Few large-scale studies have demonstrated the efficacy of tobramycin nebulization in bronchiectasis. We evaluated the efficacy and safety of nebulized tobramycin inhalation solution (TIS) in adults ...with bronchiectasis with Pseudomonas aeruginosa infection.
Can TIS effectively reduce sputum P aeruginosa density and improve the bronchiectasis-specific quality of life in patients with bronchiectasis with P aeruginosa infection?
This was a phase 3, 16-week, multicenter, randomized, double-blind, placebo-controlled trial. Eligible adults with bronchiectasis were recruited from October 2018 to July 2021. On the basis of usual care, patients nebulized TIS (300 mg/5 mL twice daily) or normal saline (5 mL twice daily) via vibrating-mesh nebulizer. Treatment consisted of two cycles, each consisting of 28 days on-treatment and 28 days off-treatment. The coprimary end points included changes from baseline in P aeruginosa density and Quality-of-Life Bronchiectasis Respiratory Symptoms score on day 29.
The modified intention-to-treat population consisted of 167 patients in the tobramycin group and 172 patients in the placebo group. Compared with placebo, TIS resulted in a significantly greater reduction in P aeruginosa density (adjusted mean difference, 1.74 log10 colony-forming units/g; 95% CI, 1.12-2.35; P < .001) and greater improvement in Quality-of-Life Bronchiectasis Respiratory Symptoms score (adjusted mean difference, 7.91; 95% CI, 5.72-10.11; P < .001) on day 29. Similar findings were observed on day 85. TIS resulted in a significant reduction in 24-h sputum volume and sputum purulence score on days 29, 57, and 85. More patients became culture negative for P aeruginosa in the tobramycin group than in the placebo group on day 29 (29.3% vs 10.6%). The incidence of adverse events and serious adverse events were comparable between the two groups.
TIS is an effective treatment option and has an acceptable safety profile in patients with bronchiectasis with P aeruginosa infection.
ClinicalTrials.gov; No. NCT03715322; URL: www.clinicaltrials.gov
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Osteosarcoma is a malignant bone tumor with extremely high invasion, metastasis and mortality. The prognosis of patients with osteosarcoma remains poor. The ErbB receptor family was found to be ...overexpressed in human cancers and associated with poor prognosis. However, the role of ErbB receptor family in osteosarcoma has not been fully understood. The present study aimed to investigate the clinicopathological and prognostic significances of ErbB receptors in primary osteosarcoma. Western blot (WB), reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization (FISH) were used to detect the protein and gene expression of ErbB receptors in 60 primary osteosarcoma specimens and 30 non-neoplastic bone tissues. WB and RT-qPCR analyses showed that the protein and mRNA expression levels of EGFR, ErbB3 and ErbB4 in osteosarcoma specimens were significantly higher than those in non-neoplastic bone tissues. Seventeen (28.33%), 15 (25.00%) and 15 (25.00%) osteosarcoma specimens presented with amplification of EGFR, ErbB3 and ErbB4 gene, respectively, which were significantly higher compared with non-neoplastic bone tissues. The amplification of ErbB3 and ErbB4 in osteosarcoma was associated with advanced surgical stage. The amplification of EGFR, ErbB3, ErbB4 and the co-amplification of EGFR-ErbB3, EGFR-ErbB4, ErbB3-ErbB4 was linked with poor response to chemotherapy and distant metastasis. The amplification of EGFR, ErbB3 and ErbB4, as well as their co-amplification demonstrated independent prognostic values for reduced survival time of osteosarcoma patients and may serve as potential therapeutic targets for osteosarcoma patients in the future.
Depression and insomnia are highly related-insomnia is a common symptom among depression patients, and insomnia can result in depression. Although depression patients and insomnia patients should be ...treated with different approaches, the lack of practical biological markers makes it difficult to discriminate between depression and insomnia effectively.
This study aimed to disclose critical vocal features for discriminating between depression and insomnia.
Four groups of patients, comprising six severe-depression patients, four moderate-depression patients, ten insomnia patients, and four patients with chronic pain disorder (CPD) participated in this preliminary study, which aimed to record their speaking voices. An open-source software, openSMILE, was applied to extract 384 voice features. Analysis of variance was used to analyze the effects of the four patient statuses on these voice features.
statistical analyses showed significant relationships between patient status and voice features. Patients with severe depression, moderate depression, insomnia, and CPD reacted differently to certain voice features. Critical voice features were reported based on these statistical relationships.
This preliminary study shows the potential in developing discriminating models of depression and insomnia using voice features. Future studies should recruit an adequate number of patients to confirm these voice features and increase the number of data for developing a quantitative method.
