High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes.

Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac). Further functional characterization suggested several transcription factors (TFs) with preferential allelic binding to baaSNPs. We also incorporated multi-omics data to prioritize 102 candidate regulatory target genes for baaSNPs and revealed prevalent long-range regulatory effects and cell-specific IR-relevant biological functional enrichment on them. Specifically, we experimentally verified the distal regulatory mechanism at IRS1 locus, in which rs952227-A reinforces IRS1 expression by long-range chromatin interaction and preferential binding to the transcription factor HOXC6 to augment the enhancer activity. Finally, based on our STARR-seq screening data, we predicted the enhancer activity of 227,343 noncoding SNPs associated with IR-relevant phenotypes (fasting insulin adjusted for BMI, HDL cholesterol, and triglycerides) from the largest available GWAS summary statistics. We further provided an open resource (http://www.bigc.online/fnSNP-IR) for better understanding genetic regulatory mechanisms of IR-relevant phenotypes.

SIRT1: An Intermediator of Key Pathways Regulating Pulmonary Diseases.

Silent information regulator type-1 (SIRT1), a nicotinamide adenine dinucleotide+-dependent deacetylase, is a member of the sirtuins family and has unique protein deacetylase activity. SIRT1 participates in physiological as well as pathophysiological processes by targeting a wide range of protein substrates and signalings. In this review, we described the latest progress of SIRT1 in pulmonary diseases. We have introduced the basic information and summarized the prominent role of SIRT1 in several lung diseases, such as acute lung injury, acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung cancer, and aging-related diseases.

Cost-effectiveness analysis of bevacizumab for cerebral radiation necrosis treatment based on real-world utility value in China.

BACKGROUND: Bevacizumab shows superior efficacy in cerebral radiation necrosis (CRN) therapy, but its economic burden remains heavy due to the high drug price. This study aims to evaluate the cost-effectiveness of bevacizumab for CRN treatment from the Chinese payers' perspective. METHODS: A decision tree model was developed to compare the costs and health outcomes of bevacizumab and corticosteroids for CRN therapy. Efficacy and safety data were derived from the NCT01621880 trial, which compared the effectiveness and safety of bevacizumab monotherapy with corticosteroids for CRN in nasopharyngeal cancer patients, and demonstrated that bevacizumab invoked a significantly higher response than corticosteroids (65.5% vs. 31.5%, P < 0.001) with no significant differences in adverse events between two groups. The utility value of the "non-recurrence" status was derived from real-world data. Costs and other utility values were collected from an authoritative Chinese network database and published literature. The primary outcomes were total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). The uncertainty of the model was evaluated via one-way and probabilistic sensitivity analyses. RESULTS: Bevacizumab treatment added 0.12 (0.48 vs. 0.36) QALYs compared to corticosteroid therapy, along with incremental costs of $ 2010 ($ 4260 vs. $ 2160). The resultant ICER was $ 16,866/QALY, which was lower than the willingness-to-pay threshold of $ 38,223/QALY in China. The price of bevacizumab, body weight, and the utility value of recurrence status were the key influential parameters for ICER. Probabilistic sensitivity analysis revealed that the probability of bevacizumab being cost-effectiveness was 84.9%. CONCLUSION: Compared with corticosteroids, bevacizumab is an economical option for CRN treatment in China.

Species Delimitation, Phylogenomics, and Biogeography of Sulawesi Flying Lizards: A Diversification History Complicated by Ancient Hybridization, Cryptic Species, and Arrested Speciation.

