inhibitor of apoptosis protein 1 and 2 (cIAP1/2) and X-linked
inhibitor of apoptosis protein (XIAP) are key apoptosis regulators
and promising new cancer therapeutic targets. This study describes
a set of non-peptide, small-molecule Smac (second mitochondria-derived
activator of caspases) mimetics that are selective inhibitors of cIAP1/2
over XIAP. The most potent and most selective compounds bind to cIAP1/2
with affinities in the low nanomolar range and show >1,000-fold
for cIAP1 over XIAP. These selective cIAP inhibitors effectively induce
degradation of the cIAP1 protein in cancer cells at low nanomolar
concentrations and do not antagonize XIAP in a cell-free functional
assay. They potently inhibit cell growth and effectively induce apoptosis
at low nanomolar concentrations in cancer cells with a mechanism of
action similar to that of other known Smac mimetics. Our study shows
that binding of Smac mimetics to XIAP BIR3 is not required for effective
induction of apoptosis in tumor cells by Smac mimetics. These potent
and highly selective cIAP1/2 inhibitors are powerful tools in the
investigation of the role of these IAP proteins in the regulation
of apoptosis and other cellular processes.
Cardiogenesis requires proper specification, proliferation, and differentiation of cardiac progenitor cells (CPCs). The differentiation of CPCs to specific cardiac cell types is likely guided by a comprehensive network comprised of cardiac transcription factors and epigenetic complexes. In this review, we describe how the ATP-dependent chromatin remodeling SWI/SNF complexes work synergistically with transcription and epigenetic factors to direct specific cardiac gene expression during CPC differentiation. Furthermore, we discuss how SWI/SNF may prime chromatin for cardiac gene expression at a genome-wide level. A detailed understanding of SWI/SNF-mediated CPC differentiation will provide important insight into the etiology of cardica defects and help design novel therapies for heart disease.
Amyloid β peptides
form fibrils that are commonly assumed to have a dry, homogeneous,
and static internal structure. To examine these assumptions, fibrils
under various conditions and different ages have been examined with
multidimensional infrared spectroscopy. Each peptide in the fibril
had a 13C=18O label in the backbone of
one residue to disinguish the amide I′ absorption due to that
residue from the amide I′ absorption of other residues. Fibrils
examined soon after they formed, and reexamined after 1 year in the
dry state, exhibited spectral changes confirming that structurally
significant water molecules were present in the freshly formed fibrils.
Results from fibrils incubated in solution for 4 years indicate that
water molecules remained trapped within fibrils and mobile over the
4 year time span. These water molecules are structurally significant
because they perturb the parallel β-sheet hydrogen bonding pattern
at frequent intervals and at multiple points within individual fibrils,
creating structural heterogeneity along the length of a fibril. These
results show that the interface between β-sheets in an amyloid
fibril is not a “dry zipper”, and that the internal
structure of a fibril evolves while it remains in a fibrillar state.
These features, water trapping, structural heterogeneity, and structural
evolution within a fibril over time, must be accommodated in models
of amyloid fibril structure and formation.
Stable isotopes; 18O; 13C; spectral crosspeaks; linear excitons; ultrafast vibrational laser spectroscopy; 2D infrared photon echo experiment
We previously reported the discovery of a class of spirooxindoles as potent and selective small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors). We report herein our efforts to improve their pharmacokinetic properties and in vivo antitumor activity. Our efforts led to the identification of 9 (MI-888) as a potent MDM2 inhibitor (Ki = 0.44 nM) with a superior pharmacokinetic profile and enhanced in vivo efficacy. Compound 9 is capable of achieving rapid, complete, and durable tumor regression in two types of xenograft models of human cancer with oral administration and represents the most potent and efficacious MDM2 inhibitor reported to date.
