To explore the neural mechanisms of negative emotion regulation in patients with post-traumatic stress disorder (PTSD).
Twenty PTSD patients and 20 healthy subjects were recruited. Event-related functional magnetic resonance imaging (fMRI) was used to investigate the modification of emotional responses to negative stimuli. Participants were required to regulate their emotional reactions according to the auditory regulation instructions via headphones, to maintain, enhance or diminish responses to negative stimuli during fMRI scans.
The PTSD group showed poorer modification performance than the control group when diminishing responses to negative stimuli. On fMRI, the PTSD group showed decreased activation in the inferior frontal cortex, inferior parietal lobule, insula and putamen, and increased activation in posterior cingulate cortex and amygdala during up-regulation of negative emotion. Similar decreased activation regions were found during down-regulation of negative emotion, but no increased activation was found.
Trauma exposure might impair the ability to down-regulate negative emotion. The present findings will improve our understanding of the neural mechanisms of emotion regulation underlying PTSD.
We aimed to assess the effectiveness and feasibility of head-and-neck Computed Tomography Angiography (CTA) with low tube voltage and low concentration contrast media combined with iterative reconstruction algorithm.
92 patients were randomly divided into group A and B: patients in group A received a conventional scan with 120 kVp and contrast media of 320 mgI/ml. Patients in group B, 80 kVp and contrast media of 270 mgI/ml were used along with iterative reconstruction algorithm techniques. Image quality, radiation dose and the effectively consumed iodine amount between two groups were analyzed and compared.
Image quality of CTA of head-and-neck vessels obtained from patients in group B was significantly improved quantitatively and qualitatively. In addition, CT attenuation values in group B were also significantly higher than that in group A (p<0.001). Furthermore, compared with the protocol whereby 120 kVp and 320 mgI/dl were administrated, the mean radiation dose and consumed iodine amount in protocol B were also reduced by 50% and 15.6%, respectively (p<0.001).
With the help of iterative reconstruction algorithm techniques, the head-and-neck CTA with diagnostic quality can be adequately acquired with low tube voltage and low concentration contrast media. This method could be potentially extended to include any part of the body to reduce the risks related to ionizing radiation.
Artery stiffening is known as an important pathological change that precedes small vessel dysfunction, but underlying cellular mechanisms are still elusive. This paper reports the development of a flow co-culture system that imposes a range of arterial-like pulse flow waves, with similar mean flow rate but varied pulsatility controlled by upstream stiffness, onto a 3-D endothelial-smooth muscle cell co-culture. Computational fluid dynamics results identified a uniform flow area critical for cell mechanobiology studies. For validation, experimentally measured flow profiles were compared to computationally simulated flow profiles, which revealed percentage difference in the maximum flow to be <10, <5, or <1% for a high, medium, or low pulse flow wave, respectively. This comparison indicated that the computational model accurately demonstrated experimental conditions. The results from endothelial expression of proinflammatory genes and from determination of proliferating smooth muscle cell percentage both showed that cell activities did not vary within the identified uniform flow region, but were upregulated by high pulse flow compared to steady flow. The flow system developed and characterized here provides an important tool to enhance the understanding of vascular cell remodeling under flow environments regulated by stiffening.
Electronic supplementary material
The online version of this article (doi:10.1007/s10616-012-9445-2) contains supplementary material, which is available to authorized users.
Arterial stiffening; Co-culture; Flow culture chamber; Flow pulsatility; Shear stress
It has been suggested that paclitaxel and gemcitabine modulate the immune system. This paper reports the safety and efficacy of paclitaxel plus gemcitabine followed by interleukin-2 (IL-2)and granulocyte macrophage colony-stimulating factor (GM-CSF), the PGIG chemobiotherapy, for patients with metastatic melanoma. All patients received 175 mg/m2 paclitaxel on day 1 and 800 mg/m2 gemcitabine on day two. IL-2 and GM-CSF were administered from day 4 to day 8 at a dosage of 2 MIU/m2 and 100 μg, respectively. The PGIG chemobiotherapy was repeated every 21 d. Serum cytokine levels at baseline and at the end of the second cycle were measured via flow cytometry. Twenty-seven patients with metastatic melanoma accepted PGIG chemobiotherapy from August 2009 to March 2011. There were five patients that exhibited a partial response, 14 patients that exhibited a stable response and eight that displayed progressive disease. Therefore, the response rate was 18.5%, and the disease control rate was 70.4%. The median time to progression and median survival were 4 mo and 8 mo, respectively. The one-year and two-year survival rates were 25.9% and 18.5%, respectively. Frequent side effects included chills, fever, arthralgia, rash and pruritus. Among the 13 patients who experienced a rash and pruritus and the 14 patients who did not suffer from this side effect, the response rates and disease control rates were 30.8% vs 7.1% and 77% vs 64.2%, respectively. No relationship between serum IL-6 levels, clinical response, and either skin side effect was observed. The PGIG chemobiotherapy is safe and effective for the treatment of patients with advanced melanoma, but randomized trials are necessary to validate this effect.
