AIM: To evaluate the clinical outcome of re-operation for recurrent abdominal liposarcoma following multidisciplinary team cooperation.
METHODS: Nineteen consecutive patients who had recurrent abdominal liposarcoma underwent re-operation by the retroperitoneal sarcoma team at our institution from May 2009 to January 2012. Patient demographic and clinical data were reviewed retrospectively. Multidisciplinary team discussions were held prior to treatment, and re-operation was deemed the best treatment. The categories of the extent of resection were as follows: gross total resection (GTR), palliative resection and partial resection. Surgical techniques were divided into discrete lesion resection and combined contiguous multivisceral resection (CMR). Tumor size was determined as the largest diameter of the specimen. Patients were followed up at approximately 3-monthly intervals. For survival analysis, a univariate analysis was performed using the Kaplan-Meier method, and a multivariate analysis was performed using the Cox proportional hazards model.
RESULTS: Nineteen patients with recurrent abdominal liposarcoma (RAL) underwent 32 re-operations at our institute. A total of 51 operations were reviewed with a total follow-up time ranging from 4 to 120 (47.4 ± 34.2) mo. The GTR rate in the CMR group was higher than that in the non-CMR group (P = 0.034). CMR was positively correlated with intra-operative bleeding (correlation coefficient = 0.514, P = 0.010). Six cases with severe postoperative complications were recorded. Patients with tumor sizes greater than 20 cm carried a significant risk of profuse intra-operative bleeding (P = 0.009). The ratio of a highly malignant subtype (dedifferentiated or pleomorphic) in recurrent cases was higher compared to primary cases (P = 0.027). Both single-factor survival using the Kaplan-Meier model and multivariate analysis using the Cox proportional hazards model showed that overall survival was correlated with resection extent and pathological subtype (P < 0.001 and P = 0.02), however, relapse-free interval (RFI) was only correlated with resection extent (P = 0.002).
CONCLUSION: Close follow-up should be conducted in patients with RAL. Early re-operation for relapse is preferred and gross resection most likely prolongs the RFI.
Overall survival; Recurrent abdominal liposarcoma; Relapse-free interval
Nanoparticles with strong optical absorption at near-infrared (NIR) wavelengths can efficiently convert optical energy into thermal energy, and have shown multimodality in biological and biomedical applications. In this work, a new type of thermal ablation-enhanced transdermal delivery methodology is developed based on hollow copper sulfide nanoparticles (HCuSNPs) with intense photothermal coupling effects. Application of nanosecond-pulsed NIR laser allows rapid heating of the nanoparticles and instantaneous heat conduction. This provides very short periods of time but extremely high temperatures (estimated over 100°C) in local regions, with focused thermal ablation of the stratum corneum. Because the discontinuous light from the pulsed laser minimized heat accumulation, the average temperature of the irradiated skin area only increases to ~40–50°C. The extent of thermal ablation of skin, i.e. removal of the stratum corneum, viable epidermis, or the dermis, can be controlled by adjusting the laser power. The skin disruption by HCuSNP-mediated photothermal ablation significantly increases the permeability of macromolecule drugs such as human growth hormone, providing effective and controlled percutaneous delivery. This technique offers compelling opportunities to overcome low oral bioavailability of small- and large-molecular-weight drugs, avoiding the pain and inconvenience of long-term s.c. injections while enabling sustained and controlled delivery.
nanoparticle; transdermal; drug delivery; near-infrared laser; photothermal ablation
Marinimicrobium sp. strain LS-A18 is a fructan-degrading organism isolated from a brine sample from a marine solar saltern in Jiaozhou Bay, China. The draft genome sequence of this bacterium is 3,815,107 bp in length, with a G+C content of 59.03%. To our knowledge, this is the first genome announcement of a fructan-degrading strain of the genus Marinimicrobium.
