OBJECTIVE--To study whether passive smoking at work is a risk factor for coronary heart disease. DESIGN--Case-control study. SETTING--Xi'an, China. SUBJECTS--59 patients with coronary heart disease and 126 controls, all Chinese women with full time jobs, who had never smoked cigarettes. RESULTS--The crude odds ratio for passive smoking from husband was 2.12 (95% confidence interval 1.06 to 4.25) and at work was 2.45 (1.23 to 4.88). The final logistic regression model, with passive smoking from husband and at work as the base, included age, history of hypertension, type A personality, and total cholesterol and high density lipoprotein cholesterol concentrations; the adjusted odds ratios for passive smoking from husband and at work were 1.24 (0.56 to 2.72) and 1.85 (0.86 to 4.00) respectively. For passive smoking at work, statistically significant linear trends of increasing risks (for both crude and adjusted odds ratios) with increasing exposures (amount exposed daily, number of smokers, number of hours exposed daily, and cumulative exposure) were observed. When these exposure variables were analysed as continuous variables, the crude and adjusted odds ratios were also significant. CONCLUSION--Passive smoking at work is a risk factor for coronary heart disease. Urgent public health measures are needed to reduce smoking and to protect non-smokers from passive smoking in China.
In vivo imaging/spectroscopic biomarkers for solid tumor aggressiveness are needed in the clinic to facilitate cancer diagnosis and treatment strategies. In mouse models of human melanoma and breast cancer we were able to detect the metabolic differences among tumors of different metastatic potential and between normal and cancer tissues by optical imaging of the mitochondrial redox state of snap-frozen tissue samples. Such metabolic differences indicate that tumors of different aggressiveness have different metabolic homeostasis, which supports that kinetic parameters such as rate constant(s) can also serve as bio-markers for cancer aggressiveness and treatment response. Here we present our preliminary study on the mouse xenografts of the aggressive and indolent human breast cancer cell lines using the hyperpolarized 13C-NMR (HP-NMR) technique. By recording the time courses of 13C-pyruvate tracer and its metabolite signals in vivo, particularly the 13C-lactate signal, the apparent rate constants of both the forward and reverse reactions catalyzed by lactate dehydrogenase (LDH) were extracted via the ratiometric modeling of the two-site exchange reaction that we developed. Data from four breast tumors (MCF-7, MDA-MB-468, and MDA-MB-231 medium and large) with different aggressiveness are included. We demonstrate the feasibility to quantify the apparent rate constants of LDH reactions in breast tumor xenografts.
Regulator of Cullins-1 (ROC1) or RING box protein-1 (RBX1) is an essential RING component of Cullin-RING ligase (CRL). Our previous studies showed that ROC1 is required for the growth of several cancer cell lines while ROC1 siRNA silencing inactivates CRL, leading to cell cycle arrest, cell senescence and/or apoptosis. However, it is completely unknown whether ROC1 knockdown triggers autophagic response by inactivating CRL. Moreover, the role of ROC1 in liver cancer remains elusive. In this study, we reported that ROC1 knockdown significantly inhibited the growth of liver cancer cells by sequentially and independently inducing autophagy and p21-dependent cell senescence. Mechanism analysis revealed that ROC1 silencing triggered autophagy by inhibition of mammalian target of rapamycin (mTOR) activity due to accumulation of mTOR-inhibitory protein Deptor, a substrate of CRL. Consistently, Deptor knockdown significantly blocked autophagy response upon ROC1 silencing. Biologically, autophagy response upon ROC1 silencing was a survival signal, and blockage of autophagy pathway sensitized cancer cells to apoptosis. Finally, we demonstrated that ROC1 was overexpressed in hepatocellular carcinomas, which is associated with poor prognosis of liver cancer patients. These findings suggest that ROC1 is an appealing drug target for liver cancer and provide a proof-of-concept evidence for a novel drug combination of ROC1 inhibitor and an autophagy inhibitor for effective treatment of liver cancer by enhancing apoptosis.
