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1.
Sci Total Environ ; 781: 146712, 2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33812102

RESUMEN

Potential release quantity and quality of dissolved organic matter (DOM) from hydrochar (HDOM) in various environmental conditions were investigated. Corn cobs were utilized as model agricultural residue to prepare the hydrochar. Four extracts, ultra-pure water, acid solution, alkali solution and salt solution, and two temperatures, 20 °C and 60 °C, were adopted to imitate various environmental conditions. Excitation-emission spectrophotometry with parallel factor analysis was used to evaluate the chemical properties of HDOM. The results showed that the dissolved organic carbon in the HDOM was high, ranging from 46 to 268 mg g-1. Four components were confirmed in the HDOM: mixed substances of humic-like and protein-like components, marine humic-like substances, terrestrial humic-like substances and tyrosine-like substances. Alkalinity and high temperature conditions could enhance the leaching amount of HDOM, particularly humic-like substances, and change the relative proportion of components and the chemical quality. In addition, values of the fluorescence indexes indicated that the HDOM was high microbial availability. Released HDOM may result in significant impacts in ecosystem functionality. These findings reveal the potential release characteristics of HDOM in the environment, opening new doors to understanding the environmental impacts of hydrochar and guiding its rational application.

2.
Artículo en Inglés | MEDLINE | ID: mdl-33804553

RESUMEN

This systematic review adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) guidelines and used the method of network meta-analysis to compare the effects of different types of interventions from different perspectives which were abilities of daily life activity, psychological health, social functioning, and overall life quality. The eligibility criteria were: (1) Participants were adults above 18 years old with disabilities; (2) Interventions could be classified into active exercise, passive therapy, psychological education, psychosocial support program, multi-disciplinary program, and usual care; (3) Outcomes should be the patient-reported outcome measures (PROMs) that could be classified into abilities of daily life activity, psychological health, social functioning, and overall life quality; (4) Randomized designed and published in English. The keywords and their search field were: (1) "people with disabilities/disability", "disabled", "handicapped", or "disable people" in titles or abstracts; (2) AND "randomized" or "randomised" in titles or abstracts; (3) NOT "design", "protocol", or "review" in titles. After searching in databases of Medline (EBSCO), PubMed, CINAHL, and Ovid, 16 studies were included. As a result, active exercise and passive therapy are most likely to be the best interventions for overall life quality, psychological education and passive therapy are most likely to be the best interventions for abilities of daily life activity, and psychosocial support programs are most likely to be the best intervention for psychological health and social functioning.

3.
Dent Mater J ; 2021 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-33814531

RESUMEN

Human induced pluripotent stem cells (hiPSCs) are exciting for regenerative medicine due to their multi-potent differentiation. SB431542 bioactive molecule can activate bone morphogenetic protein-signalling in osteoblasts. The objectives were to: (1) develop a novel injectable calcium phosphate cement (CPC)-SB431542 scaffold for dental/craniofacial bone engineering; and (2) investigate cell proliferation and osteo-differentiation of hiPSC-derived mesenchymal stem cells (hiPSC-MSCs) on CPC-SB431542 scaffold. Three groups were tested: CPC control; CPC with SB431542 inside CPC (CPCSM); CPC with SB431542 in osteogenic medium (CPC+SMM). SB431542 in CPC promoted stem cell proliferation and viability. hiPSC-MSCs differentiated into osteogenic lineage and synthesized bone minerals. CPC with SB431542 showed much greater osteo-expressions and more bone minerals than those without SB431542. In conclusion, hiPSC-MSCs on CPC scaffold containing SB431542 showed excellent osteo-differentiation and bone mineral synthesis for the first time. CPC was a suitable scaffold for delivering stem cells and SB431542 to promote bone regeneration in dental/craniofacial applications.