Menopausal symptoms have been suggested to be an indicator of better prognosis among patients treated for breast cancer, because women who experience these symptoms usually have a lower level of estrogen. We tested this hypothesis in a population-based, prospective cohort study involving 4,842 women with stage 0 to III primary breast cancer who were enrolled in the Shanghai Breast Cancer Survival Study between March 2002 and April 2006, were aged 20 to 75 years, and were recruited 6 months post-diagnosis. They were followed-up by in-person surveys and record linkages with the vital statistics registry. Cox regression analysis was used to evaluate the association of menopausal symptoms at baseline with breast cancer recurrence. Approximately 56% of patients experienced at least one menopausal symptom, including hot flashes, night sweats, and/or vaginal dryness at baseline. During a median follow-up period of 5.3 years, 720 women had a recurrence. Experiencing hot flashes or having ≥2 menopausal symptoms was associated with lower risk of recurrence among premenopausal women (hazard ratio [HR]=0.77, 95% confidence interval [CI]: 0.62-0.96 for hot flashes; 0.73, 0.56-0.96 for ≥2 menopausal symptoms). Lower recurrence risk in relation to hot flashes was also observed among women who were not overweight/obese (HR=0.78, 95% CI: 0.64-0.99), those with relatively low waist-to-hip ratio (WHR) (HR=0.77, 95% CI: 0.61-0.97), and those who used tamoxifen (HR=0.75, 95% CI: 0.58-0.98). Consistently experiencing multiple menopausal symptoms was associated with lower recurrence risk among women with low WHR or who used tamoxifen. This large, population-based cohort study of women with breast cancer confirms that experiencing menopausal symptoms is an indicator of favorable breast cancer prognosis.
Membrane-tethered proteins (mammalian surface display) are increasingly being used for novel therapeutic and biotechnology applications. Maximizing surface expression of chimeric proteins on mammalian cells is important for these applications. We show that the cytoplasmic domain from the B7-1 antigen, a commonly used element for mammalian surface display, can enhance the intracellular transport and surface display of chimeric proteins in a Sar1 and Rab1 dependent fashion. However, mutational, alanine scanning and deletion analysis demonstrate the absence of linear ER export motifs in the B7 cytoplasmic domain. Rather, efficient intracellular transport correlated with the presence of predicted secondary structure in the cytoplasmic tail. Examination of the cytoplasmic domains of 984 human and 782 mouse type I transmembrane proteins revealed that many previously identified ER export motifs are rarely found in the cytoplasmic tail of type I transmembrane proteins. Our results suggest that efficient intracellular transport of B7 chimeric proteins is associated with the structure rather than to the presence of a linear ER export motif in the cytoplasmic tail, and indicate that short (less than ~ 10-20 amino acids) and unstructured cytoplasmic tails should be avoided to express high levels of chimeric proteins on mammalian cells.
Previous studies suggest that melatonin may act on cancer growth through a variety of mechanisms, most notably by direct anti-proliferative effects on breast cancer cells and via interactions with the estrogen pathway. Three genes are largely responsible for mediating the downstream effects of melatonin: melatonin receptors 1a and 1b (MTNR1a and MTNR1b), and Arylalkylamine N-acetyltransferase (AANAT). It is hypothesized that genetic variation in these genes may lead to altered protein production or function. To address this question, we conducted a comprehensive evaluation of the association between common single nucleotide polymorphisms (SNPs) in the MTNR1a, MTNR1b, and AANAT genes and breast cancer risk among 2,073 cases and 2,083 controls, using a two-staged analysis of genome-wide association (GWAS) data among women of the Shanghai Breast Cancer Study. Results demonstrate two SNPS were consistently associated with breast cancer risk across both study stages. Compared with MTNR1b rs10765576 major allele carriers (GG or GA), a decreased risk of breast cancer was associated with the AA genotype (OR=0.78, 95% CI=0.62–0.97, p=0.0281). Although no overall association was seen in the combined analysis, the effect of MTNR1a rs7665392 was found to vary by menopausal status (p-value for interaction=0.001). Premenopausal women with the GG genotype were at increased risk for breast cancer as compared to major allele carriers (TT or TG) (OR=1.57, 95% CI=1.07–2.31, p=0.020), while post-menopausal women were at decreased risk (OR=0.58, 95% 0.36–0.95, p=0.030). No significant breast cancer associations were found for variants in AANAT. These results suggest that common genetic variation in the MTNR1a and 1b genes may contribute to breast cancer susceptibility, and that associations may vary by menopausal status. Given that multiple variants in high linkage disequibrium with MTNR1b rs76653292 have been associated with altered function or expression of insulin and glucose family members, further research may focus on clarifying this relationship.
