Persistent activation of Survivin and its overexpression contribute to the formation, progression and metastasis of several different tumor types. Therefore, Survivin is an ideal target for RNA interference mediated-growth inhibition. Blockade of Survivin using specific short hairpin RNAs (shRNA) can significantly reduce prostate tumor growth. RNA interference does not fully ablate target gene expression, owing to the idiosyncrasies associated with shRNAs and their targets. To enhance the therapeutic efficacy of Survivin-specific shRNA, we employed a combinatorial expression of Survivin-specific shRNA and gene associated with retinoid-interferon-induced mortality-19 (GRIM-19). Then, the GRIM-19 coding sequences and Survivin-specific shRNAs were used to create a dual expression plasmid vector and were carried by an attenuated strain of Salmonella enteric serovar typhimurium (S. typhimurium) to treat prostate cancer in vitro and in vivo. We found that the co-expressed Survivin-specific shRNA and GRIM-19 synergistically and more effectively inhibited prostate tumor proliferation and survival, when compared with treatment with either single agent alone in vitro and in vivo. This study has provided a novel cancer gene therapeutic approach for prostate cancer.
GRIM-19; prostate cancer; RNAi; Salmonella enterica serovar typhimurium; Survivin; tumor cell growth
To explore the neuroprotective effect and optimize the therapeutic dose and time window of picroside II by orthogonal test and the expression of myelin basic protein (MBP) in cerebral ischemic injury in rats. Bilateral common carotid artery occlusion (BCCAO) was used to establish forebrain ischemia models. The successful rat models were grouped according to orthogonal experimental design and injected picroside II intraperitoneally at different ischemic time with different doses. Myelin sheath fast green staining(FGS) and transmission electron microscopy (TEM) were used to observe nerve fiber myelin; the expression of MBP was tested qualitatively and quantitatively by immunohistochemical assay (IHC) and Western blot (WB); Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the transcription level of MBP mRNA.
The protective effect of picroside II was presented by increasing the expression of MBP and decreasing demyelination after cerebral ischemic injury. The best therapeutic time window and dose was (1) ischemia 2.0 h with picroside II 10 mg/kg body weight according to the results of FGS, IHC and WB; (2) ischemia 1.5 h with picroside II 20 mg/kg according to the analysis of RT-PCR.
Given the principle of the longest time window and the lowest therapeutic dose, the optimized therapeutic dose and time window should be injecting picroside II intraperitoneally with 10-20 mg/kg body weight at ischemia 1.5-2.0 h in cerebral ischemic injury.
Picroside II; Therapeutic dose; Time window; Cerebral ischemia; MBP; Rats
In the X-ray repair cross-complementing group 1 (XRCC1) gene, a polymorphism, Arg399Gln (rs25487), has been shown to change neoconservative amino acid and thus result in alternation of DNA repair capacity. Numerous studies have investigated the association between Arg399Gln and breast cancer risk in the American population, but yielding inconsistent results. This study aimed to clarify the role of this polymorphism in susceptibility to breast cancer.
Literatures were searched in multiple databases including PubMed, Springer Link, Ovid, EBSCO and ScienceDirect databases up to April 2013. A comprehensive meta-analysis was conducted to estimate the overall odds ratio (OR), by integrating data from 18 case control studies of 10846 cases and 11723 controls in the American population.
Overall, significant association was observed between the Arg399Gln polymorphism and breast cancer risk under the random-effects model (OR for dominant model = 1.12, 95% CI: 1.02–1.24, Pheterogeneity = 0.003; OR for additive model = 1.07, 95% CI: 1.01–1.14, Pheterogeneity = 0.017). Further sensitivity analysis supported the robust stability of this current result by showing similar ORs before and after removal of a single study.
This meta-analysis suggests that the XRCC1 Arg399Gln polymorphism may significantly contribute to susceptibility of breast cancer in the American population.