4.
Biochimie ; 2021 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-33794342

RESUMEN

Polyamides (PAs) are powerful DNA ligands that can bind the minor groove of DNA with high affinity and specificity. While the characterization of PA-DNA behavior has focused principally on hairpin PAs 6-8 rings in size, there is increasing evidence that their behavior does not necessarily reflect the complexities that are emerging from studies of larger hairpin PAs, particularly concerning sequence mismatch tolerance and observed but unaddressed high PA-target site binding stoichiometries. To explore these complexities in more detail, kinetics studies of binding a large anti-HPV hairpin polyamide to an isolated DNA recognition site are described. Using a fluorescence assay, two distinct binding phases are observed for the first time in hairpin PA literature. PA14 concentration dependence analysis indicates that the faster binding event is diffusion-controlled; the apparent, second event is significantly slower (350-1500 fold). Both association phases are sampled in 1:1 complexes, consistent with cooperative binding of two PA molecules even under this condition. Fitting of the slow phase to a biexponential model yields two λon,app that differ by 4-5-fold, which is consistent with the high mismatch tolerance and binding site stoichiometry previously observed. A/T patterns in the recognition sequence do not affect these decay constants significantly. Dissociation decay constants are among the slowest reported for hairpin PAs (10-3 s-1), independent of A/T pattern, and may point to the efficacy of PA14 as an antiviral.

5.
Environ Pollut ; 278: 116822, 2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33677223

RESUMEN

Hydrodynamic conditions often affect the eutrophication process and play a key role in algal growth in reservoirs. A promising approach for controlling algal blooms in reservoirs is to create adverse hydrodynamic conditions by implementing reservoir operation strategies. However, research on this method is still nascent and does not support practical applications due to the lack of quantitative hydrodynamic thresholds. In this paper, field observations of algal growth from April 2015 to August 2016 were conducted, and a three-dimensional (3D) model that couples hydrodynamics and water temperatures for the Zipingpu Reservoir was established. Low flow velocities (V) and low Reynolds numbers (Re) in the Longchi tributary are favorable for dinoflagellate growth and accumulation, which can explain why dinoflagellate blooms are more likely to occur in the tributary. A temperature of 18-22 °C is considered a precondition for Peridiniopsis penardii blooms, suggesting that freshwater dinoflagellate species may prefer lower temperatures than marine dinoflagellate species. Shallow mixing layer depth (Zmix) is conducive to Peridiniopsis penardii gathering in the upper water layers and promotes growth. The shallow euphotic layer depth (Zeu) was speculated to promote the dominance of this species by stimulating its heterotrophy and inhibiting other algal autotrophy. Furthermore, a boundary line analysis was introduced to characterize the relationships between algal biomass and hydrodynamic indicators. Thus, the thresholds for V, Re, and Zmix/Zeu were determined to be 0.034 m s-1, 6.7 × 104, and 1.7, respectively. Either accelerating horizontal flow to exceed the thresholds of V and Re or facilitating vertical mixing to exceed the threshold of Zmix/Zeu can prevent dinoflagellate blooms. Therefore, the summarized hydrodynamic threshold system is suggested to be an effective standard for controlling dinoflagellate blooms in the reservoir. Moreover, this study can provide a useful reference for understanding the mechanism of freshwater dinoflagellate blooms.

6.
J Hazard Mater ; 414: 125499, 2021 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-33662789

RESUMEN

In biological fluids, micro- or nano-size particles are prone to adsorb proteins and form a layer. The ambient air fine particulate matter (PM2.5) is inhaled via the lung, penetrates biological barriers and eventually reaches systemic blood circulation. However, there are very few data available regarding the adsorption of proteins on PM2.5. Here, we compared protein corona formed in plasma after bronchoalveolar lavage fluid (BALF) exposure with those formed in plasma alone. Using purified coronal proteins, we explored their adsorption behaviors on PM2.5 and their influence on biological reactivity of PM2.5. Liquid-chromatography tandem mass-spectrometry (LC-MS/MS) analysis revealed that exposure to BALF significantly changed the blood protein profile on PM2.5. Regardless of the presence of BALF, the protein corona on PM2.5 contained an abundance of serum albumin, hemoglobin (Hb) and fibrinogen (Fg) proteins. Using Fg as a corona surrogate, we found that van der Waals interactions, hydrophobic interactions, π-π stacking and electrostatic attractions contributed to the Fg adsorption and led to the conformational changes of Fg. In addition, Fg decoration decreased cellular internalization of PM2.5 and corresponding subsequent oxidative stress responses in a murine RAW264.7 macrophage. These results support the view that the formation of PM2.5 corona should be considered for toxicity assessment of PM2.5.