chemobiotherapy; metastatic melanoma; paclitaxel; pruritus; rash; gemcitabine; pilot study
Pancreatic cancers are typically resistant to chemo and radiation therapy and are predisposed to distant metastases. Circulating tumor cells (CTCs) are tumor cells disseminated from primary and metastatic sites and can be isolated from peripheral blood. CTC may overcome the limitation of the current available tumor markers, CA19-9. As a surrogate for ‘real-time biopsy’, CTCs allow recurrent assessment of a tumor’s biological activity. We review the current methodologies for CTCs extraction and characterization including antibody-based immunological assays, PCR-based assays, and novel technologies based on the physical or biological characteristics of CTCs. CTCs also provide an accessible link to the existence of epithelial to mesenchymal transition, tumor stem cell markers, and ongoing clonal mutations and epigenetic changes in the tumor. We also explore the potential of using CTC profiling in diagnosis, selection of neoadjuvant and adjuvant therapy, detection of recurrent disease, examination of pharmacodynamic biomarkers, as well as in gene therapy and immunotherapy for pancreatic cancer. Ongoing CTC characterization not only has the potential to represent all cells shed from primary pancreatic tumor and each metastatic site, but also allows dynamic sampling at multiple time points during the clinical course to identify the subpopulations of CTCs and the specific molecules driving metastasis and chemo resistance. We predict that CTC genotyping and phenotyping will play an increasing role in personalized therapy and in identification of novel therapeutic targets as well as monitoring the course and status of the disease.
circulating tumor cells; pancreatic cancer
Pancreatic cancer is the fourth leading cause of cancer related deaths in North America. The poor survival statistics are due to the fact that there are no reliable tests for early diagnosis and no effective therapies once metastasis has occurred. Surgical resection is the only curative treatment for pancreatic cancer; however, only less than 15% of the patients are eligible for surgery at diagnosis. New therapies are urgently needed for this malignant disease. And combinational therapy including surgery, chemotherapy and molecular targeted therapy may further improve the efficacy of individual therapies. However, a reliable mouse model which mimics the human disease and can be used for testing the surgical treatment and surgery-based combinational therapy is not available. In this study, we have established a mouse model for curative surgical resection of pancreatic cancer. Human pancreatic cancer cells were used to create orthotopic xenografts in nude mice, distal pancreatectomy was performed using imaging-guided technology to remove the pancreatic tumors, and sham surgery was performed in the control group. All mice survived the operation and no complication was observed. Surgical resection at early stage improved the survival rate and quality of life of the mice compared with the sham surgery and surgical resection at the late stage. If combined with other therapies such as chemotherapy and molecular targeted therapy, it could further improve the outcome of pancreatic cancer. This mouse model is a useful tool to study the surgical therapy and the tumor recurrence of pancreatic cancer, and could potentially impact the therapeutic choices for this deadly disease.