ROC1; Cullin-RING ligase; autophagy; senescence; Deptor
Incoherent twin boundaries (ITBs) are widespread and play a crucial role in unidirectional deformation behavior of materials, however, the intrinsic role of individual ITB under cyclic loading remains elusive. Here we show the fatigue cracking behavior of Cu bicrystal with an ITB as its sole interface for the first time. The slip bands (SBs) could transfer through the ITB; meanwhile, the ITB could migrate with the motion of partial dislocations. Both the penetrability and mobility contribute to the higher fatigue cracking resistance of the ITB and hence the fatigue crack nucleates along the SBs preferentially. These new findings not only shed light on the fatigue cracking mechanisms of a penetrable boundary with direct evidence but also could provide important implications for future interfacial optimization of metallic materials.
Genes involved in the planar cell polarity (PCP) signaling pathway are essential for a number of developmental processes in mammals, such as convergent extension and ciliogenesis. Tissue-specific PCP effector genes of the PCP signaling pathway are believed to mediate PCP signals in a tissue- and cell type-specific manner. However, how PCP signaling controls the morphogenesis of mammalian tissues remains unclear. In this study, we investigated the role of inturned (Intu), a tissue-specific PCP effector gene, during hair follicle formation in mice. Tissue-specific disruption of Intu in embryonic epidermis resulted in hair follicle morphogenesis arrest because of the failure of follicular keratinocyte to differentiate. Targeting Intu in the epidermis resulted in almost complete loss of primary cilia in epidermal and follicular keratinocytes, and a suppressed hedgehog signaling pathway. Surprisingly, the epidermal stratification and differentiation programs and barrier function were not affected. These results demonstrate that tissue-specific PCP effector genes of the PCP signaling pathway control the differentiation of keratinocytes through the primary cilia in a cell fate- and context-dependent manner, which may be critical in orchestrating the propagation and interpretation of polarity signals established by the core PCP components.
Planar cell polarity; Intu; cilia; keratinocyte; epidermis; hair follicle
Shedding of a pharmacological target from cells, giving rise to a soluble target that can also bind therapeutic proteins, is a common phenomenon. In this study, a minimal physiologically based pharmacokinetic model was used to simulate the pharmacokinetics of trastuzumab and the simultaneous binding of the compound to soluble (in blood and tissue interstitial space) and membrane-bound (in the tissue interstitial space) forms of human epidermal growth factor receptor 2 (HER2). The parameter values describing binding of trastuzumab to HER2 were largely derived from in vitro data, and the effects of varying HER2 levels, the affinity difference between membrane-bound HER2 and shed antigen, and slow binding kinetics were investigated. The model simulates a sharp decrease in trough drug concentrations at concentrations of soluble target between 500 and 1,000 ng/ml in plasma. This corresponds with the clinical concentration range of soluble target wherein changes in half-life of trastuzumab have been observed.
The outcome of umbilical cord blood transplantation (UCBT) is compromised by low hematopoietic stem cell (HSC) doses leading to prolonged time to engraftment, delayed immunological reconstitution and late memory T-cell skewing. Exposure of UCB to dimethyl-prostaglandin E2 (dmPGE2) increases HSC in vivo. We determined that exposure of UCB T lymphocytes to dmPGE2 modified Wnt signaling resulting in T cell factor (TCF)-mediated transcription. Wnt signaling upregulated interleukin (IL)-7R and IL-2Rβ, resulting in enhanced survival mediated by the homeostatic cytokines IL-7 and IL-15. dmPGE2 also induced components of the Wnt pathway and Wnt receptors, thereby priming UCB T cells to receive signals via Wnt ligands in vivo. We observed that the Wnt transcription factor TCF7 and its target EOMES were elevated in the T cells of patients who received PGE2-treated UCBs. Consistent with the role of Wnt/β-catenin signaling to induce and maintain naive, memory precursors and long-lived central memory CD8+ cells, these patients also had increased fractions of CD8+CD45RO-CD62L+ plus CD8+CD45RO+CD62L+ subsets encompassing these T-cell populations. These effects of the PGE2/Wnt/β-catenin axis may have significant implications for harnessing immunity in the context of UCBT, where impaired immune reconstitution is associated with late memory T-cell skewing.
