IMPORTANCE: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of ...relapse and death are needed. OBJECTIVE: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. INTERVENTIONS: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. MAIN OUTCOMES AND MEASURES: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. RESULTS: Among 443 women who were randomized, 434 were included in the full analysis set (mean SD age, 46 9.9 years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio HR for risk of recurrence or death, 0.64 95% CI, 0.42-0.95; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 95% CI, 0.38-0.92; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 95% CI, 0.47-1.19; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 95% CI, 0.46-1.13; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. CONCLUSIONS AND RELEVANCE: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01112826
Dentineogenesis starts on odontoblasts, which synthesise and secrete non-collagenous proteins (NCPs) and collagen. When dentine is injured, dental pulp progenitors/mesenchymal stem cells (MSCs) can ...migrate to the injured area, differentiate into odontoblasts and facilitate formation of reactionary dentine. Dental pulp progenitor cell/MSC differentiation is controlled at given niches. Among dental NCPs, dentine sialophosphoprotein (DSPP) is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family, whose members share common biochemical characteristics such as an Arg-Gly-Asp (RGD) motif. DSPP expression is cell- and tissue-specific and highly seen in odontoblasts and dentine. DSPP mutations cause hereditary dentine diseases. DSPP is catalysed into dentine glycoprotein (DGP)/sialoprotein (DSP) and phosphoprotein (DPP) by proteolysis. DSP is further processed towards active molecules. DPP contains an RGD motif and abundant Ser-Asp/Asp-Ser repeat regions. DPP-RGD motif binds to integrin αVβ3 and activates intracellular signalling via mitogen-activated protein kinase (MAPK) and focal adhesion kinase (FAK)-ERK pathways. Unlike other SIBLING proteins, DPP lacks the RGD motif in some species. However, DPP Ser-Asp/Asp-Ser repeat regions bind to calcium-phosphate deposits and promote hydroxyapatite crystal growth and mineralisation via calmodulin-dependent protein kinase II (CaMKII) cascades. DSP lacks the RGD site but contains signal peptides. The tripeptides of the signal domains interact with cargo receptors within the endoplasmic reticulum that facilitate transport of DSPP from the endoplasmic reticulum to the extracellular matrix. Furthermore, the middle- and COOH-terminal regions of DSP bind to cellular membrane receptors, integrin β6 and occludin, inducing cell differentiation. The present review may shed light on DSPP roles during odontogenesis.
Summary
Background
The patatin‐like phospholipase 3 (PNPLA3) rs738409 gene polymorphism is an important genetic determinant of non‐alcoholic fatty liver disease (NAFLD). However, the associations ...between liver fat and metabolic traits in rs738409 G allele carriers and the allelic influence on this association have not been fully studied.
Aim
To investigate the influence of the PNPLA3 gene polymorphism on the association of liver fat with serum metabolic factors and carotid atherosclerosis.
Methods
Liver fat was measured by quantitative ultrasound in 4300 subjects in the Shanghai Changfeng community and analysed for its association with obesity and metabolic factors in individuals with the PNPLA3 CC, CG and GG genotypes.
Results
Non‐alcoholic fatty liver disease occurred in 37.9% and 28.8% of the subjects with the GG and CC genotypes respectively (P < 0.001). Liver fat was significantly associated with body mass index, waist circumference, serum triglycerides, high‐density lipoprotein cholesterol, fasting blood glucose and insulin in the PNPLA3 rs738409 G allele carriers (P < 0.001). Compared with the CC homozygotes, the GG homozygotes presented higher liver fat and liver fibrosis scores despite their better metabolic status (comparison of regression line slopes, P < 0.05). An increase in liver fat was accompanied by a significant increase in the average and maximum carotid intima‐media thickness in subjects with the PNPLA3 CC genotype but not in those with the GG genotype.
Conclusions
PNPLA3 rs738409 G allele carriers were found to be more susceptible to the metabolic‐related hepatic steatosis, and developed NAFLD and liver fibrosis despite presenting relatively better metabolic statuses and lower risks for carotid atherosclerosis.
