Metal-Free Reductive Coupling of para-Quinone Methides with 4-Cyanopyridines Enabled by Pyridine-Boryl Radicals: Access to Pyridylated Diarylmethanes with Anti-Cancer Activity.

Reported herein is a streamlined protocol to produce pyridylated diarylmethanes through pyridine-boryl radical induced reductive coupling between para-quinone methides (p-QMs) and 4-cyanopyridines using bis(pinacolato)diboron (B2 pin2 ) as a templated reagent. The metal-free process is characterized by an operationally simple approach, excellent chemoselectivity (1,2- vs. 1,6-selectivity), and a broad substrate scope with good functional group compatibility. The mechanistic studies provided important insights into the reductive cross-coupling process between diarylmethyl radical and pyridine-boryl radical. Moreover, part of the obtained pyridylated diarylmethane products were screened against a panel of cancer cell lines, and 3 v was confirmed to significantly inhibit the proliferation of head and neck squamous cell carcinoma (HNSCC) cells. This method offers a platform for the preparation of new lead compounds with antitumor activity.

Demethylzeylasteral (T-96) initiates extrinsic apoptosis against prostate cancer cells by inducing ROS-mediated ER stress and suppressing autophagic flux.

BACKGROUND: Demethylzeylasteral (T-96) is a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF) that has been reported to exhibit anti-neoplastic effects against several types of cancer cells. However, the potential anti-tumour effects of T-96 against human Prostate cancer (CaP) cells and the possible underlying mechanisms have not been well studied. RESULTS: In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Mechanistically, T-96 promoted the initiation of autophagy but inhibited autophagic flux by inducing ROS-mediated endoplasmic reticulum (ER) stress which subsequently activated the extrinsic apoptosis pathway in CaP cells. These findings implied that T-96-induced ER stress activated the caspase-dependent apoptosis pathway to inhibit proliferation of CaP cells. Moreover, we observed that T-96 enhances the sensitivity of CaP cells to the chemotherapeutic drug, cisplatin. CONCLUSIONS: Taken together, our data demonstrated that T-96 is a novel modulator of ER stress and autophagy, and has potential therapeutic applications against CaP in the clinic.

A highly fluorescent lanthanide metal-organic framework as dual-mode visual sensor for berberine hydrochloride and tetracycline.

A microscale highly fluorescent Eu metal-organic framework (Eu-MOF) was synthesized with terephthalic acid and 1H-1,2,4-triazole-3,5-diamine by one-pot hydrothermal method. And it was characterized by scanning electron microscope, Fourier transform infrared spectroscopy, powder X-ray diffraction, fluorescence spectroscopy, thermogravimetric analysis, and energy dispersive X-ray mapping. The prepared Eu-MOF has high quantum yield of 30.99%, excellent water dispersibility, good fluorescence stability, and favorable thermal stability. Based on the distinctly different fluorescence responses of different emission, the prepared Eu-MOF was used as dual-mode visual sensor for the sensitive detection of berberine hydrochloride and tetracycline. The limits of detection are 78 nM and 17 nM, respectively. The sensing mechanism was also discussed. Moreover, a filter paper sensor has been designed for sensing tetracycline with a notable fluorescence color change from blue to red. The prepared Eu-MOF is promising to be developed as a multi-mode luminescent sensor for visual detection in biochemical analysis. Graphical abstract Illustration of the synthesis of Eu-MOF and its sensing applications for berberine hydrochloride and tetracycline.

Early biochemical response to ursodeoxycholic acid and long-term prognosis of primary biliary cirrhosis: results of a 14-year cohort study.

UNLABELLED: The biochemical response to ursodeoxycholic acid (UDCA) in primary biliary cirrhosis is a strong predictor of long-term outcome and thus facilitates the rapid identification of patients needing new therapeutic approaches. Numerous criteria for predicting outcome of treatment have been studied based on biochemical response to UDCA at 1 year. We sought to determine whether an earlier biochemical response at 3 or 6 months could as efficiently identify patients at risk of poor outcome, as defined by liver-related death, liver transplantation, and complications of cirrhosis. We analyzed the prospectively collected data of 187 patients with a median follow-up of 5.8 years (range, 1.3-14 years). The survival rates without adverse outcome at 5 years and 10 years were 86% and 63%. Under UDCA therapy, laboratory liver parameters experienced the most prominent improvement in the first 3 months (P < 0.0001) and then stayed relatively stable for the following months. The Paris, Barcelona, Toronto, and Ehime definitions, but not the Rotterdam definition, applied at 3, 6, and 12 months significantly discriminated the patients in terms of long-term outcome. Compared with biochemical responses evaluated after 1 year of UDCA therapy, biochemical responses at the third month demonstrated higher positive predictive value (PPV) but lower negative predictive value (NPV) and increased negative likelihood ratio (NLR) by all definitions; biochemical responses at the sixth month showed higher or the same PPV and NPV and lower NLR by all definitions. CONCLUSION: For the previously published criteria, biochemical responses at the sixth month can be used in place of those evaluated after 1 year of UDCA therapy. Our findings justify a more rapid identification of patients who need new therapeutic approaches.

