MRI Features May Predict Molecular Features of Glioblastoma in Isocitrate Dehydrogenase Wild-Type Lower-Grade Gliomas.

BACKGROUND AND PURPOSE: Isocitrate dehydrogenase (IDH) wild-type lower-grade gliomas (histologic grades II and III) with epidermal growth factor receptor (EGFR) amplification or telomerase reverse transcriptase (TERT) promoter mutation are reported to behave similar to glioblastoma. We aimed to evaluate whether MR imaging features could identify a subset of IDH wild-type lower-grade gliomas that carry molecular features of glioblastoma. MATERIALS AND METHODS: In this multi-institutional retrospective study, pathologically confirmed IDH wild-type lower-grade gliomas from 2 tertiary institutions and The Cancer Genome Atlas constituted the training set (institution 1 and The Cancer Genome Atlas, 64 patients) and the independent test set (institution 2, 57 patients). Preoperative MRIs were analyzed using the Visually AcceSAble Rembrandt Images and radiomics. The molecular glioblastoma status was determined on the basis of the presence of EGFR amplification and TERT promoter mutation. Molecular glioblastoma was present in 73.4% and 56.1% in the training and test sets, respectively. Models using clinical, Visually AcceSAble Rembrandt Images, and radiomic features were built to predict the molecular glioblastoma status in the training set; then they were validated in the test set. RESULTS: In the test set, a model using both Visually AcceSAble Rembrandt Images and radiomic features showed superior predictive performance (area under the curve = 0.854) than that with only clinical features or Visually AcceSAble Rembrandt Images (areas under the curve = 0.514 and 0.648, respectively; P < . 001, both). When both Visually AcceSAble Rembrandt Images and radiomics were added to clinical features, the predictive performance significantly increased (areas under the curve = 0.514 versus 0.863, P < .001). CONCLUSIONS: MR imaging features integrated with machine learning classifiers may predict a subset of IDH wild-type lower-grade gliomas that carry molecular features of glioblastoma.

The influence of preoperative epidural labor analgesia on postoperative pain in parturients undergoing emergency cesarean section : A retrospective analysis.

BACKGROUND: Intense noxious input from the periphery may result in central sensitization and hyperexcitability, thus accentuating subsequent postoperative pain. Parturients who undergo emergency cesarean section (C-sec) after experiencing labor pain often develop labor pain-induced sensitization. OBJECTIVE: This retrospective study evaluated whether parturients without epidural labor analgesia (ELA) who underwent emergency C­sec, experienced more severe postoperative pain and required more rescue analgesics during the postoperative period. METHODS: The institution's medical database was searched for parturients who underwent emergency C­sec under spinal anesthesia for any reason between January 2013 and December 2016. Those who underwent elective C­sec under spinal anesthesia were included as the reference arm. Parturients were divided into three groups: ELA, no-ELA and elective. Characteristics of patients and perioperative outcomes were evaluated. As primary outcomes, numerical rating scale (NRS) for postoperative pain (0-10) was recorded up to 96 h postoperatively, and use of rescue analgesics was evaluated at 6, 24, and 48 h postoperatively. RESULTS: In the ELA, no-ELA, and elective groups, 61, 73, and 88 parturients, respectively, were ultimately enrolled. The NRS for pain were similar among the three groups, except at 6 h postoperatively. Parturients in the no-ELA group demonstrated significantly higher NRS at 6 h postoperatively than those in the ELA group (P = 0.01).More patients in the no-ELA group required rescue analgesics than in the ELA (P = 0.001) and elective groups (P < 0.001) at 6-24 h postoperatively. Moreover, the proportion of patients requiring rescue analgesics ≥2 times was also significantly higher in the no-ELA group (vs. the ELA group, P = 0.004; vs. the elective group, P < 0.001). CONCLUSION: Parturients undergoing emergency C­sec without ELA management during labor experienced greater postoperative pain and a greater use of rescue analgesics during the postoperative period. The findings suggest that administration of ELA before emergency C­sec may act as pre-emptive analgesia against postoperative pain.

