Experimental systems that provide temporal and spatial control of chemical gradients are required for probing into the complex mechanisms of eukaryotic cell chemotaxis. However, no current technique can simultaneously generate stable chemical gradients and allow fast gradient changes. We developed a microfluidic system with microstructured membranes for exposing neutrophils to fast and precise changes between stable, linear gradients of the known chemoattractant Interleukin-8 (IL-8). We observed that rapidly lowering the average concentration of IL-8 within a gradient, while preserving the direction of the gradient, resulted in temporary neutrophil depolarization. Fast reversal of the gradient direction while increasing or decreasing the average concentration also resulted in temporary depolarization. Neutrophils adapted and maintained their directional motility, only when the average gradient concentration was increased and the direction of the gradient preserved. Based on these observations we propose a two-component temporal sensing mechanism that uses variations of chemokine concentration averaged over the entire cell surface and localized at the leading edge, respectively, and directs neutrophil responses to changes in their chemical microenvironment.
Graphene has been predicted to play a role in post-silicon electronics due to the extraordinary carrier mobility. Chemical vapor deposition of graphene on transition metals has been considered as a major step towards commercial realization of graphene. However, fabrication based on transition metals involves an inevitable transfer step which can be as complicated as the deposition of graphene itself. By ambient-pressure chemical vapor deposition, we demonstrate large-scale and uniform depositon of high-quality graphene directly on a Ge substrate which is wafer scale and has been considered to replace conventional Si for the next generation of high-performance metal-oxide-semiconductor field-effect transistors (MOSFETs). The immiscible Ge-C system under equilibrium conditions dictates graphene depositon on Ge via a self-limiting and surface-mediated process rather than a precipitation process as observed from other metals with high carbon solubility. Our technique is compatible with modern microelectronics technology thus allowing integration with high-volume production of complementary metal-oxide-semiconductors (CMOS).
Transforming growth factor-betas (TGF-βs), including beta2 (TGF-β2), constitute a superfamily of multifunctional cytokines with important implications in morphogenesis, cell differentiation and tissue remodeling. TGF-β2 is thought to play important roles in multiple developmental processes and neuron survival. However, before we carried out these investigations, a TGF-β2 gene down-regulated transgenic animal model was needed. In the present study, expressional silencing TGF-β2 was achieved by select predesigning interference short hairpin RNAs (shRNAs) targeting mouse TGF-β2 genes.
Four homozygous transgenic offspring were generated by genetic manipulation and the protein expressions of TGF-β2 were detected in different tissues of these mice. The transgenic mice were designated as Founder 66, Founder 16, Founder 53 and Founder 41. The rates of TGF-β2 down-expression in different transgenic mice were evaluated. The present study showed that different TGF-β2 expressions were detected in multiple tissues and protein levels of TGF-β2 decreased at different rates relative to that of wild type mice. The expressions of TGF-β2 proteins in transgenic mice (Founder 66) reduced most by 52%.
The present study generated transgenic mice with TGF-β2 down-regulated, which established mice model for systemic exploring the possible roles of TGF-β2 in vivo in different pathology conditions.
TGF-β2; Knock down; Transgenic mouse; Protein levels; Distributions
Cellular senescence suppresses cancer by arresting the proliferation of cells at risk for malignant transformation. Recently, senescent cells were shown to secrete numerous cytokines, growth factors and proteases that can alter the tissue microenvironment and may promote age-related pathology. To identify small molecules that suppress the senescence-associated secretory phenotype (SASP), we developed a screening protocol using normal human fibroblasts and a library of compounds that are approved for human use. Among the promising library constituents was the glucocorticoid corticosterone. Both corticosterone and the related glucocorticoid cortisol decreased the production and secretion of selected SASP components, including several pro-inflammatory cytokines. Importantly, the glucocorticoids suppressed the SASP without reverting the tumor suppressive growth arrest, and were efficacious whether cells were induced to senesce by ionizing radiation or strong mitogenic signals delivered by oncogenic RAS or MAP kinase kinase 6 overexpression. Suppression of the prototypical SASP component IL-6 required the glucocorticoid receptor, which, in the presence of ligand, inhibited IL-1α signaling and NF-κB transactivation activity. Accordingly, co-treatments combining glucocorticoids with the glucocorticoid antagonist RU-486 or recombinant IL-1α efficiently reestablished NF-κB transcriptional activity and IL-6 secretion. Our findings demonstrate feasibility of screening for compounds that inhibit the effects of senescent cells. They further show that glucocorticoids inhibit selected components of the SASP, and suggest that corticosterone and cortisol, two FDA-approved drugs, might exert their effects in part by suppressing senescence-associated inflammation.