surgical resection; imaging; pancreatic cancer; mouse model; distal pancreatectomy; combinational therapy
Bone marrow-derived macrophages (BMMs) treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF), differentiate into GM-CSF-induced mouse bone marrow-derived macrophages (GM-BMMs) or M-CSF-induced mouse bone marrow-derived macrophages (M-BMMs), which have an M1 or M2 profile, respectively. GM-BMMs produce large amounts of proinflammatory cytokines and mediate resistance to pathogens, whereas M-BMMs produce anti-inflammatory cytokines that contribute to tissue repair and remodeling. M-BMMs stimulated with lipopolysaccharide (LPS) are in an antiinflammatory state, with an IL-12low IL-10high phenotype. However, the regulation of this process remains unclear. Klf10 belongs to the family of Krüppel-like transcription factors and was initially described as a TGF-β inducible early gene 1. IL-12p40 is upregulated in LPS-stimulated M-BMMs from Klf10-deficient mice, but downregulated during Klf10 overexpression. Klf11, another member of the Krüppel-like factor family, can also repress the production of IL-12p40. Furthermore, Klf10 binds to the CACCC element of the IL-12p40 promoter and inhibits its transcription. We have therefore identified Klf10 as a transcription factor that regulates the expression of IL-12p40 in M-BMMs.
IL-12p40; Inflammatory factor; Klf10; Macrophage; Transcription factor
Kawasaki disease (KD) is pediatric systemic vasculitis with the classic complication of coronary artery aneurysm (CAA). It is the leading cause of acquired cardiovascular diseases in children. Some severe cases present with multi-organ involvement or neurological dysfunction. To identify the role of the glutamate receptor, ionotropic, N-methyl-d-aspartate 3A (GRIN3A) in KD, we investigated genetic variations in GRIN3A in a Taiwanese cohort of 262 KD patients (76 with and 186 without CAA complications). We used univariate and multivariate regression analyses to identify the associations between clinical characteristics and GRIN3A genetic variations in KD. According to univariate regression analysis, CAA formation in KD was significantly associated with fever duration (p < 0.0001), first Intravenous immunoglobulin (IVIG) used (days after day one of fever) (p < 0.0001), and the GRIN3A (rs7849782) genetic variant (p < 0.001). KD patients with GG+GC genotype showed a lower rate of developing CAA (GG+GC genotype: odds ratio = 0.26; 95% CI = 0.14–0.46). Significant associations were identified between KD with CAA complication and the GRIN3A (rs7849782) genetic variant by using multivariate regression analysis. Specifically, significant correlations were observed between KD with CAA complications and the presence of GG+GC genotypes for the GRIN3A rs7849782 single-nucleotide polymorphism (full model: odds ratio = 0.25; 95% CI = 0.14–0.46). Our results suggest that a polymorphism of the GRIN3A gene may play a role in KD pathogenesis.
Enterovirus 71 (EV71) has caused several epidemics of hand, foot and mouth diseases (HFMD) in Asia. No effective EV71 vaccine is available. A randomized and open-label phase I clinical study registered with ClinicalTrials.gov #NCT01268787, aims to evaluate the safety, reactogenicity and immunogenicity of a formalin-inactivated EV71 vaccine candidate (EV71vac) at 5- and 10-µg doses. In this study we report the cross-neutralizing antibody responses from each volunteer against different subgenotypes of EV71 and CVA16.
Sixty eligible healthy adults were recruited and vaccinated. Blood samples were obtained on day 0, 21 and 42 and tested against B1, B4, B5, C2, C4A, C4B and CVA16 for cross-neutralizing antibody responses.
The immunogenicity of both 5- and 10- µg doses were found to be very similar. Approximately 45% of the participants had <8 pre-vaccination neutralization titers (Nt) against the B4 vaccine strain. After the first EV71vac immunization, 95% of vaccinees have >4-fold increase in Nt, but there was no further increase in Nt after the second dose. EV71vac induced very strong cross-neutralizing antibody responses in >85% of volunteers without pre-existing Nt against subgenotype B1, B5 and C4A. EV71vac elicited weak cross-neutralizing antibody responses (∼20% of participants) against a C4B and Coxsackie virus A16. Over 90% of vaccinated volunteers did not develop cross-neutralizing antibody responses (Nt<8) against a C2 strain. EV71vac can boost and significantly enhance the neutralizing antibody responses in volunteers who already had pre-vaccination antibodies against EV71 and/or CVA16.
EV71vac is efficient in eliciting cross-neutralizing antibody responses against EV71 subgenotypes B1, B4, B5, and C4A, and provides the rationale for its evaluation in phase II clinical trials.
