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The Ontario Ministry of Health funded a reintegration unit to transition hospitalized patients who no longer required acute care to alternate level of care (ALC), such as long-term care. In its first year, 102 (3.5%) patients of the hospital's waiting-for-ALC population were transferred, with 37.3% transferred on the day of ALC readiness. The reintegration unit reduced direct hospital costs by $861,000. Using case costing, we modelled optimized scenarios including all transfers on the day of ALC readiness and increased transfers to the reintegration unit; this helped reduce avoided direct costs by $2.3-$5.4 million. Acute-care bed capacity could have increased by 11%. We outline strategies to optimize future performance of the reintegration unit.

The combination of histone deacetylase (HDAC) and autophagy inhibitor has been considered as a novel cancer therapeutic strategy. To find novel HDAC inhibitors that can inhibit autophagy, several new series of oxazole- and thiazole-based HDAC inhibitors were designed and synthesized by replacing the phenyl cap in SAHA with 5-phenyloxazoles and 5-phenylthiazoles. The representative oxazole derivative, compound 21, showed better enzymatic inhibitory activity than SAHA (vorinostat). Compound 21 induced G2/M cell cycle arrest and its antiproliferative activity is 10-fold better than SAHA in multiple tumor cell lines. Western blot analysis showed that compound 21 can markedly increase the acetylation levels of tubulin, histone H3, and histone H4. Contrary to SAHA, compound 21 was found to inhibit autophagy. Additionally, compound 21 induced cell apoptosis via the Bax/Bcl-2 and caspase-3 pathways. Ultimately, compound 21 exhibited higher oral antitumor potency than SAHA in a A549 xenograft model. Our results indicated that compound 21 may be further developed as a promising anticancer agent.

Wei Wang,1,* Qiang Li,2,* Ge Huang,3 Bing-yao Lin,1 Dongzi Lin,1 Yan Ma,1 Zhao Zhang,4 Tao Chen,1 Jie Zhou1 1Department of Laboratory, Foshan Fourth People’s Hospital, Foshan, 528000, People’s Republic of China; 2Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510000, People’s Republic of China; 3Intensive Care Unit, Foshan Fourth People’s Hospital, Foshan, 528000, People’s Republic of China; 4Research and Development Centre, South China Institute of Biomedicine, Guangdonglongsee Biomedical Co., Ltd, Guangzhou, 510000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhao ZhangResearch and Development Centre, South China Institute of© Biomedicine, Guangdonglongsee Biomedical Co., Ltd, 5/F Building A, No. 83 Ruihe Road, Huangpu District, Guangzhou, 510535, People’s Republic of ChinaEmail zhangzhao0402@163.comGe HuangIntensive Care Unit, Foshan Fourth People’s Hospital, No. 106, Jinlan Road, Foshan, 528000, People’s Republic of ChinaEmail Lang.x.c.d@sina.comPurpose: The poor prognosis of hepatocellular carcinoma (HCC) urgent us to discover early and effective biomarkers. In this study, we applied tandem mass tag (TMT)-based proteomic analysis to discover potential protein markers for HCC identification and differentiation.Patients and Methods: Fifteen patients, well-differentiated (G1, N = 5), moderate-differentiated (G2, N = 5), and poorly differentiated (G3, N = 5), with 30 matched pair tissues (both tumor and adjacent non-tumor tissues derived from the same patient) were enrolled. All samples were subjected to TMT labeling and LC−MS/MS analysis. The identified proteins were subsequently assigned to GO and KEGG for predicting function. The identified protein candidates were validated using immunohistochemistry (IHC).Results: A total of 1010 proteins were identified. Of these, 154 differentially expressed proteins (DEPs), 100 up-regulated and 54 down-regulated, were found between tumor and adjacent non-tumor tissues; 12 DEPs, 9 up-regulated and 3 down-regulated, were found between G1 and G3 tissues; 8 DEPs, 5 up-regulated and 3 down-regulated, were found between G1 and G2 tissues; 11 DEPs, 8 up-regulated and 3 down-regulated, were found between G2 and G3 tissues. Among them, ASS1 and CPS1 were significantly up-regulated while UROD and HBB were significantly down-regulated in G3 compared with G1 and G2 tumors. Three proteins, CYB5A, FKBP11 and YBX1, were significantly up-regulated in G1 compared with both G2 and G3 tumors. The 7 biomarker candidates were further verified by IHC.Conclusion: A variety of DEPs related to the histological differentiation of HCC were identified, among which ASS1, CPS1, URPD and HBB proteins were potential biomarkers for distinguishing poorly differentiated HCC, while CYB5A, FKBP11 and YBX1 were potential biomarkers for distinguishing well-differentiated HCC. Our findings may further provide a new insight facilitating the diagnosis and prognosis of HCC.Keywords: tandem mass tag, proteomic analysis, hepatocellular carcinoma, histological differentiation, diagnosis, prognosis