aging; cancer; inflammation; IL-6; IL-8; MMP-3
Interferons (IFN) are essential antiviral cytokines that establish the cellular antiviral state through upregulation of hundreds of interferon-stimulated genes (ISGs), most of which have uncharacterized functions and mechanisms. We identified Cholesterol-25-hydroxylase (Ch25h) as an antiviral ISG that can convert cholesterol to a soluble antiviral factor, 25-hydroxycholesterol (25HC). Ch25h expression or 25HC treatment in cultured cells broadly inhibits enveloped viruses including VSV, HSV, HIV, and MHV68 as well as acutely pathogenic EBOV, RVFV, RSSEV, and Nipah viruses under BSL4 conditions. As a soluble oxysterol, 25HC inhibits viral entry by blocking membrane fusion between virus and cell. In animal models, Ch25h-knockout mice were more susceptible to MHV68 lytic infection. Moreover, administration of 25HC in humanized mice suppressed HIV replication and rescued T-cell depletion. Thus, our studies demonstrate a unique mechanism by which IFN achieves its antiviral state through the production of a natural oxysterol to inhibit viral entry and implicate membrane-modifying oxysterols as potential antiviral therapeutics.
The testicular receptor 4 (TR4) is a member of the nuclear receptor superfamily that controls various biological activities. A protective role of TR4 against oxidative stress has recently been discovered. We here examined the protective role of TR4 against ionizing radiation (IR) and found that small hairpin RNA mediated TR4 knockdown cells were highly sensitive to IR-induced cell death. IR exposure increased the expression of TR4 in scramble control small hairpin RNA expressing cells but not in TR4 knockdown cells. Examination of IR-responsive molecules found that the expression of Gadd45a, the growth arrest and DNA damage response gene, was dramatically decreased in Tr4 deficient (TR4KO) mice tissues and could not respond to IR stimulation in TR4KO mouse embryonic fibroblast cells. This TR4 regulation of GADD45A was at the transcriptional level. Promoter analysis identified four potential TR4 response elements located in intron 3 and exon 4 of the GADD45A gene. Reporter and chromatin immunoprecipitation (ChIP) assays provided evidence indicating that TR4 regulated the GADD45A expression through TR4 response elements located in intron 3 of the GADD45A gene. Together, we find that TR4 is essential in protecting cells from IR stress. Upon IR challenges, TR4 expression is increased, thereafter inducing GADD45A through transcriptional regulation. As GADD45A is directly involved in the DNA repair pathway, this suggests that TR4 senses genotoxic stress and up-regulates GADD45A expression to protect cells from IR-induced genotoxicity.
TR4; GADD45A; Ionizing radiation; Mouse embryonic fibroblast; Genotoxic stress; TR4 response element
Hong Kong has a tripartite healthcare system, where western medicine provided in both public and private sectors coexist with Chinese medicine practice. The purpose of this study is to measure fragmentation of ambulatory care experienced by the non-institutionalized population aged 15 and over in such a tripartite system, thus shed light on the ongoing primary care reform.