The slow afterhyperpolarization that follows an action potential is generated by the activation of small-conductance calcium-activated potassium channels (SK channels). The slow ...afterhyperpolarization limits the firing frequency of repetitive action potentials (spike-frequency adaption) and is essential for normal neurotransmission. SK channels are voltage-independent and activated by submicromolar concentrations of intracellular calcium. They are high-affinity calcium sensors that transduce fluctuations in intracellular calcium concentrations into changes in membrane potential. Here we study the mechanism of calcium gating and find that SK channels are not gated by calcium binding directly to the channel α-subunits. Instead, the functional SK channels are heteromeric complexes with calmodulin, which is constitutively associated with the α-subunits in a calcium-independent manner. Our data support a model in which calcium gating of SK channels is mediated by binding of calcium to calmodulin and subsequent conformational alterations in the channel protein.
Pre-harvest sprouting (PHS) of wheat reduces the quality of wheat grain, and improving PHS tolerance is a priority in certain wheat growing regions where conditions favorable for PHS exist. Two new ...Viviparous-1 allelic variants related to PHS tolerance were investigated on B genome of bread wheat, and designated as Vp-1Bb and Vp-1Bc, respectively. Sequence analysis showed that Vp-1Bb and Vp-1Bc had an insertion of 193-bp and a deletion of 83-bp fragment, respectively, located in the third intron region of the Vp-1B gene. The insertion and deletion affected the expression level of the Vp1 at mature seed stage, more correctly spliced transcripts were observed from the genotypes with either insertion or deletion than that of the wild type. Based on these insertions and deletions, a co-dominant STS marker of Vp-1B gene was developed and designated as Vp1B3, which in most cases could amplify either 845 or 569-bp fragment from the tolerant cultivars, and 652-bp from the susceptible ones. This Vp1B3 marker was mapped to chromosome 3BL using a set of Chinese Spring nulli-tetrasomic and ditelosomic lines. A total of 89 white-grained Chinese wheat cultivars and advanced lines, were used to validate the relationship between the polymorphic fragments of Vp1B3 and PHS tolerance. Statistical analysis indicated that Vp1B3 was strongly associated with PHS tolerance in this set of Chinese germplasm, suggesting that Vp1B3 could be used as an efficient and reliable co-dominant marker in the evaluation of wheat germplasm for PHS tolerance and marker-assisted breeding for PHS tolerant cultivars.
• Sewage sludge-based adsorbent (SZ) was prepared via microwave irradiation. • The SZ adsorbent had a regular and highly porous surface. • The relative price of SZ is much lower than that of ...commercial activated carbons. • The SZ is an alternative adsorbent for the removal of Cu
2+ from water.
The materials with adsorbent properties were produced from urban sewage sludge by two different procedures via microwave irradiation: (1) by one single pyrolysis stage (SC); (2) by chemical activation with ZnCl
2 (SZ). The BET, SEM and FT-IR have been used to evaluate the pore structural parameters and surface chemistry of the adsorbents, respectively. Subsequently they were used for adsorption of Cu(II) from aqueous solutions. The effects of various experimental parameters, such as pH, temperature were investigated in a batch-adsorption technique. The results showed that the adsorption of Cu(II) was maximal at pH 5.0. The kinetic study demonstrated that the adsorption process was followed the second-order kinetic equation. The experimental adsorption isotherm data were well fitted with Langmuir model and the maximum adsorption capacity of Cu(II) were found to be 3.88 and 10.56
mg/g for SC and SZ, respectively, in the solution of pH 5.0. Thermodynamic parameters such as changes in the enthalpy (Δ
H
0), entropy (Δ
S
0) and free energy (Δ
G
0) indicate that Cu(II) adsorption onto SC and SZ is an endothermic and spontaneous process in nature at 15–45
°C. These results indicate that the sewage sludge-derived material via microwave induced ZnCl
2 activation is an effective and alternative adsorbent for the removal of Cu(II) from aqueous solution.