umbilical cord blood transplantation; immune reconstitution; prostaglandin E2; Wnt/β-catenin pathway
FMS-like tyrosine kinase 3 (FLT3) normally functions in the survival/proliferation of hematopoietic stem/progenitor cells, but its constitutive activation by internal tandem duplication (ITD) mutations correlates with a poor prognosis in AML. The development of FLT3 tyrosine kinase inhibitors (TKI) is a promising strategy, but resistance that arises during the course of treatment caused by secondary mutations within the mutated gene itself poses a significant challenge. In an effort to predict FLT3 resistance mutations that might develop in patients, we used saturation mutagenesis of FLT3/ITD followed by selection of transfected cells in FLT3 TKI. We identified F621L, A627P, F691L and Y842C mutations in FLT3/ITD that confer varying levels of resistance to FLT3 TKI. Western blotting confirmed that some FLT3 TKI were ineffective at inhibiting FLT3 autophosphorylation and signaling through MAP kinase, STAT5 and AKT in some mutants. Balb/c mice transplanted with the FLT3/ITD Y842C mutation confirmed resistance to sorafenib in vivo but not to lestaurtinib. These results indicate a growing number of FLT3 mutations that are likely to be encountered in patients. Such knowledge, combined with known remaining sensitivity to other FLT3 TKI, will be important to establish as secondary drug treatments that can be substituted when these mutants are encountered.
acute myeloid leukemia; mutant FLT3; drug resistance; tyrosine kinase inhibitors
The unfolded protein response (UPR) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. However, tumor-specific UPR transducers are largely unknown. In the present study, we identified CD147, a cancer biomarker, as an UPR inducer in hepatocellular carcinoma (HCC). The expression of the major UPR target, Bip, was found to be positively associated with CD147 in human hepatoma tissues. By phosphorylating FAK and Src, CD147-enhanced TFII-I tyrosine phosphorylation at Tyr248. CD147 also induced p-TFII-I nuclear localization and binding to the Bip promoter where endoplasmic reticulum (ER) stress response element 1 (ERSE1) (−82/−50) is the most efficient target of the three ERSEs, thus increasing transcription of Bip. Furthermore, by inducing UPR, CD147 inhibited HCC cell apoptosis and decreased cell Adriamycin chemosensitivity, thus decreasing the survival rate of hepatoma-bearing nude mice. Together, these results reveal pivotal roles for CD147 in modulating the UPR in HCC and raise the possibility that CD147 is a target that promotes HCC cell apoptosis and increases the sensitivity of tumors to anti-cancer drugs. Therefore, CD147 inhibition provides an opportunity to enhance the efficacy of existing agents and represents a novel target for HCC treatment.
CD147; unfolded protein response (UPR); hepatocellular carcinoma (HCC); Bip; apoptosis; chemosensitivity
To evaluate the impact of risk minimisation policies on the use of rosiglitazone-containing products and on glycaemic control among patients in Denmark and the UK.
Design, setting and participants
We used population-based data from the Aarhus University Prescription Database (AUPD) in northern Denmark and from the General Practice Research Database (GPRD) in the UK.
Main outcome measures
We examined the use of rosiglitazone during its entire period of availability on the European market (2000–2010) and evaluated changes in the glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels among patients discontinuing this drug.
During 2000–2010, 2321 patients with records in AUPD used rosiglitazone in northern Denmark and 25 428 patients with records in GPRD used it in the UK. The proportion of rosiglitazone users among all users of oral hypoglycaemic agents peaked at 4% in AUPD and at 15% in GPRD in May 2007, the month of publication of a meta-analysis showing increased cardiovascular morbidity associated with rosiglitazone use. 12 months after discontinuation of rosiglitazone-containing products, the mean change in HbA1c was −0.16% (95% CI −3.4% to 3.1%) in northern Denmark and −0.17% (95% CI −0.21% to 0.13%) in the UK. The corresponding mean changes in FPG were 0.01 mmol/L (95% CI −7.3 to 7.3 mmol/L) and 0.03 mmol/L (95% CI −0.22 to 0.28 mmol/L).
