Prevalence of intrinsic capacity decline among community-dwelling older adults: a systematic review and meta-analysis.

BACKGROUND: The concept of intrinsic capacity (IC) was introduced to define healthy aging and active aging based on functional capacity, yet there is limited understanding of the risk of IC decline at a population level. AIMS: To consolidate existing evidence for rates of IC decline and risk factors among community-dwelling adults 60 years or older. METHODS: According to the PRISMA guidelines, the literature search was independently conducted by two researchers in 8 databases from inception to January 2024 without language restrictions using combinations of free words and subject words. Qualities of included studies were assessed using Joanna Briggs Institute's (JBI's) critical appraisal checklist for prevalence studies. To pool the data, a random-effect meta-analysis was performed, followed by subgroup analysis and sensitivity analysis. All analyses were performed by Stata14.0. RESULTS: From 1594 records, 15 studies were extracted with 33,070 participants for meta-analysis. The pooled prevalence of IC decline in community settings was 67.8% (95% CI: 57.0-78.5%; P < 0.001). The prevalence of IC decline in China (66.0%; 95% CI: 53.2-78.9%) was found to be slightly lower than in other countries/regions (73.0%; 95% CI: 59.8-86.3%); however, this difference was not statistically significant. Other subgroup analyses revealed no statistically significant differences in prevalence. Age, hypertension, diabetes, gender, education level, living status, smoking, regular exercise, marital status, and osteoarthritis are associated with IC decline. CONCLUSION: More than two-thirds of older adults in the community are affected by IC decline, and age, hypertension, diabetes, female sex, low education level, living alone, smoking, irregular exercise, unmarried, and osteoarthritis are all risk factors for IC decline.

Comparative analysis of complete chloroplast genomes of Synotis species (Asteraceae, Senecioneae) for identification and phylogenetic analysis.

BACKGROUND: The Synotis (C. B. Clarke) C. Jeffrey & Y. L. Chen is an ecologically important genus of the tribe Senecioneae, family Asteraceae. Because most species of the genus bear similar morphology, traditional morphological identification methods are very difficult to discriminate them. Therefore, it is essential to develop a reliable and effective identification method for Synotis species. In this study, the complete chloroplast (cp.) genomes of four Synotis species, S. cavaleriei (H.Lév.) C. Jeffrey & Y.L. Chen, S. duclouxii (Dunn) C. Jeffrey & Y.L. Chen, S. nagensium (C.B. Clarke) C. Jeffrey & Y.L. Chen and S. erythropappa (Bureau & Franch.) C. Jeffrey & Y. L. Chen had been sequenced using next-generation sequencing technology and reported here. RESULTS: These four cp. genomes exhibited a typical quadripartite structure and contained the large single-copy regions (LSC, 83,288 to 83,399 bp), the small single-copy regions (SSC, 18,262 to 18,287 bp), and the inverted repeat regions (IR, 24,837 to 24,842 bp). Each of the four cp. genomes encoded 134 genes, including 87 protein-coding genes, 37 tRNA genes, 8 rRNA genes, and 2 pseudogenes (ycf1 and rps19). The highly variable regions (trnC-GCA-petN, ccsA-psaC, trnE-UUC-rpoB, ycf1, ccsA and petN) may be used as potential molecular barcodes. The complete cp. genomes sequence of Synotis could be used as the potentially effective super-barcode to accurately identify Synotis species. Phylogenetic analysis demonstrated that the four Synotis species were clustered into a monophyletic group, and they were closed to the Senecio, Crassocephalum and Dendrosenecio in tribe Senecioneae. CONCLUSIONS: This study will be useful for further species identification, evolution, genetic diversity and phylogenetic studies within this genus Synotis and the tribe Senecioneae.

Preparation, Characterization and Evaluation of Nintedanib Amorphous Solid Dispersions with Enhanced Oral Bioavailability.