pH sensors based on up-conversion nanoparticles (UCNPs) are widely studied due to their effective elimination of background signals. However, ratiometric pH measurement depending on blue and red luminescence under NIR irradiation has been seldom reported for the lack of simultaneous strong blue and red emissions for traditional UCNPs. In this work, we designed NaGdF4:Yb,Tm@NaYF4:Yb,Eu@NaYF4:Yb,Nd@NaYF4 core–triple shell (CTS) UCNPs as fluorescent materials to realize blue/red ratiometric pH measurement. On the basis of Gd3+-mediated interfacial energy transfer and Yb3+-mediated energy migration, CTS particles present intense luminescence and a high red/blue (615 nm/450 nm) peak intensity ratio of 0.47 at 808 nm excitation. Composed of these particles and pH indicator bromocresol green, the pH sensor exhibits ratiometric responses in a pH range of 4–7 according to blue/red luminescence intensity ratios, avoiding the common errors as well as potential mutual fluorescence signal interference. Owing to strong overall luminescence and additional red emission of CTS UCNPs distinctly improving the signal-to-noise ratio, this ratiometric sensor reveals high sensitivity. Moreover, the employed excitation wavelength of 808 nm can not only eliminate autofluorescence signals, but also alleviate severe temperature rise in biosamples under continuous irradiation, ensuring accurate pH determination. More intriguingly, a CCD RGB camera serves as a collector to record luminescence signals, further promoting commercial feasibility. The successful application of CTS UCNPs on sensors indeed realizes blue/red ratiometric measurement towards pH under 808 nm irradiation, also pointing out a novel way for pH sensors with high sensitivity and accuracy.

Thiol-containing small molecules such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) play a key role in a wide range of physiological processes. But it is a challenging work to distinguish these biothiols since they have a similar structure and reactivity. An “AIE + ICT” ratiometric fluorescent probe is synthesized by incorporating TPE into the coumarin ring through a Schiff-base CN. The sensing mechanism of the probe lies on the nucleophilicity of the sulfhydryl group and the adjacent amino group of Hcy/Cys, breaking the Schiff-base CN in the probe structure and forming a five or six-membered ring thiazolidine adduct. Only Hcy/Cys triggers an obvious ratiometric change from orange-yellow to blue. The ratiometric probe can detect Hcy/Cys quantitatively, and the lower limits of detection for Hcy and Cys are 0.554 μM and 1.816 μM, respectively. Moreover, the probe showed a slight preference for Hcy over Cys. The difference in the sensing behavior of the probe for Hcy/Cys is believed to be the consequence of the more highly efficient ICT and PET of thiazolidine adducts. Preliminary studies show that the probe has low cytotoxicity, is cell-permeable and can be employed for the ratiometric fluorescence imaging of exogenous and endogenous Cys in living cells.

The construction of cyclobutanes has attracted much attention because of its unique four-membered ring skeleton. Herein, we report the highly enantioselective direct vinylogous Michael reaction of β,γ-unsaturated pyrazole amides and nitroolefin using a squaramide catalyst. Cyclobutane derivatives were obtained by subsequent cyclization in good yields (up to 85%) with excellent enantioselectivities (up to 99% ee). Importantly, the large-scale reaction experiment confirmed the reliability of the vinylogous reaction. Furthermore, the synthetic utility of the vinylogous adducts and cyclobutane derivatives has been realized.

Aged citrus peels (chenpi) have been used as a dietary supplement for gastrointestinal health maintenance in China. Recently, it was reported to exhibit anti-obesity activity. However, the relationship between the modulation effect of chenpi on gut microbiota and obesity prevention is not clearly understood. In this study, mice were fed with a high-fat diet (HFD), HFD supplemented with 0.25%- and 0.5%-chenpi extract, and normal diet, respectively, for 11 weeks. Chenpi extract significantly increased fecal short chain fatty acids by 43% for acetic acid and 86% for propionic acid. In addition, chenpi could decrease the prevalence of Proteobacteria and the ratio of Firmicutes to Bacteroidetes by about 88% and 70%, respectively. Moreover, this study was the first work to demonstrate the dynamics of two beneficial bacteria-Akkermansia spp. and Allobaculum spp. in a dose- and time-dependent manner for chenpi treatment via monitoring the dynamic change of the gut microbiota. Metagenomic analysis of the gut microbiota showed that several pathways, such as a two-component system, a tight junction, Staphylococcus aureus infection and others, were enhanced dynamically. The improved biological process of metabolism especially in benzoate derivatives might refer to the increased metabolic transformation of polymethoxyflavones from chenpi in the colon. Our study indicated that the modulation effect of chenpi on the gut microbiota may be an important pathway for its anti-obesity mechanisms.