The biota of Sulawesi is noted for its high degree of endemism and for its substantial levels of in situ biological diversification. While the island's long period of isolation and dynamic tectonic history have been implicated as drivers of the regional diversification, this has rarely been tested in the context of an explicit geological framework. Here, we provide a tectonically informed biogeographical framework that we use to explore the diversification history of Sulawesi flying lizards (the Draco lineatus Group), a radiation that is endemic to Sulawesi and its surrounding islands. We employ a framework for inferring cryptic speciation that involves phylogeographic and genetic clustering analyses as a means of identifying potential species followed by population demographic assessment of divergence-timing and rates of bi-directional migration as means of confirming lineage independence (and thus species status). Using this approach, phylogenetic and population genetic analyses of mitochondrial sequence data obtained for 613 samples, a 50-SNP data set for 370 samples, and a 1249-locus exon-capture data set for 106 samples indicate that the current taxonomy substantially understates the true number of Sulawesi Draco species, that both cryptic and arrested speciations have taken place, and that ancient hybridization confounds phylogenetic analyses that do not explicitly account for reticulation. The Draco lineatus Group appears to comprise 15 species-9 on Sulawesi proper and 6 on peripheral islands. The common ancestor of this group colonized Sulawesi ~11 Ma when proto-Sulawesi was likely composed of two ancestral islands, and began to radiate ~6 Ma as new islands formed and were colonized via overwater dispersal. The enlargement and amalgamation of many of these proto-islands into modern Sulawesi, especially during the past 3 Ma, set in motion dynamic species interactions as once-isolated lineages came into secondary contact, some of which resulted in lineage merger, and others surviving to the present. [Genomics; Indonesia; introgression; mitochondria; phylogenetics; phylogeography; population genetics; reptiles.].

Preoperative structural-functional coupling at the default mode network predicts surgical outcomes of temporal lobe epilepsy.

OBJECTIVE: Structural-functional coupling (SFC) has shown great promise in predicting postsurgical seizure recurrence in patients with temporal lobe epilepsy (TLE). In this study, we aimed to clarify the global alterations in SFC in TLE patients and predict their surgical outcomes using SFC features. METHODS: This study analyzed presurgical diffusion and functional magnetic resonance imaging data from 71 TLE patients and 48 healthy controls (HCs). TLE patients were categorized into seizure-free (SF) and non-seizure-free (nSF) groups based on postsurgical recurrence. Individual functional connectivity (FC), structural connectivity (SC), and SFC were quantified at the regional and modular levels. The data were compared between the TLE and HC groups as well as among the TLE, SF, and nSF groups. The features of SFC, SC, and FC were categorized into three datasets: the modular SFC dataset, regional SFC dataset, and SC/FC dataset. Each dataset was independently integrated into a cross-validated machine learning model to classify surgical outcomes. RESULTS: Compared with HCs, the visual and subcortical modules exhibited decoupling in TLE patients (p < .05). Multiple default mode network (DMN)-related SFCs were significantly higher in the nSF group than in the SF group (p < .05). Models trained using the modular SFC dataset demonstrated the highest predictive performance. The final prediction model achieved an area under the receiver operating characteristic curve of .893 with an overall accuracy of .887. SIGNIFICANCE: Presurgical hyper-SFC in the DMN was strongly associated with postoperative seizure recurrence. Furthermore, our results introduce a novel SFC-based machine learning model to precisely classify the surgical outcomes of TLE.

Lenvatinib plus pembrolizumab in the patients with advanced previously treated endometrial cancer: A cost-effectiveness analysis in the United States and in China.

PURPOSE: To investigate the cost-effectiveness of lenvatinib plus pembrolizumab (LP) compared to chemotherapy as a second-line treatment for advanced endometrial cancer (EC) from the United States and Chinese payers' perspective. METHODS: In this economic evaluation, a partitioned survival model was constructed from the perspective of the United States and Chinese payers. The survival data were derived from the clinical trial (309-KEYNOTE-775), while costs and utility values were sourced from databases and published literature. Total costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were estimated. The robustness of the model was evaluated through sensitivity analyses, and price adjustment scenario analyses was also performed. RESULTS: Base-case analysis indicated that LP wouldn't be cost-effective in the United States at the WTP threshold of $200 000, with improved effectiveness of 0.75 QALYs and an additional cost of $398596.81 (ICER $531392.20). While LP was cost-effective in China, with improved effectiveness of 0.75 QALYs and an increased overall cost of $62270.44 (ICER $83016.29). Sensitivity analyses revealed that the above results were stable. The scenario analyses results indicated that LP was cost-effective in the United States when the prices of lenvatinib and pembrolizumab were simultaneously reduced by 61.95% ($26.5361/mg for lenvatinib and $19.1532/mg for pembrolizumab). CONCLUSION: LP isn't cost-effective in the patients with advanced previously treated endometrial cancer in the United States, whereas it is cost-effective in China. The evidence-based pricing strategy provided by this study could benefit decision-makers in making optimal decisions and clinicians in general clinical practice. More evidence about budget impact and affordability for patients is needed.