Bcl-2 and Bcl-xL are critical regulators of apoptosis that are overexpressed in a variety of human cancers and pharmacological inhibition of Bcl-2 and Bcl-xL represents a promising strategy for cancer treatment. Using a structure-based design approach, we have designed BM-1197 as a potent and efficacious dual inhibitor of Bcl-2 and Bcl-xL. BM-1197 binds to Bcl-2 and Bcl-xL proteins with Ki values less than 1 nM and shows >1,000-fold selectivity over Mcl-1. Mechanistic studies performed in the Mcl-1 knockout mouse embryonic fibroblast (MEF) cells revealed that BM-1197 potently disassociates the heterodimeric interactions between anti-apoptotic and pro-apoptotic Bcl-2 family proteins, concomitant with conformational changes in Bax protein, loss of mitochondrial membrane potential and subsequent cytochrome c release to the cytosol, leading to activation of the caspase cascade and apoptosis. BM-1197 exerts potent growth-inhibitory activity in 7 of 12 small cell lung cancer cell lines tested and induces mechanism-based apoptotic cell death. When intravenously administered at daily or weekly in H146 and H1963 small-cell lung cancer xenograft models, it achieves complete and long-term tumor regression. Consistent with its targeting of Bcl-xL, BM-1197 causes transit platelet reduction in mice. Collectively, our data indicate that BM-1197 is a promising dual Bcl-2/Bcl-xL inhibitor which warrants further investigation as a new anticancer drug.
We have designed, synthesized and evaluated a series of new compounds based upon our previously reported bivalent Smac mimetics. This led to the identification of compound 12 (SM-1200), which binds to XIAP, cIAP1 and cIAP2 with Ki values of 0.5 nM, 3.7 nM and 5.4 nM, respectively, inhibits cell growth in the MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines with IC50 values of 11.0 nM and 28.2 nM, respectively. Compound 12 has a much improved pharmacokinetic profile over our previously reported bivalent Smac mimetics and is highly effective in induction of rapid and durable tumor regression in the MDA-MB-231 xenograft model. These data indicate that compound 12 is a promising Smac mimetic and warrants extensive evaluation as a potential candidate for clinical development.
Small-molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereo-chemistry in this class of compounds has a major effect on their binding affinities to MDM2; with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a Ki value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.
Part of quercetin flows into the colon after escaping the absorption of the small intestine and will be degraded by colonic microbiota. The catabolites in the colon partially determine the physiological activity of quercetin.
Seven gut bacteria isolated from human feces were utilized to in vitro ferment quercetin. Their catabolites were analyzed with high-performance liquid chromatography and mass spectrometry, and the antioxidant activities of their fermented broths were compared with that of quercetin.
One metabolite, 3,4-dihydroxyphenylacetic acid, was produced by both C. perfringens and B. fragilis transforming quercetin. No other metabolites were detected in the other fermented broths. The antioxidant activities of all strains fermenting quercetin reached the highest values at the concentration of 1 mg/mL quercetin in broth; the fermented products of C. perfringens and B. fragilis presented stronger activities than those of other strains at most concentrations of quercetin in broth. Additionally, all of the fermented broths presented a decline of the antioxidant activities compared to quercetin. Therefore, the antioxidant activity of quercetin will be lost when it reaches the human colon because of the gut bacterial fermentation.
This is the first study to report that quercetin can be degraded by C. perfringens and B. fragilis and transformed to the same metabolite, 3,4-dihydroxyphenylacetic acid, and that antioxidant activities decline when quercetin is fermented by seven gut bacteria.
quercetin; gut bacteria; catabolites; antioxidant activity
Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with Ki values of < 1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete and durable tumor regression in vivo at a well-tolerated dose-schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.
Curcumin, a natural product derived from the plant Curcuma longa, has been found to have anti-inflammatory, antineoplastic and antifibrosis effects. It has been reported that curcumin attenuates allergic airway inflammation in mice through inhibiting NF-κB and its downstream transcription factor GATA3. It also has been proved the antineoplastic effect of curcumin through down-regulating Notch1 receptor and its downstream nuclear transcription factor NF-κB levels. In this study, we aimed to investigate the anti-inflammatory effect of curcumin on acute allergic asthma and its underlying mechanisms. 36 male BALB/c mice were randomly divided into four groups (normal, asthma, asthma+budesonide and asthma+curcumin groups). BALF (bronchoalveolar lavage fluid) and lung tissues were analyzed for airway inflammation and the expression of Notch1, Notch2, Notch3, Notch4 and the downstream transcription factor GATA3. Our findings showed that the levels of Notch1 and Notch2 receptors were up-regulated in asthma group, accompanied by the increased expression of GATA3. But the expression of Notch2 receptor was lower than Notch1 receptor. Curcumin pretreatment improved the airway inflammatory cells infiltration and reversed the increasing levels of Notch1/2 receptors and GATA3. Notch3 receptor was not expressed in all of the four groups. Notch4 receptor protein and mRNA expression level in the four groups had no significant differences. The results of the present study suggested that Notch1 and Notch2 receptor, major Notch1 receptor, played an important role in the development of allergic airway inflammation and the inhibition of Notch1–GATA3 signaling pathway by curcumin can prevent the development and deterioration of the allergic airway inflammation. This may be a possible therapeutic option of allergic asthma.