To investigate the bioactive compounds that contribute to the α-glucosidase inhibitory activity of rosemary, phenolics and triterpene acids were characterized and quantified using quadrupole-Orbitrap mass spectrometry and enzyme assay. Two phenolic diterpenes (carnosol and hydroxy p-quinone carnosic acid) and two triterpene acids (betulinic acid and ursolic acid) were identified as potent α-glucosidase inhibitors. Carnosol, a major diterpene in rosemary, showed significant α-glucosidase inhibitory activity with IC50 value of 12 μg mL-1, and its inhibition mode was competitive. The inhibition mechanism of carnosol on α-glucosidase was further investigated by a combination of surface plasmon resonance (SPR) spectroscopy, fluorescence quenching studies and molecular-modeling techniques. The SPR assay suggested that carnosol had a high affinity to α-glucosidase with equilibrium dissociation constant (KD) value of 72.6 M. Fluorescence quenching studies indicated that the binding between carnosol and α-glucosidase was spontaneous and mainly driven by hydrophobic forces. Molecular docking studies revealed that carnosol bound to the active site of α-glucosidase. Furthermore, the oral administration of carnosol at 30 mg kg-1 significantly reduced the postprandial blood glucose levels of normal mice. This is the first report on the α-glucosidase inhibition and hypoglycemic activity of phenolic diterpenes, and these results could facilitate the utilization of rosemary as a dietary supplement for the treatment of diabetes.

To study the changes of anterior soft tissue swelling after anterior cervical subtotal corpectomy, titanium mesh fusion and internal fixation.From November 2015 to July 2018, 151 patients with cervical spondylotic myelopathy were treated with anterior single corpectomy, titanium mesh fusion and internal fixation, including 109 males and 42 females, aged 44 to 81 (59.77±8.34) years. Through postoperative follow up observation, the CAll patients were followed up for 15 to 40(28.00±3.52) months. One week after the operation, the swelling of anterior soft tissue reached the peak, and then decreased. At 8 months after the operation, the swelling of anterior soft tissue on CAnterior subtotal cervical corpectomy, titanium mesh bone graft fusion and internal fixation can cause swelling of the anterior soft tissue. One week after operation, we should pay more attention to the aggravation of the swelling of the anterior soft tissue to avoid the occurrence of dysphagia, respiratory obstruction, asphyxia and other complications.

Nobiletin is abundant in citrus peels and demonstrates good anti-obesity bioactivity. However, its anti-obesity mechanisms still remain unclear. This study aims to explore the bidirectional interaction between nobiletin and gut microbiota in mice fed with a high-fat diet. For the colonic bioconversion, more demethylated metabolites with higher biological activity were found in feces than nobiletin in the 48 h excretion study and 8 week consecutive dosing study. Moreover, long-term oral intake of nobiletin would modify the gut microbiota with improved demethylation ability and enhanced production of short chain fatty acids. The comparison of metabolite profiles in mouse liver and feces indicated that gut microbiota might have a higher biotransformation activity on nobiletin than the host. Two bacteria at the genus level, Allobaculum and Roseburia, remained enriched by nobiletin after the 4- and 8-week feedings. They might correlate with the enhanced nobiletin biotransformation and actively contribute to the health benefits of nobiletin in vivo. These results suggested that the bidirectional interaction of nobiletin and gut microbiota played an important role on the anti-obesity effect of nobiletin.

A simple and efficient protocol for para-selective C–H amination of 1-naphthylamide derivatives under silver catalysis is described. This reaction system could proceed without the help of directing group and a broad range of substrates were proved to be well tolerated. In addition, control experiments suggested that this reaction might not proceed via a single-electron-transfer process.

