The recent discovery of active Brown Adipose Tissue (BAT) in adult humans has opened new avenues for obesity research and treatment, as reduced BAT activity seem to be implicated in human energy imbalance, diabetes, and hypertension. However, clinical applications are currently limited by the lack of non-invasive tools for measuring mass and function of this tissue in humans. Here we present a new magnetic resonance imaging method based on the normally invisible intermolecular multiple-quantum coherence 1H MR signal. This method, which doesn’t require special hardware modifications, can be used to overcome partial volume effect, the major limitation of MR-based approaches that are currently being investigated for the detection of BAT in humans. With this method we can exploit the characteristic cellular structure of BAT to selectively image it, even when (as in humans) it is intimately mixed with other tissues. We demonstrate and validate this method in mice using PET scans and histology. We compare this methodology with conventional 1H MR fat fraction methods. Finally, we investigate its feasibility for the detection of BAT in humans.
Background. To explore the potential role of natural-resistance-associated macrophage protein 1 (NRAMP1) gene, vitamin D receptor (VDR) gene, (human leukocyte antigen, (HLA-DRB1) HLA) -DRB1 gene, and HLA-DQB1 gene polymorphisms in susceptibility to tuberculosis (TB) in the Chinese Kazakh population. Methods. A case-control study was performed on the Chinese Kazak population. Genetic polymorphisms of NRAMP1 gene (3′UTR) and VDR gene (TaqI and FokI) were analysed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing analysis in TB patients and healthy controls. Genetic polymorphisms of HLA-DRB1 gene and HLA-DQB1 gene in the two groups were detected with polymerase chain reaction-sequence-specific primers (PCR-SSPs) technique and sequencing analysis. Results. There was statistically significant difference in the 3′UTR polymorphism between the TB patients and healthy controls in the Chinese Kazak population (P = 0.002; OR = 1.859; 95% CI = 1.182–2.926). Significant difference was observed in the FokI polymorphism between the TB patients and healthy controls (P = 0.001; OR = 1.530; 95% CI = 1.007–2.325). It does not disclose any significant association between the disease and TaqI (P > 0.05). Alleles HLA-DRB1∗04 and HLA-DQB1∗0201 occurred more frequently in patients than in controls (P = 0.011 and 0.002; OR = 1.889 and 1.802; 95% CI = 1.153–3.095 and 1.230–2.639, resp.). Conclusions. Polymorphisms in the NRAMP1 gene, VDR gene, HLA-DRB1 gene, and HLA-DQB1 gene are statistically associated with susceptibility to TB in the Chinese Kazakh population.
Wilson's disease (WD) is an autosomal recessive inherited disorder caused by mutations in the ATPase Cu2+ transporting beta polypeptide gene (ATP7B). The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B deficiency were documented. The ATP7B gene was analyzed for mutations in 18 Chinese Han families with WD by direct sequencing. Cell viability and apoptosis analysis of ATP7B small interfering RNA (siRNA)-treated human liver carcinoma (HepG2) cells were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst 33342 staining. Finally, the expression of B-cell CLL/lymphoma 2 (BCL2), BCL2-associated X protein (BAX), sterol regulatory element binding protein 1 (SREBP1), and minichromosome maintenance protein 7 (MCM7) of ATP7B siRNA-treated cells were tested by real-time polymerase chain reaction (real-time PCR) and Western blot analysis. Twenty different mutations including four novel mutations (p.Val145Phe, p.Glu388X, p.Thr498Ser and p.Gly837X) in the ATP7B gene were identified in our families. Haplotype analysis revealed that founder effects for four mutations (p.Arg778Leu, p.Pro992Leu, p.Ile1148Thr and p.Ala1295Val) existed in these families. Transfection of HepG2 cells with ATP7B siRNA resulted in decreased mRNA expression by 86.3%, 93.1% and 90.8%, and decreased protein levels by 58.5%, 85.5% and 82.1% at 24, 48 and 72 hours, respectively (All P<0.01). In vitro study revealed that the apoptotic, cell cycle and lipid metabolism pathway may be involved in the mechanism of WD. Our results revealed that the genetic cause of 18 Chinese families with WD and ATP7B deficiency-induce apoptosis may result from imbalance in cell cycle and lipid metabolism pathway.