Publication of evidence concerning the potential cardiovascular risks of rosiglitazone was associated with an irreversible decline in the use of rosiglitazone-containing products in Denmark and the UK. The mean changes in HbA1c and FPG after drug discontinuation were slight.
diabetes mellitus; drug safety; glucose-lowering drugs; rosiglitazone; thiazolidinediones
To evaluate the effects of heart rate and heart rate variability on image quality, patient dose and diagnostic accuracy of 320-detector row CT.
94 patients were prospectively enrolled. Heart rate was defined as the mean value of different intervals elapsing between two consecutive R waves in an electrocardiogram (R–R intervals) and the heart rate variability was calculated as the standard deviation from the average heart rate. The image quality was evaluated by four grades, according to motion artefacts (“step artefacts” and “blurring artefacts”). The diagnostic accuracy was analysed in 43 patients who were scheduled for invasive coronary angiography (ICA). The coeffects of heart rate and heart rate variability on image quality, radiation dose and diagnostic accuracy were evaluated by multivariate regression.
The mean image quality score was 1.2±0.5 and the mean effective dose was 14.8±9.8 mSv. The results showed that heart rate (74.0±11.2 beats per minute) was the single factor influencing image quality (p<0.001) and radiation dose (p<0.001), while heart rate variability (3.7±4.6) had no significant effect on them (p=0.16 and p=0.47, respectively). For 43 patients who underwent ICA, heart rate and heart rate variability showed no influence on the accuracy (p=0.17 and p=0.12, respectively). Overall sensitivity was 97.4% (37/38), specificity was 99.4% (351/353), positive predictive value was 94.9% (37/39) and negative predictive value was 99.7% (351/352).
320-detector row CT, with improved longitudinal coverage of detector, resolves step artefact and high patient dose caused by irregular heart rate. However, it is still recommended to control heart rate to a lower level to eliminate blurring artefact and radiation dose.
The present study investigated the relationships among oxidative stress, β-amyloid and cognitive abilities in the APP/PSEN1 double-transgenic mouse model of Alzheimer’s disease. In two experiments, long-term dietary supplements were given to aged APP/PSEN1 mice containing vitamin C alone (1g/kg diet, Expt. 1) or in combination with a high (750 IU/kg diet, Expts. 1 and 2) or lower (400 IU/kg diet, Expt. 2) dose of vitamin E. Oxidative stress, measured by F4-neuroprostanes or malondialdehyde, was elevated in cortex of control-fed APP/PSEN1 mice and reduced to wild-type levels by vitamin supplementation. High dose vitamin E with C was less effective at reducing oxidative stress than vitamin C alone or the low EC diet combination. The high-dose combination also impaired water maze performance in mice of both genotypes. In Experiment 2 the lower vitamin EC treatment attenuated spatial memory deficits in APP/PSEN1 mice and improved performance in wild-type mice in the water maze. Amyloid deposition was not reduced by antioxidant supplementation in either experiment.
Vitamin C; Vitamin E; oxidative stress; Alzheimer’s disease; cognition
Hepatic oval cells (HOCs) are recognized as facultative liver progenitor cells that
play a role in liver regeneration after acute liver injury. Here, we investigated the
in vitro proliferation and differentiation characteristics of
HOCs in order to explore their potential capacity for intrahepatic transplantation.