This is a cross-sectional secondary data analysis using the Thematic Household Survey, which was conducted by the Hong Kong Census and Statistics Department during November 2009 to February 2010 to collect territory-wide health-related information. Among 18,226 individuals with two or more ambulatory visits during the past 12 months before interview, we grouped each visit into one of the three care segments—public western, private western and Chinese medicine. Two individual-level measures were used to quantify longitudinal fragmentation of care across segments over the one-year period: Most Frequent Provider Continuity Index (MFPC) and Fragmentation of Care Index (FCI). Both are analyzed for distribution and subgroup comparison. A Tobit model was used to further examine the determinants of fragmentation.
More than a quarter of individuals sought care in two or all three segments, with an average MFPC of 65% and FCI of 0.528. Being older, female, married, unemployed, uninsured, or born in mainland China, with lower education, lower income, higher number of chronic conditions or poorer health were found to have experienced higher fragmentation of care. We also found that, fragmentation of care increased with the total number of ambulatory care visits and it varied significantly depending on what segment the individual chose to visit most frequently—those chose private western clinics had lower FCI, compared with those chose public western or Chinese medicine as the most frequently visited segment.
Even measured at healthcare segment level, people in Hong Kong experienced modest fragmentation of care. Individuals’ health beliefs—as a result of the persistent habitual tendency and latitude incentivized by the system—may be behind the fragmented care we saw. Efforts are needed to alter health beliefs, targeting subgroups of vulnerable population, and create environments that promote better coordinated primary care.
Fragmentation; Continuity of care; Ambulatory care; Chinese medicine; Primary care
Treating neuropathic pain is a major clinical challenge, and the underlying mechanisms of neuropathic pain remain elusive. We hypothesized that neuropathic pain–inducing nerve injury may elicit neuronal alterations that recapitulate events that occur during development. Here, we report that WNT signaling, which is important in developmental processes of the nervous system, plays a critical role in neuropathic pain after sciatic nerve injury and bone cancer in rodents. Nerve injury and bone cancer caused a rapid-onset and long-lasting expression of WNTs, as well as activation of WNT/frizzled/β-catenin signaling in the primary sensory neurons, the spinal dorsal horn neurons, and astrocytes. Spinal blockade of WNT signaling pathways inhibited the production and persistence of neuropathic pain and the accompanying neurochemical alterations without affecting normal pain sensitivity and locomotor activity. WNT signaling activation stimulated production of the proinflammatory cytokines IL-18 and TNF-α and regulated the NR2B glutamate receptor and Ca2+-dependent signals through the β-catenin pathway in the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the WNT signaling pathway may be an effective approach for treating neuropathic pain, including bone cancer pain.
To identify a novel pathogenic gene mutation present in a Chinese family with hereditary hemorrhagic telangiectasia (HHT) and to determine if an intron mutation may influence the transcriptional activity of the ACVRL1 gene.
HHT family members were ascertained following the presentation of proband and involved subjects. All family members (n = 5) and 113 healthy individuals were genotyped for the variant in intron 6 c.772+27G>C of ACVRL1 gene. The genomic structure of ACVRL1 in affected HHT patients and healthy individuals was determined by long range PCR and sequencing. The expression of ACVRL1 mRNA and protein in patients with HHT was evaluated using real-time polymerase chain reaction and immunoblot analysis. Luciferase activity assay and electrophoretic mobility shift assay (EMSA) were performed to uncover the mechanism of intron-related transcriptional regulation.
Only one novel mutation in intron 6 (c.772+27G>C) of ACVRL1 gene, no other mutation, abnormal splice, gross genomic deletion or rearrangement was found in this HHT2 family. Compared with healthy individuals, ACVRL1 mRNA and protein were significantly decreased in affected HHT2 individuals. Luciferase activity assay demonstrated that the transcriptional activity of the mutated ACVRL1 was significantly lower than that of the wild-type of intron 6; EMSA results showed that intron 6 c.772+27G>C mutation was able to inhibit the binding of transcriptional factor Sp1.
A novel intron mutation in ACVRL1 gene is associated with familial HHT2. The mechanisms may be involved in the down-regulation of ACVRL1 gene transcription.