curcumin; asthma; airway inflammation; Notch; GATA3
Mesorhizobium huakuii 7653R occurs either in nitrogen-fixing symbiosis with its host plant, Astragalus sinicus, or free-living in the soil. The M. huakuii 7653R genome has recently been sequenced. To better understand the complex biochemical and developmental changes that occur in 7653R during bacteroid development, RNA-Seq and Microarrays were used to investigate the differential transcriptomes of 7653R bacteroids and free-living cells. The two approaches identified several thousand differentially expressed genes. The most prominent up-regulation occurred in the symbiosis plasmids, meanwhile gene expression is concentrated to a set of genes (clusters) in bacteroids to fulfill corresponding functional requirements. The results suggested that the main energy metabolism is active while fatty acid metabolism is inactive in bacteroid and that most of genes relevant to cell cycle are down-regulated accordingly. For a global analysis, we reconstructed a protein-protein interaction (PPI) network for 7653R and integrated gene expression data into the network using Cytoscape. A highly inter-connected subnetwork, with function enrichment for nitrogen fixation, was found, and a set of hubs and previously uncharacterized genes participating in nitrogen fixation were identified. The results described here provide a broader biological landscape and novel insights that elucidate rhizobial bacteroid differentiation, nitrogen fixation and related novel gene functions.
Pre-eclampsia (PE) is thought to be a pregnancy-induced autoimmune disease. Despite several strategies carried out for targeting specific factors relevant to its pathogenesis, PE remains potentially fatal to some patients. Here, we reported a way to isolate mesenchymal stem cells (MSCs) from decidua. The MSCs not only exhibited differentiation and self-renewal capacities, they also possessed immunomodulatory functions and secreted some soluble mediators including IL-6, TGF-β, IDO, VEGF and COX-2. Most importantly, the MSCs were specifically provided with the ability to suppress T cells proliferation by IDO in response to inflammatory cytokine IFN-γ. Moreover, we developed a Th1 cell-induced PE mouse model which displayed a high level of pathogenesis factor TNF-α. Strikingly, MSCs-based therapy significantly ameliorated both clinical and histopathological severity of PE symptoms including decreasing the blood pressure and proteinuria, suppressing glomerulonephritis, protecting the feto-placental development. The therapy also reversed abnormal TNF-α expression in uterine and splenic lymphocytes. These data suggest that MSCs may ameliorate Th1-induced PE-like symptoms in mice via the suppression of TNF-α and MSCs-based therapy may provide a potential novel method for PE.
Geographic barriers and Quaternary climate changes are two major forces driving the evolution, speciation, and genetic structuring of extant organisms. In this study, we used Pinus armandii and eleven other Asian white pines (subsection Strobus, subgenus Pinus) to explore the influences of geographic factors and Pleistocene climatic oscillations on species in South China, a region known to be centers of plant endemism and biodiversity hotspots. Range-wide patterns of genetic variation were investigated using chloroplast and mitochondrial DNA markers, with extensive sampling throughout the entire range of P. armandii. Both cpDNA and mtDNA revealed that P. armandii exhibits high levels of genetic diversity and significant population differentiation. Three geographically distinct subdivisions corresponding to the Qinling-Daba Mountains (QDM), Himalaya-Hengduan Mountains (HHM) and Yungui Plateau (YGP) were revealed in mainland China by cpDNA. Their break zone was located in the southeastern margin of the Qinghai-Tibetan Plateau (QTP). A series of massive mountains, induced by the QTP uplift, imposed significant geographic barriers to genetic exchange. The disjunct distribution patterns of ancestral haplotypes suggest that a large continuous population of the white pines may have existed from southwest to subtropical China. Repeated range shifts in response to the Pleistocene glaciations led to the isolation and diversification of the subtropical species. The two Taiwanese white pines share a common ancestor with the species in mainland China and obtain their chloroplasts via long-distance pollen dispersal from North Asian pines. Distinct genetic patterns were detected in populations from the Qinling-Daba Mountains, Yungui Plateau, Himalaya-Hengduan Mountains, and subtropical China, indicating significant contributions of geographic factors to the genetic differentiation in white pines. Our study depicts a clear picture of the evolutionary history of Chinese white pines and highlights the heterogeneous contributions of geography and Pleistocene climatic fluctuations to the extremely high plant species diversity and endemism in South China.