Prevalence and risk factors of depression among elderly people in nursing homes from 2012 to 2022: a systematic review and meta-analysis.

OBJECTIVES: To determine a pooled prevalence of depression and its influencing factors among nursing home residents. METHOD: PsycINFO, PubMed, Embase, and Web of Science were searched for studies investigating the prevalence and risk factors of late-life depression among nursing home residents between January 2012 and November 2022. Two reviewers independently completed the literature screening, data extraction and quality assessment. A random-effects model was utilized to pool the prevalence of depression and summarize the influencing factors. RESULTS: This meta-analysis included 48 studies involving 28,501 participants. The pooled prevalence of depressive mood and major depressive disorder was 53% and 27%, respectively. The rate of depressive mood is higher in lower-middle-income countries (60.0%), compared with high- (53.0%) and upper-middle-income countries (44.0%). The rate of depressive mood (35.0%) is higher among females than male (19.0%). Depression was influenced by factors, including male (OR = 0.28), insufficient income (OR = 3.53), comorbidities (OR = 2.66), pain (OR = 2.67; r = 0.31), functional disability (r = 0.33), loneliness (r = 0.43), number of chronic health problems (r = 0.18), social support (r = -0.28), activities of daily living (r = -0.43), subjective health (r = -0.28), autonomy (r = -0.41), environment (r = -0.50) and physical (r = -0.57) and psychological health (r = -0.65). CONCLUSION: The prevalence of depressive mood is high among nursing home residents, especially in lower-middle-income countries. It is influenced by factors including gender, income, social support, daily activities, environment, physical and psychological health and autonomy. Understanding those factors can provide evidence-based recommendations for improved awareness, prevention and better management of late-life depression.

Taraxerone exerts antipulmonary fibrosis effect through Smad signaling pathway and antioxidant stress response in a Sirtuin1-dependent manner.

Idiopathic pulmonary fibrosis treatments are limited, often with severe side effects, highlighting the need for novel options. Taraxerone has diverse biomedical properties, but its mechanism remains unclear. This study investigates taraxerone's impact and the mechanisms involved in bleomycin-induced pulmonary fibrosis in mice. After establishing a pulmonary fibrosis mouse model, taraxerone was intraperitoneally injected continuously for 14-28 days. The in vivo antifibrotic and antioxidative stress effects of taraxerone were assessed. In vitro, the influence of taraxerone on transforming growth factor-ß1-induced myofibroblast transformation and oxidative stress was investigated. Subsequently, quantitative polymerase chain reaction screened the histone deacetylase and Sirtuin family, and taraxerone's effects on SIRT1 were assessed. After SIRT1 siRNA treatment, changes in myofibroblast transformation and antioxidant capacity in response to taraxerone were observed. Acetylation and phosphorylation levels of Smad3 were evaluated. We also examined the binding levels of SIRT1 with Pho-Smad3 and Smad3, as well as the nuclear localization of Smad2/3. EX527 confirmed SIRT1's in vivo action in response to taraxerone. In vitro experiments suggested that taraxerone inhibited myofibroblast differentiation by activating SIRT1 and reducing oxidative stress. We also observed a new interaction between SIRT1 and the Smad complex. Taraxerone activates SIRT1, enabling it to bind directly to Smad3. This leads to reduced Smad complex phosphorylation and limited nuclear translocation. As a result, the transcription of fibrotic factors is reduced. In vivo validation confirms taraxerone's SIRT1-mediated antifibrotic effectiveness. This suggests that targeting SIRT1-mediated inhibition of myofibroblast differentiation could be a key strategy in taraxerone-based therapy for pulmonary fibrosis.

The Glucose-Succinate Pathway: A Crucial Anaerobic Metabolic Pathway in the Scallop Chlamys farreri Experiencing Heat Stress.