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson’s disease (PD); nevertheless, development of dual hIDO1 and ...hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to 23, which manifested IC50 values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice. 23 showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar, 23 likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
Urban air quality, which is related to the health of local residents of the Pearl River Delta Region, China, (PRD) has been a hot topic among the masses and academic circles. In addition to economic ...growth, China’s rapidly increasing urbanization rate has also brought great pressure on urban air quality, in the Region, where due to its huge economic size and population, urban air quality has become the focus of local residents. This study first analyzed the spatio-temporal trends and correlation of land use and PM
2.5
average annual concentration, which represents air quality in the PRD from 2000 to 2018, and according to Moran index, PM
2.5
concentration in this area has spatial correlation in the study time. Secondly, the spatial error model of the PRD was constructed by using spatial effect, spatial modeling theory and spatial model estimation. The spatial-temporal evolution and influencing factors of PM
2.5
concentration were discussed in fixed overall effect. The results showed that the area of cultivated land in the PRD decreased and the area of artificial surface increased year by year, while the PM
2.5
concentration increased first and then decreased. In addition, the area of cultivated land and forestland were negatively correlated, while the area of grassland and water body were positively correlated with PM
2.5
concentration. The conclusion of this study has a certain theoretical reference for urban land use planning and air quality assurance.
Tumor‐infiltrating T cell repertoire has been demonstrated to be closely associated with anti‐tumor immune response. However, the relationship between T cell repertoire in tumor tissue and prognosis ...has never been reported in Hepatocellular carcinoma (HCC). We performed the high‐throughput T cell receptor (TCR) sequencing to systematically characterize the infiltrating T cell repertoires of tumor and matched adjacent normal tissues from 23 HBV‐associated HCC patients. Significant differences on usage frequencies of some Vβ, Jβ, and Vβ‐Jβ paired genes have been found between the 2 groups of tissue samples, but no significant difference of TCR repertoire diversity could be found. Interestingly, the similarity of TCR repertoires between paired samples or the TNM stage alone could not be helpful to evaluate the prognosis of patients very well, but their combination could serve as an efficient prognostic indicator that the patients with early stage and high similarity showed a better prognosis. This is the first attempt to assess the potential value of TCR repertoire in HCC prognosis, and our findings could serve as a complement for the characterization of TCR repertoire in HCC.
Our study focus on the relationship between the tissue TCR repertoire and the prognosis of HCC patients. We found that the similarity of TCR repertoire between tumor and matched adjacent normal tissues combined with the TNM stage could be helpful to evaluate the prognosis of patients. This is the first study (as far as we know) to assess the potential value of TCR repertoire in HCC prognosis and our findings could serve as a complement for the characterization of TCR repertoire in HCC.
The construction and the operation of multi-reservoir has severely altered the downstream design flood. This paper quantified the flood frequency modifications caused by multi-reservoir regulation ...with recorded data and a numerical model composed of peaks-over-threshold (POT) samples and time-trend models. The whole research was carried out in Dongjiang River Basin, Southern China. Results showed that (1) Sampling with the POT method could eliminate fake changes in change detection and prevent the underestimation of the design floods with an exceeding probability over 90% and the overestimation of the design floods with an exceeding probability less than 80%; (2) Multi-reservoir regulation severely reduced design flood when the exceeding probability was greater than 1% and smaller than 95%. The 10-year floods were mitigated the most. However, when the exceeding probability was over 95%, the impact was insignificant; (3) Flood mitigation was positively correlated to the number of reservoirs, but negatively correlated to the distance between the affecting reservoir and the affected station. However, when multiple reservoirs took effect on the design flood in one station, the closest reservoir did not necessarily take the most effect. The results of this research will amplify the theoretical basis for flood protection and the planning of regulation.
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•New ε-N-thioglutaryllysine derivatives displayed potent SIRT5 inhibition.•Derivative 8 manifested most selective and potent inhibition with an IC50 of 120 nM to SIRT5.•8 is likely to ...react with NAD+ and form stable thio-intermediates.
SIRT5 has been implicated in various physiological processes and human diseases, including cancer. Development of new highly potent, selective SIRT5 inhibitors is still needed to investigate disease-related mechanisms and therapeutic potentials. We here report new ε-N-thioglutaryllysine derivatives, which were designed according to SIRT5-catalysed deacylation reactions. These ε-N-thioglutaryllysine derivatives displayed potent SIRT5 inhibition, of which the potential photo-crosslinking derivative 8 manifested most potent inhibition with an IC50 value of 120 nM to SIRT5, and low inhibition to SIRT1-3 and SIRT6. The enzyme kinetic assays revealed that the ε-N-thioglutaryllysine derivatives inhibit SIRT5 by lysine-substrate competitive manner. Co-crystallographic analyses demonstrated that 8 binds to occupy the lysine-substate binding site by making hydrogen-bonding and electrostatic interactions with SIRT5-specific residues, and is likely positioned to react with NAD+ and form stable thio-intermediates. Compound 8 was observed to have low photo-crosslinking probability to SIRT5, possibly due to inappropriate position of the diazirine group as observed in SIRT5:8 crystal structure. This study provides useful information for developing drug-like inhibitors and cross-linking chemical probes for SIRT5-related studies.