The Japanese National Hospital Organization evidence-based medicine (EBM) Study group for Adverse effects of Corticosteroid therapy (J-NHOSAC) is a Japanese hospital-based cohort study investigating the safety of the initial use of glucocorticoids (GCs) in patients with newly diagnosed autoimmune diseases. Using the J-NHOSAC registry, the purpose of this observational study is to analyse the rates, characteristics and associated risk factors of intracellular infections in patients with newly diagnosed autoimmune diseases who were initially treated with GCs.
A total 604 patients with newly diagnosed autoimmune diseases treated with GCs were enrolled in this registry between April 2007 and March 2009. Cox proportional-hazards regression was used to determine independent risk factors for serious intracellular infections with covariates including sex, age, co-morbidity, laboratory data, use of immunosuppressants and dose of GCs. Survival was analysed according to the Kaplan-Meier method and was assessed by the log-rank test. There were 127 serious infections, including 43 intracellular infections, during 1105.8 patient-years of follow-up. The 43 serious intracellular infections resulted in 8 deaths. After adjustment for covariates, diabetes (Odds ratio [OR]: 2.5, 95% confidence interval [95% CI] 1.1–5.9), lymphocytopenia (≦1000/μl, OR: 2.5, 95% CI 1.2–5.2) and use of high-dose (≧30 mg/day) GCs (OR: 2.4, 95% CI 1.1–5.3) increased the risk of intracellular infections. Survival curves showed lower intracellular infection-free survival rate in patients with diabetes, lymphocytopaenia and high-dose GCs treatments.
Patients with newly diagnosed autoimmune diseases were at high risk of developing intracellular infection during initial treatment with GCs. Our findings provide background data on the risk of intracellular infections of patients with autoimmune diseases. Clinicians showed remain vigilant for intracellular infections in patients with autoimmune diseases who are treated with GCs.
The human mitochondrial ATP-dependent Lon protease functions in regulating the metabolism and quality control of proteins and mitochondrial DNA (mtDNA). However, the role of Lon in cancer is not well understood. Therefore, this study was undertaken to investigate the importance of Lon in cervical cancer cells from patients and in established cell lines. Microarray analysis from 30 cancer and 10 normal cervical tissues were analyzed by immunohistochemistry for Lon protein levels. The expression of Lon was also examined by immunoblotting 16 fresh cervical cancer tissues and their respective non-tumor cervical tissues. In all cases, Lon expression was significantly elevated in cervical carcinomas as compared to normal tissues. Augmented Lon expression in tissue microarrays did not vary between age, tumor-node-metastasis grades, or lymph node metastasis. Knocking down Lon in HeLa cervical cancer cells by lentivrial transduction resulted in a substantial decrease in both mRNA and protein levels. Such down-regulation of Lon expression significantly blocked HeLa cell proliferation. In addition, knocking down Lon resulted in decreased cellular bioenergetics as determined by measuring aerobic respiration and glycolysis using the Seahorse XF24 extracellular flux analyzer. Together, these data demonstrate that Lon plays a potential role in the oncogenesis of cervical cancer, and may be a useful biomarker and target in the treatment of cervical cancer. Lon; immunohistochemistry; cervical cancer; cell proliferation; cellular bioenergetics.
Dynamic structural and functional remodeling of the Central Nervous System occurs throughout the lifespan of the organism from the molecular to the systems level. MRI offers several advantages to observe this phenomenon: it is non-invasive and non-destructive, the contrast can be tuned to interrogate different tissue properties and imaging resolution can range from cortical columns to whole brain networks in the same session.
To measure these changes reliably, functional maps generated over time with high resolution fMRI need to be registered accurately. This article presents a new method for the automatic registration of thin cortical MR volumes that are aligned with the functional maps. These acquisitions focus on the primary somato-sensory cortex, a region in the anterior parietal part of the brain, responsible for fine touch and proprioception.
Currently, these slabs are acquired in approximately the same orientation from acquisition to acquisition and then registered by hand. Because they only cover a small portion of the cortex, their direct automatic registration is difficult. To address this issue, we propose a method relying on an intermediate image, acquired with a surface coil that covers a larger portion of the head to which the slabs can be registered. Because images acquired with surface coils suffer from severe intensity attenuation artifact, we also propose a method to register these. The results from data sets obtained with 3 squirrel monkeys show a registration accuracy of 30 micrometers.).