Various computational models have been developed to transfer annotations of gene essentiality between organisms. However, despite the increasing number of microorganisms with well-characterized sets of essential genes, selection of appropriate training sets for predicting the essential genes of poorly-studied or newly sequenced organisms remains challenging. In this study, a machine learning approach was applied reciprocally to predict the essential genes in 21 microorganisms. Results showed that training set selection greatly influenced predictive accuracy. We determined four criteria for training set selection: (1) essential genes in the selected training set should be reliable; (2) the growth conditions in which essential genes are defined should be consistent in training and prediction sets; (3) species used as training set should be closely related to the target organism; and (4) organisms used as training and prediction sets should exhibit similar phenotypes or lifestyles. We then analyzed the performance of an incomplete training set and an integrated training set with multiple organisms. We found that the size of the training set should be at least 10% of the total genes to yield accurate predictions. Additionally, the integrated training sets exhibited remarkable increase in stability and accuracy compared with single sets. Finally, we compared the performance of the integrated training sets with the four criteria and with random selection. The results revealed that a rational selection of training sets based on our criteria yields better performance than random selection. Thus, our results provide empirical guidance on training set selection for the identification of essential genes on a genome-wide scale.
Flying fishes are extraordinary aquatic vertebrates capable of gliding great distances over water by exploiting their enlarged pectoral fins and asymmetrical caudal fin. Some 50 species of extant flying fishes are classified in the Exocoetidae (Neopterygii: Teleostei), which have a fossil record no older than the Eocene. The Thoracopteridae is the only pre-Cenozoic group of non-teleosts that shows an array of features associated with the capability of over-water gliding. Until recently, however, the fossil record of the Thoracopteridae has been limited to the Upper Triassic of Austria and Italy. Here, we report the discovery of exceptionally well-preserved fossils of a new thoracopterid flying fish from the Middle Triassic of China, which represents the earliest evidence of an over-water gliding strategy in vertebrates. The results of a phylogenetic analysis resolve the Thoracopteridae as a stem-group of the Neopterygii that is more crown-ward than the Peltopleuriformes, yet more basal than the Luganoiiformes. As the first record of the Thoracopteride in Asia, this new discovery extends the geographical distribution of this group from the western to eastern rim of the Palaeotethys Ocean, providing new evidence to support the Triassic biological exchanges between Europe and southern China. Additionally, the Middle Triassic date of the new thoracopterid supports the hypothesis that the re-establishment of marine ecosystems after end-Permian mass extinction is more rapid than previously thought.
Thoracopteridae; Exocoetidae; flying fish; predator-driven evolution; Triassic
Supportive therapy is recommended before laboratory confirmation of this disease.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in China. The incidence and clinical and laboratory characteristics of SFTS are not clearly defined. During May 22–October 2, 2011, a total of 24 patients with fever, thrombocytopenia, and leukopenia were clinically diagnosed as having SFTS in Yiyuan County, Shandong Province, China. We conducted laboratory tests for these SFTS patients. SFTS virus (SFTSV) infection was confirmed in 22 patients by using reverse transcription PCR and ELISA by acute-phase and convalescent-phase serum samples. Clinical and laboratory manifestations included fever (100%), gastrointestinal symptoms (91%), myalgia (55%), chills (41%), thrombocytopenia (100%), and leukopenia (95%).
severe fever with thrombocytopenia syndrome; SFTS; severe fever with thrombocytopenia syndrome virus; SFTSV; viruses; bunyavirus; epidemiology; clinical characteristics; laboratory characteristics; Shandong Province; China
In this study, 24 standard nontuberculous mycobacteria (NTM) species strains including 12 slowly growing mycobacteria strains and 12 rapidly growing mycobacteria strains were subjected to drug susceptibility testing using microplate Alamar Blue assay-based 7H9 broth. The most active antimicrobial agents against the 24 NTM strains were streptomycin, amikacin, the fluoroquinolones, and the tetracyclines. Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium bolletii, and Mycobacterium simiae are resistant to most antimicrobial agents. The susceptibility results of this study from 24 NTM standard strains can be referenced by clinicians before susceptibility testing for clinical isolates is performed or when conditions do not allow for susceptibility testing. The application of broth-based methods is recommended by the Clinical and Laboratory Standards Institute, and the documentation of the susceptibility patterns of standard strains of mycobacteria can improve the international standardization of susceptibility testing methods.
Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease; therefore, an accurate molecular diagnosis is essential for appropriate disease treatment and family planning. The prevalence of RP in China had been reported at 1 in 3800, resulting in an estimated total of 340,000 Chinese RP patients. However, genetic studies of Chinese RP patients have been very limited. To date, no comprehensive molecular diagnosis has been done for Chinese RP patients. With the emergence of next-generation sequencing (NGS), comprehensive molecular diagnosis of RP is now within reach. The purpose of this study was to perform the first NGS-based comprehensive molecular diagnosis for Chinese RP patients.
Thirty-one well-characterized autosomal recessive RP (arRP) families were recruited. For each family, the DNA sample from one affected member was sequenced using our custom capture panel, which includes 163 retinal disease genes. Variants were called, filtered, and annotated by our in-house automatic pipeline.
Twelve arRP families were successfully molecular diagnosed, achieving a diagnostic rate of approximately 40%. Interestingly, approximately 63% of the pathogenic mutations we identified are novel, which is higher than that observed in a similar study on European descent (45%). Moreover, the clinical diagnoses of two families were refined based on the pathogenic mutations identified in the patients.
We conclude that comprehensive molecular diagnosis can be vital for an accurate clinical diagnosis of RP. Applying this tool on patients from different ethnic groups is essential for enhancing our knowledge of the global spectrum of RP disease-causing mutations.
Next-generation sequencing–based comprehensive molecular diagnosis of 31 families with autosomal recessive retinitis pigmentosa (arRP) was performed. This is the first such study of a Chinese arRP patient cohort, revealing a total of 10 novel putatively pathogenic mutations.
retinitis pigmentosa; next-generation sequencing; molecular diagnosis; Chinese population
Small field dosimetry is challenging due to the finite size of the conventional detectors that underestimate the dose distribution. With the fast development of the dynamic proton beam delivery system, it is essential to find a dosimeter which can be used for 3D dosimetry of small proton fields. We investigated the feasibility of using a proton formula PRESAGE® for 3D dosimetry of small fields in a uniform scanning proton beam delivery system with dose layer stacking technology. The relationship between optical density and the absorbed dose was found to be linear through small volume cuvette studies for both photon and proton irradiation. Two circular fields and three patient-specific fields were used for proton treatment planning calculation and beam delivery. The measured results were compared with the calculated results in the form of lateral dose profiles, depth dose, isodose plots and gamma index analysis. For the circular field study, lateral dose profile comparison showed that the relative PRESAGE® profile falls within ± 5% from the calculated profile for most of the spatial range. For unmodulated depth dose comparison, the agreement between the measured and calculated results was within 3% in the beam entrance region before the Bragg peak. However, at the Bragg peak, there was about 20% underestimation of the absorbed dose from PRESAGE®. For patient-specific field 3D dosimetry, most of the data points within the target volume passed gamma analysis for 3% relative dose difference and 3 mm distance to agreement criteria. Our results suggest that this proton formula PRESAGE® dosimeter has the potential for 3D dosimetry of small fields in proton therapy, but further investigation is needed to improve the dose under-response of the PRESAGE® in the Bragg peak region.
Improving the early prediction and detection of diabetic nephropathy (DN) remains a great challenge in disease management. The aim of this study was to evaluate the early detection power of urinary vitamin D-binding protein (VDBP) for the diagnosis of DN. Urine samples were obtained from 45 healthy volunteers and 105 diabetic patients with normoalbuminuria (DM group), microalbuminuria (DN1 group) and macroalbuminuria (DN2 group) (n=35 per group). The VDBP expression patterns in urine from patients and controls were quantified by western blot analysis. The excretion levels of urinary VDBP were quantified with enzyme-linked immunosorbent assay. The quantification results were obtained by correcting for creatinine expression and showed that urinary VDBP levels were significantly elevated in the patients of the DN1 and DN2 groups compared with those of the DM group and normal controls (1,011.33±325.30 and 1,406.34±239.66 compared with 466.54±213.63 and 125.48±98.27 ng/mg, respectively) (P<0.001). Receiver operating characteristic analysis of urinary VDBP levels for the diagnosis of DN rendered an optimum cut-off value of 552.243 ng/mg corresponding to 92.86% sensitivity and 85.00% specificity, which also showed an area under the ROC curve of 0.966. In conclusion, the findings of the present study suggest that urinary VDBP may be a potential biomarker for the early detection and prevention of DN. Further studies are required to examine the pathogenic mechanisms of elevated VDBP levels and their role in the diagnosis of DN.