Ultrafast Transient Spectroscopy of Trans-Polyacetylene in the Midinfrared Spectral Range.

Trans-polyacetylene [t-(CH)_{x}] possesses twofold ground state degeneracy. Using the Su-Schrieffer-Heeger Hamiltonian, scientists predicted charged solitons to be the primary photoexcitations in t-(CH)_{x}; this prediction, however, has led to sharp debate. To resolve this saga, we use subpicosecond transient photomodulation spectroscopy in the mid-IR spectral range (0.1-1.5 eV) in neat t-(CH)_{x} thin films. We show that odd-parity singlet excitons are the primary photoexcitations in t-(CH)_{x}, similar to many other nondegenerate π-conjugated polymers. The exciton transitions are characterized by two photoinduced absorption (PA) bands at 0.38 and 0.6 eV, and an associated photoluminescence band at ∼1.5 eV having similar polarization memory. The primary excitons undergo internal conversion within ∼100 fs to an even-parity (dark) singlet exciton with a PA band at ∼1.4 eV. We also find ultrafast photogeneration of charge polarons when pumping deep into the polymer continuum band, which are characterized by two other PA bands in the mid-IR and associated photoinduced IR vibrational modes.

Whole-Tumor Histogram and Texture Analyses of DTI for Evaluation of IDH1-Mutation and 1p/19q-Codeletion Status in World Health Organization Grade II Gliomas.

BACKGROUND AND PURPOSE: Prediction of the isocitrate dehydrogenase 1 (IDH1)-mutation and 1p/19q-codeletion status of World Health Organization grade ll gliomas preoperatively may assist in predicting prognosis and planning treatment strategies. Our aim was to characterize the histogram and texture analyses of apparent diffusion coefficient and fractional anisotropy maps to determine IDH1-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas. MATERIALS AND METHODS: Ninety-three patients with World Health Organization grade II gliomas with known IDH1-mutation and 1p/19q-codeletion status (18 IDH1 wild-type, 45 IDH1 mutant and no 1p/19q codeletion, 30 IDH1-mutant and 1p/19q codeleted tumors) underwent DTI. ROIs were drawn on every section of the T2-weighted images and transferred to the ADC and the fractional anisotropy maps to derive volume-based data of the entire tumor. Histogram and texture analyses were correlated with the IDH1-mutation and 1p/19q-codeletion status. The predictive powers of imaging features for IDH1 wild-type tumors and 1p/19q-codeletion status in IDH1-mutant subgroups were evaluated using the least absolute shrinkage and selection operator. RESULTS: Various histogram and texture parameters differed significantly according to IDH1-mutation and 1p/19q-codeletion status. The skewness and energy of ADC, 10th and 25th percentiles, and correlation of fractional anisotropy were independent predictors of an IDH1 wild-type in the least absolute shrinkage and selection operator. The area under the receiver operating curve for the prediction model was 0.853. The skewness and cluster shade of ADC, energy, and correlation of fractional anisotropy were independent predictors of a 1p/19q codeletion in IDH1-mutant tumors in the least absolute shrinkage and selection operator. The area under the receiver operating curve was 0.807. CONCLUSIONS: Whole-tumor histogram and texture features of the ADC and fractional anisotropy maps are useful for predicting the IDH1-mutation and 1p/19q-codeletion status in World Health Organization grade II gliomas.

Prediction of IDH1-Mutation and 1p/19q-Codeletion Status Using Preoperative MR Imaging Phenotypes in Lower Grade Gliomas.

