New sesquiterpenoids from the flowers of pentanema britannicum (L.) D.Gut.Larr.

Five new sesquiterpenoids, (4S, 5S, 6S, 7S, 8 R)-5,6-dihydroxy-1-acetoxy-10(14)-en-britannilactone (1), (4S, 5 R, 6S, 7S, 8 R)-5,6-dihydroxy-1-acetoxy-10(14)-en-britannilactone (2), 6-O-propionyl-britannilactone (3), 1ß-hydroxy-3α-acetoxyeudesma-11(13)-en-12,8ß-olide (4) and 1ß,5ß-dihydroxyeudesma-11(13)-en-12,8ß-olide (5), along with twelve known ones were isolated from the flowers of Pentanema britannicum (L.) D.Gut.Larr. Among them, compounds 1 and 2 were stereoisomers which belong to 1,10-seco-eudesmane sesquiterpenoid with rare double bond between C-10 and C-14. The structures of the isolated compounds were elucidated by various spectroscopic methods, including 1D and 2D NMR experiments.

Hair Follicle-Targeted Delivery of Azelaic Acid Micro/Nanocrystals Promote the Treatment of Acne Vulgaris.

Purpose: Acne vulgaris is a chronic inflammatory skin disorder centered on hair follicles, making hair follicle-targeted delivery of anti-acne drugs a promising option for acne treatment. However, current researches have only focused on the delivering to healthy hair follicles, which are intrinsically different from pathologically clogged hair follicles in acne vulgaris. Patients and Methods: Azelaic acid (AZA) micro/nanocrystals with different particle sizes were prepared by wet media milling or high-pressure homogenization. An experiment on AZA micro/nanocrystals delivering to healthy hair follicles was carried out, with and without the use of physical enhancement techniques. More importantly, it innovatively designed an experiment, which could reveal the ability of AZA micro/nanocrystals to penetrate the constructed clogged hair follicles. The anti-inflammatory and antibacterial effects of AZA micro/nanocrystals were evaluated in vitro using a RAW264.7 cell model stimulated by lipopolysaccharide and a Cutibacterium acnes model. Finally, both the anti-acne effects and skin safety of AZA micro/nanocrystals and commercial products were compared in vivo. Results: In comparison to commercial products, 200 nm and 500 nm AZA micro/nanocrystals exhibited an increased capacity to target hair follicles. In the combination group of AZA micro/nanocrystals and ultrasound, the ability to penetrate hair follicles was further remarkably enhanced (ER value up to 9.6). However, toward the clogged hair follicles, AZA micro/nanocrystals cannot easily penetrate into by themselves. Only with the help of 1% salicylic acid, AZA micro/nanocrystals had a great potential to penetrate clogged hair follicle. It was also shown that AZA micro/nanocrystals had anti-inflammatory and antibacterial effects by inhibiting pro-inflammatory factors and Cutibacterium acnes. Compared with commercial products, the combination of AZA micro/nanocrystals and ultrasound exhibited an obvious advantage in both skin safety and in vivo anti-acne therapeutic efficacy. Conclusion: Hair follicle-targeted delivery of AZA micro/nanocrystals provided a satisfactory alternative in promoting the treatment of acne vulgaris.

PAI-1 Regulates the Cytoskeleton and Intrinsic Stiffness of Vascular Smooth Muscle Cells.