Based on the 2009 Thematic Household Survey in Hong Kong, this study compared health status and utilization of health care services in Hong Kong between migrants from Mainland China and natives. Overall, Mainland migrants reported lower socioeconomic conditions, worse health status, and less health care services utilization than the natives. After controlling for socio-demographic factors, we found that the migrants were 1.2 times more likely to report fair or poor health and 0.78 times less likely to report having a usual source of care, compared with the natives. Mainland migrants also had fewer physician visits and relied more on the public sector. Within the migrant group, those who had language advantage had more visits, and the recent arrivals who stayed in Hong Kong for three years or less had fewer visits and were far less likely to have a usual source of care. The findings underscore migration as an important social determinant of health in Hong Kong. A combination of targeted social and health policies is needed to help Mainland migrants better integrate into society and to improve their access to care. Programs should be tailored to address varying needs from different subgroups among migrants.
migrants; primary care; utilization; disparity; social determinant of health; Hong Kong; China
The importance of CD4+ and CD8+ T cells in protection against tuberculosis (TB) is well known, however, the association between changes to the T cell repertoire and disease presentation has never been analyzed. Characterization of T-cells in TB patients in previous study only analyzed the TCR β chain and omitted analysis of the Vα family even though α chain also contribute to antigen recognition. Furthermore, limited information is available regarding the heterogeneity compartment and overall function of the T cells in TB patients as well as the common TCR structural features of Mtb antigen specific T cells among the vast numbers of TB patients.
CDR3 spectratypes of CD4+ and CD8+ T cells were analyzed from 86 patients with TB exhibiting differing degrees of disease severity, and CDR3 spectratype complexity scoring system was used to characterize TCR repertoire diversity. TB patients with history of other chronic disease and other bacterial or viral infections were excluded for the study to decrease the likely contribution of TCRs specific to non-TB antigens as far as possible. Each patient was age-matched with a healthy donor group to control for age variability. Results showed that healthy controls had a normally diversified TCR repertoire while TB patients represented with restricted TCR repertoire. Patients with mild disease had the highest diversity of TCR repertoire while severely infected patients had the lowest, which suggest TCR repertoire diversity inversely correlates with disease severity. In addition, TB patients showed preferred usage of certain TCR types and have a bias in the usage of variable (V) and joining (J) gene segments and N nucleotide insertions.
Results from this study promote a better knowledge about the public characteristics of T cells among TB patients and provides new insight into the TCR repertoire associated with clinic presentation in TB patients.
Orbital apex syndrome has been described previously as a syndrome involving damage to the oculomotor nerve (III), trochlear nerve (IV), abducens nerve (VI), and ophthalmic branch of the trigeminal nerve (V1), in association with optic nerve dysfunction. It may be caused by inflammatory, infectious, neoplastic, iatrogenic, or vascular processes.
A 73-year-old female having hypertension and rheumatoid arthritis stage 4 under long-term corticosteroid therapy presented to us with the right side orbital apex syndrome. Her magnetic resonance imaging (MRI) of orbit showed progression of a lesion at the right orbital apex and adjacent right superior orbital fissure with mild extension to the right posterior ethmoid sinus. She underwent endoscopic endonasal transethmoid approach with the removal of the lesion. The pathology showed a picture of fungal infection and the culture of the specimen proved Aspergillus fumigatus. Her postoperative course was smooth until 5 days after surgery, when she suffered a massive spontaneous subarachnoid hemorrhage resulting from a ruptured aneurysm, which was proven by computed tomography angiography (CTA) of brain. Unfortunately, she expired due to central failure.
In cases of immunocompromised patients having orbital apex syndrome, fungal infection should be kept in mind. One of the most lethal but rare sequels of CNS fungal infection is intracranial aneurysms. Early diagnosis and radical resection, combined with antifungal medications is the key to save this particular group of patients.