A high-quality chromosome-level genome assembly of the endangered tree Kmeria septentrionalis.

Kmeria septentrionalis is a critically endangered tree endemic to Guangxi, China, and is listed on the International Union for Conservation of Nature's Red List. The lack of genetic information and high-quality genome data has hindered conservation efforts and studies on this species. In this study, we present a chromosome-level genome assembly of K. septentrionalis. The genome was initially assembled to be 2.57 Gb, with a contig N50 of 11.93 Mb. Hi-C guided genome assembly allowed us to anchor 98.83% of the total length of the initial contigs onto 19 pseudochromosomes, resulting in a scaffold N50 of 135.08 Mb. The final chromosome-level genome, spaning 2.54 Gb, achieved a BUSCO completeness of 98.9% and contained 1.67 Gb repetitive elements and 35,927 coding genes. This high-quality genome assembly provides a valuable resource for understanding the genetic basis of conservation-related traits and biological properties of this endangered tree species. Furthermore, it lays a critical foundation for evolutionary studies within the Magnoliaceae family.

[Clinical characteristics of primary biliary cirrhosis complicating Sjögren syndrome].

OBJECTIVE: To explore the clinical characteristics of primary biliary cirrhosis (PBC) with Sjögren syndrome (SS) so as to seek diagnostic rationales. METHODS: Sixty-four PBC patients, 57 SS patients and 93 PBC with SS patients were recruited from Peking Union College Hospital between 2006 and 2009. And their clinical, laboratory and pathological data were analyzed. RESULTS: The patients of PBC with SS (53 ± 10) years were older than those of PBC (50 ± 11) years (P < 0.05) or SS (48 ± 14) years (P < 0.05) ; Comparing PBC with SS and SS, fever was more in SS (P < 0.05) ;compare with PBC, the positive rates of anti-centromere antibody (ACA) (P < 0.05) and anti-SSA antibody (P < 0.05) increased obviously in PBC with SS. Comparing with SS, the positive rate of anti-SSA antibody (P < 0.05) and anti-SSB antibody (P < 0.05) were apparently increased obviously in PBC with SS. CONCLUSION: PBC with SS is a special subgroup with the characteristic both PBC and SS. But it can not differentiate from PBC or SS, Anti-SSA antibody and ACA are helpful for diagnosis of PBC with SS.

GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21.

As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing.

[The clinical observation of different therapeutic strategies in combined primary biliary cirrhosis and Sjögren syndrome].

OBJECTIVE: To investigate the role of different therapeutic regimens in primary biliary cirrhosis (PBC)complicating Sjögren syndrome (SS). METHODS: A total of 79 patients diagnosed as PBC complicating SS were enrolled and randomly divided into three groups: Group U (29 patients) received ursodeoxycholic acid (UDCA) alone, Group UP (37 patients) received UDCA and prednisolone, Group UA (13 patients) received UDCA and azathioprine. The clinical and laboratory data were collected at 0, 3, 6 and 12 months after treatment. RESULTS: Fatigue and pruritus were improved in each group with no difference among them (P > 0.05). The levels of ALT, AST, alkaline phophatase (ALP), gamma-glutamyl transferase (GGT), TBil, DBil, IgG, and IgM in the three groups were all decreased after treatment (P < 0.05), while there were no statistical differences among the three groups (P > 0.05). CONCLUSIONS: The combination therapy of UDCA with prednisolone or azathioprine was not better than UDCA alone. The therapeutic policy of PBC complicating SS involved in the liver should settle PBC mainly.

Uncovering potential single nucleotide polymorphisms, copy number variations and related signaling pathways in primary Sjogren's syndrome.