Melatonin; gene; polymorphism; breast cancer; risk
The authors evaluated the prognostic effects of obesity and weight change after breast cancer diagnosis. A total of 5042 breast cancer patients aged 20–75 were identified through the population-based Shanghai Cancer Registry approximately 6 months after cancer diagnosis and recruited into the study between 2002 and 2006. Participants were followed by in-person interviews supplemented by record linkage with the Shanghai Vital Statistics Registry database. Anthropometric measurements were taken and information on sociodemographic, clinical, and lifestyle factors was collected through in-person interviews. During the median follow-up of 46 months, 442 deaths and 534 relapses/breast cancer-specific deaths were documented. Women with body mass index (BMI) ≥30 at diagnosis had higher mortality than women with 18.5≤BMI<25; the multivariate adjusted hazard ratios (HRs) were 1.55 (95% confidence interval (95% CI): 1.10–2.17) for total mortality and 1.44 (95% CI: 1.02–2.03) for relapse/disease-specific mortality. Similar results were found for pre- and post-diagnostic obesity. Women who gained ≥5kg or lost >1kg had higher mortality than those who maintained their weight. No association was observed between waist-to-hip ratio and mortality. Our study suggests that obesity and weight change after diagnosis are inversely associated with breast cancer prognosis. Weight control is important among women with breast cancer.
Body mass index; central obesity; weight change; breast cancer; survival
Few data are available regarding depression among Asian breast cancer survivors.
We estimated the prevalence of depression and its correlates among 1400 participants of a population-based cohort study of women with stage 0–IV breast cancer in Shanghai, China. Through in-person interviews conducted at 6 months and 18 months post-diagnosis and review of medical charts, information on sociodemographic and clinical factors and quality of life (QOL) were collected. Depression was measured by the 20-item Center for Epidemiologic Studies Depression Scale 18 months after diagnosis.
Approximately 26% of participants had mild to severe depression and 13% fulfilled the criteria of clinical depression at 18 months post-diagnosis. Women with lower income were more likely to have depression than those with higher income (prevalence: 16.6% vs. 6.9% for mild depression and 17.1% vs. 5.5% for clinical depression, respectively). Depression was more common among women who were widowed (18.9%) or divorced/separated/single (16.4%) than those who were married (11.8%). Women with comorbidity were more likely to have clinical depression (17.3% vs 11.2%). Multivariate analysis showed that low income, marital status, comorbidity, and low QOL scores were independent predictors for depression. We did not find that prevalence of depression differed by menopausal status, estrogen or progesterone receptor status, disease stage, or cancer-related treatments.