Clusters or scattered HOCs were detected in the portal area and interlobular bile
duct in the liver of rats subjected to the modified 2-acetylaminofluorene and partial
hepatectomy method. Isolated HOCs were positive for c-kit and CD90 staining (99.8%
and 88.8%, respectively), and negative for CD34 staining (3.6%) as shown by
immunostaining and flow cytometric analysis. In addition, HOCs could be
differentiated into hepatocytes and bile duct epithelial cells after leukemia
inhibitory factor deprivation. A two-cuff technique was used for orthotopic liver
transplantation, and HOCs were subsequently transplanted into recipients. Biochemical
indicators of liver function were assessed 4 weeks after transplantation. HOC
transplantation significantly prolonged the median survival time and improved the
liver function of rats receiving HOCs compared to controls (P=0.003, Student
t-test). Administration of HOCs to rats also receiving liver
transplantation significantly reduced acute allograft rejection compared to control
liver transplant rats 3 weeks following transplantation (rejection activity index
score: control=6.3±0.9; HOC=3.5±1.5; P=0.005). These results indicate that HOCs may
be useful in therapeutic liver regeneration after orthotopic liver
Hepatic oval cells; Proliferation; Differentiation; Liver transplantation
Several Bmp genes are expressed in the developing mouse tooth germ from the initiation to the late-differentiation stages, and play pivotal roles in multiple steps of tooth development. In this study, we investigated the requirement of BMP activity in early tooth development by transgenic overexpression of the extracellular BMP antagonist Noggin. We show that overexpression of Noggin in the dental epithelium at the tooth initiation stage arrests tooth development at the lamina/early-bud stage. This phenotype is coupled with a significantly reduced level of cell proliferation rate and a down-regulation of Cyclin-D1 expression, specifically in the dental epithelium. Despite unaltered expression of genes known to be implicated in early tooth development in the dental mesenchyme and dental epithelium of transgenic embryos, the expression of Pitx2, a molecular marker for the dental epithelium, became down-regulated, suggesting the loss of odontogenic fate in the transgenic dental epithelium. Our results reveal a novel role for BMP signaling in the progression of tooth development from the lamina stage to the bud stage by regulating cell proliferation and by maintaining odontogenic fate of the dental epithelium.
BMP signaling; BMP antagonist; Noggin overexpression; tooth progression; Cyclin-D; transgenic mice
Background and Objectives
The macrophage is an important early cellular marker related to risk of future rupture of atherosclerotic plaques. Two-channel two-photon luminescence (TPL) microscopy combined with optical coherence tomography (OCT) was used to detect, and further characterize the distribution of aorta-based macrophages using plasmonic gold nanorose as an imaging contrast agent.
Study Design/Materials and Methods
Nanorose uptake by macrophages was identified by TPL microscopy in macrophage cell culture. Ex vivo aorta segments (8 × 8 × 2 mm3) rich in macrophages from a rabbit model of aorta inflammation were imaged by TPL microscopy in combination with OCT. Aorta histological sections (5 µm in thickness) were also imaged by TPL microscopy.
Merged two-channel TPL images showed the lateral and depth distribution of nanorose-loaded macrophages (confirmed by RAM-11 stain) and other aorta components (e.g., elastin fiber and lipid droplet), suggesting that nanorose-loaded macrophages are diffusively distributed and mostly detected superficially within 20 µm from the luminal surface of the aorta. Moreover, OCT images depicted detailed surface structure of the diseased aorta.
Results suggest that TPL microscopy combined with OCT can simultaneously reveal macrophage distribution with respect to aorta surface structure, which has the potential to detect vulnerable plaques and monitor plaque-based macrophages overtime during cardiovascular interventions.
atherosclerosis; macrophage; nanorose; two-photon luminescence microscopy; optical coherence tomography; photothermal wave imaging
We are interested in investigating whether cancer therapy may alter the mitochondrial redox state in cancer cells to inhibit their growth and survival. The redox state can be imaged by the redox scanner that collects the fluorescence signals from both the oxidized-flavoproteins (Fp) and the reduced form of nicotinamide adenine dinucleotide (NADH) in snap-frozen tissues and has been previously employed to study tumor aggressiveness and treatment responses. Here, with the redox scanner we investigated the effects of chemotherapy on mouse xenografts of a human diffuse large B-cell lymphoma cell line (DLCL2). The mice were treated with CHOP therapy, i.e., cyclophosphamide (C) + hydroxydoxorubicin (H) + Oncovin (O) + prednisone (P) with CHO administration on day 1 and prednisone administration on days 1–5. The Fp content of the treated group was significantly decreased (p = 0.033) on day 5, and the mitochondrial redox state of the treated group was slightly more reduced than that of the control group (p = 0.048). The decrease of the Fp heterogeneity (measured by the mean standard deviation) had a border-line statistical significance (p = 0.071). The result suggests that the mitochondrial metabolism of lymphoma cells was slightly suppressed and the lymphomas became less aggressive after the CHOP therapy.