7.
J Orthop Surg Res ; 16(1): 213, 2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33761991

RESUMEN

BACKGROUND: This study compared the biomechanics of artificial pedicle fixation in spine reconstruction with a 3-dimensional (3D)-printed prosthesis after total en bloc spondylectomy (TES) by finite element analysis. METHODS: A thoracolumbar (T10-L2) finite element model was developed and validated. Two models of T12 TES were established in combination with different fixation methods: Model A consisted of long-segment posterior fixation (T10/11, L1/2) + 3D-printed prosthesis; and Model B consisted of Model A + two artificial pedicle fixation screws. The models were evaluated with an applied of 7.5 N·m and axial force of 200 N. We recorded and analyzed the following: (1) stiffness of the two fixation systems, (2) hardware stress in the two fixation systems, and (3) stress on the endplate adjacent to the 3D-printed prosthesis. RESULTS: The fixation strength of Model B was enhanced by the screws in the artificial pedicle, which was mainly manifested as an improvement in rotational stability. The stress transmission of the artificial pedicle fixation screws reduced the stress on the posterior rods and endplate adjacent to the 3D-printed prosthesis in all directions of motion, especially in rotation. CONCLUSIONS: After TES, the posterior long-segment fixation combined with the anterior 3D printed prosthesis could maintain postoperative spinal stability, but adding artificial pedicle fixation increased the stability of the fixation system and reduced the risk of prosthesis subsidence and instrumentation failure.

8.
Appl Opt ; 60(3): 513-525, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33690423

RESUMEN

Flame chemiluminescence tomography (FCT) is a non-intrusive method that is based on using cameras to measure projections, and it plays a crucial role in combustion diagnostics and measurement. Mathematically, the inversion problem is ill-posed, and in the case of limited optical accessibility in practical applications, it is rank deficient. Therefore, the solution process should ideally be supported by prior information, which can be based on the known physics. In this work, the total variation (TV) regularization has been combined with the well-known algebraic reconstruction technique (ART) for practical FCT applications. The TV method endorses smoothness while also preserving typical flame features such as the flame front. Split Bregman iteration has been adopted for TV minimization. Five different noise conditions and the chosen regularization parameter have been tested in numerical studies. Additionally, for the 12 perspectives, an experimental FCT system is demonstrated, which is utilized to recover the three-dimensional (3D) chemiluminescence distribution of candle flames. Both the numerical and experimental studies show that the typical line artifacts that appear with the conventional ART algorithm when recovering the continuous chemiluminescence field of the flames are significantly reduced with the proposed algorithm.

9.
Chemosphere ; 275: 130034, 2021 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-33652285

RESUMEN

Polybrominated diphenyl ethers (PBDEs), a kind of flame retardants, were widely used in the furniture, textile and electronics industries. Because of their lipophilic, persistent and bio-accumulative properties, PBDEs were listed on the Stockholm Convention as typical persistent organic pollutants (POPs). We have previously reported that a highly active, quinone-type metabolite of PBDEs (PBDEQ) causes DNA damage and subsequently triggers apoptosis. However, it is remaining unclear whether PBDEQ provokes protein damage and stimulates corresponding signaling cascade. Using human normal liver (LO2) cells as an in vitro model, we demonstrated that PBDEQ causes oxidative protein damage through excess reactive oxygen species (ROS). Consistently, we found PBDEQ exposure causes the depletion of protein thiol group, the appearance of carbonyl group and the accumulation of protein aggregates. Endoplasmic reticulum (ER) stress was involved in the repair of oxidized proteins. Under the scenario of severe damage, LO2 cells degrade oxidized proteins through ubiquitin-proteasome system (UPS) and autophagy. The blockage of these protein degradation pathways aggravates PBDEQ-induced cytotoxicity in LO2 cells, whilst antioxidant N-acetyl-cysteine (NAC) rescues PBDEQ-induced oxidative protein damage conversely. In summary, our current study first demonstrated PBDEQ-induced protein oxidative damage in LO2 cells, which offer a better understanding of the cytotoxicity of PBDEs and corresponding metabolites.