Depression is common among Asian women with breast cancer. Routine screening and prevention of depression are warranted among women with breast cancer.
depression; breast cancer; prevalence; risk factor
In a population-based cohort study of 5014 women with stage 0–III breast cancer, we evaluated weight change patterns from diagnosis to 6, 18, and 36 months post-diagnosis. Patients were recruited to the study approximately 6 months after cancer diagnosis between 2002 and 2006 and followed through 36 months post-diagnosis. The medians of weight change from diagnosis to 6, 18, and 36 months post-diagnosis were 1.0 kg, 2.0 kg, and 1.0 kg, respectively. Approximately 26% of survivors gained ≥5% of their at-diagnosis body weight during the first 6 months after diagnosis, while 37% and 33% of women gained the same percentage of weight at 18 and 36 months post-diagnosis. More weight gain was observed among women who had a more advanced disease stage, were younger, had lower body mass index at diagnosis, were premenopausal, or received chemotherapy or radiotherapy during the first 6 months after cancer diagnosis. Multivariate analyses indicated that age at diagnosis, body size, comorbidity, and disease stage independently predicted weight gain from diagnosis to 36 months post-diagnosis. In summary, weight gain is common over the first 3 years after breast cancer diagnosis among Chinese women. More research is needed to investigate measures to prevent weight gain in breast cancer survivors.
weight change pattern; breast cancer; survivor; Chinese population
SurA is the primary periplasmic molecular chaperone that facilitates the folding and assembling of outer membrane proteins (OMPs) in Gram-negative bacteria. Deletion of the surA gene in Escherichia coli leads to a decrease in outer membrane density and an increase in bacterial drug susceptibility. Here, we conducted mutational studies on SurA to identify residues that are critical for function. One mutant, SurAV37G, significantly reduced the activity of SurA. Further characterization indicated that SurAV37G was structurally similar to, but less stable than, the wild-type protein. The loss of activity in SurAV37G could be restored through the introduction of a pair of Cys residues and the subsequent formation of a disulfide bond. Inspired by this success, we created three additional SurA constructs, each containing a disulfide bond at different regions of the protein between two rigid secondary structural elements. The formation of disulfide bond in these mutants has no observable detrimental effect on protein activity, indicating that SurA does not undergo large-scale conformational change while performing its function.
Acute type A aortic dissection (AAAD) remains one of the most lethal conditions requiring surgical repair, and is associated with a high rate of postoperative mortality and morbidity. Despite the satisfactory clinical outcomes achieved with the frozen elephant trunk technique so far, controversies still exist regarding the use of this aggressive approach in patients with AAAD. In this study, we seek to analyze the early outcomes of the Sun’s procedure, which is an approach integrating total arch replacement using a 4-branched graft with implantation of a special stented graft in the descending aorta, and identify the risk factors for postoperative mortality and morbidity of the Sun’s procedure in patients with AAAD.
Clinical data of 398 consecutive AAAD patients undergoing the Sun’s procedure were analyzed. The associations between 20 preoperative and intraoperative variables and early mortality were assessed by univariate and multivariate analysis.
Early mortality occurred in 31 patients (7.8%, 31/398), with leading causes including multi-organ failure in 16 patients (51.6%), permanent neurologic deficit in 6 (19.4%), and low cardiac output syndrome in 4 (12.9%). Permanent neurologic deficit and spinal cord injury occurred, each in 10 patients (2.5%, 10/398). Five significant risk factors for early mortality were identified with multivariate analysis: preexisting cerebrovascular disease [relative risk (RR) 14.76; P<0.001], acute heart failure (RR 18.18; P=0.001), spinal cord malperfusion (RR 60.13; P<0.002), visceral malperfusion (RR 30.25; P<0.001) and cardiopulmonary bypass time >190 minutes (RR 3.62; P=0.007).
The Sun’s procedure has generated a relatively lower mortality rate in 398 patients with AAAD. Patients with preexisting cerebrovascular disease, acute heart failure, spinal cord malperfusion, visceral malperfusion and long cardiopulmonary bypass time are at a higher risk of early mortality.
Aortic dissection; stented graft; surgery; outcome; mortality; complication
The effects of diet on breast cancer are controversial and whether the effects vary with hormone receptor status has not been well investigated. This study evaluated the associations of dietary factors with risk for breast cancer overall and by hormone receptor status of tumors among Chinese women.