Recently, the increase in marine temperatures has become an important global marine environmental issue. The ability of energy supply in marine animals plays a crucial role in avoiding the stress of elevated temperatures. The investigation into anaerobic metabolism, an essential mechanism for regulating energy provision under heat stress, is limited in mollusks. In this study, key enzymes of four anaerobic metabolic pathways were identified in the genome of scallop Chlamys farreri, respectively including five opine dehydrogenases (CfOpDHs), two aspartate aminotransferases (CfASTs) divided into cytoplasmic (CfAST1) and mitochondrial subtype (CfAST2), and two phosphoenolpyruvate carboxykinases (CfPEPCKs) divided into a primitive type (CfPEPCK2) and a cytoplasmic subtype (CfPEPCK1). It was surprising that lactate dehydrogenase (LDH), a key enzyme in the anaerobic metabolism of the glucose-lactate pathway in vertebrates, was absent in the genome of scallops. Phylogenetic analysis verified that CfOpDHs clustered according to the phylogenetic relationships of the organisms rather than substrate specificity. Furthermore, CfOpDHs, CfASTs, and CfPEPCKs displayed distinct expression patterns throughout the developmental process and showed a prominent expression in muscle, foot, kidney, male gonad, and ganglia tissues. Notably, CfASTs displayed the highest level of expression among these genes during the developmental process and in adult tissues. Under heat stress, the expression of CfASTs exhibited a general downregulation trend in the six tissues examined. The expression of CfOpDHs also displayed a downregulation trend in most tissues, except CfOpDH1/3 in striated muscle showing significant up-regulation at some time points. Remarkably, CfPEPCK1 was significantly upregulated in all six tested tissues at almost all time points. Therefore, we speculated that the glucose-succinate pathway, catalyzed by CfPEPCK1, serves as the primary anaerobic metabolic pathway in mollusks experiencing heat stress, with CfOpDH3 catalyzing the glucose-opine pathway in striated muscle as supplementary. Additionally, the high and stable expression level of CfASTs is crucial for the maintenance of the essential functions of aspartate aminotransferase (AST). This study provides a comprehensive and systematic analysis of the key enzymes involved in anaerobic metabolism pathways, which holds significant importance in understanding the mechanism of energy supply in mollusks.

Assessment of bidirectional relationships between brain imaging-derived phenotypes and stroke: a Mendelian randomization study.

BACKGROUND: Stroke is a major cause of mortality and long-term disability worldwide. Whether the associations between brain imaging-derived phenotypes (IDPs) and stroke are causal is uncertain. METHODS: We performed two-sample bidirectional Mendelian randomization (MR) analyses to explore the causal associations between IDPs and stroke. Summary data of 587 brain IDPs (up to 33,224 individuals) from the UK Biobank and five stroke types (sample size range from 301,663 to 446,696, case number range from 5,386 to 40,585) from the MEGASTROKE consortium were used. RESULTS: Forward MR indicated 14 IDPs belong to projection fibers or association fibers were associated with stroke. For example, higher genetically determined mean diffusivity (MD) in the right external capsule was causally associated with an increased risk of small vessel stroke (IVW OR = 2.76, 95% CI 2.07 to 3.68, P = 5.87 × 10-12). Reverse MR indicated that genetically determined higher risk of any ischemic stroke was associated with increased isotropic or free water volume fraction (ISOVF) in body of corpus callosum (IVW ß = 0.23, 95% CI 0.14 to 0.33, P = 3.22 × 10-7). This IDP is a commissural fiber and it is not included in the IDPs identified by forward MR. CONCLUSIONS: We identified 14 IDPs with statistically significant evidence of causal effects on stroke or stroke subtypes. We also identified potential causal effects of stroke on one IDP of commissural fiber. These findings might guide further work toward identifying preventative strategies at the brain imaging levels.

Cost-effectiveness analysis of ovarian function preservation with GnRH agonist during chemotherapy in premenopausal women with early breast cancer.