BACKGROUND: Plasma concentration of PAI-1 (plasminogen activator inhibitor-1) correlates with arterial stiffness. Vascular smooth muscle cells (SMCs) express PAI-1, and the intrinsic stiffness of SMCs is a major determinant of total arterial stiffness. We hypothesized that PAI-1 promotes SMC stiffness by regulating the cytoskeleton and that pharmacological inhibition of PAI-1 decreases SMC and aortic stiffness. METHODS: PAI-039, a specific inhibitor of PAI-1, and small interfering RNA were used to inhibit PAI-1 expression in cultured human SMCs. Effects of PAI-1 inhibition on SMC stiffness, F-actin (filamentous actin) content, and cytoskeleton-modulating enzymes were assessed. WT (wild-type) and PAI-1-deficient murine SMCs were used to determine PAI-039 specificity. RNA sequencing was performed to determine the effects of PAI-039 on SMC gene expression. In vivo effects of PAI-039 were assessed by aortic pulse wave velocity. RESULTS: PAI-039 significantly reduced intrinsic stiffness of human SMCs, which was accompanied by a significant decrease in cytoplasmic F-actin content. PAI-1 gene knockdown also decreased cytoplasmic F-actin. PAI-1 inhibition significantly increased the activity of cofilin, an F-actin depolymerase, in WT murine SMCs, but not in PAI-1-deficient SMCs. RNA-sequencing analysis suggested that PAI-039 upregulates AMPK (AMP-activated protein kinase) signaling in SMCs, which was confirmed by Western blotting. Inhibition of AMPK prevented activation of cofilin by PAI-039. In mice, PAI-039 significantly decreased aortic stiffness and tunica media F-actin content without altering the elastin or collagen content. CONCLUSIONS: PAI-039 decreases intrinsic SMC stiffness and cytoplasmic stress fiber content. These effects are mediated by AMPK-dependent activation of cofilin. PAI-039 also decreases aortic stiffness in vivo. These findings suggest that PAI-1 is an important regulator of the SMC cytoskeleton and that pharmacological inhibition of PAI-1 has the potential to prevent and treat cardiovascular diseases involving arterial stiffening.

GARNL3 identified as a crucial target for overcoming temozolomide resistance in EGFRvIII-positive glioblastoma.

OBJECT: Amplification of the epidermal growth factor receptor (EGFR) and its active mutant type III (EGFRvIII), frequently occurr in glioblastoma (GBM), contributing to chemotherapy and radiation resistance in GBM. Elucidating the underlying molecular mechanism of temozolomide (TMZ) resistance in EGFRvIII GBM could offer valuable insights for cancer treatment. METHODS: To elucidate the molecular mechanisms underlying EGFRvIII-mediated resistance to TMZ in GBM, we conducted a comprehensive analysis using Gene Expression Omnibus and The cancer genome atlas (TCGA) databases. Initially, we identified common significantly differentially expressed genes (DEGs) and prioritized those correlating significantly with patient prognosis as potential downstream targets of EGFRvIII and candidates for drug resistance. Additionally, we analyzed transcription factor expression changes and their correlation with candidate genes to elucidate transcriptional regulatory mechanisms. Using estimate method and databases such as Tumor IMmune Estimation Resource (TIMER) and CellMarker, we assessed immune cell infiltration in TMZ-resistant GBM and its relationship with candidate gene expression. In this study, we examined the expression differences of candidate genes in GBM cell lines following EGFRvIII intervention and in TMZ-resistant GBM cell lines. This preliminary investigation aimed to verify the regulatory impact of EGFRvIII on candidate targets and its potential involvement in TMZ resistance in GBM. RESULTS: Notably, GTPase Activating Rap/RanGAP Domain Like 3 (GARNL3) emerged as a key DEG associated with TMZ resistance and poor prognosis, with reduced expression correlating with altered immune cell profiles. Transcription factor analysis suggested Epiregulin (EREG) as a putative upstream regulator of GARNL3, linking it to EGFRvIII-mediated TMZ resistance. In vitro experiments confirmed EGFRvIII-mediated downregulation of GARNL3 and decreased TMZ sensitivity in GBM cell lines, further supported by reduced GARNL3 levels in TMZ-resistant GBM cells. CONCLUSION: GARNL3 downregulation in EGFRvIII-positive and TMZ-resistant GBM implicates its role in TMZ resistance, suggesting modulation of EREG/GARNL3 signaling as a potential therapeutic strategy.

GWAS combined with QTL mapping reveals the genetic loci of leaf morphological characters in Nicotiana tabacum.