vitamin D binding protein; urine; diabetic nephropathy
We previously demonstrated that lobeline effectively inhibited dopamine transporter (DAT)-mediated dopamine (DA) transportation. Therefore, the present study aimed to investigate whether lobeline shows protective effects against neurotoxin-induced cell death in vivo. Mice were administered 30 mg/kg 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) and treated with 80 mg/kg L-dopa, 10 mg/kg GBR12935 or 1 or 3 mg/kg lobeline, respectively, via injection. Rotarod and swim tests as well as tyrosine hydroxylase (TH) immunohistochemistry were carried out to evaluate the effects of these drugs. Compared with L-DA and GBR12935, lobeline (3 mg/kg administered via intraperitoneal injection) on behavior and dopaminergic neurons. Compared with L-DA and GBR12935, lobeline (3 mg/kg injected subcutaneously) significantly reduced MPTP induced locomotive deficits detected in behavioral tests. In addition, TH immunostaining showed that lobeline (3 mg/kg) markedly decreased the neurotoxin-induced immunoreactivity loss in the substantia nigra and striatum. Lobeline may be useful in the protection of dopaminergic neurons and may alleviate the symptoms of Parkinson’s disease.
lobeline; 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine; dopamine transporter; substantia nigra; Parkinson’s disease
It is known that psychological stress affects reproduction in women, but it is unknown whether the effect is by impairing implantation. Although studies suggest that long periods of auditory or restraint stress may inhibit implantation in rats and mice, the exact stage of pregnancy at which stress impairs implantation is unclear. Furthermore, whether stress impairs implantation by decreasing the heparin-binding epidermal growth factor-like growth factor (HB-EGF), estrogen and/or progesterone and whether by acting on embryos or on the uterus need further investigations. In this study, a 24-h restraint stress was initiated at 15:30 of day 3 (regimen 1) or at 07:30 (regimen 2) or 15:30 of day 4 (regimen 3) of pregnancy (vaginal plug = day 1) to observe effects of restraint stress applied at different peri-implantation stages on implantation. Among the three regimens, whereas regimens 1 and 3 affected neither term pregnancy nor litter size, regimen 2 reduced both. Further observations indicated that regimen 2 of restraint stress also delayed blastocyst hatching and the attachment reaction, decreased serum concentrations of progesterone and estradiol, and down regulated the expression of HB-EGF in both the endometrium and blastocysts. Taken together, the results suggested that restraint stress inhibited mouse implantation in a temporal window-dependent manner and by impairing blastocyst activation and hatching and uterine receptivity via down-regulating HB-EGF, estrogen and progesterone. Thus, the stress applied within the implantation window impaired implantation by acting on both embryos and the uterus.
Polyhydroxyalkanoates (PHAs) have attracted increasing attention as “green plastic” due to their biodegradable, biocompatible, thermoplastic, and mechanical properties, and considerable research has been undertaken to develop low cost/high efficiency processes for the production of PHAs. MaoC-like hydratase (MaoC), which belongs to (R)-hydratase involved in linking the β-oxidation and the PHA biosynthetic pathways, has been identified recently. Understanding the regulatory mechanisms of (R)-hydratase catalysis is critical for efficient production of PHAs that promise synthesis an environment-friendly plastic.