BACKGROUND AND PURPOSE: WHO grade II gliomas are divided into three classes: isocitrate dehydrogenase (IDH)-wildtype, IDH-mutant and no 1p/19q codeletion, and IDH-mutant and 1p/19q-codeleted. Different molecular subtypes have been reported to have prognostic differences and different chemosensitivity. Our aim was to evaluate the predictive value of imaging phenotypes assessed with the Visually AcceSAble Rembrandt Images lexicon for molecular classification of lower grade gliomas. MATERIALS AND METHODS: MR imaging scans of 175 patients with lower grade gliomas with known IDH1 mutation and 1p/19q-codeletion status were included (78 grade II and 97 grade III) in the discovery set. MR imaging features were reviewed by using Visually AcceSAble Rembrandt Images (VASARI); their associations with molecular markers were assessed. The predictive power of imaging features for IDH1-wild type tumors was evaluated using the Least Absolute Shrinkage and Selection Operator. We tested the model in a validation set (40 subjects). RESULTS: Various imaging features were significantly different according to IDH1 mutation. Nonlobar location, larger proportion of enhancing tumors, multifocal/multicentric distribution, and poor definition of nonenhancing margins were independent predictors of an IDH1 wild type according to the Least Absolute Shrinkage and Selection Operator. The areas under the curve for the prediction model were 0.859 and 0.778 in the discovery and validation sets, respectively. The IDH1-mutant, 1p/19q-codeleted group frequently had mixed/restricted diffusion characteristics and showed more pial invasion compared with the IDH1-mutant, no codeletion group. CONCLUSIONS: Preoperative MR imaging phenotypes are different according to the molecular markers of lower grade gliomas, and they may be helpful in predicting the IDH1-mutation status.

Risk factors to predict the development of chronic kidney disease in patients with lupus nephritis.

Objectives We analyzed the clinical follow-up results of 88 lupus nephritis patients to find prognostic factors for the development of chronic kidney disease in ethnically homogeneous Korean patients with biopsy-proven lupus nephritis. Methods Sociodemographic, clinical, laboratory, and treatment-related data at the time of kidney biopsy and during follow-up were obtained. Renal biopsy specimens were reclassified according to the International Society of Pathology/Renal Pathology Society classification, separately, by two renal pathologists blinded to the previous classification. Univariate and multivariate analyses were performed using the Cox proportional hazard regression model to identify independent risk factors for chronic kidney disease in lupus nephritis patients. Results Eighteen of 88 patients (20.5%) developed chronic kidney disease during a mean follow-up of 47.6 months (range: 12-96 months). Patients who developed chronic kidney disease were older at onset of lupus nephritis, had less education, and were more likely to have hypertension; they had lower serum albumin levels, lower platelet levels, higher serum creatinine levels, lower estimated glomerular filtration rate, higher chronicity index, and lower frequency of anti-ribosomal P antibodies, and they were less likely to be in complete remission in the first year. In stepwise multivariable analyses, hypertension, lower glomerular filtration rate, and failure to achieve complete remission in the first year of treatment were significant predictors of the development of chronic kidney disease in lupus nephritis patients. Conclusions These findings suggest that patients with hypertension and decreased kidney function at the onset of lupus nephritis and showing a poor response to immunosuppressive drugs in the first year should be monitored carefully and managed aggressively to avoid deterioration of kidney function.

Diet-induced obesity reduces the production of influenza vaccine-induced antibodies via impaired macrophage function.

Obesity is a metabolic disease characterized by low-level chronic inflammation. Obese individuals are susceptible to infection by viruses, and vaccination against these pathogens is less effective than in nonobese individuals. Here, we sought to explore the immunological environment in a mouse model of obesity induced by a high-fat diet (HFD). HFD treatment increased the body weight and epididymal fat mass. The proportion of activated B cells, T cells, and macrophages was similar between mice in the HFD group and the regular-fat diet (RFD) group. The Th1 cell subpopulation in the HFD group was increased, whereas the proportion of Treg cells was reduced compared with the RFD group. Moreover, T-cell proliferation and cytokine production did not differ between the groups when cells were stimulated with anti-CD3 and anti-CD28 antibodies in vitro. In macrophages, phagocytic activity was higher in mice fed an HFD than in those fed an RFD, but expression levels of CD86 and MHC class II antigens were similar. When macrophages were cultured in vitro, the proportion of CD86-expressing macrophages was lower in those isolated from mice in the HFD group than in those isolated from the RFD group. Furthermore, lipopolysaccharide-induced interleukin 6 (IL-6) and tumor necrosis factor alpha secretions were significantly reduced in macrophages isolated from the HFD group. In addition, influenza vaccine-induced antibodies in the HFD group diminished more rapidly than in the RFD group. These results suggest that poor functionality of macrophages during obesity might contribute to a reduction in vaccine efficacy.

