Liver kinase B1 (LKB1) is mutationally inactivated in Peutz-Jeghers syndrome and in a variety of cancers including human papillomavirus (HPV)-caused cervical cancer. However, the significance of LKB1 ...mutations in cervical cancer initiation and progress has not been examined. Herein, we demonstrated that, in mouse embryonic fibroblasts, loss of LKB1 and transduction of HPV16 E6/E7 had an additive effect on constraining cell senescence while promoting cell proliferation and increasing glucose consumption, lactate production and ATP generation. Knockdown of LKB1 increased and ectopic expression of LKB1 decreased glycolysis, anchorage-independent cell growth, and cell migration and invasion in HPV-transformed cells. In the tumorigenesis and lung metastasis model in syngeneic mice, depletion of LKB1 markedly increased tumor metastatic colonies in lungs without affecting subcutaneous tumor growth. We showed that HPV16 E6/E7 enhanced the expression of hexokinase-ll (HK-II) in the glycolytic pathway through elevated c-MYC. Ectopic LKB1 reduced HK-II along with glycolysis. The inverse relationship between HK-II and LKB1 was also observed in normal and HPV-associated cervical lesions. We propose that LKB1 acts as a safeguard against HPV-stimulated aerobic glycolysis and tumor progression. These findings may eventually aid in the development of therapeutic strategy for HPV-associated malignancies by targeting cell metabolism.
We report constraints on the dark photon effective kinetic mixing parameter (κ) with data taken from two p-type point-contact germanium detectors of the CDEX-10 experiment at the China Jinping ...Underground Laboratory. The 90% confidence level upper limits on κ of solar dark photon from 205.4 kg-day exposure are derived, probing new parameter space with masses (m_{V}) from 10 to 300 eV/c^{2} in direct detection experiments. Considering dark photon as the cosmological dark matter, limits at 90% confidence level with m_{V} from 0.1 to 4.0 keV/c^{2} are set from 449.6 kg-day data, with a minimum of κ=1.3×10^{-15} at m_{V}=200 eV/c^{2}.
The associated risk of phthalate exposure, both parent compounds in the home and their metabolites in urine, to childhood allergic and respiratory morbidity, after adjusting for exposures of indoor ...pollutants, especially bioaerosols, was comprehensively assessed. Levels of five phthalates in settled dust from the homes of 101 children (3–9 years old) were measured, along with their corresponding urinary metabolites. Other environmental risk factors, including indoor CO2, PM2.5, formaldehyde, 1,3‐β‐d‐glucan, endotoxin, allergen and fungal levels, were concomitantly examined. Subject’s health status was verified by pediatricians, and parents recorded observed daily symptoms of their children for the week that the home investigation visit took place. Significantly increased level of benzylbutyl phthalate, in settled dust, was associated with test case subjects (allergic or asthmatic children). Higher levels of dibutyl phthalate and its metabolites, mono‐n‐butyl phthalate, and mono‐2‐ethylhexyl phthalate were found to be the potential risk factors for the health outcomes of interest. Similarly, indoor fungal exposure remained a significant risk factor, especially for reported respiratory symptoms. The relative contribution from exposure to phthalates and indoor biocontaminants in childhood allergic and respiratory morbidity is, for the first time, quantitatively assessed and characterized.
Practical Implications
For asthmatic and allergic children living in subtropical and highly developed environments like homes in Taiwan, controlling environmental exposure of phthalates may be viewed as equally important as avoiding indoor microbial burdens, for the management of allergy‐related diseases. It is also recognized that multidisciplinary efforts will be critical in realizing the true underlying mechanisms associated with these observations.
Summary
Background Quantitative analysis of intravenous immunoglobulin (IVIg) treatment against toxic epidermal necrolysis (TEN) is lacking.
Objectives To provide a meta‐analysis evidence‐based ...examination of IVIg efficacy against TEN.
Methods A systematic review and meta‐analysis of literature published before 31 July 2011 was conducted. In observational controlled studies with at least eight patients with TEN receiving IVIg treatment, a pooled estimate of mortality risk was determined, comparing IVIg and supportive care. Statistical analyses were performed on raw data to compare the clinical differences between (i) high‐dose and low‐dose IVIg treatment in adult patients and (ii) paediatric and adult patients treated with IVIg.
Results Seventeen studies met inclusion criteria. Overall mortality rate of patients with TEN treated with IVIg was 19·9%. The pooled odds ratio (OR) for mortality from six observational controlled studies comparing IVIg and supportive care was 1·00 95% confidence interval (CI) 0·58–1·75; P = 0·99. The pooled OR for mortality in patients treated with high‐dose IVIg vs. supportive care was 0·63 (95% CI 0·27–1·44; P = 0·27). Adults treated with high‐dose IVIg exhibited significantly lower mortality than those treated with low‐dose IVIg (18·9% vs. 50%, respectively; P = 0·022); however, multivariate logistic regression model adjustment indicated that IVIg dose does not correlate with mortality (high vs. low dose: OR 0·494; 95% CI 0·106–2·300; P = 0·369). Paediatric patients treated with IVIg had significantly lower mortality than adults (0% vs. 21·6%; P = 0·001).
Conclusions Although high‐dose IVIg exhibited a trend towards improved mortality and children treated with IVIg had a good prognosis, the evidence does not support a clinical benefit of IVIg. Randomized controlled trials are necessary.
See also the Commentary by Walsh and Creamer
Highlights • Baicalin prevents depressive-like behaviors induced by CORT. • Baicalin reverses the increased mRNA and protein expression of SGK1 in the hippocampus induced by CORT. • Baicalin ...increases the hippocampal protein expression of 11β-HSD2, GRα and BDNF in CORT-treated mice.
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