Sulphur bioconversion in landfill cover soils, including the metabolism of sulphur‐oxidizing bacteria (SOB) and sulphate‐reducing bacteria (SRB), is one of the important processes affecting H₂S ...emission from landfills. In this study, two landfills with or without landfill gas collection and utilization system were investigated to characterize the role of biotic and abiotic factors affecting diversity and activity of SOB and SRB in the landfill cover soils. The results revealed that the potential sulphur oxidation rates (SORs) and sulphate reduction rates (SRRs) varied with landfill sites and depths. SOR was significantly correlated with pH and SO₄ ²⁻, while SRR was significantly related with pH. The populations of both SOB and SRB were low in the acidic landfill cover soils (pH = 4·7–5·37). Cloning and terminal restriction fragment length polymorphism profiles of soxB and dsrB showed that SOB including Halothiobacillus, Thiobacillus, Thiovirga and Bradyrhizobium, and SRB including Desulfobacca, Desulforhabdus and Syntrophobacter dominated in the landfill cover soils, and their distributions were affected mainly by pH value and organic matter contents of soils. SIGNIFICANCE AND IMPACT OF THE STUDY: High diversity of sulphur‐oxidizing bacteria (SOB) and sulphate‐reducing bacteria (SRB) presented in the landfill cover soils. Among the physicochemical properties of soils (moisture content, pH, organic materials, SO₄ ²⁻, acid volatile sulphide and total sulphur), pH was the most important factor affecting the diversity and activity of SOB and SRB in the landfill cover soils. Higher pH of landfill cover soils (i.e. neutral or slight alkaline) was favourable for the growth of SOB and SRB, leading to a rapid bioconversion of sulphur. These findings are helpful to optimize sulphur biotransformation in landfill cover soils and to control odour pollution at landfills.
Aim: Thalassaemia is a good candidate disease for control by preventive genetic programmes in developing countries. Accurate population frequency data are needed for planning the control of ...thalassaemia in the high risk Guangdong Province of southern China. Methods: In total, 13 397 consecutive samples from five geographical areas of Guangdong Province were analysed for both haematological and molecular parameters. Results: There was a high prevalence of carriers of α thalassaemia (8.53%), β thalassaemia (2.54%), and both α and β thalassaemia (0.26%). Overall, 11.07% of the population in this area were heterozygous carriers of α and β thalassaemia. The mutation spectrum of α and β thalassaemia and its constitution were fully described in this area. This study reports the true prevalence of silent α thalassaemia in the southern China population for the first time. In addition, two novel mutations that give rise to α thalassaemia, one deletion resulting in β thalassaemia, and a rare deletion (−−THAI allele) previously unreported in mainland China were detected. The frequency of the most common mutation, the Southeast Asian type of deletion (−−SEA, accounting for 48.54% of all α thalassaemias) was similar to the total of two α+ thalassaemia deletions (−α3.7 and −α4.2, accounting for 47.49% of α thalassaemia). Conclusion: Both α and β thalassaemia are widely distributed in Guangdong Province of China. The knowledge gained in this study will enable the projected number of pregnancies at risk to be estimated and a screening strategy for control of thalassaemia to be designed in this area.
Agents designed to block or alter cytokinesis can kill or stop proliferation of cancer cells. We aimed to identify cytokinesis-related proteins that are overexpressed in hepatocellular carcinoma ...(HCC) cells and might be targeted to slow liver tumor growth.
Using the Oncomine database, we compared the gene expression patterns in 16 cancer microarray datasets and assessed gene enrichment sets using gene ontology. We performed immunohistochemical analysis of an HCC tissue microarray and identified changes in protein levels that are associated with patient survival times. Candidate genes were overexpressed or knocked down with small hairpin RNAs in SMMC7721, MHCC97H, or HCCLM3 cell lines; we analyzed their proliferation, viability, and clone-formation ability and their growth as subcutaneous or orthotopic xenograft tumors in mice. We performed microarray analyses to identify alterations in signaling pathways and immunoblot and immunofluorescence assays to detect and localize proteins in tissues. Yeast 2-hybrid screens and mass spectrometry combined with co-immunoprecipitation experiments were used to identify binding proteins. Protein interactions were validated with co-immunoprecipitation and proximity ligation assays. Chromatin immunoprecipitation, promoter luciferase activity, and quantitative real-time polymerase chain reaction analyses were used to identify factors that regulate transcription of specific genes.