Apoptosis resistance is a hallmark of human cancer. Research in the last two decades has identified key regulators of apoptosis, including inhibitor of apoptosis proteins (IAPs). These critical apoptosis regulators have been targeted for the development of new cancer therapeutics. In this article, we will discuss three members of IAP proteins, namely XIAP, cIAP1 and cIAP2, as cancer therapeutic targets and the progress made in developing new cancer therapeutic agents to target these IAP proteins.
Bcl-2 and Bcl-xL anti-apoptotic proteins are attractive cancer therapeutic targets. We have previously reported the design of 4,5-diphenyl-1H-pyrrole-3-carboxylic acids as a class of potent Bcl-2/Bcl-xL inhibitors. In the present study, we report our structure-based optimization for this class of compounds based upon the crystal structure of Bcl-xL complexed with a potent lead compound. Our efforts accumulated into the design of compound 30 (BM-957), which binds to Bcl-2 and Bcl-xL with Ki <1 nM and has low nanomolar IC50 values in cell growth inhibition in cancer cell lines. Significantly, compound 30 achieves rapid, complete and durable tumor regression in the H146 small-cell lung cancer xenograft model at a well-tolerated dose-schedule.
In the intrinsic pathway of apoptosis, cell-damaging signals promote the release of cytochrome c from mitochondria, triggering activation of the Apaf-1 and caspase-9 apoptosome. The ubiquitin E3 ligase MDM2 decreases the stability of the proapoptotic factor p53. We show that it also coordinated apoptotic events in a p53-independent manner by ubiquitylating the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. HUWE1 ubiquitylates the antiapoptotic factor Mcl-1, and we found that HUWE1 also ubiquitylated PP5 (protein phosphatase 5), which indirectly inhibited apoptosome activation. Breast cancers that are positive for the tyrosine receptor kinase HER2 (human epidermal growth factor receptor 2) tend to be highly aggressive. In HER2-positive breast cancer cells treated with the HER2 tyrosine kinase inhibitor lapatinib, MDM2 was degraded and HUWE1 was stabilized. In contrast, in breast cancer cells that acquired resistance to lapatinib, the abundance of MDM2 was not decreased and HUWE1 was degraded, which inhibited apoptosis, regardless of p53 status. MDM2 inhibition overcame lapatinib resistance in cells with either wild-type or mutant p53 and in xenograft models. These findings demonstrate broader, p53-independent roles for MDM2 and HUWE1 in apoptosis and specifically suggest the potential for therapy directed against MDM2 to overcome lapatinib resistance.
Bcl-2 and Bcl-xL are key apoptosis regulators and attractive cancer therapeutic targets. We have designed and optimized a class of small-molecule inhibitors of Bcl-2 and Bcl-xL containing a 4,5-diphenyl-1H-pyrrole-3-carboxylic acid core structure. A 1.4 Å resolution crystal structure of a lead compound, 12, complexed with Bcl-xL has provided a basis for our optimization. The most potent compounds, 14 and 15, bind to Bcl-2 and Bcl-xL with subnanomolar Ki values and are potent antagonists of Bcl-2 and Bcl-xL in functional assays. Compounds 14 and 15 inhibit cell growth with low nanomolar IC50 values in multiple small-cell lung cancer cell lines and induce robust apoptosis in cancer cells at concentrations as low as 10 nM. Compound 14 also achieves strong antitumor activity in an animal model of human cancer.
Employing a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. An initial lead compound with a new scaffold was designed based upon the crystal structure of Bcl-xL and FDA-approved drugs and was found to have an affinity of 100 μM to both Bcl-2 and Bcl-xL. Linking this weak lead to another weak-affinity fragment derived from Abbott's ABT-737 led to an improvement of the binding affinity by a factor of >10,000. Further optimization ultimately yielded compounds with subnanomolar binding affinities to both Bcl-2 and Bcl-xL and potent cellular activity. The best compound (21) binds to Bcl-xL and Bcl-2 with Ki < 1 nM, inhibits cell growth in the H146 and H1417 small-cell lung cancer cell lines with IC50 values of 60–90 nM and induces robust cell death in the H146 cancer cell line at 30–100 nM.