Rigid registration; longitudinal studies; attenuation artifacts in MR; primates
There is a need for radioprotectors that protect normal tissues from ionizing radiation in patients receiving high doses of radiation and during nuclear emergencies. We investigated the possibility of creating an efficient oral radioprotector based on the natural pigment melanin that would act as an internal shield and protect the tissues via Compton scattering followed by free radical scavenging. CD-1 mice were fed melanin-containing black edible mushrooms Auricularia auricila-judae before 9 Gy total body irradiation. The location of the mushrooms in the body before irradiation was determined by in vivo fluorescent imaging. Black mushrooms protected 80% of mice from the lethal dose, while control mice or those given melanin-devoid mushrooms died from gastrointestinal syndrome. The crypts of mice given black mushrooms showed less apoptosis and more cell division than those in control mice, and their white blood cell and platelet counts were restored at 45 days to preradiation levels. The role of melanin in radioprotection was proven by the fact that mice given white mushrooms supplemented with melanin survived at the same rate as mice given black mushrooms. The ability of melanin-containing mushrooms to provide remarkable protection against radiation suggests that they could be developed into oral radioprotectors.
apoptosis; black mushrooms; GI syndrome; melanin; radioprotection
The underlying mechanism of ischemic stroke is not completely known. Regulatory T cells (Tregs), a subset of T cells, play a pivotal role in the pathophysiological process of ischemic stroke. However, there is also controversy over the role of Tregs in stroke. Hence, the function of Tregs in ischemic stroke has triggered a heated discussion recently. In this paper, we reviewed the current lines of evidence to describe the full view of Tregs in stroke. We would like to introduce the basic concepts of Tregs and then discuss their paradox function in ischemic stroke. On one side, Tregs could protect brain against ischemic injury via modulating the inflammation process. On the other side, they exaggerated the insult by causing microvascular dysfunction. They also interfered with the neurological function recovery. In addition, the reasons for this paradox role would be discussed in the review and the prospective of the clinical application of Tregs was also included. In conclusion, Tregs contributed to the outcome of ischemic stroke, while more lines of evidence are needed to understand how Tregs regulate the immune system and influence the outcome of stroke.
To analyze the significance of endoplasmic reticulum stress (ERS) in the development of diethylnitrosamine (DEN)-induced liver cancer in rats, critical regulatory factors in ERS signaling pathways were investigated in the present study. The results showed that the expression of ERS-related proteins gradually increased in the early and mid-term stages of carcinogenesis, while in the later stages, the expression of these proteins did not change significantly after reaching a peak. ERS is involved in DEN-induced rat liver injury, the proliferation of liver cells and the occurrence and development of liver cirrhosis. However, ERS did not affect hepatoma cell growth following the formation of rat liver cancer in the current study.
endoplasmic reticulum stress; diethylnitrosamine; rats; liver cancer
Diabetes mellitus (DM) is one of the primary causes of premature death and disability worldwide. We performed a systematic review and meta-analysis of the published literature regarding the trends in prevalence, awareness, treatment, and control of diabetes mellitus in mainland China. PUBMED, EMBASE, Chinese Biomedical Database, China National Infrastructure database, Chinese Wan Fang database, and Chongqing VIP database were searched. Fifty-six eligible studies were included. Increasing trends in the prevalence, treatment, and control of diabetes in mainland China from 1979 to 2012 were observed. The pooled prevalence, awareness, treatment, and control of diabetes mellitus were 6.41%, 45.81%, 42.54%, and 20.87%, respectively. A higher prevalence of diabetes mellitus was found in urban (7.48%, 95%CI = 5.45~9.50) than rural (6.53%, 95%CI = 4.30~8.76) areas. Furthermore, an increasing chronological tendency was shown in different subgroups of age with regard to the prevalence of diabetes. A higher awareness of DM was found in urban (44.25%, 95%CI = 32.60~55.90) than rural (34.27%, 95%CI = 21.00~47.54) populations, and no significant differences were found in the treatment, and control of diabetes among the subgroups stratified by gender and location. From 1979 to 2012, the prevalence, treatment, and control of diabetes mellitus increased; nevertheless, there was no obvious improvement in the awareness of diabetes.