Light-harvesting chlorophyll a/b-binding (LHCB) protein complexes of photosystem II are integral to the formation of thylakoid structure and the photosynthetic process. They play an important role in ...photoprotection, a crucial process in leaf development under low-temperature stress. Nonetheless, potential key genes directly related to low-temperature response and albino phenotype have not been precisely identified in tea plant. Moreover, there are no studies simultaneously investigating multiple albino tea cultivars with different temperature sensitivity.
The study aimed to clarify the basic characteristics of CsLHCB gene family members, and identify critical CsLHCB genes potentially influential in leaf color phenotypic variation and low-temperature stress response by contrasting green and albino tea cultivars. Concurrently, exploring the differential expression of the CsLHCB gene family across diverse temperature-sensitive albino tea cultivars.
We identified 20 putative CsLHCB genes according to phylogenetic analysis. Evolutionary relationships, gene duplication, chromosomal localization, and structures were analyzed by TBtools; the physiological and biochemical characteristics were analyzed by protein analysis websites; the differences in coding sequences and protein accumulation in green and albino tea cultivars, gene expression with maturity were tested by molecular biology technology; and protein interaction was analyzed in the STRING database.
All genes were categorized into seven groups, mapping onto 7 chromosomes, including three tandem and one segmental duplications. They all own a conserved chlorophyll A/B binding protein domain. The expression of CsLHCB genes was tissue-specific, predominantly in leaves. CsLHCB5 may play a key role in the process of leaf maturation and senescence. In contrast to CsLHCB5, CsLHCB1.1, CsLHCB2, and CsLHCB3.2 were highly conserved in amino acid sequence between green and albino tea cultivars. In albino tea cultivars, unlike in green cultivars, the expression of CsLHCB1.1, CsLHCB1.2, and CsLHCB2 was down-regulated under low-temperature stress. The accumulation of CsLHCB1 and CsLHCB5 proteins was lower in albino tea cultivars. Greater accumulation of CsLHCB2 protein was detected in RX1 and RX2 compared to other albino cultivars.
CsLHCB1.1, CsLHCB1.2, and CsLHCB2 played a role in the response to low-temperature stress. The amino acid sequence site mutation of CsLHCB5 would distinguish the green and albino tea cultivars. The less accumulation of CsLHCB1 and CsLHCB5 had a potential influence on albino leaves. Albino cultivars more sensitive to temperature exhibited lower CsLHCB gene expression. CsLHCB2 may serve as an indicator of temperature sensitivity differences in albino tea cultivars. This study could provide a reference for further studies of the functions of the CsLHCB family and contribute to research on the mechanism of the albino in tea plant.
We previously reported that REBACIN effectively eliminates persistent high-risk human papillomavirus (hrHPV) infection. Here, we conducted a prospective multicenter cohort study to evaluate the ...safety and effectiveness of REBACIN, taking into account factors such as specific hrHPV subtype and patient's age.
According to inclusion/exclusion criteria and participant willingness, 3252 patients were divided into REBACIN group while 249 patients into control group. Patients in REBACIN group received one course treatment of intravaginal administration of REBACIN while no treatment in control group. After drug withdrawal, participants in both groups were followed up.
The clearance rate of persistent hrHPV infection in REBACIN group was 60.64%, compared to 20.08% in control group. Specifically, the clearance rates for single-type infection of HPV16 or HPV18 were 70.62% and 69.23%, respectively, which was higher than that of HPV52 (59.04%) or HPV58 (62.64%). In addition, the single, double, and triple/triple+ infections had a clearance rate of 65.70%, 53.31%, and 38.30%, respectively. Moreover, 1635 patients under 40 years old had a clearance rate of 65.14%, while it was 55.08% for 1447 patients over 40 years old. No serious adverse effects were found.
This study confirmed that REBACIN can effectively and safely eliminate persistent hrHPV infection, which the clearance rate of HPV16/18 is higher than that of HPV52/58, the clearance rate of single-type infection is higher than that of multiple-type infections, and the clearance rate in young patients is higher than that in elder patients, providing a guidance for REBACIN application in clearing hrHPV persistent infection in real-world settings.
Chinese Clinical Trial Registry
Registration Number: ChiCTR1800015617
http://www.chictr.org.cn/showproj.aspx?proj=26529
Date of Registration: 2018-04-11
•REBACIN is safe and effective for eliminating persistent high-risk HPV infection in a real-world clinical setting.•HPV16/18 is cleared more easily than HPV52/58.•Single-type infections are cleared more easily than multiple-type infections.•Young patients have a higher clearance rate than older patients.•Providing valuable guidance for clinical use of REBACIN while also suggesting potential areas for future basic research.
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