The objective was to validate an online nomogram developed based on the French collaborative national database on upper urinary tract urothelial carcinoma (UUT-UC) using a different cohort.
The study ...comprised 328 patients with UUT-UC who underwent radical nephroureterectomy. The discrimination of models was quantified using Harrell's concordance index. The relationship between the model-derived and actuarial cancer-specific mortality was graphically explored within calibration plots. Calibration was also assessed using the quartiles of the predicted survival at 3 and 5 years and calculation of the corresponding observed Kaplan-Meier estimates. Clinical net benefit was evaluated constructing decision curve analysis.
The discrimination accuracy of the nomograms at 3 and 5 years was 71.6% and 71.8%, respectively. Although nomograms discriminated well by Kaplan-Meier curves, and log-rank tests were all highly significant, the calibration plots tended to exaggerate the overestimation of mortality between predicted and observed probabilities at 3 and 5 years for survival. When compared with the AJCC/UICC staging system, the nomograms performed well across a wide range of threshold probabilities using decision curve analysis.
The online nomogram is a highly accurate prognostic tool for patients with UUT-UC treated with radical nephroureterectomy. The model can provide an accurate estimate of the individual risk of cancer-specific mortality. Further improvement and implementation of novel molecular marker is needed.
Proteostatic regulation of tyrosine hydroxylase (TH), the rate‐limiting enzyme in dopamine biosynthesis, is crucial for maintaining proper brain neurotransmitter homeostasis. Variants of the TH gene ...are associated with tyrosine hydroxylase deficiency (THD), a rare disorder with a wide phenotypic spectrum and variable response to treatment, which affects protein stability and may lead to accelerated degradation, loss of TH function and catecholamine deficiency. In this study, we investigated the effects of the TH cofactor tetrahydrobiopterin (BH4) on the stability of TH in isolated protein and in DAn‐ differentiated from iPSCs from a human healthy subject, as well as from THD patients with the R233H variant in homozygosity (THDA) and R328W and T399M variants in heterozygosity (THDB). We report an increase in TH and dopamine levels, and an increase in the number of TH+ cells in control and THDA cells. To translate this in vitro effect, we treated with BH4 a knock‐in THD mouse model with Th variant corresponding to R233H in patients. Importantly, treatment with BH4 significantly improved motor function in these mice, as demonstrated by increased latency on the rotarod test and improved horizontal activity (catalepsy). In conclusion, our study demonstrates the stabilizing effects of BH4 on TH protein levels and function in THD neurons and mice, rescuing disease phenotypes and improving motor outcomes. These findings highlight the therapeutic potential of BH4 as a treatment option for THDA patients with specific variants and provide insights into the modulation of TH stability and its implications for THD management.
Total reactive nitrogen oxides (NOy) are among the key components in the chemistry of ozone production. In order to improve the understanding of the formation mechanisms of high‐ozone events in ...Beijing, China, an intensive experiment on the reactive nitrogen oxides was carried out at the observatory of Peking University during the Campaign of Air Quality Research in Beijing and surrounding areas in 2006 (CAREBeijing‐2006) campaign. In this study, analysis focusing on the data of high O3 episodes was performed to examine the relationship between the concentration of total oxidant and the composition of NOy. High levels of NO and NOy were observed in the morning rush hours, indicating the influences of fresh emissions from local traffic. However, the ratio of NO to NOy was only 11–60% in the morning, implying that there was a substantial amount of aged air pollutants remained overnight in the stagnant air mass. Significant increases in the NOz mixing ratio (= NOy‐NOx) were observed during the period from the morning toward early afternoon, consistent with the increasing oxidant level. Ozone production efficiency of NOx (OPEx), which was derived from the NOz‐Ox regression, was found to range from 3.9 to 9.7 mol/mol in Beijing. Furthermore, it was revealed that the daily NOz maximum was proportional to the NOx peak level in the morning, and that OPEx decreased with the increases of NOz in a hyperbolic form. According to the results, abatement in NOx emission would not be effective toward reducing ozone concentrations in Beijing.