The rate of and risk factors for frequent hospitalization in systemic lupus erythematosus: results from the Korean lupus network registry.

Objectives The survival rate of patients with systemic lupus erythematosus has improved in the last few decades, but the rate of hospitalization and health care costs for these patients remain higher than in the general population. Thus, we evaluated the rate of hospitalization and associated risk factors in an inception cohort of Korean patients with lupus. Methods Of the 507 patients with systemic lupus erythematosus enrolled in the KORean lupus NETwork, we investigated an inception cohort consisting of 196 patients with systemic lupus erythematosus presenting within 6 months of diagnosis based on the American College of Rheumatology classification criteria. We evaluated the causes of hospitalization, demographic characteristics, and laboratory and clinical data at the time of systemic lupus erythematosus diagnosis of hospitalized patients and during a follow-up period. We calculated the hospitalization rate as the number of total hospitalizations divided by the disease duration, and defined "frequent hospitalization" as hospitalization more than once per year. Results Of the 196 patients, 117 (59.6%) were admitted to hospital a total of 257 times during the 8-year follow-up period. Moreover, 22 (11.2%) patients were hospitalized frequently. The most common reasons for hospitalization included disease flares, infection, and pregnancy-related morbidity. In the univariate regression analysis, malar rash, arthritis, pericarditis, renal involvement, fever, systemic lupus erythematosus disease activity index > 12, hemoglobin level < 10 mg/dl, albumin level < 3.5 mg/dl, and anti-Sjögren's syndrome A positivity were associated with frequent hospitalization. Finally, multivariate analysis showed that arthritis, pericarditis, and anti-Sjögren's syndrome A antibody positivity at the time of diagnosis were risk factors for frequent hospitalization. Conclusions Our results showed that frequent hospitalization occurred in 11.2% of hospitalized patients and arthritis, pericarditis, and anti-Sjögren's syndrome A antibody positivity at the time of diagnosis were risk factors for frequent hospitalization.

Clinical and microbiological effects of a subantimicrobial dose of oral doxycycline on periodontitis in dogs.

Doxycycline is regarded as an effective treatment for periodontal inflammation. In humans, it has been shown that the long-term administration of a subantimicrobial dose of doxycycline (SDD) does not induce antimicrobial effects on the subgingival microflora and furthermore does not affect antimicrobial susceptibility. The present study was designed to evaluate the influence of oral administration of SDD on normal periodontal microflora and antimicrobial susceptibility in dogs. Experimental periodontitis was induced in 12 experimental dogs using a silk and wire-twisted ligature for 60 days. After the periodontitis induction period, the ligature was removed, and dental cleaning (subgingival and supragingival ultrasonic scaling) was performed. The dogs were randomly assigned to one of two groups: an SDD group with six dogs receiving 2 mg/kg PO once daily and a control group with six dogs receiving a placebo. At weeks 0, 4 and 8, clinical periodontal parameters were evaluated. After the clinical assessments, subgingival plaque was sampled and then cultured in an anaerobic system for one week, and the total anaerobes, Porphyromonas spp., Bacteroides spp. and Pasteurella spp. counts were investigated. Using the agar dilution method, the minimum bactericidal concentration of doxycycline was evaluated and the resistance for doxycycline was monitored during this experimental phase. The clinical periodontal status of the SDD group was significantly improved compared to the control group (P <0.05). Bacterial counts were not significantly different between the two experimental groups (P > 0.05), and antibacterial resistance was not established in the SDD group during the experimental periods (P <0.05). These results suggest that the once daily oral regimen of 2 mg/kg of doxycycline could serve as a SDD in dogs.

Exogenous administration of DLK1 ameliorates hepatic steatosis and regulates gluconeogenesis via activation of AMPK.

