Urinary tract infections (UTIs) are one of the most common diseases by which humans seek medical help and are caused mainly by uropathogenic Escherichia coli (UPEC). Studying the virulence and ...antibiotic resistance of UPEC with respect to various phylogenetic groups is of utmost importance in developing new therapeutic agents. Thus, in this study, we analysed the virulence factors, antibiotic resistance and phylogenetic groups among various UPEC isolates from children with UTIs. The phylogenetic analysis revealed that majority of the strains responsible for UTIs belonged to the phylogenetic groups B2 and D. Of the 58 E. coli isolates, 79·31% belonged to group B2, 15·51% to group D, 3·44% to group A and 1·72% to B1. Simultaneously, the number of virulence factors and antibiotic resistance exhibited were also significantly high in groups B2 and D compared to other groups. Among the isolates, 44·8% were multidrug resistant and of that 73% belonged to the phylogenetic group B2, indicating the compatibility of antibiotic resistance and certain strains carrying virulence factor genes. The antibiotic resistance profiling of UPEC strains elucidates that the antimicrobial agents such as chloramphenicol, cefoxitin, cefepime, ceftazidime might still be used in the therapy for treating UTIs. SIGNIFICANCE AND IMPACT OF THE STUDY: As the antibiotic resistance pattern of uropathogenic Escherichia coli varies depending on different geographical regions, the antibiotic resistance pattern from this study will help the physicians to effectively administer antibiotic therapy for urinary tract infections. In addition, the frequency of virulence factors and antibiotic resistance genes among various phylogenic groups could be effectively used to draw new targets for uropathogenic Escherichia coli antibiotic‐independent therapies. The study emphasizes need of public awareness on multidrug resistance and for more prudent use of antimicrobials.
The epithelial to mesenchymal transition (EMT) that occurs during embryonic development has begun to attract attention as a potential mechanism for tumor cell metastasis. Snail is a well-known ...Zn-finger transcription factor that promotes EMT by repressing E-cadherin expression. It is known that Snail is phosphorylated by GSK3β and degraded by β-TrCP-mediated ubiquitination. Here we described another protein kinase, CK1, whose phosphorylation of Snail is required for the subsequent GSK3β phosphorylation. Specific inhibition or depletion of CK1ζ inhibits the phosphorylation and degradation of Snail and promotes cell migration, suggesting a central role of CK1ζ in the EMT process. Furthermore, our study uncovered distinct roles and steps of Snail phosphorylation by CK1ζ and GSK3β.Taken together, we identified CK1ζ as a new component of the Snail-mediated EMT process, providing insight into the mechanism of human cancer metastasis. Oncogene (2010) 29, 3124-3133; doi: 10.1038/onc.2010.77; published online 22 March 2010 Keywords: snail; casein kinase 1; EMT; GSK3β;metastasis
Objective: To investigate whether drugs targeting peripheral cannabinoid-1 (CB1) receptor ameliorate adiposity comparable to central CB1-receptor antagonist or not. Measurements: Receptor binding ...assay and functional assay in vitro. Pharmacokinetic parameters in mice, brain uptake clearance of compounds in rats and antagonism on the CB1-agonist-induced hypothermia in mice. Diet consumption, body weight changes, hepatic gene expression of sterol-regulatory element-binding protein-1 (SREBP-1) and plasma/tissue concentrations of compounds in HF diet-induced obese (HF-DIO) mice after acute and chronic treatment. Results: Compound-1, an SR141716A derivative, is a peripheral CB1-receptor-selective antagonist that is 10 times less potent than SR141716A in in vitro evaluations. Although the plasma concentrations of Compound-1 are five times higher than those of SR141716A, its potency is still 10 times lower than that of SR141716A in reducing the consumption of normal or HF diet by mice. Through evaluations of brain uptake and the effect on CB1-agonist-induced hypothermia, it was verified that the blood–brain barrier (BBB) penetration of Compound-1 is much lower than that of SR141716A. In HF-DIO mice, chronic treatment by Compound-1 showed dose-dependent antiobesity activities, while its brain distribution was very low as compared with that of SR141716A. Compound-1’s effective doses for antiobesity activity were just over 30 mg kg−1. However, Compound-1 completely suppressed the elevated hepatic SREBP-1 expression even at 10 mg kg−1. Conclusion: These results suggest that (1) central CB1 receptors mediate anorectic response of CB1-receptor antagonists and (2) peripheral modulations, including SREBP-1 expression, are not major mechanisms in the antiobesity effects of CB1-receptor antagonists.
Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by ...phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or γ-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy.
S.Y. Park, S.‐H. Kim, S.‐H. Choi, H. Sung, M.‐N. Kim, J.H. Woo, Y.S. Kim, S.‐K. Park, J.‐H. Lee, K.‐H. Lee, S.‐G. Lee, D.J. Han, S.‐O. Lee. Clinical and radiological features of invasive pulmonary ...aspergillosis in transplant recipients and neutropenic patients. Transpl Infect Dis 2010: 12: 309–315. All rights reserved
: Invasive pulmonary aspergillosis (IPA) is an important cause of mortality in transplant recipients and in patients with neutropenia. Although IPA has been studied extensively in neutropenic patients, there are limited data on IPA in recipients of solid organ transplants (SOTs). We compared the clinical features and radiologic findings of 27 SOT recipients with IPA with those of 35 neutropenic patients with IPA. The SOT recipients were more likely than neutropenic patients to show peribronchial consolidation (31% vs. 7%; P=0.03) or ground‐glass opacity (38% vs. 7%; P=0.007) and less likely to have fever (22% vs. 80%; P<0.001), macro‐nodules (35% vs. 67%; P=0.02), mass‐like consolidation (27% vs. 67%; P=0.004), halo signs (8% vs. 56%; P<0.001), or air‐crescent signs (0% vs. 22%; P=0.01).
Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic ...breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.
Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 95% CI 0·437–0·994, one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 75% of 92 vs 14 16% of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.
Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.
Pfizer, Shinpoong, and Daewoong Korea and Takeda.
There have been limited data on the risk of onward transmission from individuals with Omicron variant infections who return to work after a 5-day isolation.
To evaluate the risk of transmission from ...healthcare workers (HCWs) with Omicron variant who returned to work after a 5-day isolation and the viable-virus shedding kinetics.
This investigation was performed in a tertiary care hospital, Seoul, South Korea. In a secondary transmission study, we retrospectively reviewed the data of HCWs confirmed as COVID-19 from March 14th to April 3rd, 2022 in units with five or more COVID-19-infected HCWs per week. In the viral shedding kinetics study, HCWs with Omicron variant infection who agreed with daily saliva sampling were enrolled between February and March, 2022.
Of the 248 HCWs who were diagnosed with COVID-19 within 5 days of the return of an infected HCW, 18 (7%) had contact with the returned HCW within 1–5 days after their return. Of these, nine (4%) had an epidemiologic link other than with the returning HCW, and nine (4%) had contact with the returning HCW, without any other epidemiologic link. In the study of the kinetics of virus shedding (N = 32), the median time from symptom onset to negative conversion of viable virus was four days (95% confidence interval: 3–5).
Our data suggest that the residual risk of virus transmission after 5 days of isolation following diagnosis or symptom onset is low.
A
bstract
We compute the contribution of order
α
S
2
α
2
to the cross section of a top-antitop pair in association with at least one heavy Standard Model boson —
Z
,
W
±
, and Higgs — by including ...all effects of QCD, QED, and weak origin and by working in the automated M
ad
G
raph
5_
a
MC@NLO framework. This next-to-leading order contribution is then combined with that of order
α
S
3
α
, and with the two dominant lowest-order ones,
α
S
2
α
and
α
S
α
2
, to obtain phenomenological results relevant to a 8, 13, and 100 TeV
pp
collider.
We aimed to evaluate the long-term clinical outcomes and prognostic factors of symptomatic intracranial unruptured vertebrobasilar artery dissection (siu-VBD).
A total of 191 patients (M:F = 127:64; ...median age, 46 years) with siu-VBD were treated between January 2001 and December 2008. Presentations, treatments, outcomes, and prognostic factors were retrospectively analyzed.
Clinical manifestations were ischemic symptoms with headache (n = 97) or without headache (n = 13) and headache without ischemic symptoms (n = 81). Forty-six patients (24.1%) underwent endovascular treatment. The remaining 145 patients (75.9%) were medically treated with anticoagulants (n = 49), antiplatelets (n = 48), or analgesics alone (n = 48). Clinical follow-up data were available in 178 patients (102 ischemic and 76 nonischemic) at 15 to 102 months (mean, 46 months). None of the siu-VBD hemorrhaged. All 76 patients without ischemic presentation had favorable outcomes (modified Rankin Scale, 0-1). Of the 102 patients with ischemic presentation, outcomes were favorable in 92 and unfavorable in 10 patients. Four patients died; 3 died of causes unrelated to VBD, and one died as a result of basilar artery (BA) dissection. Old age (odds ratio OR 1.099; 95% confidence interval CI 1.103-1.204; p = 0.042) and BA involvement (OR 11.886; 95% CI 1.416-99.794; p = 0.023) were independent predictors of unfavorable outcomes in siu-VBD with ischemic presentation.
Clinical outcomes for siu-VBD were favorable in all patients without ischemic symptoms and in most patients with ischemic presentation. None of the siu-VBD caused subarachnoid hemorrhage. Old age and BA involvement were independent predictors of unfavorable outcome in siu-VBD with ischemic presentation.
We report on the Balloon-borne Investigation of Temperature and Speed of Electrons in the corona (BITSE) mission launched recently to observe the solar corona from
≈
3
Rs to 15 Rs at four ...wavelengths (393.5, 405.0, 398.7, and 423.4 nm). The BITSE instrument is an externally occulted single stage coronagraph developed at NASA’s Goddard Space Flight Center in collaboration with the Korea Astronomy and Space Science Institute (KASI). BITSE used a polarization camera that provided polarization and total brightness images of size
1024
×
1024
pixels. The Wallops Arc Second Pointer (WASP) system developed at NASA’s Wallops Flight Facility (WFF) was used for Sun pointing. The coronagraph and WASP were mounted on a gondola provided by WFF and launched from the Fort Sumner, New Mexico station of Columbia Scientific Balloon Facility (CSBF) on September 18, 2019. BITSE obtained 17,060 coronal images at a float altitude of
≈
128,000
feet (
≈
39
km) over a period of
≈
4
hrs. BITSE flight software was based on NASA’s core Flight System, which was designed to help develop flight quality software. We used EVTM (Ethernet Via Telemetry) to download science data during operations; all images were stored on board using flash storage. At the end of the mission, all data were recovered and analyzed. Preliminary analysis shows that BITSE imaged the solar minimum corona with the equatorial streamers on the east and west limbs. The narrow streamers observed by BITSE are in good agreement with the geometric properties obtained by the Solar and Heliospheric Observatory (SOHO) coronagraphs in the overlapping physical domain. In spite of the small signal-to-noise ratio (
≈
14
) we were able to obtain the temperature and flow speed of the western steamer. In the heliocentric distance range 4 – 7 Rs on the western streamer, we obtained a temperature of
≈
1.0
±
0.3
MK and a flow speed of
≈
260
km s
−1
with a large uncertainty interval.
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