Serotonin (5-hydroxytryptamine, 5-HT) signaling is thought to modulate nervous system development. Genetic and pharmacological studies support the idea that altered 5-HT signaling during development can have enduring consequences on brain function and behavior. Recently, we discovered that 5-HT can modulate thalamic axon guidance in vitro and in vivo. Embryonic thalamic axons transiently express the 5-HT transporter (SERT; Slc6a4) and accumulate 5-HT, suggesting that the SERT activity of these axons may regulate 5-HT-modulated guidance cues. We tested whether pharmacologically blocking SERT using selective 5-HT reuptake inhibitors (SSRIs) would impact the action of 5-HT on thalamic axon responses to netrin-1 in vitro. Surprisingly, we observed that two high-affinity SSRIs, racemic citalopram ((RS)-CIT) and paroxetine, affect the outgrowth of embryonic thalamic axons, but differ with respect to their dependence on SERT blockade. Using a recently developed ‘citalopram insensitive' transgenic mouse line and in vitro pharmacology, we show that the effect of (RS)-CIT effect is SERT independent, but rather arises from R-CIT activation of the orphan sigma-1 receptor(σ1, Oprs1). Our results reveal a novel σ1 activity in modulating axon guidance and a 5-HT independent action of a widely prescribed SSRI. By extension, (RS)-CIT and possibly other structurally similar SSRIs may have other off-target actions that can impact neural development and contribute to therapeutic efficacy or side effects.
serotonin; antidepressants; citalopram; SSRI; brain development; sigma-1 receptor; antidepressants; development/developmental disorders; fetal programming; molecular & cellular neurobiology; serotonin; transporters
Recently, melanoma has become the most malignant and commonly occurring skin cancer. Melanoma is not only the major source (75%) of deaths related to skin cancer, but also it is hard to be treated by the conventional drugs. Recent research indicated that angiogenesis is an important factor for tumor initiation, expansion, and response to therapy. Thus, we proposed a novel multi-scale agent-based computational model that integrates the angiogenesis into tumor growth to study the response of melanoma cancer under combined drug treatment.
Our multi-scale agent-based model can simulate the melanoma tumor growth with angiogenesis under combined drug treatment. The significant synergistic effects between drug Dox and drug Sunitinib demonstrated the clinical potential to interrupt the communication between melanoma cells and its related vasculatures. Also, the sensitivity analysis of the model revealed that diffusivity related to the micro-vasculatures around tumor tissues closely correlated with the spread, oscillation and destruction of the tumor.
Simulation results showed that the 3D model can represent key features of melanoma growth, angiogenesis, and its related micro-environment. The model can help cancer researchers understand the melanoma developmental mechanism. Drug synergism analysis suggested that interrupting the communications between melanoma cells and the related vasculatures can significantly increase the drug efficacy against tumor cells.
Microenvironment; Drug synergism; Agent-based model; Multi-scale; Melanoma; Anti-angiogenesis
Salvia splendens Ker-Gawl, most commonly used in China to add a splash of brilliant color to the surroundings during the warm season, is subject to heat stress, which can greatly affect its growth and yield.
To gain a comprehensive understanding of heat-tolerance mechanisms of S. splendens, we assessed the heat-stress responses and characterized the proteomes of leaves from two varieties, Vista (heat resistant) and King (heat sensitive). Denaturing two-dimensional gel electrophoresis (2–DE) and tandem mass spectrometry were used to identify heat-responsive proteins. Heat stress induced the reversible inactivation of photosystem II reaction centers and increased the amounts of antioxidative enzymes, thereby decreasing oxidative damage. Vista leaves had a much greater ability than King leaves to develop light-protective and oxygen-scavenging systems in response to heat stress. More than 1213 leaf proteome spots were reproducibly detected in the gels, with a total of 33 proteins in each leaf type differentially regulated when Salvia splendens were heat stress treated. Of these proteins, 23 and 28 from Vista and King, respectively, were identified.
Most of the identified proteins are involved in photosynthesis, metabolism, protein processing, or stress response, indicating that many different processes work together to establish a new cellular homeostasis in response to heat stress.
In the evaluation of a healthcare system, it is of interest to identify factors associated with the usage of different healthcare facilities and with different levels of medical expenditure.