The anisotropic deformation behavior and forming limit of hot-rolled Al/Mg/Al three-layered composite sheets have been investigated in detail. Uniaxial tensile tests were conducted on composite sheets at 0°, 45°, and 90° to the rolling direction. The results show that the properties of the hot-rolled 5052/AZ31/5052 three-layered composite sheet with fine grain distribution and diffusion layer of 18.71 μm were anisotropic and showed temperature dependence. The 0° direction showed the highest n value and the 90° direction the lowest. The highest Lankford parameter was found in the 45° direction, with the maximum $$ \bar{r} $$ value and minimum absolute value of $$ \Delta r $$ at 230°C. Moreover, hemispherical punch tests revealed that the composite sheet exhibited better formability at 230°C than 170°C, especially in the biaxial stress state. In the equibiaxial tensile stress state, significant anisotropy of the thickness distribution and different fracture appearance were also observed.

A series of 5-phenyloxazole-2-carboxylic acid derivatives were synthesized, and their structure–activity relationships (SARs) were studied. N,5-diphenyloxazole-2-carboxamides 6, 7, and 9, which mimicked ABT751, showed improved cytotoxicity compared with ABT751. Compound 9 exhibited the highest antiproliferative activities against Hela A549, and HepG2 cancer cell lines, with IC50 values of 0.78, 1.08, and 1.27 μM, respectively. Furthermore, compound 9 showed selectivity for human cancer cells over normal cells, and this selectivity was greater than those of ABT751 and colchicine. Preliminary mechanism studies suggested that compound 9 inhibited tubulin polymerization and led to cell cycle arrest at G2/M phase. Molecular docking studies indicated that compound 9 bound to the colchicine binding site of tubulin. Our findings provided insights into useful SARs for further structural modification of inhibitors of tubulin polymerization.

Objective In the present study, we aimed to establish a novel score to predict long-term mortality of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients who underwent percutaneous coronary intervention (PCI). Methods A total of 2,174 NSTE-ACS patients from the CORFCHD-ZZ study were enrolled as the derivation cohort. The validation cohort including 1,808 NSTE-ACS patients were from the CORFCHD-PCI study. Receiver operating characteristic analysis and area under the curve (AUC) evaluation were used to select the candidate variables. The model performance was validated internally and externally. The primary outcome was cardiac mortality (CM). We also explored the model performance for all-cause mortality (ACM). Results Initially, 28 risk factors were selected and ranked according to their AUC values. Finally, we selected age, N-terminal pro-B-type natriuretic peptide, and creatinine to develop a novel prediction model named “ABC” model. The ABC model had a high discriminatory ability for both CM (C-index: 0.774, p Conclusion In the present study, we developed and validated a novel model to predict mortality in patients with NSTE-ACS who underwent PCI. This model can be used as a credible tool for risk assessment and management of NSTE-ACS after PCI.

Background This preclinical study in sheep sought to demonstrate the initial safety and feasibility of a novel transcatheter mitral valve system (Mi-thos valve) composed of a self-expanding frame and a bovine pericardial tissue bioprosthesis. Methods The valve was implanted in 26 sheep using a transapical approach for short- and long-term evaluation. The technical feasibility, safety, durability, and valve function were evaluated during and 6 months after the procedure using intracardiac and transthoracic echocardiography, multisliced computed tomography, histological analysis, and electron microscopy. Results The success rate of valve implantation was 100%, and the immediate survival rate after surgery was 84%. Five animals died within 90 min after the development of the prosthetic valve due to an acute left ventricular outflow tract obstruction (n = 2) and sudden intraoperative ventricular fibrillation (n = 3). Twelve animals died within 1 month due to acute left heart dysfunction. Mild (n = 5) and moderate (n = 2) paravalvular leakage occurred in seven animals, and two moderate PVL animals died of chronic heart failure within three months. Multimodality imaging studies of the remaining seven animals showed excellent function and alignment of the valves, with no coronary artery obstruction, no left ventricular outflow tract obstruction, no severe transvalvular gradients and no paravalvular leakage. Macroscopic evaluation demonstrated stable, secure positioning of the valve, with full endothelialization of the valve leaflets without injury to the ventricular or atrial walls. Histological and electron microscopic examinations at six months showed no obvious macro- or microcalcification in the leaflets. Conclusions Preclinical studies indicate that transcatheter implantation of the Mi-thos valve is technically safe and feasible. The durability, functionality, and lack of leaflet calcification were all verified in animal experiments. The information from these preclinical studies will be applied to patient selection criteria and the first-in-human studies.

As part of our continuous studies on dietary supplements for diabetes, 1 new phenolic diterpene, 7-butoxyrosmanol (1), and 3 known ones (2-4) were isolated from Rosmarinus officinalis. The new structure was elucidated based on comprehensive spectroscopic methods, including multiple nuclear magnetic resonance techniques, mass spectrometry, and x-ray diffraction analysis. In addition, compound 1 showed moderate activity against pancreatic lipase with an IC50 value of 46.2 μM.