10.
J Anim Sci ; 2021 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-33687436

RESUMEN

Mitochondria play an important role in controlling oocyte developmental competence. Our previous studies showed that glycine can regulate mitochondrial function and improve oocyte maturation in vitro. However, the mechanisms by which glycine affects mitochondrial function during oocyte maturation in vitro have not been fully investigated. In this study, we induced a mitochondrial damage model in oocytes with the Bcl-2-specific antagonist ABT-199. We investigated whether glycine could reverse the mitochondrial dysfunction induced by ABT-199 exposure and whether it is related to calcium regulation. Our results showed that ABT-199 inhibited cumulus expansion, decreased the oocyte maturation rate and the intracellular glutathione (GSH) level, caused mitochondrial dysfunction, induced oxidative stress, which was confirmed by decreased mitochondrial membrane potential (Δ⍦m) and the expression of mitochondrial function-related genes (PGC-1α), and increased reactive oxygen species (ROS) levels and the expression of apoptosis-associated genes (Bax, caspase-3, CytC). More importantly, ABT-199-treated oocytes showed an increase in the intracellular free calcium concentration ([Ca 2+]i) and had impaired cortical type 1 inositol 1,4,5-trisphosphate receptors (IP3R1) distribution. Nevertheless, treatment with glycine significantly ameliorated mitochondrial dysfunction, oxidative stress and apoptosis, glycine also regulated [Ca 2+]i levels and IP3R1 cellular distribution, which further protects oocyte maturation in ABT-199-induced porcine oocytes. Taken together, our results indicate that glycine has a protective action against ABT-199-induced mitochondrial dysfunction in porcine oocytes.

11.
Nanoscale ; 13(9): 5058-5068, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33650622

RESUMEN

The dissolution of polysulfides in an electrolyte is a thermodynamically favorable process, which in theory means that the shuttle effect in lithium-sulfur batteries (LSBs) cannot be completely suppressed. So, it is very important to modify the separator to prevent the migration of polysulfides to the lithium anode. The traditional coating modification process of the separator is cumbersome and uses a solvent that is harmful to the environment, and too many inactive components affect the overall energy density of the battery. It is thus imperative to find a simple and environmentally friendly modification process of the separator. In this study, a fast chemical film-forming method is proposed to modify the separator of a lithium-sulfur battery using tannic acid (TA) and cobalt ions (Co2+). This method requires only simple steps and environmentally friendly raw materials to obtain a thin coating (only 5.83 nm) that can effectively inhibit the shuttle effect. The lithium-sulfur battery with the TA-Co separator shows superior long cycle performance. After 500 cycles at 0.5 C, the capacity decay rate of each cycle is only 0.065%. On the other hand, the TA-Co separator can inhibit the growth of lithium dendrites and help to build a stable lithium anode, which can exhibit minimal polarization (56 mV) in a lithium-lithium symmetrical battery at the current density of 2 mA cm-2. The rapid and simple modification method proposed in this study has a certain reference value for the future large-scale application of lithium sulfur batteries.