A survey was conducted in January and February of 2012 in China. It focused on the middle-aged and elderly with age of 45 and above. A total of 2,093 people from 1,152 households were surveyed.
For inpatient treatment, the probability of using grade III hospitals, which had the highest level of care, was positively associated with age, being married, living in urban areas, and having higher income. For outpatient treatment, the probability of using grade III hospitals was positively associated with age, being married, working in enterprises, living in urban areas, living in central and western regions, and having higher income, and negatively associated with being farmers. The total and out-of-pocket (OOP) medical expenses were analyzed separately. It was found that the expense level was associated with age, education, occupation, living in urban areas, type of hospital used, insurance being used, and per capita income.
The access to healthcare and level of medical expenditure were found as associated with demographic characteristics. In addition, differences between areas and regions were observed. Such results may be useful for identifying vulnerable population and for tuning future healthcare development policies.
Double-hit or triple-hit B-cell lymphomas (DHL and THL) are rare subtype lymphomas usually associated with poor prognosis. It is defined by two or three recurrent chromosome translocations; MYC/8q24 loci, usually in combination with the t (14; 18) (q32; q21) bcl-2 gene or/and BCL6/3q27 chromosomal translocation. DHL was often observed both in de-novo diffuse large B cell lymphomas (DLBCL). It is otherwise unclassifiable, showing features intermediate that of large B-cell lymphoma and Burkitt lymphoma. Here, we present two follicular lymphoma patients; one transformed to THL, another transformed to DHL. Both cases revealed aggressive clinical courses with poor prognosis and associated with acquisition of c-Myc gene (MYC) and central nervous system (CNS) involvement. We reviewed the related literature, correlated the immunophenotype and clinical manifestations such as response to therapy and prognosis. Although the incidence of DHT and THL is low, cytogenetic and FISH analyses should be included when B-cell lymphoma patients experience relapse or refractory course of disease. We concluded that c-Myc may contribute to aggressive transformation, and more mechanism-based therapy should be explored.
Double hit; follicular lymphoma; MYC; BCL2; BCL6; cases report
Allogeneic stem cell transplantation (allo-SCT) is a potential cure for patients with malignant lymphoma that is based on the graft-versus-lymphoma (GVL) effect. Myeloablative conditioning allo-SCT is associated with high mortality and morbidity, particularly in patients older than 45 years, heavily pretreated patients (prior hematopoietic stem cell transplantation or more than two lines of conventional chemotherapy) or patients affected by other comorbidities. Therefore, conventional allo-SCT is restricted to younger patients (<50 to 55 years) in good physical condition. Over the last decade, allo-SCT with reduced-intensity conditioning (RIC-allo-SCT) has been increasingly used to treat patients with lymphoma. This treatment is associated with lower toxicity and substantial decrease in the incidence of transplant-related mortality, and has the potential to lead to long-term remissions. Therefore, patients who are not suitable to undergo conventional allo-SCT can benefit from the potentially curative GVL effects of allo-SCT. Although RIC-allo-SCT has improved the survival of lymphoma patients, high post-transplant relapse rates or disease progression mainly results in treatment failure. Thus, further improvement is clearly needed. The role and timing of RIC-allo-SCT in the treatment of lymphoma remains unclear. Therefore, more prospective studies should clarify the effectiveness of this method. In this article, we review the recent literature on RIC-allo-SCT as a treatment for major lymphoma subtypes. Areas that require further investigation in the context of clinical trials are also highlighted.
Reduced intensity conditioning (RIC); allogeneic stem cell transplantation (RIC-allo-SCT); Hodgkin’s lymphoma; indolent lymphoma; aggressive lymphoma
1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea 14a (AR9281), a potent and selective soluble epoxide hydrolase inhibitor, was recently tested in a phase 2a clinical setting for its effectiveness in reducing blood pressure and improving insulin-resistance in pre-diabetic patients. In a mouse model of diet induced obesity, AR9281 attenuated the enhanced glucose excursion following an intraperitoneal glucose tolerance test. AR9281 also attenuated the increase in blood pressure in angiotensin-II-induced hypertension in rats. These effects were dose-dependent and well correlated with inhibition of the sEH activity in whole blood, consistent with a role of sEH in the observed pharmacology in rodents.