Primary Sjogren's syndrome (pSS) is a complex systemic autoimmune disease, which is difficult to accurately diagnose due to symptom diversity in patients, especially at earlier stages. We tried to find potential single nucleotide polymorphisms (SNPs), copy number variations (CNVs) and related signaling pathways. Genomic DNA was extracted from peripheral blood of 12 individuals (7 individuals from 3 pSS pedigrees and 5 sporadic cases) for whole-exome sequencing (WES) analysis. SNPs and CNVs were identified, followed by functional annotation of genes with SNPs and CNVs. Gene expression profile (involving 64 normal controls and 166 cases) was downloaded from the Gene Expression Omnibus database (GEO) dataset for differentially expression analysis. Sanger sequencing and in vitro validation was used to validate the identified SNPs and differentially expressed genes, respectively. A total of 5 SNPs were identified in both pedigrees and sporadic cases, such as FES, PPM1J, and TRAPPC9. A total of 3402 and 19 CNVs were identified in pedigrees and sporadic cases, respectively. Fifty-one differentially expressed genes were associated with immunity, such as BATF3, LAP3, BATF2, PARP9, and IL15RA. AMPK signaling pathway and cell adhesion molecules (CAMs) were the most significantly enriched signaling pathways of identified SNPs. Identified CNVs were associated with systemic lupus erythematosus, mineral absorption, and HTLV-I infection. IL2-STAT5 signaling, interferon-gamma response, and interferon-alpha response were significantly enriched immune related signaling pathways of identified differentially expressed genes. In conclusion, our study found some potential SNPs, CNVs, and related signaling pathways, which could be useful in understanding the pathological mechanism of pSS.

Facile synthesis and biological evaluation of tryptamine-piperazine-2,5-dione conjugates as anticancer agents.

A facile and efficient route to synthesize N-heterocyclic fused tryptamine-piperazine-2,5-dione conjugates was developed via a post-Ugi cascade reaction. The targeted compounds were prepared by means of a mild reaction and simple operation procedure, which could be applied to a broad scope of starting materials. Compound 6h was demonstrated to induce significant growth inhibition of AsPC-1 and SW1990 human pancreatic cancer cell lines (IC50 = 6 ± 0.85 µM). Our protocol allows for the construction of a structurally diverse compound library and paves a new avenue for the discovery of pancreatic cancer drug candidates.

Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy.

Mitochondria, as the powerhouse of most cells, are not only responsible for the generation of adenosine triphosphate (ATP) but also play a decisive role in the regulation of apoptotic cell death, especially of cancer cells. Safe potential delivery systems which can achieve organelle-targeted therapy are urgently required. In this study, for effective pancreatic cancer therapy, a novel mitochondria-targeted and ROS-triggered drug delivery nanoplatform was developed from the TPP-TK-CPI-613 (TTCI) prodrug, in which the ROS-cleave thioketal functions as a linker connecting mitochondrial targeting ligand TPP and anti-mitochondrial metabolism agent CPI-613. DSPE-PEG2000 was added as an assistant component to increase accumulation in the tumor via the EPR effect. This new nanoplatform showed effective mitochondrial targeting, ROS-cleaving capability, and robust therapeutic performances. With active mitochondrial targeting, the formulated nanoparticles (TTCI NPs) demonstrate much higher accumulation in mitochondria, facilitating the targeted delivery of CPI-613 to its acting site. The results of in vitro antitumor activity and cell apoptosis revealed that the IC50 values of TTCI NPs in three types of pancreatic cancer cells were around 20~30 µM, which was far lower than those of CPI-613 (200 µM); 50 µM TTCI NPs showed an increase in apoptosis of up to 97.3% in BxPC3 cells. Therefore, this mitochondria-targeted prodrug nanoparticle platform provides a potential strategy for developing safe, targeting and efficient drug delivery systems for pancreatic cancer therapy.

A multiple genomic data fused SF2 prediction model, signature identification, and gene regulatory network inference for personalized radiotherapy.