The dissolution and bioavailability challenges posed by poorly water-soluble drugs continue to drive innovation in pharmaceutical formulation design. Nintedanib (NDNB) is a typical BCS class II drug that has been utilized to treat idiopathic pulmonary fibrosis (IPF). Due to the low solubility, its oral bioavailability is relatively low, limiting its therapeutical effectiveness. It is crucial to enhance the dissolution and the oral bioavailability of NDNB. In this study, we focused on the preparation of amorphous solid dispersions (ASD) using hot melt extrusion (HME). The formulation employed Kollidon® VA64 (VA64) as the polymer matrix, blended with the NDNB at a ratio of 9:1. HME was conducted at temperatures ranging from 80 °C to 220 °C. The successful preparation of ASD was confirmed through various tests including polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). The in-vitro cumulative release of NDNB-ASD in 2 h in a pH 6.8 medium was 8.3-fold higher than that of NDNB (p < 0.0001). In a pH 7.4 medium, it was 10 times higher (p < 0.0001). In the in-vivo pharmacokinetic experiments, the area under curve (AUC) of NDNB-ASD was 5.3-fold higher than that of NDNB and 2.2 times higher than that of commercially available soft capsules (Ofev®) (p < 0.0001). There was no recrystallization after 6 months under accelarated storage test. Our study indicated that NDNB-ASD can enhance the absorption of NDNB, thus providing a promising method to improve NDNB bioavailability in oral dosages.

Enhanced silicate weathering accelerates forest carbon sequestration by stimulating the soil mineral carbon pump.

Enhanced silicate rock weathering (ERW) is an emerging strategy for carbon dioxide removal (CDR) from the atmosphere to mitigate anthropogenic climate change. ERW aims at promoting soil inorganic carbon sequestration by accelerating geochemical weathering processes. Theoretically, ERW may also impact soil organic carbon (SOC), the largest carbon pool in terrestrial ecosystems, but experimental evidence for this is largely lacking. Here, we conducted a 2-year field experiment in tropical rubber plantations in the southeast of China to evaluate the effects of wollastonite powder additions (0, 0.25, and 0.5 kg m-2) on both soil organic and inorganic carbon at 0-10 cm depth. We found that ERW significantly increased the concentration of SOC and HCO3 -, but the increases in SOC were four and eight times higher than that of HCO3 - with low- and high-level wollastonite applications. ERW had positive effects on the accrual of organic carbon in mineral-associated organic matter (MAOM) and macroaggregate fractions, but not on particulate organic matter. Path analysis suggested that ERW increased MAOM mainly by increasing the release of Ca, Si, and Fe, and to a lesser extent by stimulating root growth and microbial-derived carbon inputs. Our study indicates that ERW with wollastonite can promote SOC sequestration in stable MOAM in surface soils through both the soil mineral carbon pump and microbial carbon pump. These effects may have been larger than the inorganic CDR during our experiment. We argue it is essential to account for the responses of SOC in the assessments of CDR by ERW.

Recombinant human luteinizing hormone increases endometrial thickness in women undergoing assisted fertility treatments: a systematic review and meta-analysis.

Introduction: The optimal dosage of recombinant human luteinizing hormone (r-hLH) and its impact on endometrial thickness (EMT) when administered alongside recombinant human follicle-stimulating hormone (r-hFSH) during controlled ovarian stimulation (COS) for in vitro fertilization/intracytoplasmic sperm injection and embryo transfer are uncertain, which formed the aims of this systematic review and meta-analysis. Method: A search was performed in PubMed, Cochrane Library, Web of Science, EMBASE, CNKI, and Wanfang from its inception to 10 July 2023. Twenty-seven Randomized controlled trials comparing r-hFSH/r-hLH co-treatment with r-hFSH alone during in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) were included. Pooled odds ratios (OR) for dichotomous data and mean differences (MD) for continuous data, with their respective 95% confidence intervals (CI), were generated. Meta-analysis employed fixed-effect or random-effect models based on heterogeneity, using Q-test and I2-index calculations. The main outcomes included EMT on trigger day, clinical pregnancy rate (CPR) and live birth rate (LBR). Results: r-hFSH/r-hLH significantly increased EMT on trigger day (MD = 0.27; 95% CI, 0.11-0.42; I2 = 13%), but reduced oocyte number (MD = -0.60; 95% CI, -1.07 to -0.14; I2 = 72%) and high-quality embryos (MD = -0.76; 95% CI, -1.41 to -0.10; I2 = 94%) than r-hFSH alone, more pronounced with the gonadotrophin-releasing hormone agonist long protocol. A subgroup analysis showed r-hLH at 75 IU/day increased CPR (OR = 1.23; 95% CI, 1.02-1.49; I2 = 16%) and EMT on trigger day (MD = 0.40; 95% CI, 0.19-0.61; I2 = 0%). Participants ≥35 years of age exhibited decreased retrieved oocytes (MD = -1.26; 95% CI, -1.78 to -0.74; I2 = 29%), but an increase in EMT on trigger day (MD = 0.26; 95% CI, 0.11-0.42; I2 = 29%). Conclusion: r-hFSH/r-hLH during COS significantly improved EMT compared to r-hFSH alone. An r-hLH dose of 75 IU/day may be considered for optimal pregnancy outcomes, which still require further clinical studies to support this dosing regime. Systematic Review Registration: [www.crd.york.ac.uk/PROSPERO], identifier [CRD42023454584].