Intracellular proteins are degraded by a number of proteases including the ubiquitin-proteasome pathway (UPP). Impairments in the UPP occur during the aging of a variety of tissues, although little is known in regards to age-related alterations to the UPP during the aging of adipose tissue. The UPP is known to be involved in regulating the differentiation of a variety of cell types, although the potential changes in UPP during adipose differentiation have not been fully elucidated. Simultaneously elucidating how the UPP is altered in aging adipose tissue and adipocyte differentiation, and determining the effects of proteasome inhibition on adipocyte homeostasis and differentiation, are critical issues to elucidate experimentally. Adipogenesis continues throughout the life of adipose tissue, with continual differentiation of pre-adipocytes essential to maintaining tissue function during aging, while UPP alterations in mature adipocytes is likely to directly modulate adipose function during aging. In the current study we demonstrate that aging induces alterations in the activity and expression of principal components of the UPP. Additionally, we show that multiple changes in the UPP occur during the differentiation of 3T3-L1 cells into adipocytes. In vitro data link observed UPP alterations to increased levels of oxidative stress and altered adipose biology relevant to both aging and differentiation. Taken together, these data demonstrate that changes in the UPP occur in response to adipose aging and adipogenesis, and strongly suggest that proteasome inhibition is sufficient to decrease adipose differentiation, as well as increase oxidative stress in mature adipocytes, both of which likely promote deleterious effects on adipose aging.
adipocyte; aging; insulin resistance; obesity; proteolysis; ubiquitin; pathology
Iodine deficiency and iodine excess are both associated with adverse health consequences. Iodine deficiency during pregnancy leads to insufficient maternal thyroid hormone, subsequently causing irreversible adverse effects on the neurological and cognitive functions of the offspring. The results of our previous epidemiological study suggested that mild iodine excess might increase the prevalence of subclinical hypothyroidism. In the present study, female Wistar rats maintained on low-iodine grain were randomly assigned to three groups based on iodated water concentration: low iodine (LI, 1.2 μg/d), normal iodine (NI, 5–6 μg/d), and 3-fold high iodine (3HI, 15–16 μg/d). The present study investigated whether higher-than-normal iodine intake (3HI) by rats from before pregnancy until breastfeeding affects the postnatal (PN) neurodevelopment (PN7 and PN45) of their offspring during particularly sensitive periods in brain development.
After 12 weeks of treatment (before pregnancy), iodine concentrations in urine and thyroid tissue and circulating thyroxine of adult females correlated with iodine intake. Brain-derived neurotrophic factor (BDNF) expression in the hippocampi of pups on PN7 and PN45 was decreased in 3HI group compared to the NI controls (P < 0.05, all) On PN7 and PN45, the BDNF levels of the 3HI pups were 83.5% and 88.8%, respectively, that of the NI pups. In addition, the 3HI group had a higher neuroendocrine-specific protein A (NSP-A) level than the NI controls on PN7 (P < 0.05). NSP-A levels of the 3HI pups were 117.0% that of the NI pups. No significant difference was observed in the expressions of c-Fos or c-Jun in the hippocampal CA1 region of the 3HI group compared to the controls (P > 0.05). Results from the Morris water maze test revealed that pups of the 3HI group had mild learning and spatial memory deficits.
The neurodevelopmental and cognitive deficits of the 3HI pups were mild and temporary, likely related to the changes in hippocampal protein expressions of BDNF and NSP-A.
Iodine deficiency; Iodine excess; Thyroid hormone; Hippocampus; Neurodevelopment
The epidermal growth factor receptor (EGFR) signaling pathway and angiogenesis in brain cancer act as an engine for tumor initiation, expansion and response to therapy. Since the existing literature does not have any models that investigate the impact of both angiogenesis and molecular signaling pathways on treatment, we propose a novel multi-scale, agent-based computational model that includes both angiogenesis and EGFR modules to study the response of brain cancer under tyrosine kinase inhibitors (TKIs) treatment.