12.
Orthop Surg ; 2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33709625

RESUMEN

OBJECTIVE: To explore the kinematic biomechanical changes and symmetry in the left and right sides of the facet joints of lumbar spine segments under different functional loads. METHODS: Participants (n = 10) performing standing flexion and extension movements were scanned using computed tomography (CT) and dual fluoroscopy imagine system. Instantaneous images of the L3 -S1 vertebrae were captured, and by matching a three-dimensional CT model with contours from dual fluoroscopy images, in vivo facet joint movements were reproduced and analyzed. Translations and rotations of lumbar vertebral (L3 and L4 ) facet joints of data were compared for different loads (0, 5, 10 kg). The participants performed flexion and extension movements in different weight-bearing states, the translations and angles changes were calculated respectively. RESULTS: From standing to extension, there were no statistical differences in rotation angles for the facet joint processes of different vertebral segment levels under different weight loads (P > 0.05). Mediolateral axis and cranio-caudal translations under different weight loads were not statistically different for vertebral segment levels (P > 0.05). Anteroposterior translations for L3 (1.4 ± 0.1 mm) were greater than those for L4 (1.0 ± 0.1 mm) under the different load conditions (P = 0.04). Bilaterally, mediolateral, anteroposterior, and cranio-caudal translations of the facet joints under different weights (0, 10 kg) for each segment level (L3 and L4 ) were symmetric (P > 0.05). From flexion to standing, there were no statistical differences in rotation angles for different weights (0, 5, 10 kg) for each level (L3 and L4 ) (P > 0.05). There were no statistical differences between mediolateral, anteroposterior, and cranio-caudal translations at each segment level (L3 and L4 ) under different loads (P > 0.05). Under the condition of no weight (0 kg), L3 mediolateral translations on the left side (1.7 ± 1.6 mm) were significantly greater (P = 0.03) than those on the right side (1.6 ± 1.6 mm). Left side (1.0 ± 0.7 mm) L4 mediolateral translations were significantly smaller (P = 0.03) than those on the right side (1.1 ± 0.7 mm). There were no statistical differences between different weights for either anteroposterior and cranio-caudal translations (P > 0.05). There were no statistical differences for mediolateral, anteroposterior, and cranio-caudal translations for 10 kg (P > 0.05). CONCLUSION: Lumbar spine facet joint kinematics did not change significantly with increased loads. Anteroposterior translations for L3 were greater than those for L4 of the vertebral segments are related to the coronal facet joint surface. Changes in facet surface symmetry indicates that the biomechanical pattern between facet joints may change.

13.
J Am Heart Assoc ; 10(6): e018744, 2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33682431

RESUMEN

Background It is unknown whether clinical events identified with administrative claims have similar prognosis compared with trial-adjudicated events in cardiovascular clinical trials. We compared the prognostic significance of claims-based end points in context of trial-adjudicated end points in the DAPT (Dual Antiplatelet Therapy) study. Methods and Results We matched 1336 patients aged ≥65 years who received percutaneous coronary intervention in the DAPT study with the CathPCI registry linked to Medicare claims. We compared death at 21 months post-randomization using Cox proportional hazards models among patients with ischemic events (myocardial infarction or stroke) and bleeding events identified by: (1) both trial adjudication and claims; (2) trial adjudication only; and (3) claims only. A total of 47 patients (3.5%) had ischemic events identified by both trial adjudication and claims, 24 (1.8%) in trial adjudication only, 15 (1.1%) in claims only, and 1250 (93.6%) had no ischemic events, with annualized unadjusted mortality rates of 12.8, 5.5, 14.9, and 1.26 per 100 person-years, respectively. A total of 44 patients (3.3%) had bleeding events identified with both trial adjudication and claims, 13 (1.0%) in trial adjudication only, 65 (4.9%) in claims only, and 1214 (90.9%) had no bleeding events, with annualized unadjusted mortality rates of 11.0, 16.8, 10.7, and 0.95 per 100 person-years, respectively. Among patients with no trial-adjudicated events, patients with events in claims only had a high subsequent adjusted mortality risk (hazard ratio (HR) ischemic events: 31.5; 95% CI, 8.9‒111.9; HR bleeding events 23.9; 95% CI, 10.7‒53.2). Conclusions In addition to trial-adjudicated events, claims identified additional clinically meaningful ischemic and bleeding events that were prognostically significant for death.

14.
Artículo en Inglés | MEDLINE | ID: mdl-33650291

RESUMEN

The continuous growth of the solid electrolyte interface (SEI) and material crushing are the fundamental reasons that hinder the application of Ge anodes in lithium-ion batteries. The conventional carbon coating modification methods are challenging to solve Ge deformation crushing during discharge/charge cycles. Due to the chemical stability and high melting point of carbon (3500 ℃), Ge/carbon hybridization at the atomic level is challenging. By selecting a suitable carbon source and introducing an active medium, we have achieved the Ge/carbon doping at the atom-level, and this Ge/carbon anode shows excellent electrochemical performance. The reversible capacity is maintained at 1127 mAh g-1 after 1000 cycles (2 A g-1 (2-71 cycles), 4 A g-1 (72-1000 cycles)) with a retention of 84% compared to the second cycle. The thickness of the SEI is only 17.4 nm after 1000 cycles. The excellent electrochemical performance and stable SEI fully reflect the application potential of this material.