STUDY QUESTION: Is it economically worthwhile to use GnRH agonist (GnRHa) to prevent menopausal symptoms (MS) and protect fertility in premenopausal women with breast cancer (BC) during chemotherapy from the US perspective? SUMMARY ANSWER: It is cost-effective to administer GnRHa during chemotherapy in order to forefend MS in premenopausal patients with BC when the willingness-to-pay (WTP) threshold is $50 000.00 per quality-adjusted life-year (QALY), and to preserve fertility in young patients with BC who undergo oocyte cryopreservation (OC), or no OC, when the WTP thresholds per live birth are $71 333.33 and $61 920.00, respectively. WHAT IS KNOWN ALREADY: Chemotherapy often results in premature ovarian insufficiency (POI) in premenopausal survivors of BC, causing MS and infertility. Administering GnRHa during chemotherapy has been recommended for ovarian function preservation by international guidelines. STUDY DESIGN, SIZE, DURATION: Two decision-analytic models were developed, respectively, for preventing MS and protecting fertility over a 5-year period, which compared the cost-effectiveness of two strategies: adding GnRHa during chemotherapy (GnRHa plus Chemo) or chemotherapy alone (Chemo). PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were early premenopausal women with BC aged 18-49 years who were undergoing chemotherapy. Two decision tree models were constructed: one for MS prevention and one for fertility protection from the US perspective. All data were obtained from published literature and official websites. The models' primary outcomes included QALYs and incremental cost-effectiveness ratios (ICERs). The robustness of the models was tested by sensitivity analyses. MAIN RESULTS AND THE ROLE OF CHANCE: In the MS model, GnRHa plus Chemo resulted in an ICER of $17 900.85 per QALY compared with Chemo, which was greater than the WTP threshold of $50 000.00 per QALY; therefore, GnRHa plus Chemo was a cost-effective strategy for premenopausal women with BC in the USA. Probabilistic sensitivity analysis (PSA) results showed an 81.76% probability of cost-effectiveness in the strategy. In the fertility model, adding GnRHa for patients undergoing OC and those who were unable to undergo OC resulted in ICERs of $67 933.50 and $60 209.00 per live birth in the USA, respectively. PSA indicated that GnRHa plus Chemo was more likely to be cost-effective over Chemo when the WTP for an additional live birth exceed $71 333.33 in Context I (adding GnRHa to preserve fertility in young patients with BC after OC) and $61 920.00 in Context II (adding GnRHa to preserve fertility in young patients with BC who cannot accept OC). LIMITATIONS, REASONS FOR CAUTION: The indirect costs, such as disease-related mental impairment and non-medical costs (e.g. transportation cost) were not included. All data were derived from previously published literature and databases, which might yield some differences from the real world. In addition, the POI-induced MS with a lower prevalence and the specific strategy of chemotherapy were not considered in the MS model, and the 5-year time horizon for having a child might not be suitable for all patients in the fertility model. WIDER IMPLICATIONS OF THE FINDINGS: When considering the economic burden of cancer survivors, the results of this study provide an evidence-based reference for clinical decision-making, showing that it is worthwhile to employ GnRHa during chemotherapy to prevent MS and preserve fertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Natural Science Foundation of Fujian Province [2021J02038]; and the Startup Fund for Scientific Research, Fujian Medical University [2021QH1059]. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Simulated wrapped phase optimizes phase retrieval in phase-shifting interferometry.

Phase retrieval is crucial in phase-shifting interferometry and other phase measurement techniques. However, in noisy wrapped phase maps with high steepness, discontinuities arise and cause phase unwrapping errors. To solve this problem, this Letter presents a phase retrieval method based on a simulated wrapped phase. By establishing the correspondence between the simulated and measured interferograms, the difference in wrapped phases between them can be obtained. The difference in wrapped phase map, which has sparse and wide interference fringes, has a higher reliability of phase unwrapping. The proposed method not only possesses high phase retrieval accuracy but it also simplifies the processing of interferograms. Furthermore, the layout of all interferometric systems, the parameters of optical components, and the model of the measured object are known, so the proposed method can be used as a reference for phase retrieval.

Long-term trend of future Cancer onset: A model-based prediction of Cancer incidence and onset age by region and gender.

OBJECTIVES: This study provided estimates of cancer incidence rate and onset age by Socio-demographic Index (SDI) regions and gender from 2020 to 2040, aiming to clarify the long-term patterns of future cancer onset. METHOD: Based on the incidence data from the Global Burden of Diseases (GBD) 2019 study, we constructed the Bayesian age-period-cohort model to calculate the age-standardized incidence rates (ASIR) of cancers from 2020 to 2040. Using the average annual percentage change (AAPC) to quantify the trends of ASIR and the onset age. In addition, the incidences in 2019 were fixed to distinguish the age onset changes caused by demographic and incidence from 2020 to 2040. RESULTS: Globally, two-thirds of cancers have escalating trends of incidence rate, and the proportion of cancer weighted average onset age above 60 years old will grow from 62% to 76% between 2020 and 2040. In five SDI regions, the proportion of weighted average onset age above 60 years old will rise above 10% in the next 20 years and increase sequentially with the rise of the SDI level. Preclude sex-specific cancers, the onset age is younger in men than in women in 2040. Rule out the influence of changing demographics, half of cancer's morbidity has a youth-oriented tendency globally, which is concentrated in hormone-related and digestive tract cancer. CONCLUSION: From 2020 to 2040, the incidence and onset age changes demonstrate marked geographic and gender variations in the cancer spectrum. Cancer incidence and onset age are predicted to continuously increase worldwide in the future.