Effect of Long-Term Tai Chi Therapy on the Immune-Inflammatory Pathway in Patients with Schizophrenia with Antipsychotic-Stabilized.

The primary objective of this study was to explore the influence of prolonged (24 weeks) supplementary Tai Chi therapy on cognitive capabilities and immune-inflammatory pathways in subjects diagnosed with schizophrenia. A total of 90 individuals who have been clinically diagnosed with schizophrenia were assigned to two treatment groups, namely the Tai Chi treatment (TT) group and the routine treatment (RT) group. Following a 24-week duration of intervention, the data obtained from 32 patients in the TT group and 30 patients in the RT group were meticulously analyzed. At the commencement of the investigation and upon completion of the 24-week intervention, blood samples were gathered, and clinical evaluations were executed. In plasma, the identification of nine cytokines (IL-10, IFN-γ, IL-5, GM-CSF, TNF-α, IL-13, IL-4, IL-2, and IL-12) was conducted using the multiple primer suspension chip method. The clinical evaluations encompassed CGI, WHOQUOL-BREF, SOFS, PSS, BPRS, SAPS, SANS, and RBANS. In comparison to the RT group, the patients in the TT group demonstrated decreased levels of TNF-α and IL-5 (P < 0.05). Moreover, they encountered more pronounced advancements in SAPS, SANS, PSS, SOFS, and RBANS scores (P < 0.05). Additionally, a positive connection was detected between the plasma TNF-α level in the TT group and both the SANS score and the SPFS score (P < 0.05). Tai Chi has been shown to improve clinical symptoms in patients with schizophrenia as an add-on therapy, potentially through its effects on immunomodulatory pathways.

A new isoprenyl-phenol-type meroterpenoid from mangrove endophytic fungus Aspergillus sp. GXNU-Y65.

Asperphenol A (1), a new isoprenyl-phenol-type meroterpenoid, was isolated from the mangrove endophytic fungus Aspergillus sp. GXNU-Y65 together with five known compounds (2-6). All structures were assigned using extensive NMR spectroscopic data and electronic circular dichroism (ECD) calculations. Compounds 1-6 were evaluated for their cytotoxic activity against A549 and T24 human cancer cell lines. Among them, compounds 1 and 5 exhibited moderate inhibitory activities against T24 cancer cell lines with the IC50 values of 26.71 and 43.50 µM, respectively.

Knowledge and attitude toward proton radiotherapy among oncology patients: a multi-center, cross-sectional study.

Aim: To explore the knowledge and attitude among oncology patients toward proton radiotherapy. Materials & methods: This cross-sectional study was performed using self-designed questionnaire. Results: Based on 546 valid questionnaires, mean knowledge and attitude scores of 3.4 ± 3.6 (range: 0-12) and 31.1 ± 3.5 (range: 10-50) were observed. Multivariate analysis demonstrated that higher education (p = 0.021), higher monthly income (p = 0.005), and proton radiotherapy history (p < 0.001) were independently associated with higher knowledge scores. Higher knowledge (p = 0.020), older age (p = 0.030), not smoking (p = 0.032) and medication use (p = 0.035) were independently associated with higher attitude scores. Conclusion: Oncology patients have insufficient knowledge and negative attitude toward proton radiotherapy, which might be affected by their age, education, income, proton radiotherapy history, employment, smoking and medication use.

[Box: see text].

Effect of differences in proximal neck angles on biomechanics of abdominal aortic aneurysm based on fluid dynamics.