15.
Neurosci Lett ; 752: 135831, 2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33746006

RESUMEN

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare hereditary disease characterized by cerebellar ataxia, pyramidal signs in lower limbs, and sensorimotor neuropathy. The disease is caused by bi-allelic mutations of the SACS gene encoding the sacsin protein. Over 200 mutations have been reported worldwide. Here, we report two unrelated Chinese ARSACS patients with novel mutations revealed by whole-exome sequencing (WES). One 36-year-old female patient exhibited classical ARSACS characteristics including cerebellar ataxia, pyramidal tract signs in the lower limbs and sensorimotor neuropathy, while the other 9-year-old male showed cerebellar ataxia and peripheral neuropathy. WES identified a compound heterozygous variant in the SACS gene (c.5692 G > T, p.E1898X; c.12673-12677 del TATCA, p.Y4225D fs*6) in the female patient and another compound heterozygous variant (c.1773C > A, p.S578X; c.8088-8089 in. CA, p.M2697Q fs*43) in the male patient. All of these novel mutations were predicted to be loss-of-function which affect the expression of the two important C-terminal domains (DnaJ and HEPN). These findings add new insights into the mutational and clinical spectrum of ARSACS.

16.
Biotechnol Bioeng ; 2021 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-33788275

RESUMEN

Keratinase is an attractive industrial enzyme that can specifically catalyze keratin waste to obtain value-added products. A challenge to the application of keratinase is improving catalytic capacity to achieve efficient hydrolysis. In this work, we effectively expressed the keratinase gene from Bacillus licheniformis BBE11-1 in Bacillus subtilis WB600 based on pro-peptide engineering. Partial deletion of the pro-peptide sequence and the substitution of amino acid at the pro-peptide cleavage site (P1) suggested that the 'chaperone effect' and 'cleavage efficiency' of the pro-peptide determine the activity of the mature enzyme. Subsequently, seven target sites that can increase the activity of the mature enzyme by 16%-66% were obtained through the multiple sequence alignment of pro-peptides and site-directed mutation. We further performed combinatorial mutations at six sites based on the design principle of three-codon saturation mutations and obtained mutant 2-D12 (236.8 KU/mg) with a mature enzyme activity of 186% of the original (127.6 KU/mg). Finally, continuous fermentation was carried out in a 5-L bioreactor for 22 hours, and the activity of 2-D12 mature enzyme was increased to 391.6 KU/mg. Most importantly, 2-D12 could degrade more than 90% of feather waste into amino acids and peptides within 12 hours with the aid of sulfite. This article is protected by copyright. All rights reserved.

17.
Theranostics ; 11(10): 4585-4598, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33754015

RESUMEN

Background: The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. Methods: This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. Results: The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included TP53 (53%), KRAS (26%), ARID1A (18%), LRP1B (14%) and CDKN2A (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. TP53 and KRAS mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Conclusions: Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer.

18.
Allergy ; 2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33683704

RESUMEN

This systematic review evaluates the efficacy and safety of biologicals for chronic rhinosinusitis with nasal polyps (CRSwNP) compared with the standard of care. PubMed, Embase, and Cochrane Library were searched for RCTs. Critical and important CRSwNP-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. RCTs evaluated (dupilumab-2, omalizumab-4, mepolizumab-2, and reslizumab-1) included 1236 adults, with follow-up of 20-64 weeks. Dupilumab reduces the need for surgery (NFS) or oral corticosteroid (OCS) use (RR 0.28; 95% CI 0.20-0.39, moderate certainty) and improves with high certainty smell evaluated with UPSIT score (mean difference (MD) +10.54; 95% CI +9.24 to +11.84) and quality of life (QoL) evaluated with SNOT-22 (MD -19.14; 95% CI -22.80 to -15.47), with fewer treatment-related adverse events (TAEs) (RR 0.95; 95% CI 0.89-1.02, moderate certainty). Omalizumab reduces NFS (RR 0.85; 95% CI 0.78-0.92, high certainty), decreases OCS use (RR 0.38; 95% CI 0.10-1.38, moderate certainty), and improves high certainty smell (MD +3.84; 95% CI +3.64 to +4.04) and QoL (MD -15.65; 95% CI -16.16 to -15.13), with increased TAE (RR 1.73; 95% CI 0.60-5.03, moderate certainty). There is low certainty for mepolizumab reducing NFS (RR 0.78; 95% CI 0.64-0.94) and improving QoL (MD -13.3; 95% CI -23.93 to -2.67) and smell (MD +0.7; 95% CI -0.48 to +1.88), with increased TAEs (RR 1.64; 95% CI 0.41-6.50). The evidence for reslizumab is very uncertain.