We have determined the crystal structure of a new MaoC recognized from Phytophthora capsici. The crystal structure of the enzyme was solved at 2.00 Å resolution. The structure shows that MaoC has a canonical (R)-hydratase fold with an N-domain and a C-domain. Supporting its dimerization observed in structure, MaoC forms a stable homodimer in solution. Mutations that disrupt the dimeric MaoC result in a complete loss of activity toward crotonyl-CoA, indicating that dimerization is required for the enzymatic activity of MaoC. Importantly, structure comparison reveals that a loop unique to MaoC interacts with an α-helix that harbors the catalytic residues of MaoC. Deletion of the loop enhances the enzymatic activity of MaoC, suggesting its inhibitory role in regulating the activity of MaoC.
The data in our study reveal the regulatory mechanism of an (R)-hydratase, providing information on enzyme engineering to produce low cost PHAs.
Drosophila suzukii Matsumura (spotted wing drosophila) has recently become a serious pest of a wide variety of fruit crops in the United States as well as in Europe, leading to substantial yearly crop losses. To enable basic and applied research of this important pest, we sequenced the D. suzukii genome to obtain a high-quality reference sequence. Here, we discuss the basic properties of the genome and transcriptome and describe patterns of genome evolution in D. suzukii and its close relatives. Our analyses and genome annotations are presented in a web portal, SpottedWingFlyBase, to facilitate public access.
Drosophila suzukii; genome evolution; SpottedWingFlyBase; ortholog
Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) are initially discovered as the essential hematopoietic growth factors regulating bone marrow stem cell proliferation and differentiation, and SCF in combination with G-CSF (SCF+G-CSF) has synergistic effects on bone marrow stem cell mobilization. In this study we have determined the effect of SCF and G-CSF on neurite outgrowth in rat cortical neurons. Using molecular and cellular biology and live cell imaging approaches, we have revealed that receptors for SCF and G-CSF are expressed on the growth core of cortical neurons, and that SCF+G-CSF synergistically enhances neurite extension through PI3K/AKT and NFκB signaling pathways. Moreover, SCF+G-CSF induces much greater NFκB activation, NFκB transcriptional binding and brain-derived neurotrophic factor (BDNF) production than SCF or G-CSF alone. In addition, we have also observed that BDNF, the target gene of NFκB, is required for SCF+G-CSF-induced neurite outgrowth. These data suggest that SCF+G-CSF has synergistic effects to promote neurite growth. This study provides new insights into the contribution of hematopoietic growth factors in neuronal plasticity.
This study was conducted to evaluate the apparent metabolizable energy (AME) and true metabolizable energy (TME) contents in 30 sources of corn distillers dried grains with solubles (DDGS) in adult roosters, and establish the prediction equations to estimate the AME and TME value based on its chemical composition and color score.
Twenty-eight sources of corn DDGS made from several processing plants in 11 provinces of China and others imported from the United States. DDGS were analyzed for their metabolizable energy (ME) contents, measured for color score and chemical composition (crude protein, crude fat, ash, neutral detergent fiber, acid detergent fiber), to predict the equation of ME in DDGS. A precision-fed rooster assay was used, each DDGS sample was tube fed (50 g) to adult roosters. The experiment was conducted as a randomized incomplete block design with 3 periods. Ninety-five adult roosters were used in each period, with 90 being fed the DDGS samples and 5 being fasted to estimate basal endogenous energy losses.
Results showed that the AME ranged from 5.93 to 12.19 MJ/kg, TME ranged from 7.28 to 13.54 MJ/kg. Correlations were found between ME and ash content (-0.64, P < 0.01) and between ME and yellowness score (0.39, P < 0.05) of the DDGS samples. Furthermore, the best-fit regression equation for AME content of DDGS based on chemical composition and color score was AME = 6.57111 + 0.51475 GE - 0.10003 NDF + 0.13380 ADF + 0.07057 fat - 0.57029 ash - 0.02437 L (R2 = 0.70). The best-fit regression equation for TME content of DDGS was TME = 7.92283 + 0.51475 GE - 0.10003 NDF + 0.13380 ADF + 0.07057 fat - 0.57029 ash - 0.02437 L (R2 = 0.70).
This experiment suggested that measuring the chemical composition and color score of a corn DDGS sample may provide a quality parameter for identifying corn DDGS sources energy digestibility and metabolizable energy content.