Alzheimer's disease is a neurodegenerative disease closely related to age, which is characterized by cognitive and memory impairment. Extensive studies have confirmed that Wnt/β-catenin signal pathway is involved in the occurrence and development of Alzheimer's disease. With the characteristics of holistic concept and syndrome differentiation, acupuncture is widely used in clinic. Acupuncture plays a role in the treatment of Alzheimer's disease through the regulation of each target and the whole of the pathway. The author reviewed and combed the research on acupuncture treatment of Alzheimer's disease in recent years, and reviewed the regulatory effects of acupuncture on the important components of Wnt/β-catenin signal pathway (Wnt protein, β-catenin, glycogen synthase kinase-3β) and whole, ATP-binding cassette subfamily B member 1 (ABCB1), low density lipoprotein receptor associated protein-1 (LRP-1)．.

Cancer stem cell (CSC) plays an important role in pancreatic cancer pathogenesis and treatment failure. CSCs are characterized by their ability to form tumor spheres in serum-free medium and expression of CSC related markers. In the present study, we investigated the effect atorvastatin, celecoxib and tipifarnib in combination on proliferation and apoptosis in Panc-1 sphere-forming cells. The sphere-forming cells were isolated from Panc-1 cells by sphere-forming method. These sphere-forming cells showed CSC properties. The levels of CD44, CD133 and ALDH1A1 in the sphere-forming cells were increased. Moreover, Panc-1 sphere-forming cells were resistant to chemotherapeutic drug gemcitabine. Combined atorvastatin with celecoxib and tipifarnib synergistically decreased the sphere forming ability of Panc-1 cells and the drug combination also strongly inhibited cell proliferation and promoted apoptosis in the sphere-forming cells. The effects of the drug combination on the Panc-1 sphere-forming cells were associated with decreases in the levels of CD44, CD133 and ALDH1A1, and suppression of Akt and NF-κB activation. Results of the present study indicate that the combination of atorvastatin, celecoxib and tipifarnib may represent an effective approach for inhibiting pancreatic CSCs.

Background: Alternate level of care (ALC) patients are those who reside in acute hospital beds but can be managed in non-hospital settings. They contribute to high occupancy levels in Canadian hospitals. Between 2017-18, Ontario spent 1.1 billion dollars on hospitalized patients waiting for alternate level of care (ALC) beds. To improve value for care, Ontario Ministry of Health (MOHLTC) invested into reintegration units which are designed to transfer ALC patients out of hospital and transition them back into the community or long-term care (LTC). Given today’s healthcare budget pressures, it is unclear if reactivation units are feasible. In 2018, the MOHLTC funded a reintegration unit, Pine Villa with an operational partner, Sunnybrook Hospital and community service providers (SPRINT Senior Care, LOFT) in Toronto, Ontario. The objective was to determine averted costs for ALC-patients and impact on Sunnybrook patient flow-through if ALC-patient Pine Villa transfers occurred on the day of ALC readiness. Methods: Retrospective, observational analysis of Sunnybrook ALC-patients discharged to Pine Villa between January 9, 2018 to February 4, 2019. From the healthcare payer’s perspective (MOHTLC), cost analysis was modelled for ALC patients designated for 1) LTC and 2) home with supports. Avoided costs at time of ALC readiness were determined by case-costing. Averted hospital ALC days were established. Results: If ALC patients were transferred to Pine Villa at time of ALC readiness for LTC, the healthcare system could have averted 5.4 million dollars from Sunnybrook. If the patients were transferred for home, 2.3 million dollars could have been averted. Both models increased acute Sunnybrook Hospital capacity by 34 beds. Conclusion: There is a business case supporting reintegration units if ALC-patients are discharged from the hospital on the day of ALC-readiness.