The novel angiogenesis module integrated into the agent-based tumor model is based on a set of reaction–diffusion equations that describe the spatio-temporal evolution of the distributions of micro-environmental factors such as glucose, oxygen, TGFα, VEGF and fibronectin. These molecular species regulate tumor growth during angiogenesis. Each tumor cell is equipped with an EGFR signaling pathway linked to a cell-cycle pathway to determine its phenotype. EGFR TKIs are delivered through the blood vessels of tumor microvasculature and the response to treatment is studied.
Our simulations demonstrated that entire tumor growth profile is a collective behaviour of cells regulated by the EGFR signaling pathway and the cell cycle. We also found that angiogenesis has a dual effect under TKI treatment: on one hand, through neo-vasculature TKIs are delivered to decrease tumor invasion; on the other hand, the neo-vasculature can transport glucose and oxygen to tumor cells to maintain their metabolism, which results in an increase of cell survival rate in the late simulation stages.
Multi-scale; Agent-based modeling; EGFR signaling pathway; Angiogenesis; TKI treatment
Mutations in amyloid precursor protein (APP) have been most intensely studied in brain tissue for their link to Alzheimer’s disease (AD) pathology. However, APP is highly expressed in a variety of tissues including adipose tissue, where APP is also known to exhibit increased expression in response to obesity. In our current study, we analyzed the effects of mutant APP (E693Q, D694N, K670N/M671L) expression toward multiple aspects of adipose tissue homeostasis. These data reveal significant hypoleptinemia, decreased adiposity, and reduced adipocyte size in response to mutant APP, and this was fully reversed upon high fat diet administration. Additionally, mutant APP was observed to significantly exacerbate insulin resistance, triglyceride elevations, and macrophage infiltration of adipose tissue in response to a high fat diet. Taken together, these data have significant implications for linking mutant APP expression to adipose tissue dysfunction and global changes in endocrine and metabolic function under both obesogenic and non-obesogenic conditions.
Recent studies have demonstrated a potential role for oligomeric forms of beta amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD), although it remains unclear which aspects of AD may be mediated by oligomeric Aβ. In the present study we found that primary cultures of rat cortical neurons exhibit a dose-dependent increase in cell death following Aβ oligomer administration, while primary cultures of astrocytes exhibited no overt toxicity with even the highest concentrations of oligomer treatment. Neither cell type exhibited toxicity when treated by equal concentrations of monomeric Aβ. The neuron death induced by oligomer treatment was associated with an increase in reactive oxygen species (ROS), altered expression of mitochondrial fission and fusion proteins, and JUN kinase activation. Pharmacological inhibition of JUN kinase ameliorated oligomeric Aβ toxicity in neurons. These data indicate that oligomeric Aβ is sufficient to selectively induce toxicity in neurons, but not astrocytes, with neuron death occurring in a JUN kinase-dependent manner. Additionally, these observations implicate a role for oligomeric Aβ as a contributor to neuronal oxidative stress and mitochondrial disturbances in AD.
Alzheimer’s disease; beta amyloid; neurotoxicity; protein oxidation
Mutations in the MECP2 gene cause the autism spectrum disorder Rett Syndrome (RTT). One of the most common mutations associated with RTT occurs at MeCP2 Threonine 158 converting it to Methionine (T158M) or Alanine (T158A). To understand the role of T158 mutation in the pathogenesis of RTT, we generated knockin mice recapitulating MeCP2 T158A mutation. Here we show a causal role for T158A mutation in the development of RTT-like phenotypes including developmental regression, motor dysfunction, and learning and memory deficits. These phenotypes resemble those in Mecp2-null mice and manifest through a reduction in MeCP2 binding to methylated DNA and a decrease in MeCP2 protein stability. Importantly, the age-dependent development of event-related neuronal responses are disrupted by MeCP2 mutation, suggesting that impaired neuronal circuitry underlies the pathogenesis of RTT and that assessment of event-related potentials may serve as a biomarker for RTT and treatment evaluation.
The development of pancreatic cancer is a process in which genes interact with environmental factors. We performed this study to determine the effects of the ABO blood group, obesity, diabetes mellitus, metabolic syndrome (MetS), smoking, alcohol consumption and hepatitis B viral (HBV) infection on patient survival.
A total of 488 patients with pancreatic cancer were evaluated.