Radiotherapy is one of the most important cancer treatments, but its response varies greatly among individual patients. Therefore, the prediction of radiosensitivity, identification of potential signature genes, and inference of their regulatory networks are important for clinical and oncological reasons. Here, we proposed a novel multiple genomic fused partial least squares deep regression method to simultaneously analyze multi-genomic data. Using 60 National Cancer Institute cell lines as examples, we aimed to identify signature genes by optimizing the radiosensitivity prediction model and uncovering regulatory relationships. A total of 113 signature genes were selected from more than 20,000 genes. The root mean square error of the model was only 0.0025, which was much lower than previously published results, suggesting that our method can predict radiosensitivity with the highest accuracy. Additionally, our regulatory network analysis identified 24 highly important 'hub' genes. The data analysis workflow we propose provides a unified and computational framework to harness the full potential of large-scale integrated cancer genomic data for integrative signature discovery. Furthermore, the regression model, signature genes, and their regulatory network should provide a reliable quantitative reference for optimizing personalized treatment options, and may aid our understanding of cancer progress mechanisms.

Antimitochondrial antibody-negative primary biliary cirrhosis: a subset of primary biliary cirrhosis.

OBJECTIVE: Antimitochondrial antibodies (AMA) are the hallmark in primary biliary cirrhosis (PBC); nevertheless, it has long been recognized that 5-10% patients with typical features compatible with PBC do not have detectable AMA, and they were referred to as 'AMA-negative PBC'. This study aimed to evaluate whether AMA-negative/positive PBC represents different clinical entities. METHODS: We compared the clinical, laboratory, percentage of regulatory T cells (Tregs) in peripheral blood, liver biopsy features and response to treatment of the two groups of patients. The first group was comprised of 12 patients with 'AMA-negative PBC'. The second was made up of another 12 PBC patients with positive AMA. RESULTS: Antimitochondrial antibodies-negative/positive patients were remarkably similar in terms of clinical manifestations, liver biochemistries and histological findings. The frequency of anti-nuclear antibodies, anti-smooth-muscle antibody, anti-gp210 and anti-sp100 antibody showed no significant difference between the two groups. A significantly lower mean percentage of CD4+CD25(high) T cells was observed in peripheral blood mononuclear cells of AMA-negative/positive PBC patients compared with that of the 12 control subjects (5.8+/-1.8 and 5.4+/-1.4% vs. 7.6+/-1.7% respectively; P=0.014 and 0.004). However, no difference could be found between AMA-negative and AMA-positive PBC patients (P=0.599). After 1 year treatment with ursodeoxycholic acid, the two groups showed similar response. CONCLUSION: Antimitochondrial antibody-negative/positive PBC patients are similar in clinical, laboratory, percentage of Treg in peripheral blood, liver biopsy features and response to treatment. This suggests that AMA-negative PBC may be a variant of AMA-positive PBC rather than a separate clinical entity.

Interstitial lung disease and Sjögren's syndrome in primary biliary cirrhosis: a causal or casual association?

Interstitial lung disease (ILD) has been reported in patients with primary biliary cirrhosis (PBC); however, its frequency and pathogenesis are still poorly documented. Sjogren's syndrome (SS) is fairly common among patients with PBC, but the relationship between SS and PBC also remains controversial. To determine whether ILD and SS in PBC is a causal or casual association, whether SS accompanying PBC, could be considered secondary to or associated with PBC. One hundred and nine consecutive PBC cases were analyzed, and the differences of clinical features, histological stages, and serum autoantibodies between the PBC patients with and without SS were compared. There were 46 PBC patients with SS and 63 without SS, and 11 patients met the criteria of ILD. SS is associated with PBC in the form of secondary SS. The frequency of ILD in PBC patients with SS was 21.7% while only 1.6% in PBC patients without SS (P<0.0001). ILD in PBC was related to SS, with Spearman's rank coefficient of 0.330 (P=0.000). The association of SS with PBC, significantly higher in patients with than without ILD, which supports the hypothesis that ILD and SS in PBC, may be a causal, not casual, association.

Label-free electrochemical sensor to investigate the effect of tocopherol on generation of superoxide ions following UV irradiation.

BACKGROUND: Generation of reactive oxygen species (ROS), triggered by ultraviolet radiation (UVR), is associated with carcinogenesis of the skin. UV irradiation induced superoxide anion (O2•-) is the key ROS involved in the cellular damage. The cytoprotective efficacy of an unknown anti-oxidant compound can be evaluated by analyzing the production of O2•- from treated cells. METHODS: In this study, a glass carbon electrode functionalized with nanotube@DNA-Mn3(PO4)2 composite was applied to quantitative determination of generation of highly unstable O2•- from the melanoma A375 cell line following UVR(UV, UVA and UVB). In addition, the cytoprotective efficacy of anti-oxidant α-tocopherol was evaluated by quantifying the production of O2•-. RESULTS: The results showed that, UVR triggers generation of O2•- in melanoma A375 cells, and α-tocopherol is effective in diminishing the production of O2•- following UV irradiation. By comparing the conventional cell-survival assays results, we found that our simple and quick electrochemical sensing method can quantify O2•- generation through the biological activity of an anti-oxidant compound (α-tocopherol). CONCLUSION: Our label-free electrochemical quantification method for ROS (O2•- major) in cells facing UVR stress demonstrates its potential application for high-throughput screening of anti-oxidation compounds.