19.
Noise Health ; 23(108): 42-49, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33753680

RESUMEN

Context: Sound levels in fitness classes often exceed safe levels despite studies that show many participants find high sound levels stressful. Aims: The objective is to determine if lower sound levels in spinning classes significantly impact exercise intensity and to determine if class participants prefer the music played at lower levels. Settings and Design: Observational study of 1-hour group spin classes. Methods and Materials: Sound levels were measured in 18 spin classes over two weeks. No adjustments were made in week-1 and sound levels were decreased by 3 dB in week-2. Participant preferences and data on post-class hearing changes were collected via post-class questionnaires (n = 213) and divided into three terciles based on the total sound exposure of corresponding classes. Statistical Analysis Used: Unweighted survey generalized linear models are used to sort the causal relationships between different variables simultaneously and participant responses. The Chi-square test is used to reveal statistically significant relationships between two or more categorical variables. Results: When mean sound levels exceeded 98.4 dBC, respondents were 23 times more likely to report the music as too loud than too quiet (P < 0.05), and four times more likely to prefer a decrease, rather than an increase, in sound level (P < 0.05). There was no significant difference in respondents reporting high exercise intensity between the middle (95.7-98.1 dBC) and upper (98.4-101.0 dBC) terciles, 67.1% and 71.8%, respectively (P = 0.53). Overall, 25.9% of respondents reported auditory symptoms following classes. Analysis in the context of dBA and dBC produced congruent conclusions and interpretations. Conclusions: Sound levels in many fitness classes remain dangerously high. However, music level can be lowered without a significant impact on perceived exercise intensity and many participants prefer lower sound levels than current levels.

20.
Biomaterials ; 271: 120720, 2021 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-33639563

RESUMEN

Point mutations within the DNA-binding domain of the TP53 gene occur in a significant percentage of human cancer, leading to cellular accumulation of highly stabilized mutant p53 proteins (mutp53) with tumor-promoting properties. Depletion of mutp53, through inducing either autophagic or proteasomal degradation, is an attractive strategy for the therapy of p53-mutated cancer, but the currently-known degradation inducers, almost exclusively small molecules, are inadequate. Here we show that pH-responsive zeolitic imidazolate framework-8 (ZIF-8) offers a novel solution to mutp53 degradation. ZIF-8 facilitated ubiquitination-mediated and glutathionylation-dependent proteasomal degradation of all of the nine mutp53 we tested, including six hot-spot mutp53, but not the wild-type p53 protein. Sustained elevation of intracellular Zn++ level, resulted from decomposition of the internalized ZIF-8 in the acidic endosomes, decreased the intracellular reduced glutathione (GSH): oxidized glutathione (GSSG) ratio and was essential for mutp53 glutathionylation and degradation. ZIF-8 modified with an Z1-RGD peptide, exhibiting enhanced cellular internalization and improved decomposition behavior, preferentially killed mutp53-expressing cancer cells and demonstrated remarkable therapeutic efficacy in a p53 S241F ES-2 ovarian cancer model as well as in a p53 Y220C patient-derived xenograft (PDX) breast cancer model. The ability to induce wide-spectrum mutp53 degradation gives ZIF-8 a clear advantage over other degradation-inducers, and engineered nanomaterials may be promising alternatives to small molecules for the development of mutp53-targeting drugs.

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