In the present study, we aimed to characterize gut microbiome and develop a gut microbiome-based diagnostic model in patients with coronary artery disease (CAD). Prospectively, we collected 309 fecal samples from Central China and Northwest China and carried out the sequencing of the V3-V4 regions of the 16S rRNA gene. The gut microbiome was characterized, and microbial biomarkers were identified in 152 CAD patients and 105 healthy controls (Xinjiang cohort, n = 257). Using the biomarkers, we constructed a diagnostic model and validated it externally in 34 CAD patients and 18 healthy controls (Zhengzhou cohort, n = 52). Fecal microbial diversity was increased in CAD patients compared to that in healthy controls (P = 0.021). Phylum Bacteroidetes was increased in CAD patients versus healthy controls (P = 0.001). Correspondingly, 48 microbial markers were identified through a 10-fold cross-validation on a random forest model, and an area under the curve (AUC) of 87.7% (95% CI: 0.832 to 0.916, P < 0.001) was achieved in the Xinjiang cohort (development cohort, n = 257). Notably, an AUC of 90.4% (95% CI: 0.848 to 0.928, P < 0.001) was achieved using combined analysis of gut microbial markers and clinical variables. This model provided a robust tool for the prediction of CAD. It could be widely employed to complement the clinical assessment and prevention of CAD.

Telmesteine, a useful agent for respiratory tract disorders, has been reported to be a critical active ingredient in topical compositions for dermatitis. The present study was designed to elucidate the in vitro and in vivo anti-inflammatory properties of telmesteine. LPS-induced NO production in RAW264.7 cells was significantly decreased after telmesteine treatment. TPA-induced skin inflammation as assessed by skin edema and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) was significantly decreased after telmesteine topical treatment. Further analysis results demonstrated that the anti-inflammation properties of telmesteine were associated with its ability to inhibit activation of nuclear factor kappa-κB (NF-κB) by blocking phosphoinositide 3-kinase/protein kinase B (PI3K/Akt)/IκB kinase (IKK) activities.

Background TRAIL, tumor necrosis factor-related apoptosis-inducing ligand, can selectively kill cancer cells with little or no cytotoxicity toward normal human cells and is regarded as a potential relatively safe antitumor drug. However, some cancer cells are resistant to TRAIL-induced apoptosis. Thus, reagents that potentiate TRAIL-induced cytotoxicity are needed. Herein, we investigated whether shikonin, a natural compound from the root of Lithospermum erythrorhizon, can sensitize TRAIL-resistant cells to TRAIL-induced cytotoxicity. Results The viability of A549 cells, which were resistant to TRAIL, was significantly decreased after treatment with TRAIL followed by shikonin. The underlying mechanisms by which shikonin sensitizes cells to TRAIL-induced cytotoxicity were also examined. Combined treatment with shikonin and TRAIL activated the caspase and JNK pathways, inhibited the STAT3 and AKT pathways, downregulated the expression of Mcl-1, Bcl-2, Bcl-xL, c-FLIP and XIAP and upregulated the expression of Bid. Conclusions In conclusion, the results indicated that shikonin sensitized resistant cancer cells to TRAIL-induced cytotoxicity via the modulation of the JNK, STAT3 and AKT pathways, the downregulation of antiapoptotic proteins and the upregulation of proapoptotic proteins.

Two new 29-nor-cycloartane triterpenes, amooratsanols A and B (1, 2) along with nine known compounds including two 29-nor-cycloartane triterpenes (3, 9), two lupane triterpenes (4, 5), two cycloartane triterpenes (6, 10), two dammarane triterpenes (7, 8), as well as one dinorcycloartane triterpene (11) were isolated from the leaves and twigs of Amoora tsangii (Merr.) X. M. Their structures were established by spectroscopic methods (IR, HRESIMS, and NMR). The cytotoxicity of 1-11 was evaluated against the human fibro sarcoma HT1080, esophageal cancer TE, and non-small cell lung cancer A549 cell lines by the CCK8 assay. Cycloartanes (1-3, 6, and 9-11) displayed significant cytotoxic activity with IC50 values ranging from 2.56 to 19.05 mu M. Among these triterpenes, mooratsanol A (1) showed the most potent cytotoxic activity, with IC50 values ranging from 2.56 to 5.10 mu M. (C) 2016 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.

The inhibition of angiogenesis is suggested to be an attractive strategy for cancer therapeutics. Heat shock protein 90 (Hsp90) is closely related to tumorigenesis as it regulates the stabilization and activated states of many client proteins that are essential for cell survival and tumor growth. Here, we investigated the mechanism whereby AT-533, a novel Hsp90 inhibitor, inhibits breast cancer growth and tumor angiogenesis. Based on our results, AT-533 suppressed the tube formation, cell migration, and invasion of human umbilical vein endothelial cells (HUVECs), and was more effective than the Hsp90 inhibitor, 17-AAG. Furthermore, AT-533 inhibited angiogenesis in the aortic ring, Matrigel plug, and chorioallantoic membrane (CAM) models. Mechanically, AT-533 inhibited the activation of VEGFR-2 and the downstream pathways, including Akt/mTOR/p70S6K, Erk1/2 and FAK, in HUVECs, and the viability of breast cancer cells and the HIF-1α/VEGF signaling pathway under hypoxia. In vivo, AT-533 also inhibited tumor growth and angiogenesis by inducing apoptosis and the HIF-1α/VEGF signaling pathway in breast cancer cells. Taken together, our findings indicate that the Hsp90 inhibitor, AT-533, suppresses breast cancer growth and angiogenesis by blocking the HIF-1α/VEGF/VEGFR-2 signaling pathway. AT-533 may thus be a potentially useful drug candidate for breast cancer therapy.