DNAJC12, a type III member of the HSP40/DNAJ family, has been identified as the specific co‐chaperone of phenylalanine hydroxylase (PAH) and the other aromatic amino acid hydroxylases. DNAJ proteins ...work together with molecular chaperones of the HSP70 family to assist in proper folding and maintenance of intracellular stability of their clients. Autosomal recessive mutations in DNAJC12 were found to reduce PAH levels, leading to hyperphenylalaninemia (HPA) in patients without mutations in PAH. In this work, we investigated the interaction of normal wild‐type DNAJC12 with mutant PAH in cells expressing several PAH variants associated with HPA in humans, as well as in the Enu1/1 mouse model, homozygous for the V106A‐Pah variant, which leads to severe protein instability, accelerated PAH degradation and mild HPA. We found that mutant PAH exhibits increased ubiquitination, instability, and aggregation compared with normal PAH. In mouse liver lysates, we showed that DNAJC12 interacts with monoubiquitin‐tagged PAH. This form represented a major fraction of PAH in the Enu1/1 but was also present in liver of wild‐type PAH mice. Our results support a role of DNAJC12 in the processing of misfolded ubiquitinated PAH by the ubiquitin‐dependent proteasome/autophagy systems and add to the evidence that the DNAJ proteins are important players both for proper folding and degradation of their clients.
DNAJC12 has been identified as the specific co‐chaperone of phenylalanine hydroxylase (PAH) and mutations in DNAJC12 have been associated with hyperphenylalaninemia (HPA). In this work we demonstrate a strong reduction of PAH‐like immunoreactivity and an increased ubiquitination of mutant PAH in the liver of HPA Enu1/1 mice compared with wild‐type (Wt) mice. Our results also reveal the interaction of DNAJC12 with mono‐ubiquitin‐tagged PAH, supporting a role of DNAJC12 in the processing of misfolded PAH.
With increasing maternal cannabis use, there is a need to investigate the lasting impact of prenatal exposure to Δ9-tetrahydrocannabinol (THC), the main psychotropic compound in cannabis, on ...cognitive/memory function. The endocannabinoid system (ECS), which relies on polyunsaturated fatty acids (PUFAs) to function, plays a crucial role in regulating prefrontal cortical (PFC) and hippocampal network-dependent behaviors essential for cognition and memory. Using a rodent model of prenatal cannabis exposure (PCE), we report that male and female offspring display long-term deficits in various cognitive domains. However, these phenotypes were associated with highly divergent, sex-dependent mechanisms. Electrophysiological recordings revealed hyperactive PFC pyramidal neuron activity in both males and females, but hypoactivity in the ventral hippocampus (vHIPP) in males, and hyperactivity in females. Further, cortical oscillatory activity states of theta, alpha, delta, beta, and gamma bandwidths were strongly sex divergent. Moreover, protein expression analyses at postnatal day (PD)21 and PD120 revealed primarily PD120 disturbances in dopamine D1R/D2 receptors, NMDA receptor 2B, synaptophysin, gephyrin, GAD67, and PPARα selectively in the PFC and vHIPP, in both regions in males, but only the vHIPP in females. Lastly, using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), we identified region-, age-, and sex-specific deficiencies in specific neural PUFAs, namely docosahexaenoic acid (DHA) and arachidonic acid (ARA), and related metabolites, in the PFC and hippocampus (ventral/dorsal subiculum, and CA1 regions). This study highlights several novel, long-term and sex-specific consequences of PCE on PFC-hippocampal circuit dysfunction and the potential role of specific PUFA signaling abnormalities underlying these pathological outcomes.
Multicentre study.
To define the clinical characteristics of patients with tuberculosis (TB) destroyed lung due to past TB.
We reviewed patients with TB-destroyed lung between May 2005 and June 2011.
...A total of 595 patients from 21 hospitals were enrolled. The mean age was 65.63 ± 0.47 (mean ± standard error); 60.5% were male. The mean number of lobes involved was 2.59 ± 0.05. Pleural thickening was observed in 54.1% of the patients. Mean forced vital capacity (FVC), forced expiratory volume in 1 s (FEV(1)), FEV(1)/FVC, bronchodilator response and number of exacerbations per year were respectively 2.06 ± 0.03 l (61.26% ± 0.79), 1.16 ± 0.02 l (49.05% ± 0.84), 58.03% ± 0.70, 5.70% ± 0.34, and 0.40 ± 0.04. The number of lobes involved was significantly correlated with FVC and FEV(1), and with the number of exacerbations per year. Use of long-acting muscarinic antagonists or long-acting beta-2 agonists plus inhaled corticosteroids resulted in bronchodilatory effects. Multivariable regression analysis showed that age, initial FEV(1) (%) and number of exacerbations during follow-up were independent factors affecting change in FEV(1).