The Shanghai Breast Cancer Study, a large, population-based, case-control study, enrolled 3,443 cases and 3,474 controls in 1996–1998 (phase I) and 2002–2004 (phase II); 2,676 cases had ER and PR data. Dietary intake was assessed using a validated, quantitative, food frequency questionnaire (FFQ). Odds ratios (ORs) and 95% confidence intervals (95% CI) were derived from multivariate, polychotomous, unconditional logistic regression models.
Total vegetable intake was inversely related to breast cancer risk, with an adjusted OR for the highest quintile of 0.80 (95% CI = 0.67–0.95; P trend=0.02). Reduced risk was also related to high intake of allium vegetables (P trend = 0.01) and fresh legumes (P trend = 0.0008). High intake of citrus fruits and rosaceae fruits were inversely associated with breast cancer risk (P trend = 0.003 and P trend = 0.004, respectively), although no consistent association was seen for total fruit intake. Elevated risk was observed for all types of meat and fish intake (all P trend <0.05), while intakes of eggs and milk were associated with a decreased risk of breast cancer (both P trend <0.05). There was little evidence that associations with dietary intakes varied across the four tumor subtypes or between ER+/PR+ and ER−/PR− tumors (P for heterogeneity >0.05).
Our results suggest that high intake of total vegetables, certain fruits, milk, and eggs may reduce the risk of breast cancer, while high consumption of animal-source foods may increase risk. The dietary associations did not appear to vary by ER/PR status.
dSkp2 regulates cell cycle progression by antagonizing Dap in Drosophila, which resolves the question of whether dSkp2 has a role in regulating Dap stability and suggests the possibility of using Drosophila as a model system in which to study Skp2-mediated tumorigenesis.
Cell cycle progression is controlled by a complex regulatory network consisting of interacting positive and negative factors. In humans, the positive regulator Skp2, an F-box protein, has been a subject of intense investigation in part because of its oncogenic activity. By contrast, the molecular and developmental functions of its Drosophila homologue, dSkp2, are poorly understood. Here we investigate the role of dSkp2 by focusing on its functional relationship with Dacapo (Dap), the Drosophila homologue of the cyclin-dependent kinase inhibitors p21cip1/p27kip1/p57kip2. We show that dSkp2 interacts physically with Dap and has a role in targeting Dap for ubiquitination and proteasome-mediated degradation. We present evidence that dSkp2 regulates cell cycle progression by antagonizing Dap in vivo. dSkp2 knockdown reduces cell density in the wing by prolonging the cell doubling time. In addition, the wing phenotype caused by dSkp2 knockdown resembles that caused by dap overexpression and can be partially suppressed by reducing the gene dose of dap. Our study thus documents a conserved functional relationship between dSkp2 and Dap in their control of cell cycle progression, suggesting the possibility of using Drosophila as a model system to study Skp2-mediated tumorigenesis.
The forkhead box transcription factor Foxo3a has been implicated to play a critical role in various cancers by suppressing tumor growth. Recent studies have identified Foxo3a as a key regulator of Estrogen Receptor-α (ERα). In the present study, we examined the expression of Foxo3a, and investigated its clinical significance and correlation with ER and prognostic role in patients with breast cancer. Immunohistochemical analysis was performed on tumors from 70 breast cancer patients. Interpretable Foxo3a expression was analyzed along with major clinicopathologic variables, and a comparison was made with corresponding 5-year clinical follow-up data. Foxo3a protein expression correlated with ER positivity (P<0.001), histologic grade (1, 2) (P = 0.002), axillary lymph node negativity (P<0.001) and TNM stage (1, 2) (P<0.001). Moreover, the Kaplan-Meier survival curves of the study population showed that a high expression level of Foxo3a was significantly correlated with long-term survival (P<0.0001). In a multivariate analysis, Foxo3a expression was identified as a favorable independent prognostic factor in overall survival (P = 0.038). In conclusion, our results indicated that Foxo3a expression is a favorable prognostic marker in breast cancer. In addition, Foxo3a staining could potentially be used in patient stratification in conjunction with other prognostic markers.