BACKGROUND: Leaf morphology plays a crucial role in photosynthetic efficiency and yield potential in crops. Cigar tobacco plants, which are derived from common tobacco (Nicotiana tabacum L.), possess special leaf characteristics including thin and delicate leaves with few visible veins, making it a good system for studying the genetic basis of leaf morphological characters. RESULTS: In this study, GWAS and QTL mapping were simultaneously performed using a natural population containing 185 accessions collected worldwide and an F2 population consisting of 240 individuals, respectively. A total of 26 QTLs related to leaf morphological traits were mapped in the F2 population at three different developmental stages, and some QTL intervals were repeatedly detected for different traits and at different developmental stages. Among the 206 significant SNPs identified in the natural population using GWAS, several associated with the leaf thickness phenotype were co-mapped via QTL mapping. By analyzing linkage disequilibrium and transcriptome data from different tissues combined with gene functional annotations, 7 candidate genes from the co-mapped region were identified as the potential causative genes associated with leaf thickness. CONCLUSIONS: These results presented a valuable cigar tobacco resource showing the genetic diversity regarding its leaf morphological traits at different developmental stages. It also provides valuable information for novel genes and molecular markers that will be useful for further functional verification and for molecular breeding of leaf morphological traits in crops in the future.

Thermoelectric Transport Performance in p-Type AgSbTe2-Based Materials through Entropy Engineering.

Being a major obstacle, Ag2Te has always been restricted in p-type AgSbTe2-based materials to improve their thermoelectric performance. This work reveals a stabilized AgSbTe2 through Sn/Ge alloying as synthesized by melting, annealing, and hot press. Interestingly, addition of Sn/Ge in AgSbTe2 extended the solubility limit up to ∼30% and hence suppressed Ag2Te in Ag(1-x)SnxSb(1-y)GeyTe2 compounds and led to enhanced electrical transport. Moreover, electrical and thermal transport properties of AgSbTe2 have been greatly affected by the phase transition of Ag2Te near 425 K. However, high-entropy Ag0.85Sn0.15Sb0.85Ge0.15Te2 compound results in a stabilized rock-salt structure and presents a high power factor of ∼10.8 µW cm-1 K-2 at 757 K. Besides, density functional theory reveals that available multivalence bands in Sn/Ge-doped AgSbTe2 lead to reduction in energy offsets. Meanwhile, a variety of defects appear in the Ag0.85Sn0.15Sb0.85Ge0.15Te2 sample due to entropy change, and thus lattice thermal conductivity decreases. Ultimately, a high figure of merit of ∼1.5 is attained at 757 K. This work demonstrates a roadmap for other group IV-VI materials so that the high-entropy approach may inhibit the impurity phases with extended solubility limit and result in high thermoelectric performance.

Spread of plasmids carrying antibiotic resistance genes in soil-lettuce-snail food chain.

Fertilization can change the composition of antibiotic resistance genes(ARGs) and their host bacteria in agricultural fields, while complex microbial activities help ARGs into crops and transmit them to humans through agricultural products.Therefore, this study constructed a farmland food chain with soil-lettuce-snail as a typical structure, added genetically engineered Pseudomonas fluorescens containing multidrug-resistant plasmid RP4 to track its spread in the farmland food chain, and used different fertilization methods to explore its influence on the spread and diffusion of ARGs and intl1 in the farmland food chain. It was found that exogenous Pseudomonas can enter plants from soil and pass into snails' intestines, and there is horizontal gene transfer phenomenon of RP4 plasmid in bacteria. At different interfaces of the constructed food chain, the addition of exogenous drug-resistant bacteria had different effects on the total abundance of ARGs and intl1. Fertilization, especially manure, not only promoted the spread of Pseudomonas aeruginosa and the transfer of RP4 plasmid levels, but also significantly increased the total abundance of ARGs and intl1 at all interfaces of the constructed food chain. The main ARGs host bacteria in the constructed food chain include Proteobacteria, Bacteroides, and Firmicutes, while Flavobacterium of Bacteroides is the unique potential host bacteria of RP4 plasmid. In conclusion, this study provides a reference for the risk assessment of ARGs transmitted to the human body through the food chain, and has important practical significance to reduce the antibiotic resistance contamination of agricultural products and ensure the safety of vegetable basket.