NADH; flavoprotein; DLCL2; therapeutic effect; tumor metabolism
The associations between plasma letrozole concentrations and CYP2A6 and CYP3A5 genetic variants were tested in the Exemestane and Letrozole Pharmacogenomics (ELPH) trial. ELPH is a multicenter, open-label prospective clinical trial in women randomly assigned (n ≈ 250 in each arm) to receive 2 years of treatment with either oral letrozole (2.5 mg/day) or oral exemestane (25 mg/day). CYP2A6 and CYP3A showed effects on letrozole metabolism in vitro. DNA samples were genotyped for variants in the CYP2A6 and CYP3A5 genes. plasma letrozole concentrations showed high interpatient variability (>10-fold) and were associated significantly with CYP2A6 genotypes (P < 0.0001), body mass index (BMI) (P < 0.0001), and age (P = 0.0035). However, CYP3A5 genotypes showed no association with plasma letrozole concentrations. These data suggest that CYP2A6 is the principal clearance mechanism for letrozole in vivo. CYP2A6 metabolic status, along with BMI and age, may serve as a biomarker of the efficacy of letrozole treatment or a predictor of adverse effects.
A set of 120 simple sequence repeats (SSRs) was developed from the newly assembled pear sequence and evaluated for polymorphisms in seven genotypes of pear from different genetic backgrounds. Of these, 67 (55.8 %) primer pairs produced polymorphic amplifications. Together, the 67 SSRs detected 277 alleles with an average of 4.13 per locus. Sequencing of the amplification products from randomly picked loci NAUPy31a and NAUpy53a verified the presence of the SSR loci. When the 67 primer pairs were tested on 96 individual members of eight species in the Rosaceae family, 61.2 % (41/67) of the tested SSRs successfully amplified a PCR product in at least one of the Rosaceae genera. The transferability from pear to different species varied from 58.2 % (apple) to 11.9 % (cherry). The ratio of transferability also reflected the closer relationships within Maloideae over Prunoideae. Two pear SSR markers, NAUpy43c and NAUpy55k, could distinguish the 20 different apple genotypes thoroughly, and UPGMA cluster analysis grouped them into three groups at the similarity level of 0.56. The high level of polymorphism and good transferability of pear SSRs to Rosaceae species indicate their promise for application to future molecular screening, map construction, and comparative genomic studies among pears and other Rosaceae species.
Electronic supplementary material
The online version of this article (doi:10.1007/s11105-013-0586-z) contains supplementary material, which is available to authorized users.
Simple sequence repeat (SSR); Pear; Rosaceae; Transferability
The aim of this article was to prospectively evaluate the accuracy and radiation dose of 320-detector row dynamic volume CT (DVCT) for the detection of coronary artery disease (CAD) in a high-risk population.
60 patients with a high risk of CAD underwent DVCT without preceding heart rate control and also underwent invasive coronary angiography (ICA), which served as the standard reference.
On a per segment analysis, overall sensitivity was 95.3%, specificity was 97.6%, positive predictive value was 90.6%, negative predictive value was 98.8% and Youden index was 0.93. In both heart rate subgroups, diagnostic accuracy for the assessment of coronary artery stenosis was similar. The accuracy of the subgroup with an Agatston score ≥100 was lower than that for patients with an Agatston score <100. However, the difference between DVCT and ICA results was not significant (p=0.08). The mean estimated effective dose of CT was 12.5±9.4 mSv. In those patients with heart rates less than 70 beats per minute (bpm), the mean radiation exposure of DVCT was 5.2±0.9 mSv. The effective radiation dose was significantly lower than that of ICA (14.1±5.9 mSv) (p<0.001). When the heart rate was >70 bpm, a significantly higher dose was delivered to patients with DVCT (22.6±5.2 mSv, p<0.001) than with ICA (15.0±5.3 mSv, p<0.001).