[Efficacy of Bortezomib for Maintenance therapy of Patients with Multiple Myeloma].

OBJECTIVE: To observe the efficacy of chemotherapy consisted of bortezomib as main druy in maintenance therapy for recurrence of newly diagnosed MM patients. METHODS: The clinical data and outcome of 37 MM patients during 2008-2013 were analyzed retrospectively, the 37 MM patients were divided into 2 group: 19 cases including 13 cases of newly diagnosed MM with symptoms and 6 cases of relapsed refractory MM were enrolled in group A; 17 cases of newly diagnosed MM with symptoms were enrolled in group B. The patients of group A received maintenance therapy consisted of bortezomib plus dexamethasone (VD group), while the patient group B received maintenance therapy consisted of melphalan plus prednisone(MP group), then the therapeutic efficacy of 2 group was compared. RESULTS: The overall response rate(ORR) in VD groupe was 84.2%(16/19), out of which CR rate reached 42%(8/19), PR rate reached 31.6%(6/19), MR rate reached 10.5%(3/19). During median follow-up for 21.8(5-51) months, death occurred, while the ORR in MP group was 52(9/17), out of which CR rate was 23.5%(4/17), PR rate reached 23.5%(4/17), MR rate reached 5.9%(1/17). Druing median follow-up for 16.4(4-39) months, the worteity reaced 64.7%(11/17). The differencr between 2 groups was significant(P<0.05). The median OS time of patients in VD group was 21.6 months, that in MP group was 17.9 months(P<0.05). The median PFS in VD group and MP group were 13.4 and 9.4 months respectively(P<0.001). CONCLUSION: The ORR and CR rates of bortezomib maintenance therapy for newly diagnosed and relapsed / refractory MM patients are very high, and its toxicity can be controlled, therefore, the patients need maintenance therapy after remission.

[Correlation of Thrombosis and Prothrombotic State with Coagulation Factor V Gene Polymorphism and APCR. HHcy].

OBJECTIVE: To investigate the correlation of patients with thrombosis or prothrombotic status with hyperhomocysteinemia (HHcy), activated protein C-resistance(APCR) and gene polymorphism of coagulation factor V. METHODS: Three hundred healthy voluteers were selected as controls, 223 cases of thrombosis (80 cases of cerebral infarction of CT, the MI of 82 cases of myocardial infarction, venous thrombosis of VTE 61 cases), 270 cases of patients with prothrombotic state (76 cases of pregnancy disease of PIH, 62 cases of chronic obstructive pulmonary disease (COPD), 60 cases of diabetes(DM) and 72 cases of cancer) were enrolled in this study. The plasma APCR and hyperhomocysteinemia were detected by APTT coagulation method and cycling enzyme method respectively, and restriction fragment length polymorphism(RFLP) were was used to detect the gene polymorphism of FV G1691-A, G1091-C and A1090-G in the patient and control groups. RESULTS: APCR positive rate was 62.29% and 7.33%, and the positive hyperhomocysteinemia accounted for 68.42% and 10.00% respectively in the group of the patients with venous thrombosis and the normal control group. 3 cases of heterozygous FV gene mutations were found in the APCR-positive patients with venous thrombosis. CONCLUSION: HHcy possitive rate of patients with venous thrombosis is signiticantly higher than that in control, the HHcy is one of the important causes resulting in thrombosis, the patients with venous thrombosis have proved to be with APCR, and the possitive APCR may be related with the coagulation factor V gene polymorphism.