High-fidelity single logical qubit encoding scheme assisted by single-sided quantum dot-cavity systems.

We present an encoding scheme of a single logical qubit with single-sided quantum dot (QD)-cavity systems, which is immune to the collective decoherence. By adjusting the Purcell factor to satisfy the balanced reflection condition, the detrimental effects of unbalanced reflection between the coupled and uncoupled QD-cavity systems can be effectively suppressed. Furthermore, the fidelity of each step can be increased to unity regardless of the strong coupling regime and the weak coupling regime of cavity quantum electrodynamics (QED) with the assistance of waveform correctors. The scheme requires QD-cavity systems and simple linear optical elements, which can be implemented with the currently experimental techniques.

"Cloth-to-Clothes-Like" Fabrication of Soft Actuators.

Inspired by adaptive natural organisms and living matter, soft actuators appeal to a variety of innovative applications such as soft grippers, artificial muscles, wearable electronics, and biomedical devices. However, their fabrication is typically limited in laboratories or a few enterprises since specific instruments, strong stimuli, or specialized operation skills are inevitably involved. Here a straightforward "cloth-to-clothes-like" method to prepare soft actuators with a low threshold by combining the hysteretic behavior of liquid crystal elastomers (LCEs) with the exchange reaction of dynamic covalent bonds, is proposed. Due to the hysteretic behavior, the LCEs (resemble "cloth") effectively retain predefined shapes after stretching and releasing for extended periods. Subsequently, the samples naturally become soft actuators (resemble "clothes") via the exchange reaction at ambient temperatures. As a post-synthesis method, this strategy effectively separates the production of LCEs and soft actuators. LCEs can be mass-produced in bulk by factories or producers and stored as prepared, much like rolls of cloth. When required, these LCEs can be customized into soft actuators as needed. This strategy provides a robust, flexible, and scalable solution to engineer soft actuators, holding great promise for mass production and universal applications.

[Cystic fibrosis primarily presenting with pseudo-Bartter syndrome: a report of three cases and literature review]. / 以假性Bartter综合征为主要表现的囊性纤维化患儿3ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

OBJECTIVES: To summarize the clinical characteristics and genetic variations in children with cystic fibrosis (CF) primarily presenting with pseudo-Bartter syndrome (CF-PBS), with the aim to enhance understanding of this disorder. METHODS: A retrospective analysis was performed on the clinical data of three children who were diagnosed with CF-PBS in Hunan Children's Hospital from January 2018 to August 2023, and a literature review was performed. RESULTS: All three children had the onset of the disease in infancy. Tests after admission showed hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, and genetic testing showed the presence of compound heterozygous mutation in the CFTR gene. All three children were diagnosed with CF. Literature review obtained 33 Chinese children with CF-PBS, with an age of onset of 1-36 months and an age of diagnosis of 3-144 months. Among these children, there were 29 children with recurrent respiratory infection or persistent pneumonia (88%), 26 with malnutrition (79%), 23 with developmental retardation (70%), and 18 with pancreatitis or extrapancreatic insufficiency (55%). Genetic testing showed that c.2909G>A was the most common mutation site of the CFTR gene, with a frequency of allelic variation of 23% (15/66). CONCLUSIONS: CF may have no typical respiratory symptoms in the early stage. The possibility of CF-PBS should be considered for infants with recurrent hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, especially those with malnutrition and developmental retardation. CFTR genetic testing should be performed as soon as possible to help with the diagnosis of CF.

Relationship between affiliate stigma and family quality of life among parents of children with autism spectrum disorders: The mediating role of parenting self-efficacy.