DVCT reliably provides high diagnostic accuracy without heart rate/rhythm control. However, from a dosimetric point of view, it is recommended that heart rate should be controlled to <70 bpm to decrease radiation dose.
A computational model of the glucagon/insulin-driven liver glucohomeostasis function, focusing on the buffering of glucose into glycogen, has been developed. The model exemplifies an ‘engineering’ approach to modelling in systems biology, and was produced by linking together seven component models of separate aspects of the physiology. The component models use a variety of modelling paradigms and degrees of simplification. Model parameters were determined by an iterative hybrid of fitting to high-scale physiological data, and determination from small-scale in vitro experiments or molecular biological techniques. The component models were not originally designed for inclusion within such a composite model, but were integrated, with modification, using our published modelling software and computational frameworks. This approach facilitates the development of large and complex composite models, although, inevitably, some compromises must be made when composing the individual models. Composite models of this form have not previously been demonstrated.
computational modelling; glucose homeostasis; liver; systems biology
Using a composite model of the glucose homeostasis system, consisting of seven interconnected submodels, we enumerate the possible behaviours of the model in response to variation of liver insulin sensitivity and dietary glucose variability. The model can reproduce published experimental manipulations of the glucose homeostasis system and clearly illustrates several important properties of glucose homeostasis—boundedness in model parameters of the region of efficient homeostasis, existence of an insulin sensitivity that allows effective homeostatic control and the importance of transient and oscillatory behaviour in characterizing homeostatic failure. Bifurcation analysis shows that the appearance of a stable limit cycle can be identified.
computational modelling; glucose homeostasis; liver; bifurcation analysis
BMP signaling plays crucial roles in the development of many organs, including the tooth. Equally important is BMP signaling homeostasis, as demonstrated by multiple organ defects in mice lacking the extracellular BMP antagonist Noggin. Here, we show that Noggin is initially expressed in the maxillary mesenchyme adjunct to the upper incisor at the initiation stage, and then in the developing teeth, including incisors and molars, from the bud stage. Noggin mutants develop normal molars and mandibular incisors, but form a single, medially located upper incisor that is arrested at the late bud stage. Histological and molecular marker analyses demonstrated that two distinct upper incisor placodes initiate independently at E11.5, but begin to fuse at E12.5, coupling with elevated cell proliferation rates in the developing tooth germs. We further found that Chordin and Gremlin, two other BMP antagonists, are co-expressed with Noggin in the developing lower incisor and molar teeth. These observations indicate the importance of BMP signaling homeostasis, and suggest a functional redundancy between BMP antagonists during tooth development.
BMP antagonist; BMP homeostasis; Chordin; Gremlin; tooth development; tooth fusion
To evaluate the efficacy and treatment-related toxicity of accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy for locally recurrent and irresectable rectal cancer (LRIRC).
72 patients with LRIRC who underwent the treatment were studied. Three-dimensional conformal accelerated hyperfractionation radiotherapy (3D-CAHRT) was performed and the dose was delivered with a schedule of 1.2 Gy twice daily, with an interval of at least 6 h between fractions, 5 days a week. Concurrent capecitabine chemotherapy was administered twice daily. After 36 Gy in 30 fractions over 3 weeks, patients were evaluated to define the resectability of the disease. If resection was not feasible irradiation was resumed until the total dose administered to the tumour reached 51.6–56.4 Gy.