BACKGROUND/OBJECTIVES: Activation of Notch signaling pathologically enhances lipogenesis and gluconeogenesis in the liver causing non-alcoholic fatty liver disease (NAFLD) and diabetes. Delta-like 1 homolog (DLK1), an imprinted gene that can modulate adipogenesis and muscle development in mice, was found as an inhibitory regulator of Notch signaling. Therefore, we investigated the metabolic effect of exogenous DLK1 in vitro and in vivo. SUBJECTS/METHODS: A soluble DLK1 peptide was generated with fusion between a human Fc fragment and extracellular domain of DLK1. Male db/db mice were randomly assigned to two groups: vehicle treated and DLK1-treated group (25 mg kg(-1), intraperitoneal injection, twice a week for 4 weeks). Primary mice hepatocytes and HepG2 cells were used for in vitro experiments. RESULTS: After 4 weeks of DLK1 administration, hepatic triglyceride content and lipid droplets in liver tissues, as well as serum levels of liver enzymes, were markedly decreased in db/db mice. DLK1 treatment induced phosphorylation of AMPK and ACC and suppressed nuclear expression of SREBP-1c in the mouse liver or hepatocytes, indicating regulation of fatty acid oxidation and synthesis pathways. Furthermore, DLK1-treated mice showed significantly lower levels of fasting and random glucose, with improved glucose and insulin tolerance compared with the vehicle-treated group. Macrophage infiltration and proinflammatory cytokine levels in the epididymal fat were decreased in DLK1-treated db/db mice. Moreover, DLK1 suppressed glucose production from hepatocytes, which was blocked after co-administration of an AMPK inhibitor, compound C. DLK1-treated hepatocytes and mouse liver tissues showed lower PEPCK and G6Pase expression. DLK1 triggered AKT phosphorylation followed by cytosolic translocation of FOXO1 from the nucleus in hepatocytes. CONCLUSIONS: The present study demonstrated that exogenous administration of DLK1 reduced hepatic steatosis and hyperglycemia via AMPK activation in the liver. This result suggests that DLK1 may be a novel therapeutic approach for treating NAFLD and diabetes.

Microporous carbon nanosheets with redox-active heteroatoms for pseudocapacitive charge storage.

We report microporous carbon nanosheets containing numerous redox active heteroatoms fabricated from exfoliated waste coffee grounds by simple heating with KOH for pseudocapacitive charge storage. We found that various heteroatom combinations in carbonaceous materials can be a redox host for lithium ion storage. The bio-inspired nanomaterials had unique characteristics, showing superior electrochemical performances as cathode for asymmetric pseudocapacitors.

Comparison of clinical and serological differences among juvenile-, adult-, and late-onset systemic lupus erythematosus in Korean patients.

OBJECTIVES: We investigated whether systemic lupus erythematosus (SLE) patients could be distinguished based on the time of disease onset and, if so, whether the groups differed in their clinical and laboratory features in ethnically homogeneous Korean patients. METHODS: We enrolled 201 SLE patients with available clinical data at the time of onset of SLE from the lupus cohort at Chonnam National University Hospital. Sociodemographic, clinical, and laboratory data, including autoantibodies, and concomitant diseases were found at the time of diagnosis of SLE by reviewing patient charts. We divided SLE patients according to age at SLE diagnosis into three groups: juvenile-onset SLE (JSLE, diagnosed at ≤ 18 years), adult-onset SLE (ASLE, diagnosed at 19-50 years), and late-onset SLE (LSLE, diagnosed at >50 years), and compared baseline demographic, clinical, and relevant laboratory findings. RESULTS: Of the 201 patients, 27 (14.4%), 149 (74.1%), and 25 (12.4%) were JSLE, ASLE, and LSLE patients, respectively. Fever, oral ulcers, nephritis, anemia, and thrombocytopenia were more common in JSLE patients than ASLE or LSLE patients (p < 0.05, < 0.05, 0.001, < 0.05, and < 0.05, respectively). However, Sjögren's syndrome was more frequent in LSLE patients than JSLE or ASLE patients (p < 0.05). Disease activity was significantly higher in JSLE patients than in ASLE or LSLE patients (p < 0.001). Anti-dsDNA and anti-nucleosome antibodies were found more frequently in JSLE patients and less frequently in LSLE patients (p < 0.05 and 0.005, respectively) and decreased complement levels were more common in JSLE patients and less common in LSLE patients (p < 0.001, 0.001, and < 0.05, respectively). CONCLUSIONS: Our results indicate that SLE patients present with different clinical and serological manifestations according to age at disease onset. JSLE patients have more severe disease activity and more frequent renal involvement and LSLE patients have milder disease activity, more commonly accompanied by Sjögren's syndrome, at disease onset.