BACKGROUND: The parents of children with autism spectrum disorder (ASD) are under great pressure and experience discrimination in their daily lives, which affects their family quality of life (FQOL). OBJECTIVE: METHODS: A total of 237 parents of children with ASD were recruited in a university-affiliated hospital in Guangzhou, China, from October 2020 to April 2021 by convenience sampling. The Affiliate Stigma Scale, Parenting Sense of Competence Scale and Beach Center Family Quality of Life Scale were employed for data collection. RESULTS: The results showed that affiliate stigma negatively predicts total FQOL and the dimensions of FQOL through both a direct effect and an indirect effect through parenting self-efficacy. CONCLUSIONS: The findings suggest that affiliate stigma is an important predictor of FQOL, and interventions to reduce affiliate stigma and strengthen parenting self-efficacy might be effective in improving FQOL in the parents of children with ASD.

Effects of earthworms on antibiotic resistance genes in different soil-plant systems.

Earthworms play an important role in the soil environment. To explore the difference in earthworms influence on various media in different soil-plant systems, the abundance of tetracycline, sulfonamide and quinolone resistance genes and the structure of the bacterial community were analysed from five different media including non-rhizosphere soil, rhizosphere soil, phyllosphere, root endophytes and earthworm intestine by real-time quantitative PCR and high-throughput 16S rRNA sequencing. Studies have shown that earthworms can reduce the absolute abundance of antibiotic resistance genes (ARGs) in non-rhizosphere soil. Root endophytes in the soil-cabbage system and rhizosphere soil in the soil-setaria system had the same findings. Earthworms can change the bacterial community structure, especially that of Proteobacteria and Cyanobacteria in the phyllosphere and root endophytes. Redundancy analysis (RDA) results that bacterial community change was the main factor affecting ARGs. In addition, earthworms increased the proportion of Cyanobacteria in root endophytes, and Cyanobacteria was significantly positively correlated with sul3. This study provides a scientific basis for controlling the migration and diffusion of ARGs and reducing environmental risks in soil-plant systems in the future.

Application of furazolidone in Helicobacter pylori infection eradication.

Increasing antibiotic resistance is the primary reason for treatment failure of Helicobacter pylori (H. pylori) infection. To enhance the eradication rate, minimize the development of secondary resistance, and alleviate the socioeconomic burden, it is crucial to select H. pylori-sensitive antibiotics carefully. Furazolidone has been used for H. pylori eradication in developing countries for decades due to its affordability and low resistance rate. Numerous studies have demonstrated that furazolidone-containing regimens are more efficacious than those containing other antibiotics, as both first- and second-line therapies, and are also well tolerated. However, utility of furazolidone is restricted or not optimal in certain countries due to its infrequent but potentially severe adverse effects. The decision to discontinue usage of furazolidone because of concerns regarding adverse effects may be misguided. Here we comprehensively reviewed the studies on furazolidone at different dosages and treatment durations for H. pylori eradication. Further research on the mechanisms of action and clinical trials of furazolidone are of great practical importance.

Analysis of the Relationship between Recent Small Subcortical Infarcts and Autonomic Nervous Dysfunction.

OBJECTIVE: Autonomic Nervous System (ANS) dysfunction may be involved in the pathogenesis of Cerebral Small Vessel Disease (CSVD). The study aimed to explore the relationship between Recent Small Subcortical Infarct (RSSI) and Blood Pressure Variability (BPV), and Heart Rate Variability (HRV). METHODS: A total of 588 patients from the CSVD registration research database of Henan Province were included in this study, and were divided into two groups according to the presence of RSSI. Clinical data, including demographic characteristics, disease history, laboratory indexes, 24-hour ambulatory blood pressure and electrocardiogram indicators, and imaging markers of CSVD, were collected. Univariate and binary logistic regression analyses were used to study the relationship between RSSI and indicators of laboratory, HRV and BPV in the CSVD population. RESULTS: Multivariate analysis showed that higher 24-hour mean Diastolic Blood Pressure (DBP)[Odds Ratios (OR)=1.083,95% Confidence Intervals (CI)=(1.038,1.129), p < 0.001], Standard Deviation (SD) of 24-hour DBP [OR=1.059,95%CI=(1.000,1.121), p = 0.049], nocturnal mean Systolic Blood Pressure (SBP) [OR=1.020,95%CI=(1.004,1.035), p = 0.012], nocturnal mean DBP [OR=1.025,95%CI=(1.009,1.040), p = 0.002] were independent risk factors for RSSI. In contrast, the decrease of the standard deviation of N-N intervals (SDNN) [OR=0.994,95%CI=(0.989,1.000), p = 0.035] was beneficial to the occurrence of RSSI. In addition, neutrophil counts [OR=1.138,95%CI=(1.030,1.258), p = 0.011], total cholesterol (TC) [OR=1.203,95%CI=(1.008,1.437), p = 0.041] and High-Density Lipoprotein (HDL) [OR=0.391, 95%CI=(0.195,0.786), p = 0.008] were also independently associated with the occurrence of RSSI. After adjusting for confounding factors, except for TC, the other factors remained associated with the occurrence of RSSI. CONCLUSION: Increased 24-hour mean DBP, nocturnal mean SBP and DBP, SD of 24-hour DBP and decreased SDNN were independently correlated with RSSI occurrence, suggesting that sympathetic overactivity plays a role in the pathogenesis of RSSI.