Two patients temporarily interrupted concurrent chemoradiation because of Grade IV diarrhoea. The remaining 70 patients completed the planned concurrent chemoradiation. In all patients, the complete response rate was 8.3% and the partial response rate was 51.4%. The overall response rate was 59.7% and clinical benefit rate was 93.1%. Symptomatic responses proved to be obvious and tumour resection was performed in 18 patients. The overall median survival time and median progression-free survival time were 32 and 17 months, respectively. 3 year overall survival and progression-free survival were 45.12% and 31.19%, respectively. Severely acute toxicities included Grade III–IV diarrhoea and granulocytopenia with 9.7% and 8.3% incidence respectively. Small bowel obstruction was severely late toxicity, and the incidence was 1.4%.
Three-dimensional conformal accelerated hyperfractionation field-involved re-irradiation combined with concurrent capecitabine chemotherapy might be an effective and well-tolerated regimen for patients with LRIRC.
Obesity-associated carcinogenesis is postulated to be mediated through the proliferative actions of insulin and the insulin-like growth factor (IGF) family. The aim of this study was to determine whether the insulin/IGF-1 pathway is involved in the sequential progression from metaplastic Barrett's esophagus (BE) to dysplasia to esophageal adenocarcinoma (EAC).
Fasting serum levels of insulin, glucose, IGF-1, insulin growth factor binding protein-1 (IGFBP1), and IGFBP3 were measured in 44 non-dysplastic, 9 low-grade dysplasia (LGD), 12 high-grade dysplasia (HGD), and 10 EAC subjects. Immunohistochemistry was performed on paraffin-embedded tissue derived from BE cases using rabbit monoclonal antibodies to p-mammalian target of rapamycin (mTOR) and p-AKT, mouse monoclonal antibody to Ki-67, and rabbit polyclonal antibody to p-insulin receptor substrate 1 (IRS1).
Nineteen of 44 (43.2%) BE, 5/9 (55%) LGD, 8/12 (66.7%) HGD and EAC 7/10 (70%) cases showed strong staining for p-IRS1. A significantly higher proportion of HGD/EAC subjects showed p-IRS1 staining when compared with BE/LGD subjects, 63.6% vs. 41.5%, P<0.05. p-IRS1 immunostaining was moderately correlated with strong immunostaining of the downstream mediators p-AKT and p-mTOR (Spearman correlation coefficient=0.167 and 0.27 for p-IRS1/p-AKT and for p-IRS1/p-mTOR, respectively) and the proliferation marker Ki-67 (Spearman correlation coefficient=0.20, P=0.09). However, systemic levels of insulin, IGF-1, or IGF-2 were not associated with tissue immunostaining of p-IRS1.
Activation of the insulin/IGF-1 pathway in BE may be associated with cellular proliferation and appears to have a role in the progression from metaplasia to cancer. The activation of the insulin/IGF-1 pathway at the tissue level is likely complex and does not have a simple association with systemic measures of insulin or IGF-1.
Computational mechanics has been advanced in every area of orthopedic biomechanics. The objective of this paper is to provide a general review of the computational models used in the analysis of the mechanical function of the knee joint in different loading and pathological conditions. Major review articles published in related areas are summarized first. The constitutive models for soft tissues of the knee are briefly discussed to facilitate understanding the joint modeling. A detailed review of the tibiofemoral joint models is presented thereafter. The geometry reconstruction procedures as well as some critical issues in finite element modeling are also discussed. Computational modeling can be a reliable and effective method for the study of mechanical behavior of the knee joint, if the model is constructed correctly. Single-phase material models have been used to predict the instantaneous load response for the healthy knees and repaired joints, such as total and partial meniscectomies, ACL and PCL reconstructions, and joint replacements. Recently, poromechanical models accounting for fluid pressurization in soft tissues have been proposed to study the viscoelastic response of the healthy and impaired knee joints. While the constitutive modeling has been considerably advanced at the tissue level, many challenges still exist in applying a good material model to three-dimensional joint simulations. A complete model validation at the joint level seems impossible presently, because only simple data can be obtained experimentally. Therefore, model validation may be concentrated on the constitutive laws using multiple mechanical tests of the tissues. Extensive model verifications at the joint level are still crucial for the accuracy of the modeling.