regulated the protein expression of oxidation target genes (enhancing Gpx, SOD2, and catalase, while reducing t/p-JNK, t/p-ERK, and t/p-p38 MAPK) in db/db hearts. CONCLUSION: Our findings suggest that APS has benefits in diabetic cardiomyopathy, which may be partly associated with its impact on cardiac oxidant stress.

Astragalus polysaccharides inhibit oxidation in high glucose-challenged or SOD2-silenced H9C2 cells.

INTRODUCTION: Oxidative stress plays an important role in the development of diabetic cardio-myopathy (DCM). Previously, we reported that Astragalus polysaccharides (APS) improved DCM by inhibition of cardiac oxidative stress. In this study, we evaluated the beneficial effect of APS on high glucose-induced oxidative stress in cardiomyocytes in vitro. MATERIALS AND METHODS: H9C2 cells were cultured in the presence of high concentration of glucose or transfected with siRNASOD2, followed by APS treatment. The cellular mitochondrial ultrastructure was observed using a transmission electron microscope. Cell apoptosis was detected using hairpin oligonucleotide probes and quantified by flow cytometry analysis. Superoxide production was determined by immunohistochemistry using the fluorescent dye dihydroethidium (DHE). Nitrotyrosine and 8-OH-dG antibodies were employed to detect oxidative damage to cytoplasmic proteins and oxidative stress in the nuclei, respectively. Superoxide dismutase (SOD) activity was measured utilizing the SOD Assay Kit, and SOD protein levels were analyzed by Western blotting. RESULTS: APS treatment protected cellular mitochondrial ultrastructure, reduced cell apoptosis (hairpin-1), inhibited cellular superoxide production (DHE), and reduced oxidative damage to cytoplasmic proteins (nitrotyrosine) and oxidative stress in the nuclei (8-OH-dG) in high glucose-induced and/or SOD2-silenced H9C2 cells, together with induction of SOD2 enzyme activity and increase of protein levels. CONCLUSION: Our findings indicated the beneficial effect of APS on high glucose-challenged H9C2 cells, which was associated with inhibition of oxidative stress in vitro.

Common variants in ZMIZ1 and near NGF confer risk for primary dysmenorrhoea.

Primary dysmenorrhoea, defined as painful menstrual cramps in the absence of pelvic pathology, is a common problem in women of reproductive age. Its aetiology and pathophysiology remain largely unknown. Here we performed a two-stage genome-wide association study and subsequent replication study to identify genetic factors associated with primary dysmenorrhoea in a total of 6,770 Chinese individuals. Our analysis provided evidence of a significant (P<5 × 10-8) association at rs76518691 in the gene ZMIZ1 and at rs7523831 near NGF. ZMIZ1 has previously been associated with several autoimmune diseases, and NGF plays a key role in the generation of pain and hyperalgesia and has been associated with migraine. These findings provide future directions for research on susceptibility mechanisms for primary dysmenorrhoea. Furthermore, our genetic architecture analysis provides molecular support for the heritability and polygenic nature of this condition.

CYR61 suppresses growth of human malignant melanoma.

Cysteine-rich protein 61 (CCN1/CYR61) is an important marker of proliferation and metastasis in malignant melanoma, making it a potential target for melanoma treatment. In this study, we compared the expression of CRY61 in Chinese patients with malignant melanoma with its expression in patients with other skin tumors or with no skin pathological conditions. We examined the effects of anti-human CYR61 monoclonal antibody on proliferation and evaluated the changes in CYR61 expression and cell proliferation in response to treatment with either epirubicin or interferon (IFN)-α. CYR61 was expressed at lower levels in patients with malignant melanoma than in patients with other skin tumors or with no pathology. Following the treatment of B16 cells with epirubicin and IFN-α, CYR61 levels increased, cell growth was inhibited, and proliferating cell nuclear antigen expression decreased. Thus, CYR61 could become a therapeutic target for malignant melanoma patients with high CYR61 expression.

Global stability of infection-free state and endemic infection state of a modified human immunodeficiency virus infection model.

This study proposes a modified human immunodeficiency virus (HIV) infection differential equation model with a saturated infection rate. This model has an infection-free equilibrium point and an endemic infection equilibrium point. Using Lyapunov functions and LaSalle's invariance principle shows that if the model's basic reproductive number R0 < 1, the infection-free equilibrium point is globally asymptotically stable, otherwise the endemic infection equilibrium point is globally asymptotically stable. It is shown that a forward bifurcation will occur when R0 = 1. The basic reproductive number R0 of the modified model is independent of plasma total CD4⁺ T cell counts and thus the modified model is more reasonable than the original model proposed by Buonomo and Vargas-De-León. Based on the clinical data from HIV drug resistance database of Stanford University, using the proposed model simulates the dynamics of two group patients' anti-HIV infection treatments. The simulation results have shown that the first 4 weeks' treatments made the two group patients' R'0 < 1, respectively. After the period, drug resistance made the two group patients' R'0 > 1. The results explain why the two group patients' mean CD4⁺ T cell counts raised and mean HIV RNA levels declined in the first period, but contrary in the following weeks.

Dynamics analysis and simulation of a modified HIV infection model with a saturated infection rate.

This paper studies a modified human immunodeficiency virus (HIV) infection differential equation model with a saturated infection rate. It is proved that if the basic virus reproductive number R 0 of the model is less than one, then the infection-free equilibrium point of the model is globally asymptotically stable; if R 0 of the model is more than one, then the endemic infection equilibrium point of the model is globally asymptotically stable. Based on the clinical data from HIV drug resistance database of Stanford University, using the proposed model simulates the dynamics of the two groups of patients' anti-HIV infection treatment. The numerical simulation results are in agreement with the evolutions of the patients' HIV RNA levels. It can be assumed that if an HIV infected individual's basic virus reproductive number R 0 < 1 then this person will recover automatically; if an antiretroviral therapy makes an HIV infected individual's R 0 < 1, this person will be cured eventually; if an antiretroviral therapy fails to suppress an HIV infected individual's HIV RNA load to be of unpredictable level, the time that the patient's HIV RNA level has achieved the minimum value may be the starting time that drug resistance has appeared.