The genes that were most frequently overexpressed in different types of cancer cells were involved in cell division processes. We identified 3 cytokinesis-regulatory proteins among the 10 genes most frequently overexpressed by all cancer cell types. Rac GTPase activating protein 1 (RACGAP1) was the cytokinesis-regulatory protein that was most highly overexpressed in multiple cancers. Increased expression of RACGAP1 in tumor tissues was associated with shorter survival times of patients with cancer. Knockdown of RACGAP1 in HCC cells induced cytokinesis failure and cell apoptosis. In microarray analyses, we found knockdown of RACGAP1 in SMMC7721 cells to reduce expression of genes regulated by yes-associated protein (YAP) and WW domain containing transcription regulator 1 (WWTR1 or TAZ). RACGAP1 reduced activation of the Hippo pathway in HCC cells by increasing activity of RhoA and polymerization of filamentous actin. Knockdown of YAP reduced phosphorylation of RACGAP1 and redistribution at the anaphase central spindle. We found transcription of the translocated promoter region, nuclear basket protein (TPR) to be regulated by YAP and coordinately expressed with RACGAP1 to promote proliferation of HCC cells. TPR redistributed upon nuclear envelope breakdown and formed complexes with RACGAP1 during mitosis. Knockdown of TPR in HCC cells reduced phosphorylation of RACGAP1 by aurora kinase B and impaired their redistribution at the central spindle during cytokinesis. STAT3 activated transcription of RACGAP in HCC cells.
In an analysis of gene expression patterns of multiple tumor types, we found RACGAP1 to be frequently overexpressed, which is associated with shorter survival times of patients. RACGAP1 promotes proliferation of HCC cells by reducing activation of the Hippo and YAP pathways and promoting cytokinesis in coordination with TPR.
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Background
It is gradually accepted that solid bolus swallow needs to be added to the procedure of manometry. The motility differences in the upper esophageal sphincter (UES) and lower esophageal ...sphincter (LES) were not well described. Sierra Scientific Instruments solid‐state high‐resolution manometry (HRM) system, the most popular HRM system in China, lacks the Chinese normative values for both liquid and solid bolus swallow parameters.
Methods
The esophageal HRM data of 88 healthy volunteers were analyzed. The parameters of both sphincters in resting stage were summarized and those during solid and liquid swallows were compared.
Key Results
Normative HRM values of sphincter parameters in solid and liquid bolus swallows in China were established. The UES residual pressure of solid bolus swallows was lower than that of liquid bolus (0.3±5.5 mm Hg vs 4.8±5.9 mm Hg, P=.000). The time parameters of UES relaxation between two types of bolus swallows were similar. In solid bolus swallows, the intrabolus pressure (IBP) (13.8±5.1 mm Hg vs 10.9±5.7 mm Hg, P=.000) and LES relaxation time (11.0±2.1 seconds vs 8.7±1.3 seconds, P=.000) were higher. The 4‐second integrated relaxation pressure between both bolus swallows was similar.
Conclusions & Inferences
The function of the UES and LES between solid and liquid bolus swallows is different. Chinese HRM parameters are different from the Chicago Classification (http://www.chictr.org.cn, Number ChiCTR‐EOC‐15007147).
This study demonstrated the motility differences between solid and liquid bolus swallows for both the UES and LES. It confirms the application of HRM with solid swallows. More importantly, this study provides the normative values for both liquid and solid bolus swallows of Sierra Scientific Instruments solid‐state HRM system for Chinese population.
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