Demethylzeylasteral (T-96) initiates extrinsic apoptosis against prostate cancer cells by inducing ROS-mediated ER stress and suppressing autophagic flux

BACKGROUND: Demethylzeylasteral (T-96) is a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF) that has been reported to exhibit anti-neoplastic effects against several types of cancer cells. However, the potential anti-tumour effects of T-96 against human Prostate cancer (CaP) cells and the possible underlying mechanisms have not been well studied. RESULTS: In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Mechanistically, T-96 promoted the initiation of autophagy but inhibited autophagic flux by inducing ROS-mediated endoplasmic reticulum (ER) stress which subsequently activated the extrinsic apoptosis pathway in CaP cells. These findings implied that T-96-induced ER stress activated the caspase-dependent apoptosis pathway to inhibit proliferation of CaP cells. Moreover, we observed that T-96 enhances the sensitivity of CaP cells to the chemotherapeutic drug, cisplatin. CONCLUSIONS: Taken together, our data demonstrated that T-96 is a novel modulator of ER stress and autophagy, and has potential therapeutic applications against CaP in the clinic.

Involvement of superoxide and nitric oxide in BRAF(V600E) inhibitor PLX4032-induced growth inhibition of melanoma cells.

The BRAF(V600E) inhibitor PLX4032 (Vemurafenib) is an FDA-approved new drug for the treatment of metastatic melanomas, which specifically inhibits the RAS/MEK/ERK signaling pathway to control cell proliferation and adhesion. However, no study has been carried out to investigate the role of intracellular oxidative balance in PLX4032-induced tumor growth inhibition. Herein, for the first time, superoxide (O2˙(-)) and nitric oxide (NO) generated from PLX4032-challenged melanoma cells were monitored using electrochemical sensors and conventional fluorescein staining techniques. Impacts of superoxide dismutase (SOD) and NG-monomethyl-L-arginine monoacetate (L-NMMA), a nitric oxide synthase inhibitor, were also examined to demonstrate the specificity of ROS/NO generation and its biological consequences. PLX4032 specifically triggers production of O2˙(-) and NO from BRAF(V600E) mutant A375 cells. SOD and L-NMMA could abolish the PLX4032-induced increase in intracellular O2˙(-) and NO production, thereby rescuing cell growth in BRAF mutant A375 cells (A375(BRAFV600E)). In addition, PLX4032 treatment could decrease the mitochondrial membrane potential in A375(BRAFV600E) cells. The results suggest that PLX4032 can selectively cause ROS production and depolarization of mitochondrial membranes, potentially initiating apoptosis and growth inhibition of PLX4032-sensitive cells. This work not only proposes a new mechanism for PLX4032-induced melanoma cell inhibition, but also highlights potential applications of electrochemical biosensors in cell biology and drug screening.

Connective tissue diseases in primary biliary cirrhosis: a population-based cohort study.

AIM: To establish the frequency and clinical features of connective tissue diseases (CTDs) in a cohort of Chinese patients with primary biliary cirrhosis (PBC). METHODS: Three-hundred and twenty-two Chinese PBC patients were screened for the presence of CTD, and the systemic involvement was assessed. The differences in clinical features and laboratory findings between PBC patients with and without CTD were documented. The diversity of incidence of CTDs in PBC of different countries and areas was discussed. For the comparison of normally distributed data, Student's t test was used, while non-parametric test (Wilcoxon test) for the non-normally distributed data and 2 × 2 χ(2) or Fisher's exact tests for the ratio. RESULTS: One-hundred and fifty (46.6%) PBC patients had one or more CTDs. The most common CTD was Sjögren's syndrome (SS, 121 cases, 36.2%). There were nine cases of systemic sclerosis (SSc, 2.8%), 12 of systemic lupus erythematosus (SLE, 3.7%), nine of rheumatoid arthritis (RA, 2.8%), and 10 of polymyositis (PM, 3.1%) in this cohort. Compared to patients with PBC only, the PBC + SS patients were more likely to have fever and elevated erythrocyte sedimentation rate (ESR), higher serum immunoglobulin G (IgG) levels and more frequent rheumatoid factor (RF) and interstitial lung disease (ILD) incidences; PBC + SSc patients had higher frequency of ILD; PBC + SLE patients had lower white blood cell (WBC) count, hemoglobin (Hb), platelet count, γ-glutamyl transpeptidase and immunoglobulin M levels, but higher frequency of renal involvement; PBC + RA patients had lower Hb, higher serum IgG, alkaline phosphatase, faster ESR and a higher ratio of RF positivity; PBC + PM patients had higher WBC count and a tendency towards myocardial involvement. CONCLUSION: Besides the common liver manifestation of PBC, systemic involvement and overlaps with other CTDs are not infrequent in Chinese patients. When overlapping with other CTDs, PBC patients manifested some special clinical and laboratory features which may have effect on the prognosis.