Mitochondrial outer membrane permeabilization (MOMP) is a crucial step leading to apoptotic destruction of cancer cells. Bcl-2 family proteins delicately regulate mitochondrial outer membrane integrity through protein-protein interactions, which makes the mitochondrion an ideal cell-free system for screening molecules targeting the Bcl-2 anti-apoptotic proteins. But assay conditions need to be optimized for more reliable results. In this study, we aimed at establishing a reliable functional assay using mitochondria isolated from breast cancer cells to decipher the mode of action of BH3 peptides derived from BH3-only proteins. In this study, high ionic strength buffer was adopted during the initiation of MOMP. Mitochondria isolated from human breast cancer cell lines with distinct expression patterns of Bcl-2 anti-apoptotic proteins were permeabilized by different BH3 peptides alone or in combination, with or without the presence of recombinant anti-apoptotic Bcl-2 family proteins. Cytochrome C and Smac/Diablo were tested in both supernatants and mitochondrial pellets by Western blotting.
Sufficient ionic strength was required for optimal release of Cytochrome C. Bad and Noxa BH3 peptides exhibited their bona fide antagonistic effects against Bcl-2/Bcl-xL and Mcl-1 proteins, respectively, whereas Bim BH3 peptide antagonized all three anti-apoptotic Bcl-2 members. Bad and Noxa peptides synergized with each other in the induction of MOMP when mitochondria were dually protected by both Bcl-2/Bcl-xL and Mcl-1.
This method based on MOMP is a useful screening tool for identifying BH3 mimetics with selective toxicity against breast cancer cell mitochondria protected by the three major Bcl-2 anti-apoptotic proteins.
Mitochondrion; B cell lymphoma 2 (Bcl-2); Bcl-2 homolog domain 3 (BH3); Mitochondrial outer membrane permeabilization (MOMP)
Research on the human urine proteome may lay the foundation for the discovery of relevant disease biomarkers. Post-translational modifications (PTMs) have important effects on the functions of protein biomarkers. Identifying PTMs without enrichment adds no extra steps to conventional identification procedures for urine proteomics. The only difference is that this method requires software that can conduct unrestrictive identifications of PTMs. In this study, routine urine proteomics techniques were used to identify urine proteins. Unspecified PTMs were searched by MODa and PEAKS 6 automated software, followed by a manual search to screen out in vivo PTMs by removing all in vitro PTMs and amino acid substitutions.
There were 75 peptides with 6 in vivo PTMs that were found by both MODa and PEAKS 6. Of these, 34 peptides in 18 proteins have novel in vivo PTMs compared with the annotation information of these proteins on the Universal Protein Resource website. These new in vivo PTMs had undergone methylation, dehydration, oxidation, hydroxylation, phosphorylation, or dihydroxylation.
In this study, we identified PTMs of urine proteins without the need for enrichment. Our investigation may provide a useful reference for biomarker discovery in the future.
Urine proteomics; MODa; PEAKS 6; PTMs without enrichment; In vivo PTMs
We report the discovery and characterization of SM-406 (compound 2), a potent and orally bioavailable Smac mimetic and an antagonist of the inhibitor of apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1 and cIAP2 proteins with Ki values of 66.4 nM, 1.9 nM and 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in a cell-free functional assay, induces rapid degradation of cellular cIAP1 protein and inhibits cancer cell growth in various human cancer cell lines. It has good oral bioavailability in mice, rats, non-human primates and dogs, is highly effective in induction of apoptosis in xenograft tumors and is capable of complete inhibition of tumor growth. Compound 2 is currently in Phase I clinical trials for the treatment of human cancer.
Mesenchymal stem cells (MSCs) have been used experimentally for treating inflammatory disorders, partly due to their immunosuppressive properties. Although interleukin-1β (IL-1β) is one of the most important inflammatory mediators, growing evidence indicates that IL-1β signaling elicits the immunosuppressive properties of MSCs. However, it remains unclear how IL-1β signaling accomplishes this activity. Here, we focus on the therapeutic efficacy of IL-1β-primed MSCs in the dextran sulfate sodium (DSS)-induced colitis model, in addition to the underlining mechanisms. We first found that IL-1β-primed MSCs, without any observable phenotype change in vitro, significantly attenuated the development of DSS-induced murine colitis. Moreover, IL-1β-primed MSCs modulated the balance of immune cells in the spleen and the mesenteric lymph nodes (MLNs) through elevating cyclooxygenase-2 (COX-2), IL-6 and IL-8 expression and influencing the polarization of peritoneal macrophages. Importantly, IL-1β-primed MSCs possessed an enhanced ability to migrate to the inflammatory site of the gut via upregulation of chemokine receptor type 4 (CXCR4) expression. In summary, IL-1β-primed MSCs have improved efficacy in treating DSS-induced colitis, which at least partly depends on their increased immunosuppressive capacities and enhanced migration ability.