Diabetic peripheral neuropathy (DPN) is a common microvascular complication of diabetes associated with high disability rate and low quality of life. Tang-Luo-Ning (TLN) is an effective traditional Chinese medicine for the treatment of DPN. To illustrate the underlying neural protection mechanisms of TLN, the effect of TLN on electrophysiology and sciatic nerve morphology was investigated in a model of streptozotocin-induced DPN, as well as the underlying mechanism. Sciatic motor nerve conduction velocity and digital sensory nerve conduction velocity were reduced in DPN and were significantly improved by TLN or α-lipoic acid at 10 and 20 weeks after streptozotocin injection. It was demonstrated that TLN intervention for 20 weeks significantly alleviated pathological injury as well as increased the phosphorylation of ErbB2, Erk, Bad (Ser112), and the mRNA expression of neuregulin 1 (Nrg1), GRB2-associated binding protein 1 (Gab1), and mammalian target of rapamycin (Mtor) in injured sciatic nerve. These novel therapeutic properties of TLN to promote Schwann cell survival may offer a promising alternative medicine for the patients to delay the progression of DPN. The underlying mechanism may be that TLN exerts neural protection effect after sciatic nerve injury through Nrg1/ErbB2→Erk/Bad Schwann cell survival signaling pathway.
To investigate the contributions of adenoid and tonsil size to childhood obstructive sleep apnea (OSA) and the interactions between adenotonsillar hypertrophy, age, and obesity in children with OSA.
In total, 495 symptomatic patients were recruited. The patients were assigned to four groups according to age：toddler (age 1-3, n=42), preschool (age 3-6, n=164), school (age 6-12, n=200), and adolescence (age 12-18, n=89). All subjects had tonsil size graded by otolaryngologists, adenoid size determined on lateral radiographs (Fujioka method), and a full-night polysomnography. The apnea-hypopnea index (AHI), adenoid size, and tonsil size were compared in obese and non-obese children in the four age groups. Adjusted odds ratios (ORs) and 95% confidence interval (CI) of adenotonsillar hypertrophy and OSA risk were estimated by multi-logistic regression.
The AHI was positively related to tonsil grade (r=0.33, p <0.001) and adenoid size (r=0.24, p <0.01) in all patients. Tonsil grade was positively related to AHI in all four age groups. Adenoid size was positively related to AHI in the toddler, preschool, school groups, but not in the adolescent group (r=0.11, p=0.37). Tonsil grade and adenoid size were both positively related to AHI in obese and non-obese children. In the regression model, obesity (OR=2.89; 95% CI 1.47-5.68), tonsillar hypertrophy (OR=3.15; 95% CI 2.04-4.88), and adenoidal hypertrophy (OR=1.89; 95% CI 1.19-3.00) significantly increased OSA risk.
Adenotonsillar hypertrophy and obesity are the major determinants of OSA in children. However, the influence of adenoid size decreases in adolescence.
The neuronal PAS domain protein 4 (Npas4) is a transcription factor that is almost exclusively expressed in the mammalian brain. As an activity-dependent transcription factor, Npas4 regulates the transcription of discrete genes and transcriptionally controls the experience-dependent learning and memory. In this study, we explored the impact of the psychostimulant amphetamine (AMPH) on Npas4 protein expression in the rat striatum. We found that acute systemic injection of AMPH had a minimal effect on protein levels of Npas4 in the caudate putamen (CPu) and nucleus accumbens (NAc), while AMPH readily increased protein products of the immediate early gene c-Fos in these regions. In contrast, repeated administration of AMPH (5 mg/kg, once daily for 5 days) triggered a significant increase in Npas4 expression in the NAc, although repeated AMPH did not alter Npas4 in the CPu. These data demonstrate that Npas4 is an AMPH-sensitive transcription factor. It is inducible selectively in the NAc in response to repeated AMPH administration.