BACKGROUND: This study aimed to analyze the effect of proximal neck angulation on the biomechanical indices of abdominal aortic aneurysms (AAA) and to investigate its impact on the risk of AAA rupture. METHODS: CT angiography (CTA) data of patients with AAA from January 2015 to January 2022 were collected. Patients were divided into three groups based on the angle of the proximal neck: Group A (âˆ ß ≤ 30°), Group B (30°<âˆ ß ≤ 60°), and Group C (âˆ ß > 60°). Biomechanical indices related to the rupture risk of AAA were analyzed using computational fluid dynamics modeling (CFD-Post) based on the collected data. RESULTS: Group A showed slight turbulence in the AAA lumen with a mixed laminar flow pattern. Group B had a regular low-speed eddy line characterized by cross-flow dominated by lumen blood flow and turbulence. In Group C, a few turbulent lines appeared at the proximal neck, accompanied by eddy currents in the lumen expansion area following the AAA shape. Significant differences were found in peak wall stress, shear stress, and the maximum blood flow velocity impact among the three groups. The maximum blood flow velocity at the angle of the proximal neck impact indicated the influence of the proximal neck angle on the blood flow state in the lumen. CONCLUSION: As the angle of the proximal neck increased, it caused stronger eddy currents and turbulent blood flow due to a high-speed area near the neck. The region with the largest diameter in the abdominal aortic aneurysm was prone to the highest stress, indicating a higher risk of rupture. The corner of the proximal neck experienced the greatest shear stress, potentially leading to endothelial injury and further enlargement of the aneurysm.

Integration of Plasmonic Ag(I) Clusters and Fe(II) Porphyrinates into Metal-Organic Frameworks for Efficient Photocatalytic CO2 Reduction Coupling with Photosynthesis of Pure H2O2.

Efficient photocatalytic CO2 reduction coupled with the photosynthesis of pure H2O2 is a challenging and significant task. Herein, using classical CO2 photoreduction site iron porphyrinate as the linker, Ag(I) clusters were spatially separated and evenly distributed within a new metal-organic framework (MOF), namely Ag27TPyP-Fe. With water as electron donors, Ag27TPyP-Fe exhibited remarkable performances in artificial photosynthetic overall reaction with CO yield of 36.5 µmol g-1 h-1 and ca. 100% selectivity, as well as H2O2 evolution rate of 35.9 µmol g-1 h-1. Since H2O2 in the liquid phase can be more readily separated from the gaseous products of CO2 photoreduction, high-purity H2O2 with a concentration up to 0.1 mM was obtained. Confirmed by theoretical calculations and the established energy level diagram, the reductive iron(II) porphyrinates and oxidative Ag(I) clusters within an integrated framework functioned synergistically to achieve artificial photosynthesis. Furthermore, photoluminescence spectroscopy and photoelectrochemical measurements revealed that the robust connection of Ag(I) clusters and iron porphyrinate ligands facilitated efficient charge separation and rapid electron transfer, thereby enhancing the photocatalytic activity.

The epithelial Na+ channel (ENaC) in ovarian granulosa cells modulates Ca2+ mobilization and gonadotrophin signaling for estrogen homeostasis and female fertility.

Ovarian granulosa cells are essential to gonadotrophin-regulated estrogen production, female cycle maintenance and fertility. The epithelial Na+ channel (ENaC) is associated with female fertility; however, whether and how it plays a role in ovarian cell function(s) remained unexplored. Here, we report patch-clamp and Na+ imaging detection of ENaC expression and channel activity in both human and mouse ovarian granulosa cells, which are promoted by pituitary gonadotrophins, follicle stimulating hormone (FSH) or luteinizing hormone (LH). Cre-recombinase- and CRISPR-Cas9-based granulosa-specific knockout of ENaC α subunit (Scnn1a) in mice resulted in failed estrogen elevation at early estrus, reduced number of corpus luteum, abnormally extended estrus phase, reduced litter size and subfertility in adult female mice. Further analysis using technologies including RNA sequencing and Ca2+ imaging revealed that pharmacological inhibition, shRNA-based knockdown or the knockout of ENaC diminished spontaneous or stimulated Ca2+ oscillations, lowered the capacity of intracellular Ca2+ stores and impaired FSH/LH-stimulated transcriptome changes for estrogen production in mouse and/or human granulosa cells. Together, these results have revealed a previously undefined role of ENaC in modulating gonadotrophin signaling in granulosa cells for estrogen homeostasis and thus female fertility.

Sciatic nerve stimulation alleviates neuropathic pain and associated neuroinflammation in the dorsal root ganglia in a rodent model.