mTOR signaling promotes rapid m6A mRNA methylation to regulate NK-cell activation and effector functions.

Natural killer (NK) cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of the numerous genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment. Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double knockout of METTL3/14 significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 (mTORC1) activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine (SAM) supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTORC1-SAM signal axis in regulating NK-cell activation and effector functions.

Snakehead vesiculovirus (SHVV) leader RNA interacts with host antiviral factors RPS8 and L13a and promotes virus replication.

To evade host antiviral response, viruses have evolved to take advantage of their noncoding RNAs (ncRNAs). Snakehead vesiculovirus (SHVV), a newly isolated fish rhabdovirus from diseased hybrid snakehead, has caused high mortality to the cultured snakehead fish during the past years in China. However, little is known about the mechanisms of its pathogenicity. Our study revealed that overexpression of the 30-nt leader RNA promoted SHVV replication. RNA-protein binding investigation revealed that SHVV leader RNA could interact with host 40S ribosomal protein S8 (RPS8) and 60S ribosomal protein L13a (L13a). Furthermore, we found that SHVV infection upregulated RPS8 and L13a, and in turn, overexpression of RPS8 or L13a inhibited, while knockdown of RPS8 or L13a promoted, SHVV replication, suggesting that RPS8 and L13a acted as host antiviral factors in response to SHVV infection. In addition, our study revealed that RPS8- or L13a-mediated inhibition of SHVV replication could be restored by co-transfection with leader RNA, suggesting that the interaction between leader RNA and RPS8 or L13a might affect the anti-SHVV effects of RPS8 and L13a. Taken together, these results suggest that SHVV leader RNA can interact with the host antiviral factors RPS8 and L13a, and promote SHVV replication. This study provides a better understanding of the molecular mechanism of the pathogenesis of SHVV and a potential antiviral strategy against SHVV infection.

Ribociclib plus Endocrine Therapy in Early Breast Cancer.

BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear. METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy. RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).

Enhancing music recognition using deep learning-powered source separation technology for cochlear implant users.

Cochlear implant (CI) is currently the vital technological device for assisting deaf patients in hearing sounds and greatly enhances their sound listening appreciation. Unfortunately, it performs poorly for music listening because of the insufficient number of electrodes and inaccurate identification of music features. Therefore, this study applied source separation technology with a self-adjustment function to enhance the music listening benefits for CI users. In the objective analysis method, this study showed that the results of the source-to-distortion, source-to-interference, and source-to-artifact ratios were 4.88, 5.92, and 15.28 dB, respectively, and significantly better than the Demucs baseline model. For the subjective analysis method, it scored higher than the traditional baseline method VIR6 (vocal to instrument ratio, 6 dB) by approximately 28.1 and 26.4 (out of 100) in the multi-stimulus test with hidden reference and anchor test, respectively. The experimental results showed that the proposed method can benefit CI users in identifying music in a live concert, and the personal self-fitting signal separation method had better results than any other default baselines (vocal to instrument ratio of 6 dB or vocal to instrument ratio of 0 dB) did. This finding suggests that the proposed system is a potential method for enhancing the music listening benefits for CI users.