Targeted nanoparticle-based delivery systems have been used extensively to develop effective cancer theranostics. However, how targeting ligands affect extravascular transport of nanoparticles in solid tumors remains unclear. Here, we show, using B16/F10 melanoma cells expressing melanocortin type-1 receptor (MC1R), that the nature of targeting ligands, i.e., whether they are agonists or antagonists, directs tumor uptake and intratumoral distribution after extravasation of nanoparticles from tumor vessels into the extravascular fluid space. Pegylated hollow gold nanospheres (HAuNS, diameter≈40 nm) coated with MC1R agonist are internalized upon ligand-receptor binding, whereas MC1R antagonist-conjugated HAuNS remain attached on the cell surface. Transcellular transport of agonist-conjugated HAuNS was confirmed by a multilayer tumor cell model and by transmission electron microscopy. MC1R agonist- but not MC1R antagonist-conjugated nanoparticles exhibit significantly higher tumor uptake than nontargeted HAuNS and are quickly dispersed from tumor vessels via receptor-mediated endocytosis and subsequent transcytosis. These results confirm an active transport mechanism that can be used to overcome one of the major biological barriers for efficient nanoparticle delivery to solid tumors.
Nanoparticles; Melanocortin type-1 receptor (MC1R); Transcytosis; Agonists; Antagonists
Activating mutations in the receptor tyrosine kinase KIT, most notably KIT D816V, are commonly observed in patients with systemic mastocytosis. Thus, inhibition of KIT has been a major focus for treatment of this disorder. Here we investigated a novel approach to such inhibition. Utilizing rational drug design, we targeted the switch pocket (SP) of KIT which regulates its catalytic conformation. Two SP inhibitors thus identified, DP-2976 and DP-4851, were examined for effects on neoplastic mast cell proliferation and mast cell activation. Autophosphorylation of both wild type (WT) and, where also examined, KIT D816V was blocked by these compounds in transfected 293T cells, HMC 1.1 and 1.2 human mast cell lines; and in CD34+-derived human mast cells activated by stem cell factor (SCF). Both inhibitors induced apoptosis in the neoplastic mast cell lines and reduced survival of primary bone marrow mast cells from patients with mastocytosis. Moreover, the SP inhibitors more selectively blocked SCF potentiation of FcεRI-mediated degranulation. Overall, SP inhibitors represent an innovative mechanism of KIT inhibition whose dual suppression of KIT D816V neoplastic mast cell proliferation and SCF enhanced mast cell activation may provide significant therapeutic benefits.
mastocytosis; switch pocket; KIT; KIT D816V; tyrosine kinase inhibitor; mast cell
Experimental and epidemiological evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis.
To investigate this hypothesis, a two-stage study was carried out to evaluate single nucleotide polymorphisms (SNPs) in inflammatory pathway genes in association with endometrial cancer risk. In stage 1, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage 1 SNPs significantly associated with endometrial cancer (P<0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage 2, which consisted of ten additional studies including 6,604 endometrial cancer cases and 8,511 controls.
Five of the 21 SNPs had significant allelic odds ratios and 95% confidence intervals as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples.
These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer.
This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis.
endometrial cancer; inflammation; genetic risk variants; meta-analysis
Ag and Cu nanocrystals (NCs) were assembled into ordered porous anodic alumina (OPAA) by a single-potential-step chronoamperometry technique. The composition, morphology, microstructure, and optical property were analyzed by X-ray diffraction, field-emission scanning electron microscopy, transmission electron microscopy, selected area electron diffraction, and optical absorption spectroscopy. The results indicate that metallic NCs/OPAA composite possesses a significant surface plasmon resonance absorption. For continuous electrodeposition, metallic nanowires are smooth and uniform with face-centered cubic (fcc) single-crystalline structure; however, for interval electrodeposition, the nanowires are bamboo-like or pearl-chain-like with fcc polycrystalline structure. The length of the nanoparticle nanowires or the single-crystalline nanowires can be controlled well by adjusting the experimental cycle times or the continuous depositing time. The transverse dipole resonance of metallic NCs enhances and displays a blue shift with increasing electrodeposition time or experimental cycle times, which is consistent with Zong's results but contradictory to Duan's results. The formation mechanisms of the nanoparticle nanowires and the single-crystalline nanowires were discussed in detail.