Lhx2 regulates bone remodeling in mice by modulating RANKL signaling in osteoclasts.

The LIM homeobox 2 (Lhx2) transcription factor Lhx2 has a variety of functions, including neural induction, morphogenesis, and hematopoiesis. Here we show the involvement of Lhx2 in osteoclast differentiation. Lhx2 was strongly expressed in osteoclast precursor cells but its expression was significantly reduced during receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis. Overexpression of Lhx2 in bone marrow-derived monocyte/macrophage lineage cells (BMMs), which are osteoclast precursor cells, attenuated RANKL-induced osteoclast differentiation by inhibiting the induction of nuclear factor of activated T cells c1 (NFATc1). Interestingly, interaction of Lhx2 proteins with c-Fos attenuated the DNA-binding ability of c-Fos and thereby inhibited the transactivation of NFATc1. Furthermore, Lhx2 conditional knockout mice exhibited an osteoporotic bone phenotype, which was related with increased osteoclast formation in vivo. Taken together, our results suggest that Lhx2 acts as a negative regulator of osteoclast formation in vitro and in vivo. The anti-osteoclastogenic effect of Lhx2 may be useful for developing a therapeutic strategy for bone disease.

Single-electron shuttle based on electron spin.

A nanoelectromechanical device based on magnetic exchange forces and electron spin flips induced by a weak external magnetic field is suggested. It is shown that this device can operate as a new type of single-electron "shuttle" in the Coulomb blockade regime of electron transport.

Contrast echocardiography to assess left ventricular volume and function in Beagle dogs: comparison with 3-Tesla dual source parallel cardiac magnetic resonance imaging.

This study was performed to evaluate the effect and feasibility of contrast echocardiography (CE) compared with unenhanced echocardiography (UE) and cardiac magnetic resonance imaging (CMRI) to assess left ventricular (LV) volume and function, including end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and ejection fraction (EF) in six healthy Beagles. When the dogs were conscious, LV measurements using CE were significantly higher than those obtained using UE, except for EF, and were similar to the values obtained using CMRI. Additionally, EDV, SV, and EF obtained using UE from anesthetized dogs were significantly lower than those obtained using CE or CMRI. Measurements of EDV, SV and EF using CE were not significantly different from the corresponding measurements obtained using CMRI (31.13±2.18 vs. 32.88±1.17 mL, 18.41±1.25 vs. 17.92±0.96 mL, 59.29±2.29% vs. 53.33±1.69%, respectively). Inter-observer agreements for UE (0.74±0.05) were lower than those for CE (0.80±0.04) and CMRI (0.92±0.03). In conclusion, LV function was assessed reproducibly using CE, and the measurements obtained were consistent with reference standard measurements obtained using CMRI. Measurements made using CE agreed more closely with CMRI than those made using UE.

A sub-Tenon's capsule injection of lidocaine induces extraocular muscle akinesia and mydriasis in dogs.