Metabolizable energy; Distillers dried grains with solubles; Rooster; Predictive equation
Chemoresistance is a major cause of treatment failure in patients with lung cancer. Although the extensive efforts have been made in overcoming chemoresistance, the underlying mechanisms are still elusive. Cancer cells reprogram cellular metabolism to satisfy the demands of malignant phenotype. To reveal roles of cancer metabolism in regulating chemoresistance, we profiled the metabolic characteristics in paclitaxel-resistant lung cancer cells by flux assay. Glucose and oleate metabolism were significantly different between resistant and non-resistant cells. In addition, targeting metabolism as a strategy to overcome drug resistance was investigated using specific metabolic inhibitors. Inhibition of glycolysis and oxidative phosphorylation by 2-deoxyglucose and malonate, respectively, potentiated the effects of paclitaxel on nonresistant lung adenocarcinoma cells but not paclitaxel-resistant cells. By contrast, inhibition of lipolysis by mercaptoacetate or etomoxir synergistically inhibited drug-resistant lung adenocarcinoma cell proliferation. We conclude that lipolysis inhibition potentially be a therapeutic strategy to overcome drug resistance in lung cancer.
Pain and agitation are common in patients after craniotomy. They can result in tachycardia, hypertension, immunosuppression, increased catecholamine production and increased oxygen consumption. Dexmedetomidine, an alpha-2 agonist, provides adequate sedation without respiratory depression, while facilitating frequent neurological evaluation.
The study is a prospective, randomized, double-blind, controlled, parallel-group design. Consecutive patients are randomly assigned to one of the two treatment study groups, labeled ‘Dex group’ or ‘Saline group.’ Dexmedetomidine group patients receive a continuous infusion of 0.6 μg/kg/h (10 ug/ml). Placebo group patients receive a maintenance infusion of 0.9% sodium chloride for injection at a volume and rate equal to that of dexmedetomidine. The mean percentages of time in optimal sedation, vital signs, various and adverse events, the percentage of patients requiring propofol for rescue to achieve/maintain targeted sedation (Sedation-Agitation Scale, SAS 3 to 4) and total dose of propofol required throughout the study drug infusion are collected. The percentage of patients requiring fentanyl for additional rescue to analgesia and total dose of fentanyl required are recorded. The effects of dexmedetomidine on hemodynamic and recovery responses during extubation are measured. Intensive care unit and hospital length of stay also are collected. Plasma levels of epinephrine, norepinephrine, dopamine, cortisol, neuron-specific enolase and S100-B are measured before infusion (T1), at two hours (T2), four hours (T3) and eight hours (T4) after infusion and at the end of infusion (T5) in 20 patients in each group.
The study has been initiated as planned in July 2012. One interim analysis advised continuation of the trial. The study will be completed in July 2013.
ClinicalTrials (NCT): ChiCTR-PRC-12002903.
Dexmedetomidine; Analgesia; Sedation; Prophylactic; Delayed extubation; Craniotomy
Stroke is a serious cerebrovascular disease that causes high mortality and persistent disability in adults worldwide. Stroke is also an enormous public health problem and a heavy public financial burden in the United States. Treatment for stroke is very limited. Thrombolytic therapy by tissue plasminogen activator (tPA) is the only approved treatment for acute stroke, and no effective treatment is available for chronic stroke. Developing new therapeutic strategies, therefore, is a critical need for stroke treatment. This article summarizes the discovery of new routes of treatment for acute and chronic stroke using two hematopoietic growth factors, stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF). In a study of acute stroke, SCF and G-CSF alone or in combination displays neuroprotective effects in an animal model of stroke. SCF appears to be the optimal treatment for acute stroke as the functional outcome is superior to G-CSF alone or in combination (SCF+G-CSF); however, SCF+G-CSF does show better functional recovery than G-CSF. In a chronic stroke study, the therapeutic effects of SCF and G-CSF alone or in combination appear differently as compared with their effects on the acute stroke. SCF+G-CSF induces stable and long-lasting functional improvement; SCF alone also improves functional outcome but its effectiveness is less than SCF+G-CSF, whereas G-CSF shows no therapeutic effects. Although the mechanism by which SCF+G-CSF repairs the brain in chronic stroke remains poorly understood, our recent findings suggest that the SCF+G-CSF-induced functional improvement in chronic stroke is associated with a contribution to increasing angiogenesis and neurogenesis through bone marrow-derived cells and the direct effects on stimulating neurons to form new neuronal networks. These findings would assist in developing new treatment for stroke. The article presents some promising patents on role of stem cell factor and granulocyte-colony stimulating factor in treatment of stroke.