Nanostructures; Chemical synthesis; Electron microscopy; Optical properties
The oncoprotein MDM2 negatively regulates the activity and stability of the p53 tumor suppressor, and is an important molecular target for anticancer therapy. Aided by mirror image phage display and native chemical ligation, we have previously discovered several proteolysis-resistant duodecimal D-peptide antagonists of MDM2, termed DPMI-α, β, γ. The prototypic D-peptide inhibitor DPMI-α binds (25-109)MDM2 at an affinity of 220 nM, and kills tumor cells in vitro and inhibits tumor growth in vivo by reactivating the p53 pathway. Herein, we report the design of a super-active D-peptide antagonist of MDM2, termed DPMI-δ, of which the binding affinity for (25-109)MDM2 has been improved over DPMI-α by three orders of magnitude (Kd = 220 pM). X-ray crystallographic studies validate DPMI-δ as an exceedingly potent inhibitor of the p53-MDM2 interaction, promising to be a highly attractive lead drug candidate for anticancer therapeutic development.
p53; MDM2; MDMX; D-peptides; antitumor agents; drug design; mirror image phage display; native chemical ligation
Hypertension is considered as one of the major risk factors of atherosclerosis, especially for carotid artery plaque, which is a sign for cardiovascular incapacity and cerebral infarction. As adult age, systolic blood pressure (SBP or S) tends to rise and diastolic blood pressure (DBP or D) tends to fall, thus the pulse pressure (PP) will increase. The vascular injury was directly proportional to the level of SBP, and inversely proportional to DBP. But so far, studies of the vascular injury based on SBP and DBP measurement were mostly qualitative. The exact contribution of each parameter to the vascular injury has not been quantitatively identified. In this study, we employed a mathematical model to predict the risk for plaques of carotid arteries in aged people and combined the SBP, DBP and heart rate (HR) to perform a quantitative analysis. We analyzed 1672 males who were over 60-year-old and hospitalized due to atherosclerosis-related diseases and received a 24-h arterial blood pressure monitoring (ABPM) examination. These patients were divided into 19 subgroups using the ABPM data, 24-h average SBP, DBP and HR as variables based on the ascending order of the magnitude of each element. We developed a new index, namely the dynamic level (DL) which correlated best with the plaque formation of carotid arteries among all the well-established indexes for blood pressure. We demonstrated that index DL has better correlation to plaques incidence tendency (p < 0.0001) when compared to either SBP (P < 0.05) or PP (P < 0.001) alone. The risk on incidence of the plaques of carotid arteries has positive correlation with first power of SBP and -0.8 power of DBP. This model can be used clinically to predict the occurrence of plaque formation.
Blood pressure parameters; the plaques of carotid arteries; mathematical method; vascular injury
In the mammalian central nervous system, the majority of fast excitatory synaptic transmission is mediated by glutamate acting on AMPA-type ionotropic glutamate receptors. The abundance of AMPA receptors at the synapse can be modulated through receptor trafficking, which dynamically regulates many fundamental brain functions, including learning and memory. Reversible posttranslational modifications, including phosphorylation, palmitoylation and ubiquitination of AMPA receptor subunits are important regulatory mechanisms for controlling synaptic AMPA receptor expression and function. In this review, we highlight recent advances in the study of AMPA receptor posttranslational modifications and discuss how these modifications regulate AMPA receptor trafficking and function at synapses.