BACKGROUND: Satellite glial cells (SGCs) in the dorsal root ganglia (DRG) play a pivotal role in the formation of neuropathic pain (NP). Sciatic nerve stimulation (SNS) neuromodulation was reported to alleviate NP and reduce neuroinflammation. However, the mechanisms underlying SNS in the DRG remain unclear. This study aimed to elucidate the mechanism of electric stimulation in reducing NP, focusing on the DRG. METHODS: L5 nerve root ligation (NRL) NP rat model was studied. Ipsilateral SNS performed 1 day after NRL. Behavioral tests were performed to assess pain phenotypes. NanoString Ncounter technology was used to explore the differentially expressed genes and cellular pathways. Activated SGCs were characterized in vivo and in vitro. The histochemical alterations of SGCs, macrophages, and neurons in DRG were examined in vivo on post-injury day 8. RESULTS: NRL induced NP behaviors including decreased pain threshold and latency on von Frey and Hargreaves tests. We found that following nerve injury, SGCs were hyperactivated, neurotoxic and had increased expression of NP-related ion channels including TRPA1, Cx43, and SGC-neuron gap junctions. Mechanistically, nerve injury induced reciprocal activation of SGCs and M1 macrophages via cytokines including IL-6, CCL3, and TNF-α mediated by the HIF-1α-NF-κB pathways. SNS suppressed SGC hyperactivation, reduced the expression of NP-related ion channels, and induced M2 macrophage polarization, thereby alleviating NP and associated neuroinflammation in the DRG. CONCLUSIONS: NRL induced hyperactivation of SGCs, which had increased expression of NP-related ion channels. Reciprocal activation of SGCs and M1 macrophages surrounding the primary sensory neurons was mediated by the HIF-1α and NF-κB pathways. SNS suppressed SGC hyperactivation and skewed M1 macrophage towards M2. Our findings establish SGC activation as a crucial pathomechanism in the gliopathic alterations in NP, which can be modulated by SNS neuromodulation.

Comparison of three different internal fixation methods in the treatment of femoral neck fracture.

Objective: This study aimed to assess the efficacy of three different fixation methods in treating femoral neck fractures in young patients. Methods: A retrospective analysis was conducted on 35 young patients with femoral neck fractures who underwent surgical treatment. Among them, 16, 12, and 7 patients underwent fixation with three cannulated compression screws (3CS), the femoral neck system (FNS), and the compound compression system (CCS), respectively. Data, including fracture classification, injury-to-surgery time, surgery duration, intraoperative blood loss, fluoroscopy instances, fracture healing time, complications, and Harris score at the final follow-up, were collected and analyzed to compare clinical outcomes among the three fixation methods. Results: All patients were followed for at least 6 months, exhibiting no significant differences in age, gender, injury side, fracture type, or injury-to-operation time among the three groups (P > 0.05). The FNS and CCS groups exhibited shorter operation durations and fewer intraoperative fluoroscopy instances compared to the 3CS group (P < 0.01). Despite the minimally invasive nature of 3CS, the FNS and CCS groups experienced higher intraoperative blood loss (P < 0.01). During follow-up, only one patient with 3CS fixation developed nonunion. Additionally, patients treated with 3CS demonstrated a higher incidence of femoral head necrosis and severe femoral neck shortening than the FNS and CCS groups. Excluding patients with combined nonunion, no significant difference in mean fracture healing time was observed among the three groups (P > 0.05). At the last follow-up, the FNS and CCS groups showed higher Harris scores (P < 0.05). Conclusions: Both FNS and CCS are effective internal fixation systems for the treatment of femoral neck fractures in young patients, yielding more satisfactory clinical functional outcomes than 3CS. Comparatively, the CCS system presents a higher risk of iatrogenic rotation of the proximal fracture segment. Therefore, we advocate the insertion of two to three 2.5 mm Kirschner wires from the upper edge of the femoral neck along the axial direction before CCS lag screw insertion to resist iatrogenic rotational stress.

Transforming medical students' speaking-up behaviors in medical errors: The impact of simulation and personalized debriefing.

INTRODUCTION: Sharing mental models is essential for high-performance teams, and speaking up is key for exchanging critical insights, especially during medical errors. Understanding how health providers and trainees voice their concerns is crucial for improving speaking-up behavior. This study aims to fill a gap in the literature by examining how medical students speak up when they encounter medical errors and assessing the impact of training on their speaking-up patterns. METHOD: A quasi-experimental study involving 146 students, who were divided into two groups, was conducted in Northern Taiwan. One group of students encountered life-threatening scenario before intervention, followed by a faculty-led personalized debriefing session, then a non-life-threatening scenario after the intervention. Another group of students underwent these sessions in the reverse order. Students' Speaking-up patterns, including expression style, form and attitude, and their speaking-up confidence were assessed at pre- and post-intervention scenarios. RESULTS: During pre-intervention scenario, in expression style, 50 students (34.5%) addressed their concerns to medical errors with direct expression and 14 students (9.7%) utilized indirect hint to express their concerns. In expression form, 31 students (21.4%) addressed their concerns to medical errors with affirmative sentences and 33 students (22.8%) asked questions to express their concerns. In speaking-up attitude, 47 students (32.4%) used unoffensive words, while 17 students (11.7%) used offensive words. After intervention, significantly change of speaking-up styles, forms, and attitude were observed along with their speaking-up confidence (p < 0.001). DISCUSSION: Medical students are inclined to speak up in the event of medical errors using more direct expression and affirmative sentences, along with increased speaking-up confidence after simulation scenario learning and faculty-led personalized debriefing. Healthcare educators can focus more on discussing with students the advantages and disadvantages of various approaches of speaking-up in medical errors, helping them to develop effective speaking-up behaviors in a variety of medical contexts.