Background Cystinuria is a rare inherited renal stone disease caused by mutations in the SLC3A1 and SLC7A9 genes. The Chinese cystinuria phenotype and genotype have rarely been reported in the literature. Methods For this research, the clinical features and genetic etiology were analyzed in seven children, and the clinical characteristics were summarized. The blood and urine amino acids and acylcarnitine were analyzed. Additionally, the whole coding sequence and exon-intron junctions of the SLC3A1 and SLC7A9 genes were analyzed. Results These seven patients with cystinuria were from seven unrelated Chinese families, and they were diagnosed between the ages of 1 month and 16 years old. The urinary amino acids, including ornithine, arginine, and threonine, were elevated in these patients. A homozygous c.325G>A mutation in SLC7A9 was identified in two patients, and six SLC3A1 mutations were found in five patients. Conclusions The core pedigree analysis showed that most of the parents carried mutations; however, there was no association between the clinical course and the genotype.

The frequency-space (f-x) empirical mode decomposition (EMD) denoising method has two limitations when applied to nonstationary seismic data. First, subtracting the first intrinsic mode function (IMF) results in signal damage and limited denoising. Second, decomposing the real and imaginary parts of complex data may lead to inconsistent decomposition numbers. Thus, we propose a new method named f-x spatial projection-based complex empirical mode decomposition (CEMD) prediction filtering. The proposed approach directly decomposes complex seismic data into a series of complex IMFs (CIMFs) using the spatial projection-based CEMD algorithm and then applies f-x predictive filtering to the stationary CIMFs to improve the signal-to-noise ratio. Synthetic and real data examples were used to demonstrate the performance of the new method in random noise attenuation and seismic signal preservation.

The marine alkaloids, longamide B (1), longamide B methyl ester (2), hanishin (3), and a series of non-naturally occurring analogues were synthesized in an efficient manner from inexpensive commercially available dl-aspartic acid dimethyl ester. The cytotoxicities of these natural products (1-3) and their analogues (9-15) were evaluated against human lung adenocarcinoma (A549) and human prostate cancer (PC3) cells. This is the first evaluation of the cytotoxicities of these alkaloids in these cancer cell lines and it revealed that analogue 15 had comparable cytotoxic activity to its natural parent compound, (±)-hanishin (3). This study provides useful information for further structural modification of these alkaloids in order to develop novel antitumor agents.

We describe a case of generalized cutis laxa (CL) in a 7-year-old female child. At 2 months of age, she was found to have a hoarse voice, and at 3 years, she was much smaller than her peers. Her aging face and short stature caught our attention, and the treatment of the patient was accepted by our hospital. She underwent a thorough examination. X-ray of the wrist bone showed a markedly delayed bone age, and thyroid function tests revealed significantly elevated free triiodothyronine 3 and free thyroxine 4 levels, but thyrotropin was within the normal range. Thyroid dysfunction and CL can be associated with lagged growth and development. Whether her abnormal development was due to thyroid dysfunction or CL could not be ascertained. CL is possibly more complex than it has been supposed so far, and is therefore worth to be further studied.

Four trinorsesquiterpenoids ( 1 – 4 ) were isolated from the roots of Inula racemosa and the structures of two new compounds, (4 R ,5 S ,10 S )-5-hydroxy-11,12,13-trinoreudesm-6-en-8-one ( 1 ) and (4 R ,5 R ,10 R )-4,15-epoxy-11,12,13-trinoreudesman-8-one ( 3 ), were elucidated by extensive spectroscopic analysis. Furthermore, the structure of compound 2a should be revised as (4 R ,5 R ,10 S )-5-hydroxy-11,12,13-trinoreudesm-6-en-8-one ( 2 ) and compound 2 showed antiproliferative activity against A549, HepG2, and HT1080 cell lines with IC50 values of 3.71, 5.94, and 3.95 μg/mL, respectively.