Metabolic disparities between obese and non-obese patients with polycystic ovary syndrome: implications for endometrial receptivity indicators.

OBJECTIVE: To investigate the differences in the metabolic indicators and sex hormones between obese and non-obese patients with polycystic ovary syndrome (PCOS), and their impacts on endometrial receptivity (ER). METHODS: We selected 255 individuals with PCOS, and categorized them into the obese groups, including the OP group (obese patients with PCOS) and the ON group (obese patients without PCOS), and selected 64 individuals who were categorized in the non-obese groups, namely, the control groups, which comprise the NP group (non-obese patients with PCOS) and the NN group(non-obese patients without PCOS). The one-way analysis of variance (ANOVA) and Mann-Whitney U tests were used to compare the metabolic indicators, and sex hormone-associated and ER-associated indicators between the groups. The correlation between the aforementioned clinical markers and ER was analyzed using the Pearson's correlation coefficient. RESULTS: (1) In comparison with the NP group, the OP group exhibited higher levels (p < .01) of free androgen index (FAI), anti-müllerian hormone (AMH), fasting insulin (FINS), insulin level within 60 min, 120 min, and 180 min-60minINS, 120minINS, and 180minINS, respectively, fasting blood glucose (FBG), blood glucose level within two hours (2hGlu), homeostatic model assessment for insulin resistance (HOMA-IR), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), waist-to-hip ratio (WHR), waist circumference, hip circumference, the ratio of the maximum blood flow velocity of the uterine artery during systole to the blood flow velocity of the uterine artery at the end of diastole (uterine artery S/D), and blood flow resistance index (RI) of the uterine artery. In comparison with the NP group, the OP group exhibited lower levels (p < .01) of sex hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA), high molecular weight adiponectin (HMWA), and high-density lipoprotein cholesterol (HDL-C). (2) In the PCOS group, RI was significantly positively correlated with FAI, FINS, 120minINS, HOMA-IR, and WHR (p < .01), and significantly negatively correlated with SHBG, HDL-C, and HMWA (p < .01); uterine artery S/D was significantly positively correlated with FAI, FINS, 2hGlu, HOMA-IR, LDL-C, and WHR (p < .01), significantly positively correlated with 120minINS and FBG (p < .05), and significantly negatively correlated with SHBG and HMWA (p < .01). CONCLUSION: (1) The OP group exhibited obvious metabolic disorders and poor ER, which was manifested as low levels of SHBG and HMWA, and high levels of FAI, HOMA-IR, WHR, uterine artery S/D, and RI. (2) In patients with PCOS, there was a substantial correlation between ER-associated indicators RI and uterine artery S/D and FAI, FINS, 120minINS, HOMA-IR, WHR, SHBG, and HMWA.

Utility and impact of quantitative pharmacology on dose selection and clinical development of immuno-oncology therapy.

Immuno-oncology (IO) therapies have changed the cancer treatment landscape. Immune checkpoint inhibitors (ICIs) have improved overall survival in 20-40% of patients with malignancies that were previously refractory. Due to the uniqueness in biology, modalities and patient responses, drug development strategies for IO differed from that traditionally used for cytotoxic and target therapies in oncology, and quantitative pharmacology utilizing modeling approach can be applied in all phases of the development process. In this review, we used case studies to showcase how various modeling methodologies were applied from translational science and dose selection through to label change, using examples that included anti-programmed-death-1 (anti-PD-1), anti-programmed-death ligand-1 (anti-PD-L1), anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), and anti-glucocorticoid-induced tumor necrosis factor receptor-related protein (anti-GITR) antibodies. How these approaches were utilized to support phase I-III dose selection, the design of phase III trials, and regulatory decisions on label change are discussed to illustrate development strategies. Model-based quantitative approaches have positively impacted IO drug development, and a better understanding of the biology and exposure-response relationship may benefit the development and optimization of new IO therapies.