Patients who presented as chronic carriers of HBV infection were younger at disease onset (p = 0.001) and more predominantly male (p = 0.020) than those never exposed to HBV. Patients with MetS had later disease staging (p = 0.000) and a lower degree of pathological differentiation (p = 0.008) than those without MetS. In a univariate analysis, the ABO blood group, smoking and alcohol consumption were not associated with overall survival. HBsAg–positivity and elevated fasting plasma glucose were significantly associated with unfavorable survival though not in the multivariate analysis. The presence of MetS (HR: 1.541, 95% CI: 1.095–2.169, p = 0.013), age ≥65, an elevated CA19–9 baseline level, TNM staging, the type of surgery, the degree of differentiation and chemotherapy were independently associated with overall survival.
We report, for the first time, that patients with chronic HBV infection may represent a special subtype of pancreatic cancer, who have a younger age of disease onset and male dominancy. Patients with MetS had later disease staging and a poorer histological grade. Patients with MetS demonstrated significantly poorer survival.
The present study aimed to investigate the genetic polymorphisms in exon 4 of the NOD2 gene in tuberculosis patients and healthy controls, in order to clarify whether polymorphisms in the NOD2 gene is associated with tuberculosis.
A case-control study was performed on the Chinese Han, Uygur and Kazak populations. Exon 4 of the NOD2 gene was sequenced in 425 TB patients and 380 healthy controls to identify SNPs.
The frequency of T/G genotypes for the Arg587Arg (CGT → CGG) single nucleotide polymorphism (SNP) in NOD2 was found to be significantly higher in the Uygur (34.9%) and Kazak (37.1%) populations than the Han population (18.6%). Also, the frequency of G/G genotypes for the Arg587Arg SNP was significantly higher in the Uyghur (8.3%) and Kazak (5.4%) populations than the Han population (0.9%). Meanwhile, no significant difference was found in the Arg587Arg polymorphism between the tuberculosis patients and healthy controls in the Uyghur and Kazak populations (P > 0.05) whereas, a significant difference was observed in the Arg587Arg polymorphism between the tuberculosis patients and healthy controls in the Han population (P < 0.01). The odd ratio of 2.16 (95% CI = 1.31-3.58; P < 0.01) indicated that the Arg587Arg SNP in NOD2 may be associated with susceptibility to tuberculosis in the Chinese Han population.
Our study is the first to demonstrate that the Arg587Arg SNP in NOD2 is a new possible risk factor for tuberculosis in the Chinese Han population, but not in the Uyghur and Kazak populations. Our results may reflect racial differences in genetic susceptibility to tuberculosis.
NOD2; Arg587Arg SNP; Tuberculosis; Chinese Han; Uyghur; Kazak
AIM: To investigate the association between the polymorphism of TBX21 gene and the risk of gastric cancer in a Chinese population.
METHODS: The -1993 polymorphism located in TBX21 gene promoter region was identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The risk between TBX21 gene genotype and gastric cancer was determined by multivariate logistic regression analysis in 220 gastric cancer patients and 262 cancer-free controls matched by age, sex and ethnicity.
RESULTS: Compared with the TBX21 -1993TT genotype, the -1993CC genotype exhibited a significantly elevated risk for gastric cancer [Odds ratio (OR) = 3.42, 95% confidence interval (CI): 1.41-8.31]. The relationship between the -1993 polymorphic genotype and the invasive status such as lymph node and distant metastasis was found among the gastric cancer patients (OR = 4.02, 95% CI: 1.87-8.66; OR = 7.02, 95% CI: 3.44-14.34, respectively).
CONCLUSION: TBX21 -1993 polymorphism might contribute to the risk of gastric cancer, especially to the distant metastasis.
TBX21 gene; Gastric cancer; Polymorphism; Genetic susceptibility; Association analysis
Persistent hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC) development. This study aimed to clarify whether the high HBV DNA level is associated with HCC development by comparing HBV DNA levels between HBV infected patients with and without HCC.