Decreased lung function with exacerbation, and progressive decline of FEV(1) were observed in patients with TB-destroyed lung.
Abstract Hypoxia-inducible factor 1α (HIF-1α) regulates the transcription of a number of genes under hypoxia and other extracellular stimulations. It has been shown that E-cadherin is down-regulated ...by epidermal growth factor receptor (EGF) stimulation, and that cells with low E-cadherin expression are more invasive. Our recent study demonstrated a novel mechanism by which EGF down-regulates E-cadherin expression through production of hydrogen peroxide (H2 O2 ) and the activation of p38 MAPK in human ovarian cancer cells. In this study, we were interested in examining the potential role of HIF-1α in cell invasion under normoxic conditions, specifically when cells are treated with EGF, which is known to down-regulate E-cadherin and increase invasiveness. We show that EGF treatment induces HIF-1α expression in two human ovarian cancer cell lines (SKOV3 and OVCAR5), and that this effect is diminished by treatment with a membrane-permeable H2 O2 scavenger, PEG-catalase. However, the induction of HIF-1α by EGF did not require the activation of p38 MAPK. Treatment with siRNA targeting HIF-1α reduces both basal and EGF-induced HIF-1α levels. Importantly, treatment with HIF-1α siRNA diminishes the up-regulation of Snail and Slug as well as the down-regulation of E-cadherin by EGF. The involvement of HIF-1α in the down-regulation of E-cadherin was confirmed with cobalt chloride (CoCl2 ), a hypoxia-mimetic reagent. Finally, we also show that EGF-induced cell invasion is attenuated by treatment with HIF-1α siRNA. This study demonstrates an important role for HIF-1α in mediating the effects of EGF on Snail, Slug and E-cadherin expression as well as invasiveness in human ovarian cancer cells.
Phenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A ...homozygous Pah-R261Q mouse, with a highly prevalent misfolding variant in humans, reveals the expected hepatic PAH activity decrease, systemic L-Phe increase, L-tyrosine and L-tryptophan decrease, and tetrahydrobiopterin-responsive hyperphenylalaninemia. Pah-R261Q mice also present unexpected traits, including altered lipid metabolism, reduction of liver tetrahydrobiopterin content, and a metabolic profile indicative of oxidative stress. Pah-R261Q hepatic tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates of mutant PAH that colocalize with selective autophagy markers. Together, these findings reveal that PKU, customarily considered a loss-of-function disorder, can also have toxic gain-of-function contribution from protein misfolding and aggregation. The proteostasis defect and concomitant oxidative stress may explain the prevalence of comorbid conditions in adult PKU patients, placing this mouse model in an advantageous position for the discovery of mutation-specific biomarkers and therapies.
Polyethylene (PE) membranes having various porosities are required for use as microfilters and separators in lithium ion batteries. Phthalates, whose mixtures with PE exhibit upper critical solution ...temperature (UCST)-type phase behavior, are used as diluents for the fabrication of PE membranes. However, the use of phthalates as diluents is limited because of their toxicity. Triethylolpropane tris(2-ethylhexanoate) (TEPTEH) was synthesized for use as a new nontoxic diluent for the fabrication of the PE membranes. The PE/TEPTEH blends showed UCST-type phase behavior and their phase separation temperatures decreased with increasing PE content. TEPTEH and paraffin oil (PO) mixtures were also examined as diluents to control the porosity of PE separators. PE//(TEPTEH/PO) blends also exhibited UCST-type phase behavior when TEPTEH/PO diluent mixtures contained greater than or equal to 70wt% of TEPTEH, and their phase separation temperatures decreased with increasing PO content in the diluent mixture with a fixed PE content. The average size of pores and the porosity of the membrane increased with increasing TEPTEH content in the diluent mixture. The porosity of the PE separator fabricated using a lab-scale twin extruder equipped with biaxial stretching machines also increased with increasing TEPTEH content in the diluent mixture. As a result, when the air permeability of the separator prepared from the PE/PO blend was compared with that prepared from PE/TEPTEH blend, the latter was about 2.5 times higher than the former.
•Triethylolpropane tris(2-ethylhexanoate) (TEPTEH) was synthesized.•TEPTEH was used as a new diluent for the fabrication of the PE separator.•The PE/TEPTEH blends showed UCST-type phase behavior.•Air permeability of PE/TEPTEH separator was 2.5 times higher than that of PE/PO separator.
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