Aspergillosis; fungal aneurysm; orbital apex syndrome
Glycine in the hippocampus can exert its effect on both synaptic NMDA receptors (NMDARs) and extrasynaptic functional glycine receptors (GlyRs) via distinct binding sites. Previous studies have reported that glycine induces long-term potentiation (LTP) through the activation of synaptic NMDARs. However, little is known about the potential role of the activated GlyRs that are largely located in extrasynaptic regions. We report here that relatively high levels of glycine achieved either by exogenous glycine application or by the elevation of endogenous glycine accumulation with an antagonist of the glycine transporter induced long-term depression (LTD) of excitatory postsynaptic currents (EPSCs) in hippocampal CA1 pyramidal neurons. The co-application of glycine with the selective GlyR antagonist strychnine changed glycine-induced LTD (Gly-LTD) to LTP. Blocking the postsynaptic GlyR-gated net chloride flux by manipulating intracellular chloride concentrations failed to elicit any changes in EPSCs. These results suggest that GlyRs are involved in Gly-LTD. Furthermore, this new form of chemical LTD was accompanied by the internalization of postsynaptic AMPA receptors and required the activation of NMDARs. Therefore, our present findings reveal an important function of GlyR activation and modulation in gating the direction of synaptic plasticity.
glycine; glycine receptor; NMDA receptor; LTP; LTD; synaptic plasticity; glutamate; neurophysiology; molecular & cellular neurobiology; neuropharmacology; glycine; glycine receptor; NMDA receptor; LTP; LTD
We evaluate the outcomes of irradiation by using three-dimensional radiation therapy (3D-RT) or intensity-modulated radiotherapy (IMRT) for recurrent and metastatic cervical cancer. Between 2007 and 2010, 50 patients with recurrent and metastatic cervical cancer were treated using 3D-RT or IMRT. The median time interval between the initial treatment and the start of irradiation was 12 (6–51) months. Salvage surgery was performed before irradiation in 5 patients, and 38 patients received concurrent chemotherapy. Sixteen patients underwent 3D-RT, and 34 patients received IMRT. Median follow-up for all the patients was 18.3 months. Three-year overall survival and locoregional control were 56.1% and 59.7%, respectively. Three-year progression-free survival and disease-free survival were 65.3% and 64.3%, respectively. Nine patients developed grade 3 leukopenia. Grade 5 acute toxicity was not observed in any of the patients; however, 2 patients developed Grade 3 late toxicity. 3D-RT or IMRT is effective for the treatment of recurrent and metastatic cervical cancer, with the 3-year overall survival of 56.1%, and its complications are acceptable. Long-term follow-up and further studies are needed to confirm the role of 3D-RT or IMRT in the multimodality management of the disease.
Early studies suggested that TR4 nuclear receptor might play important roles in the skeletal development, yet its detailed mechanism remains unclear.
We generated TR4 knockout mice and compared skeletal development with their wild type littermates. Primary bone marrow cells were cultured and we assayed bone differentiation by alkaline phosphatase and alizarin red staining. Primary calvaria were cultured and osteoblastic marker genes were detected by quantitative PCR. Luciferase reporter assays, chromatin immunoprecipitation (ChIP) assays, and electrophoretic mobility shift assays (EMSA) were performed to demonstrate TR4 can directly regulate bone differentiation marker osteocalcin.
We first found mice lacking TR4 might develop osteoporosis. We then found that osteoblast progenitor cells isolated from bone marrow of TR4 knockout mice displayed reduced osteoblast differentiation capacity and calcification. Osteoblast primary cultures from TR4 knockout mice calvaria also showed higher proliferation rates indicating lower osteoblast differentiation ability in mice after loss of TR4. Mechanism dissection found the expression of osteoblast markers genes, such as ALP, type I collagen alpha 1, osteocalcin, PTH, and PTHR was dramatically reduced in osteoblasts from TR4 knockout mice as compared to those from TR4 wild type mice. In vitro cell line studies with luciferase reporter assay, ChIP assay, and EMSA further demonstrated TR4 could bind directly to the promoter region of osteocalcin gene and induce its gene expression at the transcriptional level in a dose dependent manner.