Acute stroke; chronic stroke; G-CSF; hematopoietic growth factors; neuroprotection; neuronal plasticity; SCF
Epidemiological studies have demonstrated that type 2 diabetes mellitus (T2DM) and hyperinsulinemia are associated closely with endometrial carcinoma risk, although the molecular mechanism remains unclear. Insulin receptor isoformA expression is upregulated in many cancer cells and tissues, which suggests that IR-A-mediated signaling pathways may have important implications for cancer pathogenesis. We measured the expression of insulin receptor isoforms (IR-A and IR–B in the normal endometrium tissues, the endometrial carcinoma tissues and the endometrial carcinoma cell lines. We found that the total insulin receptor (IR) and IR-A expression mRNA levels and the ratio of IR-A to total IR in endometrial carcinoma specimens were significantly higher than them in control endometrial tissue specimens(P<0.05). Further analysis indicated that the tendency was more prominently in patients with T2DM. IR-A mRNA was differentially expressed in four endometrial carcinoma cell lines (Ishikawa, KLE, RL95-2 and HEC-1-A. RL95-2 cells have a low endogenous IR-A expression, and these were used to construct a stable cell line overexpressing IR-A. We found that IR-A overexpression significantly increased cell proliferation, the proportion of cells in S phase, activation of the Akt pathway and tumorigenicity of xenografts in nude mice. In contrast, there was no significant difference in the the percentage of apoptotic cells between cells overexpressing IR-A and control cells. Moreover, levels of phosphorylated ERK1/2 protein were significantly decreased in cells overexpressing IR-A relative to controls. These findings reveal the pivotal role of IR-A in endometrial cancer carcinogenesis, and suggest that the association of elevated IR-A levels with cell proliferation and tumorigenicity may be causally linked to its effect on the proportion of cells in S phase and the activation of the Akt pathway.
X-ray repair cross-complementing protein 3 (XRCC3) is an essential gene involved in the double-strand break repair pathway. Published evidence has shown controversial results about the relationship between XRCC3 Thr241Met polymorphism and clinical outcomes of non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy.
A systematic review and meta-analysis was performed to evaluate the predictive value of XRCC3 Thr241Met polymorphism on clinical outcomes of advanced NSCLC receiving platinum-based chemotherapy. Response to chemotherapy, overall survival (OS) and progression-free survival (PFS) were analyzed.
A number of 11 eligible studies were identified according to the inclusion criteria. Carriers of the variant XRCC3 241Met allele were significantly associated with good response to platinum-based chemotherapy (ThrMet/MetMet vs. ThrThr: OR = 1.509, 95% CI: 1.099–2.072, Pheterogeneity = 0.618). The XRCC3 Thr241Met polymorphism was not associated with OS (MetMet vs. ThrThr, HR = 0.939, 95% CI:0.651–1.356, Pheterogeneity = 0.112) or PFS (MetMet vs. ThrThr, HR = 0.960, 95% CI: 0.539–1.710, Pheterogeneity = 0.198). Additionally, no evidence of publication bias was observed.
This systematic review and meta-analysis shows that carriers of the XRCC3 241Met allele are associated with good response to platinum-based chemotherapy in advanced NSCLC, while the XRCC3 Thr241Met polymorphism is not associated with OS or PFS.
The protein Pspto_3016 is a 117-residue member of the protein domain family PF04237 (DUF419), which is to date a functionally uncharacterized family of proteins. In this report, we describe the structure of Pspto_3016 from Pseudomonas syringae solved by both solution NMR and X-ray crystallography at 2.5 Å resolution. In both cases, the structure of Pspto_3016 adopts a “double wing” α/β sandwich fold similar to that of protein YjbR from Escherichia coli and to the C-terminal DNA binding domain of the MotA transcription factor (MotCF) from T4 bacteriophage, along with other uncharacterized proteins. Pspto_3016 was selected by the Protein Structure Initiative of the National Institutes of Health and the Northeast Structural Genomics Consortium (NESG ID PsR293).