Immediate early gene; transcription factor; c-Fos; Le-PAS; NXF; PASD10; striatum; caudate
Astragalus memebranaceus is a traditional Chinese herbal medicine used in treatment of common cold, diarrhea, fatigue, anorexia and cardiac diseases. Recently, there are growing evidences that Astragalus extract may be a potential anti-tumorigenic agent. Some research showed that the total saponins obtained from Astragalus membranaceus possess significant antitumorigenic activity. Gastric cancer is one of the most frequent cancers in the world, almost two-thirds of gastric cancer cases and deaths occur in less developed regions. But the effect of Astragalus membranaceus on proliferation, invasion and apoptosis of gastric cancer BGC-823 cells remains unclear.
Astragalus saponins were extracted. Cells proliferation was determined by CCK-8 assay. Cell cycle and apoptosis were detected by the flow cytometry. Boyden chamber was used to evaluate the invasion and metastasis capabilities of BGC-823 cells. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice.
The results demonstrated that total Astragalus saponins could inhibit human gastric cancer cell growth both in vitro and in vivo, in additional, Astragalus saponins deceased the invasion ability and induced the apoptosis of gastric cancer BGC-823 cells.
Total Astragalus saponins inhibited human gastric cancer cell growth, decreased the invasion ability and induced the apoptosis. This suggested the possibility of further developing Astragalus as an alternative treatment option, or perhaps using it as adjuvant chemotherapeutic agent in gastric cancer therapy.
Gastric cancer; Proliferation; Invasion; Apoptosis
NMO and ATM are intertwined both clinically and pathologically. Apolipoprotein (apo) A-I, the main apolipoprotein of HDL, plays an important role in lipid metabolism in the cerebrospinal fluid and is known to suppress pro-inflammatory cytokines generated by activated T cells in some autoimmune diseases as an immune regulator. However, the differences in the levels of serum apoA-I between NMO and ATM patients are unclear.
In the present study, serum apo A-I levels were measured in 53 NMO patients, 45 ATM patients and 49 healthy subjects. We tested serum apoA-I levels in all participants and investigated EDSS scores of patients with NMO and ATM. Statistical analyses were performed by using SPSS statistical software.
We found that serum apoA-I levels in patients with NMO were significantly lower in comparison to those with ATM. We also found that serum levels of apoA-I was lower in male subjects in comparison to the female subjects in all groups although these differences were not statistically significant in patients with NMO or ATM. It is also shown in our study that serum apoA-I levels in patients with NMO were significantly elevated after receiving a high dosage of intravenous corticosteroids over a period of one week. However, we did not find any correlation between the apoA-I levels and disease disability.
From this study, we concluded that serum levels of apoA-I were lower in NMO patients compared to patients with ATM. Serum apoA-I studies might provide some useful clues to differentiate NMO cases from ATM cases.
Apolipoprotein(apo) A-I; Neuromyelitis optica; Acute ransverse myelitis
Identifying protein complexes is crucial to understanding principles of cellular organization and functional mechanisms. As many evidences have indicated that the subgraphs with high density or with high modularity in PPI network usually correspond to protein complexes, protein complexes detection methods based on PPI network focused on subgraph's density or its modularity in PPI network. However, dense subgraphs may have low modularity and subgraph with high modularity may have low density, which results that protein complexes may be subgraphs with low modularity or with low density in the PPI network. As the density-based methods are difficult to mine protein complexes with low density, and the modularity-based methods are difficult to mine protein complexes with low modularity, both two methods have limitation for identifying protein complexes with various density and modularity.
To identify protein complexes with various density and modularity, including those have low density but high modularity and those have low modularity but high density, we define a novel subgraph's fitness, fρ, as fρ= (density)ρ*(modularity)1-ρ, and propose a novel algorithm, named LF_PIN, to identify protein complexes by expanding seed edges to subgraphs with the local maximum fitness value. Experimental results of LF-PIN in S.cerevisiae show that compared with the results of fitness equal to density (ρ = 1) or equal to modularity (ρ = 0), the LF-PIN identifies known protein complexes more effectively when the fitness value is decided by both density and modularity (0<ρ<1). Compared with the results of seven competing protein complex detection methods (CMC, Core-Attachment, CPM, DPClus, HC-PIN, MCL, and NFC) in S.cerevisiae and E.coli, LF-PIN outperforms other seven methods in terms of matching with known complexes and functional enrichment. Moreover, LF-PIN has better performance in identifying protein complexes with low density or with low modularity.