Together, these results demonstrate TR4 may function as a novel transcriptional factor to play pathophysiological roles in maintaining normal osteoblast activity during the bone development and remodeling, and disruption of TR4 function may result in multiple skeletal abnormalities.
TR4; Nuclear receptor; Bone; Osteoporosis
The purpose of this study was to evaluate the antioxidant nature of tea polyphenol on S180 cells induced liver cancer in mice. In the present study, hepatocellular carcinoma was induced by tumor transplantation of liver in situ. The antitumor activity of tea polyphenol has been determined in vivo in hepatocellular carcinoma mice after treatment of drug (50, 100, 150 mg/kg body weight) by gavage for 20 days. Results showed that a significant increase in serum aspartate transaminase (AST), alkaline phosphatase (ALP), alanine aminotransfere (ALT), malondialdehyde (MDA) level, decrease in serum white blood cells (WBC), serum total protein (TP), albumin (ALB), A/G, tumor necrosis factor-α (TNF-α) and interferon-gamma (IFN-γ), liver reduced glutathione (GSH) levels were observed. In addition, the levels of enzymic and non-enzymic antioxidants were decreased when subjected to S180 cells induction. These altered enzyme levels were ameliorated significantly by administration of tea polyphenol at the concentration of 50, 100, 150 mg/kg body weight in drug-treated animals. These results indicate that the protective effect of tea polyphenol was associated with inhibition of MDA induced by S180 cells and to maintain the antioxidant enzyme levels.
S180 cell; antioxidant; AST; mice; tea polyphenol; hepatocarcinoma
Phostensin, a protein phosphatase 1 F-actin cytoskeleton-targeting subunit encoded by KIAA1949, consists of 165 amino acids and caps the pointed ends of actin filaments. Sequence alignment analyses suggest that the C-terminal region of phostensin, spanning residues 129 to 155, contains a consensus actin-binding motif. Here, we have verified the existence of an actin-binding motif in the C-terminal domain of phostensin using colocalization, F-actin co-sedimentation and single filament binding assays. Our data indicate that the N-terminal region of phostensin (1–129) cannot bind to actin filaments and cannot retard the pointed end elongation of gelsolin-actin seeds. Furthermore, the C-terminal region of phostensin (125–165) multiply bind to the sides of actin filaments and lacks the ability to block the pointed end elongation, suggesting that the actin-binding motif is located in the C-terminal region of the phostensin. Further analyses indicate that phostensin binding to the pointed end of actin filament requires N-terminal residues 35 to 51. These results suggest that phostensin might fold into a rigid structure, allowing the N-terminus to sterically hinder the binding of C-terminus to the sides of actin filament, thus rendering phostensin binding to the pointed ends of actin filaments.
phostensin; actin filament; KIAA1949; protein phosphatase 1
As part of its ongoing healthcare reform, the Hong Kong Government introduced
a voucher scheme, intended for encouraging older patients to use primary
healthcare services in the private sector, thereby, reducing burden on the
overwhelmed public sector. The voucher program is also considered one of the
strategies to further develop the public private partnership in healthcare,
a policy direction of high political priority as indicated in the Chief
Executive Policy Address in 2008-09. This study assessed whether the voucher
scheme, as implemented so far, has reached its intended goals, and how it
might be further improved in the context of public-private partnership.
This was a cross-sectional study using structured questionnaires by
face-to-face interviews with older people aged 70 or above in Hong Kong, the
target group of the demand-side voucher program.
71.2% of 1,026 older people were aware of the new voucher scheme but only
35.0% had ever used it. The majority of the older people used the vouchers
for acute curative services in the private sector (82.4%) and spent less on
preventive services. Despite the provision of vouchers valued US$30 per year
as an incentive to encourage the use of private primary care services, after
12-months of implementation, 66.2% of all respondents agreed with the
statement that "the voucher scheme does not change their health seeking
behaviours on seeing public or private healthcare professionals". The most
common reasons for no change in their behaviours included "I am used to
seeing doctors in the public system" and "The amount of the subsidy is too
low". Those who usually used a mix of public and private doctors and those
with better self-reported health condition compared to last year were more
likely to perceive a change in their own health seeking behaviours.