The effect of local anaesthetic on the extraocular muscles was investigated in dogs by injecting lidocaine into the space between Tenon's capsule and the sclera. A cross-over design was used with both eyes from five Beagle dogs randomly injected, under general anaesthesia, with 1 mL of 2% lidocaine (1 mL-lidocaine group), 2 mL of 2% lidocaine (2 mL-lidocaine group) or 2 mL of normal saline (control group). Each eye was assigned to all treatments with a minimum 14 day interval between injections. Changes in eye position, pupil diameter, and intraocular pressure (IOP) were evaluated during the procedure. All eyes in the 2 mL-lidocaine group exhibited akinesia and mydriasis (pupil diameter >10mm) with an onset time of 6.5 ± 4.9 and 4.2 ± 4.3 min, respectively. In the 1 mL-lidocaine group, akinesia was induced in nine eyes and mydriasis occurred in seven eyes at 10.7 ± 5.8 and 5.4 ± 2.4 min after the injection, respectively. No changes in eye position or pupil diameter were observed in the control group. Akinesia was maintained for 44.3 ± 26.7 min in the 1 mL-lidocaine group and for 88.5 ± 17.2 min in the 2 mL-lidocaine group. Duration of mydriasis was 51.7 ± 28.9 min in the 1 mL-lidocaine group and 82.9 ± 15.6 min in the 2 mL-lidocaine group. Marked chemosis and sub-conjunctival haemorrhage occurred in 16/30 and 15/30 eyes, respectively. No significant change in IOP was observed between the mean pre- and post-injection values in all groups. These results suggest that a sub-Tenon's injection of 2 mL of 2% lidocaine provided effective extraocular muscle akinesia and mydriasis in dogs.

Identification of a pivotal endocytosis motif in c-Met and selective modulation of HGF-dependent aggressiveness of cancer using the 16-mer endocytic peptide.

Since c-Met has an important role in the development of cancer, it is considered as an attractive target for cancer therapy. Although molecular mechanisms for oncogenic property of c-Met have been actively investigated, regulatory elements for c-Met endocytosis and its effect on c-Met signaling remain unclear. In this study, we identified a pivotal endocytic motif in c-Met and tested it for selective modulation of HGF-induced c-Met response. Using various chimeric constructs with the cytoplasmic tail of c-Met, we were able to demonstrate that a dileucine motif located in the C-terminus of c-Met acts to regulate its endocytosis. Synthetic peptide Ant-3S, consisting of antennapedia-derived protein transduction domain (designated as Ant) and c-Met-derived 16 amino-acids (designated as 3S, spanning amino-acids 1378 to 1393), rapidly moved into cancer cells and disrupted c-Met trafficking. Importantly, an extension of c-Met retention time on the membrane by Ant-3S peptide significantly decreased phosphorylation-dependent c-Met signal transduction. Additionally, the peptide effectively inhibited HGF-induced cell growth, scattering and migration. The underlying molecular mechanism for these observations has been investigated and revealed that the dileucine motif interacts with endocytic machinery, including adaptin ß and caveolin-1, for sustained and enhanced signal transduction. Finally, Ant-3S peptide specifically blocked internalization of interleukin-2 receptor α-subunit/3S chimeric protein, but not the other receptors, including Glut4, Glut8 and transferrin receptor. Such results indicate the presence of a selective endocytic assembly for c-Met. It also suggests a potential for c-Met-specific anti-cancer therapy using the identified endocytic motif in this study.

CCR5 gene polymorphism is a genetic risk factor for radiographic severity of rheumatoid arthritis.

The chemokine receptor [C-C chemokine receptor 5 (CCR5)] is expressed on diverse immune effecter cells and has been implicated in the pathogenesis of rheumatoid arthritis (RA). This study sought to determine whether single-nucleotide polymorphisms (SNPs) in the CCR5 gene and their haplotypes were associated with susceptibility to and severity of RA. Three hundred fifty-seven patients with RA and 383 healthy unrelated controls were recruited. Using a pyrosequencing assay, we examined four polymorphisms -1118 CTAT(ins) (/del) (rs10577983), 303 A>G (rs1799987), 927 C>T (rs1800024), and 4838 G>T (rs1800874) of the CCR5 gene, which were distributed over the promoter region as well as the 5' and 3' untranslated regions. No significant difference in the genotype, allele, and haplotype frequencies of the four selected SNPs was observed between RA patients and controls. CCR5 polymorphisms of -1118 CTAT(del) (P = 0.012; corrected P = 0.048) and 303 A>G (P = 0.012; corrected P = 0.048) showed a significant association with radiographic severity in a recessive model, and, as a result of multivariate logistic regression analysis, were found to be an independent predictor of radiographic severity. When we separated the erosion score from the total Sharp score, the statistical significance of CCR5 polymorphisms showed an increase; -1118 CTAT(ins) (/del) (P = 0.007; corrected P = 0.028) and 303 A>G (P = 0.007; corrected P = 0.028). Neither SNPs nor haplotypes of the CCR5 gene showed a significant association with joint space narrowing score. These results indicate that genetic polymorphisms of CCR5 are an independent risk factor for radiographic severity denoted by modified Sharp score, particularly joint erosion in RA.