IL-1β; mesenchymal stem cells; ulcerative colitis
The variable-stiffness colonoscope (VSC) appears to have advantages over the standard adult colonoscope (SAC), although data are conflicting. To provide a comprehensive up-to-date review, we conducted a meta-analysis to compare the efficacies of the VSC and SAC.
Electronic databases, including PubMed, EMBASE, the Cochrane library and the Science Citation Index, were searched to retrieve relevant trials. In addition, meeting abstracts and the reference lists of retrieved articles were reviewed for further relevant studies.
Eight randomized controlled trials (RCTs), enrolling a total of 2033 patients, were included in the meta-analysis. There was no significant heterogeneity among these studies. The cecal intubation rate was higher with the use of VSC (RR = 1.03, 95% CI 1.01 to 1.06, 8 RCTs). The VSC was also associated with fewer position changes made during colonoscopy. Time to cecal intubation was similar with VSC and SAC (WMD −0.54, 95% CI −1.40 to 0.32) but shorter in subgroup analysis with the use of VSC (WMD = −1.36, 95% CI −2.29 to −0.43). Sedation dose used with the two types of instruments showed no evidence of differences either. For all trials, only patients were blinded because of the nature of the interventions.
Use of the VSC significantly improved the cecal intubation rate and reduced ancillary maneuvers made during the procedure. Cecal intubation time was similar for the two colonoscope types over all trials, whereas a shortened time with the use of the adult VSC was seen in subgroup analysis.
Colonoscope; Variable-stiffness colonoscope; Stiffness; Meta-analysis
We have synthesized and evaluated a series of non-peptidic, bivalent Smac mimetics as antagonists of the inhibitor of apoptosis proteins and new anticancer agents. All these bivalent Smac mimetics bind to full-length XIAP with low nanomolar affinities and function as ultra-potent antagonists of XIAP. While these Smac mimetics bind to cIAP1/2 with similar low nanomolar affinities, their potencies to induce degradation of cIAP1/2 proteins in cells differ by more than 100-fold. The most potent bivalent Smac mimetics inhibit cell growth with IC50 values from 1–3 nM in the MDA-MB-231 breast cancer cell line and are 100-times more potent than the least potent compounds. Determination of intracellular concentrations for several representative compounds showed that the linkers in these bivalent Smac mimetics significantly affect their intracellular concentrations, hence the overall cellular activity. Compound 27 completely inhibits tumor growth in the MDA-MB-231 xenografts, while causing no signs of toxicity in the animals.
Antenatal ultrasound scan is a widely accepted component of antenatal care. Studies have looked at the relationship between ultrasound scanning and caesarean section (CS) in certain groups of women in China. However, there are limited data on the utilization of antenatal ultrasound scanning in the general population, including its association with CS. The purpose of this study is to describe the utilization of antenatal ultrasound screening in rural Eastern China and to explore the association between antenatal ultrasound scan and uptake of CS.
Based on a cluster randomized sample, a total of 2326 women with childbirth participated in the study. A household survey was conducted to collect socio-economic information, obstetric history and utilization of maternal health services.
Coverage of antenatal care was 96.8% (2251/2326). During antenatal care, 96.1% (2164/2251) women received ultrasound screening and the reported average number was 2.55. 46.8% women received at least 3 ultrasound scans and the maximum number reached 11. The CS rate was found to be 54.8% (1275/2326). After adjusting for socio-demographic and clinical variables, it showed a statistically significant association between antenatal ultrasound scans and uptake of CS by multivariate logistic regression model. High husband education level, high maternal age, having previous adverse pregnant outcome and pregnancy complications during the index pregnancy were also found to be risk factors of choosing a CS.
A high use of antenatal ultrasound scan in rural Eastern China is found and is influenced by socio-demographic and clinical factors. Evidence-based guidelines for antenatal ultrasound scans need to be developed and disseminated to clinicians including physicians, nurses and sonographers. Guidance about the appropriate use of ultrasound scans should also be shared with women in order to discourage unreasonable expectations and demands. It is important to monitor the use of antenatal ultrasound scan as well as the indications for caesarean section in rural China.
Ultrasonography; Prenatal; Caesarean Section; Rural Health; China