Our study showed that despite a reasonably high awareness of the voucher
scheme, its usage was low. The voucher alone was not enough to realize the
government's policy of greater use of the private primary care services.
Greater publicity and more variety of media promotion would increase
awareness but the effectiveness of vouchers in changing older people's
behaviour needs to be revisited. Designating vouchers for use of preventive
services with evidence-based practice could be considered. In addition to
the demand-side subsidies, improving transparency and comparability of
private services against the public sector might be necessary.
To explore the effects of Icaritin on chronic myeloid leukemia (CML) cells and underlying mechanisms.
CML cells were incubated with various concentration of Icaritin for 48 hours, the cell proliferation was analyzed by MTT and the apoptosis was assessed with Annexin V and Hoechst 33258 staining. Cell hemoglobinization was determined. Western blotting was used to evaluate the expressions of MAPK/ERK/JNK signal pathway and Jak-2/Phorpho-Stat3/Phorsph-Akt network-related protein. NOD-SCID nude mice were applied to demonstrate the anti-leukemia effect of Icaritin in vivo.
Icaritin potently inhibited proliferation of K562 cells (IC50 was 8 µM) and primary CML cells (IC50 was 13.4 µM for CML-CP and 18 µM for CML-BC), induced CML cells apoptosis and promoted the erythroid differentiation of K562 cells with time-dependent manner. Furthermore, Icaritin was able to suppress the growth of primary CD34+ leukemia cells (CML) and Imatinib-resistant cells, and to induce apoptosis. In mouse leukemia model, Icaritin could prolong lifespan of NOD-SCID nude mice inoculated with K562 cells as effective as Imatinib without suppression of bone marrow. Icaritin could up-regulate phospho-JNK or phospho-C-Jun and down-regulate phospho-ERK, phospho-P-38, Jak-2, phospho-Stat3 and phospho-Akt expression with dose- or time-dependent manner. Icaritin had no influence both on c-Abl and phospho-c-Abl protein expression and mRNA levels of Bcr/Abl.
Icaritin from Chinese herb medicine may be a potential anti-CML agent with low adverse effect. The mechanism of anti-leukemia for Icaritin is involved in the regulation of Bcr/Abl downstream signaling. Icaritin may be useful for an alternative therapeutic choice of Imatinib-resistant forms of CML.
The present study was aimed to investigate the effects of infusion of different fluids combined with controlled hypotension on gastric intramucosal pH (pHi) and postoperative gastrointestinal function in patients undergoing hepatocarcinoma surgery. Forty-five patients (ASA II) scheduled for surgical resection of hepatocarcinoma undergoing controlled hypotension were randomly assigned to three groups and received infusion of 20 mL/kg Ringer's solution (R group), 6% HAES(H group) or 6% Voluven group (W group). Intragastric PgCO2, pHi, hematocrit and hemoglobin were measured. The significant decrease of pHi and increase of PgCO2 were produced at 1 and 2 h after controlled hypotension in the R group (P < 0.05 or P < 0.01). The time of bowel movement after operation was shorter in the W group than the R group. Meanwhile, we also did not find obvious difference in blood gas indexes among the three groups. The infusion of HAES and Voluven during controlled hypotension could improve gastrointestinal perfusion and accelerate the recovery of postoperative gastrointestinal function.