Pspto_3016; PF04237; DUF419; structural genomics; 2KFP; 3H9X; double wing; NMR; X-ray crystallography
Biomarker identification is crucial for the selection of patients who might benefit from radiotherapy. To explore potential markers for response and prognosis in patients with locally advanced esophageal carcinoma treated with radiotherapy followed by surgery, we evaluated the expression of cell cycle checkpoint-related proteins Chk2, Cdc25C, and Cyclin D1. A total of 56 patients with locally advanced esophageal squamous cell carcinoma were treated with radiotherapy followed by surgery. Pretreatment tumor biopsy specimens were analyzed for Chk2, Cdc25C, and Cyclin D1 expression by immunohistochemistry. High expression of Chk2, Cyclin D1, and Cdc25C was observed in 44 (78.6%), 15 (26.8%), and 27 (48.2%) patients, respectively. The median survival was 16 months (range, 3–154 months), with a 5-year overall survival rate of 19.6%. Overexpression of Chk2 was associated with smoking (P = 0.021), overexpression of Cdc25C was associated with patient age (P = 0.033) and tumor length (P = 0.001), and overexpression of Cdc25C was associated with pathologic complete response (P = 0.038). Univariate analysis demonstrated that overexpression of Cdc25C and pathologic complete response was associated with better survival. In multivariate analysis, Cdc25C was the most significant independent predictor of better survival (P = 0.014) for patients treated with radiotherapy followed by surgery. Overexpression of Cdc25C was significantly associated with pathologic complete response and better survival of patients with locally advanced esophageal cancer treated with radiotherapy followed by surgery. These results suggest that Cdc25C may be a biomarker of treatment response and good prognosis for esophageal carcinoma patients. Thus, immunohistochemical staining of Cdc25C in a pretreatment specimen may be a useful method of identifying optimal treatment for patients with esophageal carcinoma.
Cdc25C; radiation response; survival; esophageal squamous cell carcinoma
Studies have suggested that the nuclear receptor corepressor 1 (NCOR1) could play an important role in human cancers. However, the detailed molecular mechanisms by which it functions in vivo to affect cancer progression are not clear. The present study elucidated the in vivo actions of NCOR1 in carcinogenesis using a mouse model (ThrbPV/PV mice) that spontaneously develops thyroid cancer. ThrbPV/PV mice harbor a dominantly negative thyroid hormone receptor β (TRβ) mutant (denoted as PV). We adopted the loss-of-the function approach by crossing ThrbPV mice with mice that globally express an NCOR1 mutant protein (NCOR1ΔID) in which the receptor interaction domains have been modified so that it cannot interact with the TRβ, or PV, in mice. Remarkably, expression of NCOR1ΔID protein reduced thyroid tumor growth, markedly delayed tumor progression, and prolonged survival of ThrbPV/PVNcor1ΔID/ΔID mice. Tumor cell proliferation was inhibited by increased expression of cyclin-dependent kinase inhibitor 1 (p21waf1/cip1; Cdkn1A), and apoptosis was activated by elevated expression of pro-apoptotic BCL-Associated X (Bax). Further analyses showed that p53 was recruited to the p53-binding site on the proximal promoter of the Cdkn1A and the Bax gene as a co-repressor complex with PV/NCOR1/histone deacetylas-3 (HDAC-3), leading to repression of the Cdkn1A as well as the Bax gene in thyroids of ThrbPV/PV mice. In thyroids of ThrbPV/PVNcor1ΔID/ΔID mice, the p53/PV complex could not recruit NCOR1ΔID and HDAC-3, leading to de-repression of both genes to inhibit cancer progression. The present studies provided direct evidence in vivo that NCOR1 could function as an oncogene via transcription regulation in a mouse model of thyroid cancer.