NM1 is a highly pathogenic North American-type porcine reproductive and respiratory syndrome virus (PRRSV). The complete genome sequence shows that NM1 shares high sequence identity (99.2 to 99.4%) to other HP-PRRSV isolates, containing two discontinuous deletions, a 1-amino-acid deletion at position 481 and a 29-amino-acid deletion at positions 533 to 651, in nonstructural protein 2.
We report the synthesis of ultrafine S nanoparticles with diameter 10 ~ 20 nm via a membrane-assisted precipitation technique. The S nanoparticles were then coated with conducting poly (3,4-ethylenedioxythiophene) (PEDOT) to form S/PEDOT core/shell nanoparticles. The ultrasmall size of S nanoparticles facilitates the electrical conduction and improves sulfur utilization. The encapsulation of conducting PEDOT shell restricts the polysulfides diffusion, alleviates self-discharging and the shuttle effect, and thus enhances the cycling stability. The resulting S/PEDOT core/shell nanoparticles show initial discharge capacity of 1117 mAh g−1 and a stable capacity of 930 mAh g−1 after 50 cycles.
Gamma-aminobutyric acid (GABA) is produced and secreted by adult pancreatic β-cells, which also express GABA receptors mediating autocrine signaling and regulating β-cell proliferation. However, whether the autocrine GABA signaling involves in β-cell progenitor development or maturation remains uncertain. By means of immunohistochemistry we analyzed the expression profiles of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) and the α1-subunit of type-A GABA receptor (GABAARα1) in the pancreas of mice at embryonic day 15.5 (E15.5), E18.5, postnatal day 1 (P1) and P7. Our data showed that at E15.5 the pancreatic and duodenum homeobox-1 (Pdx1) was expressed in the majority of cells in the developing pancreata. Notably, insulin immunoreactivity was identified in a subpopulation of pancreatic cells with a high level of Pdx1 expression. About 80% of the high-level Pdx-1 expressing cells in the pancreas expressed GAD and GABAARα1 at all pancreatic developmental stages. In contrast, only about 30% of the high-level Pdx-1 expressing cells in the E15.5 pancreas expressed insulin; i.e., a large number of GAD/GABAARα1-expressing cells did not express insulin at this early developmental stage. The expression level of GAD and GABAARα1 increased steadily, and progressively more GAD/GABAARα1-expressing cells expressed insulin in the course of pancreatic development. These results suggest that 1) GABA signaling proteins appear in β-cell progenitors prior to insulin expression; and 2) the increased expression of GABA signaling proteins may be involved in β-cell progenitor maturation.
γ-aminobutyric acid; GABA receptor; embryonic pancreas; β-cell progenitor
Germline mutations in CARD11 that result in constitutive NF-κB activation and selective B cell expansion underlie congenital B cell lymphocytosis.
Nuclear factor-κB (NF-κB) controls genes involved in normal lymphocyte functions, but constitutive NF-κB activation is often associated with B cell malignancy. Using high-throughput whole transcriptome sequencing, we investigated a unique family with hereditary polyclonal B cell lymphocytosis. We found a novel germline heterozygous missense mutation (E127G) in affected patients in the gene encoding CARD11, a scaffolding protein required for antigen receptor (AgR)–induced NF-κB activation in both B and T lymphocytes. We subsequently identified a second germline mutation (G116S) in an unrelated, phenotypically similar patient, confirming mutations in CARD11 drive disease. Like somatic, gain-of-function CARD11 mutations described in B cell lymphoma, these germline CARD11 mutants spontaneously aggregate and drive constitutive NF-κB activation. However, these CARD11 mutants rendered patient T cells less responsive to AgR-induced activation. By reexamining this rare genetic disorder first reported four decades ago, our findings provide new insight into why activating CARD11 mutations may induce B cell expansion and preferentially predispose to B cell malignancy without dramatically perturbing T cell homeostasis.