Several new series of 5,6,7-trimethoxyindole derivatives were synthesized and their structure-activity relationships (SARs) were studied. Some of these compounds exhibited strong antiproliferative activities in the submicromolar range. N-Methyl-5,6,7-trimethoxylindoles 21 and 31 displayed the highest antiproliferative activities, with IC50 values ranging from 22 to 125 nM in four human cancer cell lines and activated human umbilical vein endothelial cells (HUVECs). In addition to vascular disrupting activity verified by in vitro assays, compounds 21 and 31 displayed much higher selectivity for activated HUVECs versus quiescent HUVECs than those of colchicine and combretastatinA-4. The polymerization of cancer cell tubulin was inhibited and the cell cycle was arrested in the G2/M phase after treatment with 21 and 31. It was showed that 21 disrupted tumor vasculature by use of in vivo assay. Our results suggest that these two new compounds we synthesized may become the promising leads for the development of vascular disrupting agents.

To study the clinical, biochemical, and genetic heterogeneity of six Chinese patients and their mothers with the 3243 AG mutation, six patients (ranging from 5 to 11 years) were hospitalized. All the mothers were healthy. Mitochondrial respiratory chain enzyme activities were determined by spectrophotometry. Mitochondrial gene was analyzed in all patients. Six core pedigrees were investigated. Two patients had mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome and one had Leigh syndrome. The common initial symptoms were headache, vomiting, blurred vision, and epilepsy. m.3243AG mutation was detected in all patients and their mothers. The mutation loads ranged from 43.6% to 58% and those of their mothers ranged from 14.1% to 28.6%. Varied respiratory chain deficiencies were observed in all patients and two mothers. m.3243AG mutation can result in a wide spectrum of respiratory chain complex deficiencies. Mitochondrial DNA mutation detected in blood may be likely to transmit to offspring, and the mutation load may increase.

Psechrus kunmingensis Yin, Wang & Zhang, 1985 was first described from the female only. The first illustration of the male appeared without any text description and lacked other critical information. For this study, we collected fresh specimens of this species from diverse localities around Yunnan Province, China. Here, the male is described in detail for the first time and a supplementary description of the female is given. Based on the largest collection of P. kunmingensis specimens ever assembled, we found a remarkably high level of morphological variation in this species.

Gene editing is a kind of technologies that makes precise modification to the genome. It can be used to knock out/in and replace the specific DNA fragment, and make accurate gene editing on the genome level. The essence of the technique is the DNA sequence change with use of non homologous end link repair and homologous recombination repair, combined with specific DNA target recognition and endonuclease.This technology has wide range of development prospects and high application value in terms of scientific research, agriculture, medical treatment and other fields. In the field of gene therapy, gene editing technology has achieved cross-time success in cancers such as leukemia, genetic disorders such as hemophilia, thalassemia, multiple muscle nutritional disorders and retrovirus associated infectious diseases such as AIDS and other diseases. The preparation work for new experimental methods and animal models combined with gene editing technology is under rapid development and improvement. Laboratories around the world have also applied gene editing technique in prevention of malaria, organ transplantation, biological pharmaceuticals, agricultural breeding improvement, resurrection of extinct species, and other research areas. This paper summarizes the application and development status of gene editing technique in the above fields, and also preliminarily explores the potential application prospect of the technology in the field of traditional Chinese medicine, and discusses the present controversy and thoughts.

Long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) may cause serious side effects such as gastric mucosal damage. Resveratrol, a naturally dietary polyphenol, exhibited anti-inflammatory activity and a protective effect against gastric mucosa damage induced by NSAIDs. In this regard, we synthesized a series of resveratrol-based NSAIDs derivatives and evaluated their anti-inflammatory activity against nitric oxide (NO) overproduction in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. We identified mono-substituted resveratrol-ibuprofen combination 21 as the most potent anti-inflammatory agent, which is more active than a physical mixture of ibuprofen and resveratrol, individual ibuprofen, or individual resveratrol. In addition, compound 21 exerted potent inhibitory effects on the LPS-induced expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Furthermore, compound 21 significantly increased the survival rate in an LPS-induced acute inflammatory model and produced markedly less gastric damage than ibuprofen. It was found that compound 21 may be a potent anti-inflammatory agent for the treatment of inflammation-related diseases.

Four new species of Psechrus are described from Yunnan Province: P. changminae sp. nov., P. conicus sp. nov., P. discoideus sp. nov. and P. spatulatus sp. nov. Herewith the number of species belonging to Psechrus in Yunnan Province extended from five to nine. Illustrations and colour photos are provided, with comparison of intraspecific variation of copulatory organs.