Diagnostic Value of Serum Golgi Protein 73 for Liver Fibrosis: A Systematic Review and Meta-Analysis.

BACKGROUND: The assessment of liver fibrosis has been a critical component in the clinical management of liver diseases. We performed a meta-analysis to evaluate serum Golgi protein 73 (GP73) in the diagnosis of liver fibrosis. METHODS: A literature search was performed in eight databases until July 13, 2022. We strictly searched studies according to inclusion and exclusion criteria, extracted data, and then assessed quality. We pooled the sensitivity, specificity, and other diagnostic estimates of serum GP73 to assess liver fibrosis. Moreover, publication bias, threshold analysis, sensitivity analysis, meta-regression, subgroup analysis, and post-test probability were evaluated. RESULTS: Our research integrated 16 articles including 3,676 patients. Potential publication bias and threshold effect were not found. The pooled sensitivity, specificity, and area under the curve of the summary receiver operating characteristic curve were 0.63, 0.79, and 0.818 for significant fibrosis; 0.77, 0.76, and 0.852 for advanced fibrosis; and 0.80, 0.76, and 0.894 for cirrhosis, respectively. The aetiology was one of the important sources of heterogeneity. CONCLUSION: Serum GP73 was a feasible diagnostic marker for liver fibrosis, which is of great significance for the clinical management of liver diseases.

Adjuvant zoledronic acid therapy for postmenopausal women with early breast cancer in China: a cost-effectiveness analysis.

Combination therapy of zoledronic acid (ZOL) plus aromatase inhibitor (AI) was found to reduce bone metastasis risk and improve overall survival for treatment-naïve postmenopausal women (PMW) with hormone receptor-positive (HR+) early breast cancer (EBC), when compared with AI alone. The objective of this study was to evaluate the cost-effectiveness of adding ZOL to AI in treating PMW with HR+ EBC in China. A 5-state Markov model was constructed to evaluate the cost-effectiveness of adding ZOL to AI for PMW-EBC (HR+) over a lifetime horizon from the perspective of Chinese healthcare provider. Data used were obtained from previous reports and public data. The primary outcomes of this study were direct medical cost, life years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were performed to examine the robustness of the presented model. Over a lifetime horizon, adding ZOL to AI was projected to yield a gain of 1.286 LYs and 1.099 QALYs compared with AI monotherapy, which yielded ICER $11 140.75 per QALY with an incremental cost of $12 247.36. The one-way sensitivity analysis indicated that the cost of ZOL was the most influential factor in our study. The probability that adding ZOL to AI was cost-effective at a threshold of $30 425 per QALY in China was 91.1%. ZOL is likely to be cost-effective in reducing bone metastasis risk and improving overall survival for PMW-EBC (HR+) in China.

Surgical management of broad-based sessile vocal cord polyps: Transnasal vocal fold polypectomy versus microlaryngoscopic surgery: Our experience in 159 cases.

OBJECTIVES: In this study, we retrospectively reviewed and compared the treatment outcomes and complications of office transnasal vocal fold polypectomy (TVFP) with those of microplarygoscopic surgery (MLS) for different clinical and histopathological features of broad-based sessile vocal fold polyps. METHODS: We retrospectively reviewed the records of 159 consecutive patients with broad-based sessile vocal fold polyps treated by TVFP or MLS. The differences in efficacy and complication between these two surgical techniques were compared according to the different types of vocal fold polyps. RESULTS: Satisfactory outcomes of both TVFP and MLS treatments were reported in patients with oedematous, gelatinous and vascular types of vocal fold polyps (p > .05). The efficacy of TVFP was slightly worse than MLS in fibrous polyps group (p < .05). The TVFP-treated patients did not exhibit obvious complications, whereas several MLS-treated patients had suffered different complications. CONCLUSION: The therapeutic effects of both TVFP and MLS on the treatment of broad-based sessile vocal cord polyps are related to their clinical characteristics and histological types. Satisfactory outcomes are achieved in oedematous, gelatinous, and vascular types of polyps after either surgical procedure. TVFP has fewer surgical complications than MLS which can be a preferred option for the treatment of broad-based sessile vocal cord polyps at outpatient setting. TVFP also can be an alternative surgery option for patients who could not tolerate general anaesthesia or laryngeal suspension. In contrast, MLS has proven to be a particularly advantageous treatment in patients who have fibrous type of polyps.