hemodilution; controlled hypotension; gastric mucosa
Interstrand DNA crosslinks (ICLs) are formed by natural products of metabolism and by chemotherapeutic reagents. Work in E. coli identified a two cycle repair scheme involving incisions on one strand on either side of the ICL (unhooking) producing a gapped intermediate with the incised oligonucleotide attached to the intact strand. The gap is filled by recombinational repair or lesion bypass synthesis. The remaining monoadduct is then removed by Nucleotide Excision Repair (NER). Despite considerable effort, our understanding of each step in mammalian cells is still quite limited. In part this reflects the variety of crosslinking compounds, each with distinct structural features, used by different investigators. Also, multiple repair pathways are involved, variably operative during the cell cycle. G1 phase repair requires functions from NER, although the mechanism of recognition has not been determined. Repair can be initiated by encounters with the transcriptional apparatus, or a replication fork. In the case of the latter, the reconstruction of a replication fork, stalled or broken by collision with an ICL, adds to the complexity of the repair process. The enzymology of unhooking, the identity of the lesion bypass polymerases required to fill the first repair gap, and the functions involved in the second repair cycle are all subjects of active inquiry. Here we will review current understanding of each step in ICL repair in mammalian cells.
Chemotherapy; cisplatin; psoralen; unhooking; lesion bypass; replication arrest
Influenza-related complications continue to be a major cause of mortality worldwide. Due to unclear mechanisms, a substantial number of influenza-related deaths result from bacterial superinfections, particularly secondary pneumococcal pneumonia. Here, we report what we believe to be a novel mechanism by which influenza-induced type I IFNs sensitize hosts to secondary bacterial infections. Influenza-infected mice deficient for type I IFN-α/β receptor signaling (Ifnar–/– mice) had improved survival and clearance of secondary Streptococcus pneumoniae infection from the lungs and blood, as compared with similarly infected wild-type animals. The less effective response in wild-type mice seemed to be attributable to impaired production of neutrophil chemoattractants KC (also known as Cxcl1) and Mip2 (also known as Cxcl2) following secondary challenge with S. pneumoniae. This resulted in inadequate neutrophil responses during the early phase of host defense against secondary bacterial infection. Indeed, influenza-infected wild-type mice cleared secondary pneumococcal pneumonia after pulmonary administration of exogenous KC and Mip2, whereas neutralization of Cxcr2, the common receptor for KC and Mip2, reversed the protective phenotype observed in Ifnar–/– mice. These data may underscore the importance of the type I IFN inhibitory pathway on CXC chemokine production. Collectively, these findings highlight what we believe to be a novel mechanism by which the antiviral response to influenza sensitizes hosts to secondary bacterial pneumonia.
Transforming growth factor-β2 (TGF-β2), basic fibroblast growth factor (bFGF), and fibromodulin (FMOD) are important extracellular matrix components of the sclera and have been shown to be associated with the development of high myopia. Our aim was to examine the association between myopia and the polymorphisms within TGF-β2, bFGF, and FMOD.
The study group comprised of patients (n=195; age range: 17−24 years) with a spherical equivalent of −6.5 diopters (D) or a more negative refractive error. The control group comprised of individuals (n=94; age range: 17−25 years) with a spherical equivalent ranging from −0.5 D to +1.0 D. The subjects with astigmatism over –0.75 D were excluded from the study. High resolution melting (HRM) genotyping and restriction fragment length polymorphism (RFLP) genotyping were used to detect single nucleotide polymorphisms (SNPs). The polymorphisms detected were TGF-β2 (rs7550232 and rs991967), bFGF (rs308395 and rs41348645), and FMOD (rs7543418). Moreover, a stepwise logistic regression procedure was used to detect which of the significant SNPs contributed to the main effects of myopia development.
There were significant differences in the frequency of the A allele and A/A genotype in TGF-β2 (rs7550232; p=0.0178 and 0.03, respectively). Moreover, the haplotype distribution of haplotype 2 (Ht2; A/A) of TGF-β2 differed significantly between the two groups (p=0.014). The results of the stepwise logistic regression procedure revealed that TGF-β2 (rs7550232) contributed significantly to the development of high myopia.
TGF-β2 is an important structure of sclera and might contribute to the formation of myopia. TGF-β2 (rs7550232) polymorphisms, A allele and A/A genotype, had a protective role against the development of high myopia.