By considering both the density and the modularity, LF-PIN outperforms other protein complexes detection methods that only consider density or modularity, especially in identifying known protein complexes with low density or low modularity.
Glioblastoma multiforme (GBM) is the most malignant and aggressive type of brain tumor with an average life expectancy of less than 15 months. This is mostly due to the highly mutated genome of GBM, which is characterized by the deregulation of many key signaling pathways involving growth, proliferation, survival, and apoptosis. It is critical to explore novel diagnostic and therapeutic strategies that target these pathways to improve the treatment of malignant glioma in the future. This review summarizes the most common and important pathways that are highly mutated or deregulated in GBM and discusses potential therapeutic strategies targeting these pathways.
Signal transduction; Therapy; GBM
Epigenetic programming, dynamically regulated by histone acetylation, is a key mechanism regulating cell proliferation and survival. Little is known about the contribution of histone deacetylase (HDAC) activity to the development of pulmonary arterial hypertension (PAH), a condition characterised by profound structural remodelling of pulmonary arteries and arterioles.
Methods and results
HDAC1 and HDAC5 protein levels were elevated in lungs from human idiopathic PAH and in lungs and right ventricles from rats exposed to hypoxia. Immunohistochemistry localised increased expression to remodelled vessels in the lung. Both valproic acid (VPA), a class I HDAC inhibitor, and suberoylanilide hydroxamic acid (SAHA), an inhibitor of class I, II and IV HDACs, mitigated the development and reduced established hypoxia-induced pulmonary hypertension in the rat. Both VPA and SAHA inhibited the “imprinted” highly proliferative phenotype of fibroblasts and R-cells from pulmonary hypertensive bovine vessels and PDGF-stimulated growth of human vascular smooth muscle cells in culture. Exposure to VPA and SAHA was associated with increased levels of p21and FOXO3 and reduced expression of survivin. The significantly higher level of expression of cKIT, MCP-1, IL-6, SDF-1, PDGFb and S100A4 in the R-cells were down regulated by VPA and SAHA treatment.
Increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of HDAC inhibitors VPA and SAHA, in models of PAH, support a therapeutic strategy based on HDAC inhibition in PAH.
Rapid response to chemotherapy in metastatic colorectal cancer (mCRC) patients (response within 12 weeks of chemotherapy) may increase the chance of complete resection and improved survival. Few molecular markers predict irinotecan-induced rapid response and survival. Single-nucleotide polymorphisms (SNPs) in solute carrier genes are reported to correlate with the variable pharmacokinetics of irinotecan and folate in cancer patients. This study aims to evaluate the predictive role of 3 SNPs in mCRC patients treated with irinotecan and fluoropyrimidine-containing regimens.
Materials and Methods
Three SNPs were selected and genotyped in 137 mCRC patients from a Chinese prospective multicenter trial (NCT01282658). The chi-squared test, univariate and multivariable logistic regression model, and receiver operating characteristic analysis were used to evaluate correlations between the genotypes and rapid response. Kaplan-Meier survival analysis and Cox proportional hazard models were used to evaluate the associations between genotypes and survival outcomes. Benjamini and Hochberg False Discovery Rate correction was used in multiple testing
Genotype GA/AA of SNP rs2306283 of the gene SLCO1B1 and genotype GG of SNP rs1051266 of the gene SLC19A1 were associated with a higher rapid response rate (odds ratio [OR] =3.583 and 3.521, 95%CI =1.301-9.871 and 1.271-9.804, p=0.011 and p=0.013, respectively). The response rate was 70% in patients with both genotypes, compared with only 19.7% in the remaining patients (OR = 9.489, 95%CI = 2.191-41.093, Fisher's exact test p=0.002). Their significances were all maintained even after multiple testing (all pc < 0.05). The rs2306283 GA/AA genotype was also an independent prognostic factor of longer progression-free survival (PFS) (hazard ratio = 0.402, 95%CI = 0.171-0.945, p=0.037). None of the SNPs predicted overall survival.
Polymorphisms of solute carriers’ may be useful to predict rapid response to irinotecan plus fluoropyrimidine and PFS in mCRC patients.