LHX2 facilitates the progression of nasopharyngeal carcinoma via activation of the FGF1/FGFR axis.

BACKGROUND: Distant metastasis and recurrence remain the main obstacle to nasopharyngeal carcinoma (NPC) treatment. However, the molecular mechanisms underlying NPC growth and metastasis are poorly understood. METHODS: LHX2 expression was examined in NPC cell lines and NPC tissues using quantitative reverse transcription-polymerase chain reaction, western blotting and Immunohistochemistry assay. NPC cells overexpressing or silencing LHX2 were used to perform CCK-8 assay, colony-formation assay, EdU assay, wound-healing and invasion assays in vitro. Xenograft tumour models and lung metastasis models were involved for the in vivo assays. The Gene Set Enrichment Analysis (GSEA), ELISA assay, western blot, chromatin immunoprecipitation (ChIP) assay and Luciferase reporter assay were applied for the downstream target mechanism investigation. RESULTS: LIM-homeodomain transcription factor 2 (LHX2) was upregulated in NPC tissues and cell lines. Elevated LHX2 was closely associated with poor survival in NPC patients. Ectopic LHX2 overexpression dramatically promoted the growth, migration and invasion of NPC cells both in vitro and in vivo. Mechanistically, LHX2 transcriptionally increased the fibroblast growth factor 1 (FGF1) expression, which in turn activated the phosphorylation of STAT3 (signal transducer and activator of transcription 3), ERK1/2 (extracellular regulated protein kinases 1/2) and AKT signalling pathways in an autocrine and paracrine manner, thereby promoting the growth and metastasis of NPC. Inhibition of FGF1 with siRNA or FGFR inhibitor blocked LHX2-induced nasopharyngeal carcinoma cell growth, migration and invasion. CONCLUSIONS: Our study identifies the LHX2-FGF1-FGFR axis plays a key role in NPC progression and provides a potential target for NPC therapy.

Kindlin-2 protects pancreatic ß cells through inhibiting NLRP3 inflammasome activation in diabetic mice.

Diabetes mellitus has been a major public health problem worldwide, characterized by insulin resistance and dysfunction of ß-cells. A previous study showed that Kindlin-2 loss in ß-cells dramatically reduces insulin secretion and decreases ß-cell mass, resulting in severe diabetes-like phenotypes. It suggests that Kindlin-2 in ß-cells play an important role in regulating glucose homeostasis. However, the effect of Kindlin-2 on the function of ß-cells under chronic hyperglycemia in diabetes has not been explored. Here we report that Kindlin-2 overexpression ameliorates diabetes and improves insulin secretion in mice induced by streptozocin. In contrast, Kindlin-2 insufficiency exacerbates diabetes and promotes ß-cells dysfunction and inflammation in ß-cells induced by a high-fat diet (HFD). In vitro, Kindlin-2 overexpression prevented high-glucose (HG)-induced dysfunction in ß-cells. Kindlin-2 overexpression also decreased the expression of pro-inflammatory cytokines and NLRP3 inflammasome expression in ß-cells exposed to HG. Furthermore, the loss of Kindlin-2 aggravates the expression of inflammatory cytokines and NLRP3 induced by HG in ß-cells. Collectively, we demonstrate that Kindlin-2 protects against diabetes by inhibiting NLRP3 inflammasome activation.

Research, development, and evaluation of the practical effect of a storage inflow and outflow management system for consumables in the endocrinology department of a hospital.