There were 78 male and 12 female patients in each group and there was no statistical difference between these two group patients' average ages. The HBV DNA level in the HCC patients was 4.73 ± 1.71 Log10 IU/ml while 3.90 ± 2.01 Log10 IU/ml in non-HCC patients (P < 0.01). The HBeAg positive rate was 42.2% (38/90) in the HCC group while 13.3% (12/90) in the non-HCC group (P < 0.001). Compared with patients with HBV DNA level of < 3 Log10 IU/ml, the patients with level of 3 to < 4, 4 to < 5, 5 to < 6, or ≥ 6 Log10 IU/ml had the odds ratio for HCC of 1.380 (95% CI, 0.544-3.499), 3.671 (95% CI, 1.363-9.886), 5.303 (95% CI, 1.847-15.277) or 3.030 (95% CI, 1.143-8.036), respectively.
HBV-related HCC patients had higher HBV DNA level than non-HCC counterparts. Our findings imply that active HBV replication is associated with the HCC development.
Multiscale agent-based modeling (MABM) has been widely used to simulate Glioblastoma Multiforme (GBM) and its progression. At the intracellular level, the MABM approach employs a system of ordinary differential equations to describe quantitatively specific intracellular molecular pathways that determine phenotypic switches among cells (e.g. from migration to proliferation and vice versa). At the intercellular level, MABM describes cell-cell interactions by a discrete module. At the tissue level, partial differential equations are employed to model the diffusion of chemoattractants, which are the input factors of the intracellular molecular pathway. Moreover, multiscale analysis makes it possible to explore the molecules that play important roles in determining the cellular phenotypic switches that in turn drive the whole GBM expansion. However, owing to limited computational resources, MABM is currently a theoretical biological model that uses relatively coarse grids to simulate a few cancer cells in a small slice of brain cancer tissue. In order to improve this theoretical model to simulate and predict actual GBM cancer progression in real time, a graphics processing unit (GPU)-based parallel computing algorithm was developed and combined with the multi-resolution design to speed up the MABM. The simulated results demonstrated that the GPU-based, multi-resolution and multiscale approach can accelerate the previous MABM around 30-fold with relatively fine grids in a large extracellular matrix. Therefore, the new model has great potential for simulating and predicting real-time GBM progression, if real experimental data are incorporated.
At the dawn of the era of personalized, systems-driven medicine, computational or in silico modeling and the simulation of disease processes is becoming increasingly important for hypothesis generation and data integration in both experiment and clinics alike. Arguably, this is nowhere more visible than in oncology. To illustrate the field’s vast potential as well as its current limitations we briefly review selected works on modeling malignant brain tumors. Implications for clinical practice, including trial design and outcome prediction are also discussed.
brain tumor; computational biology; in silico cancer modeling; systems biology
Due to the lack of specific clinical manifestations and imaging features, the diagnosis of pulmonary mycosis is difficult. This study aimed to investigate the pathogens, clinical manifestations, imaging features, diagnosis and management of pulmonary mycosis.
Data on 68 patients diagnosed as pulmonary mycosis in Xiang Ya hospital from January 2001 to December 2010 were collected and their clinical manifestations, radiographic characterization, diagnostic methods and management were analyzed.
All patients were diagnosed by pathological examination. Of the 68 cases, 38 (55.9%) had pulmonary aspergillosis and 19 (27.9%) pulmonary cryptococcosis. Open-lung surgery was performed in 38 patients (55.9%), transbronchial biopsy in 15 (22.0%), and computerized tomography (CT) guided percutaneous needle biopsy in 11 (16.2%). Main symptoms were as follows: cough in 51 cases (75.0%), expectoration in 38 (55.9%), hemoptysis in 25 (37.8%), fever in 20 (29.4%), while 6 cases (11.1%) were asymptomatic. X-ray and chest CT showed masses or nodular lesions in 52 cases (76.5%), patchy lesions in 10 (14.7%), cavity formation in 15 (22.0%), and diffuse miliary nodules in 1 case. In 51 cases (75.0%) misdiagnosis before pathological examination occurred. Surgical resection was performed in 38 patients (55.9%). In 25 patients (36.7%) systemic antifungal therapy was administered, and 20 patients (29.4%) experienced complete responses or partial responses.
The main pathogens of pulmonary mycosis are Aspergillus, followed by cryptococcosis. Final diagnosis of pulmonary mycosis mainly depends on pathological examination. The clinical manifestations, imaging features, diagnostic methods and management differ depending on the pathogens. Satisfactory therapy can be obtained by both antifungal and surgical treatment.
Clinical manifestations; imaging features; pulmonary mycosis.