Comparison of nuchal translucency measurements obtained using Volume NT(TM) and two- and three-dimensional ultrasound.

OBJECTIVE: To evaluate the feasibility of Volume NT(TM) , a new technique that automatically archives mid-sagittal plane views and measures the maximum nuchal translucency (NT) thickness, by comparing its measurements with those made with conventional two- (2D) and three-dimensional (3D) techniques. METHODS: This was a prospective study of 130 singleton pregnancies undergoing NT screening at 11 + 0 to 13 + 6 weeks of gestation. Fetuses with enlarged NT or multiple anomalies and those in the prone position were excluded. Success rate of NT measurement was assessed using Volume NT(TM) , 2D and 3D techniques. In cases in which all three techniques were successful, intra- and interobserver bias and levels of agreement for NT measurements within and between techniques were evaluated using Bland-Altman plots. RESULTS: Of 130 cases enrolled into the study, 16 were excluded from analysis due to enlarged NT (n = 3), prone position (n = 2) or missing data (n = 11). Among the 114 cases analyzed, NT measurement was successful by the conventional 2D method in 95.6% (109/114) of cases and by 3D and Volume NT(TM) measurements in 103 and 93 cases, respectively. Success rate was not significantly different between methods. In 89 cases, NT values were available using all three methods. Among them, mean ± SD 2D-NT was 1.3 ± 0.4 mm, 3D-NT was 1.2 ± 0.4 mm and Volume NT(TM) was 1.3 ± 0.4 mm. The mean differences of the intra- and interobserver variability of each method were not significantly different from zero for each method. CONCLUSIONS: Volume NT(TM) , a novel technique for automated NT measurement, is apparently reproducible and comparable with conventional 2D and 3D ultrasound techniques for NT measurement.

Determination of molecular weights of caprine milk proteins by matrix-assisted laser desorption/ionization mass spectrometry.

Molecular weights (MW) of major proteins in milk of 3 Korean dairy goat breeds were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, after treatment of milk samples with the reduction buffer used in capillary electrophoresis. The MW of caprine milk proteins were compared with those of Holstein milk counterparts using commercial bovine milk protein standards. The MW of α-lactalbumin, ß-lactoglobulin, and α- and ß-casein standards were 14,197±3.4, 18,326±26.3, 23,591±13.0, and 23,967±12.8 m/z, respectively, whereas those of Holstein milk treated with the reduction buffer were 14,199±8.3, 18,397±25.9, 23,614±64.8, and 23,984±75.6 m/z, respectively. The respective MW of α-lactalbumin in Saanen, Toggenberg, and Alpine milk were 14,194±27.2, 14,266±105.9, and 14,241±13.2 m/z, which were not different from those of the bovine milk. The respective MW of ß- lactoglobulin in corresponding caprine milk were 18,840±31.5, 18,856±26.3, and 18,857±21.3 m/z, which were higher than those in the bovine milk. The MW of ß-casein in corresponding caprine milk were 23,860±27.2, 23,886±12.3, and 23,901±8.4 m/z, which were lower than those in the bovine milk. The results indicated that matrix-assisted laser desorption/ionization time-of-flight mass spectrometry could be used for rapid determination of MW of Korean caprine milk proteins without protein separation steps.