BACKGROUND: This study was designed for the research and development (R&D) and application of a storage inflow and outflow management system enabling departments to perform efficient, scientific, and information-based consumable management. METHODS: In the endocrinology department of a hospital, expert and R&D teams in consumable management were set up, and an information-based storage inflow and outflow management system for consumables was designed and developed. The system was operated on a personal computer and was divided into three modules: public consumables, bed consumables, and quality control management. The functions of the system included storage inflow and outflow, early warnings, response to user queries, and statistics on consumables. Data were derived from the hospital information system (HIS,ZHIY SOFTWARE HIS VERSION4.0) and a questionnaire survey. Economic indicators, work efficiency of consumable management, nurse burnout, consumable stockroom management, and staff satisfaction were compared under manual management, Excel-based management, and the consumable storage inflow and outflow management system. The results of the questionnaire were analysed using the R software, version 4.1.0. RESULTS: Dates were obtained from manual management, Excel-based management and the consumable storage inflow and outflow management system. Under these three methods, the daily prices of department consumables per bed were 53.43 ± 10.27 yuan, 38.65 ± 8.56 yuan, and 31.98 ± 7.36 yuan, respectively, indicating that the new management system reduced costs for the department. The time spent daily on consumable management was shortened from 119.5 (106.75, 123.5) min to 56.5 (48.5, 60.75) to 20 (17.25, 24.25) min. Nurses' emotional fatigue and job indifference scores, respectively, decreased from 22.90 ± 1.65 and 8.75 ± 1.25 under manual management to 19.70 ± 1.72 and 6.90 ± 1.37 under Excel-based management and to 17.20 ± 2.04 and 6.00 ± 1.30 under the novel system; the satisfaction of the warehouse keeper and collection staff, respectively, increased from 76.62% and 80.78% to 91.6% and 90.5% to 98.8% and 98.5% under the three successive systems. CONCLUSIONS: The storage inflow and outflow management system achieved produced good results in the storage and classification of consumables.

COX-2/sEH Dual Inhibitor Alleviates Hepatocyte Senescence in NAFLD Mice by Restoring Autophagy through Sirt1/PI3K/AKT/mTOR.

We previously found that the disorder of soluble epoxide hydrolase (sEH)/cyclooxygenase-2 (COX-2)-mediated arachidonic acid (ARA) metabolism contributes to the pathogenesis of the non-alcoholic fatty liver disease (NAFLD) in mice. However, the exact mechanism has not been elucidated. Accumulating evidence points to the essential role of cellular senescence in NAFLD. Herein, we investigated whether restoring the balance of sEH/COX-2-mediated ARA metabolism attenuated NAFLD via hepatocyte senescence. A promised dual inhibitor of sEH and COX-2, PTUPB, was used in our study to restore the balance of sEH/COX-2-mediated ARA metabolism. In vivo, NAFLD was induced by a high-fat diet (HFD) using C57BL/6J mice. In vitro, mouse hepatocytes (AML12) and mouse hepatic astrocytes (JS1) were used to investigate the effects of PTUPB on palmitic acid (PA)-induced hepatocyte senescence and its mechanism. PTUPB alleviated liver injury, decreased collagen and lipid accumulation, restored glucose tolerance, and reduced hepatic triglyceride levels in HFD-induced NAFLD mice. Importantly, PTUPB significantly reduced the expression of liver senescence-related molecules p16, p53, and p21 in HFD mice. In vitro, the protein levels of γH2AX, p53, p21, COX-2, and sEH were increased in AML12 hepatocytes treated with PA, while Ki67 and PCNA were significantly decreased. PTUPB decreased the lipid content, the number of ß-gal positive cells, and the expression of p53, p21, and γH2AX proteins in AML12 cells. Meanwhile, PTUPB reduced the activation of hepatic astrocytes JS1 by slowing the senescence of AML12 cells in a co-culture system. It was further observed that PTUPB enhanced the ratio of autophagy-related protein LC3II/I in AML12 cells, up-regulated the expression of Fundc1 protein, reduced p62 protein, and suppressed hepatocyte senescence. In addition, PTUPB enhanced hepatocyte autophagy by inhibiting the PI3K/AKT/mTOR pathway through Sirt1, contributing to the suppression of senescence. PTUPB inhibits the PI3K/AKT/mTOR pathway through Sirt1, improves autophagy, slows down the senescence of hepatocytes, and alleviates NAFLD.