Molecular Responses of Anti-VEGF Therapy in Neovascular Age-Related Macular Degeneration: Integrative Insights From Multi-Omics and Clinical Imaging.

Purpose: The purpose of this study was to investigate the molecular mechanisms underlying anti-vascular endothelial growth factor (anti-VEGF) efficacy and response variability in neovascular age-related macular degeneration (nAMD) using longitudinal proteomic and metabolomic analysis alongside three-dimensional lesion measurements. Methods: In this prospective study, 54 treatment-naive patients with nAMD underwent "3+ pro re nata" (3+PRN) anti-VEGF regimens followed for at least 12 weeks. Aqueous humors were collected pre- and post-treatment for proteomic and metabolomic analysis. Three-dimensional optical coherence tomography (OCT) and OCT angiography assessed different types of nAMD lesion volumes and areas. Results: There were 1350 proteins and 1268 metabolites that were identified in aqueous humors, with 301 proteins and 353 metabolites significantly altered during anti-VEGF treatment, enriched in pathways of angiogenesis, energy metabolism, signal transduction, and neurofunctional regulation. Sixty-seven changes of (Δ) molecules significantly correlated with at least one type of ΔnAMD lesion. Notably, proteins FGA, TALDO1, and ASPH significantly decreased during treatment, with their reductions correlating with greater lesion regression in at least two lesion types. Conversely, despite that YIPF3 also showed significant downregulation, its decrease was associated with poorer regression in total nAMD lesion and subretinal hyper-reflective material. Conclusions: This study identifies FGA, TALDO1, and ASPH as potential key molecules in the efficacy of anti-VEGF therapy, whereas YIPF3 may be a key factor in poor response. The integration of longitudinal three-dimensional lesion analysis with multi-omics provides valuable insights into the mechanisms and response variability of anti-VEGF treatment in nAMD.

Long-term safety and influence on growth in patients receiving sirolimus: a pooled analysis.

BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). CONCLUSIONS: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. TRIAL REGISTRATION: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

Small Molecules Blocking the Assembly of TCAB1 and Telomerase Complexes: Lead Discovery and Biological Activity.

The vast majority of tumor cells maintain the length of the telomeres through a telomerase-dependent maintenance mechanism, allowing for unlimited proliferation. TCAB1 is indispensable for the correct assembly of telomerase complexes and the delivery of telomerase to the telomere. Therefore, this study aimed to explore small molecules capable of interfering with the assembly of TCAB1 and the telomerase complex as novel efficient telomerase inhibitors. Through virtual screening, biological evaluation, and the confirmation of target engagement, the potential ligands of TCAB1 effectively inhibiting telomerase activity were discovered. Among them, compound 9 exhibited telomerase inhibitory activity at a two-digit nanomolar level (IC50 = 0.03 µM), which was dramatically enhanced in comparison with the previously reported telomerase inhibitors. This research, based on the blockage of telomerase assembly through disturbing TCAB1, provides a novel strategy and a potential target for telomerase inhibitor discovery.

Acyl-CoA binding protein for the experimental treatment of anorexia.

Extracellular acyl-coenzyme A binding protein [ACBP encoded by diazepam binding inhibitor (DBI)] is a phylogenetically ancient appetite stimulator that is secreted in a nonconventional, autophagy-dependent fashion. Here, we show that low ACBP/DBI plasma concentrations are associated with poor prognosis in patients with anorexia nervosa, a frequent and often intractable eating disorder. In mice, anorexia induced by chronic restraint stress (CRS) is accompanied by a reduction in circulating ACBP/DBI concentrations. We engineered a chemical-genetic system for the secretion of ACBP/DBI through a biotin-activatable, autophagy-independent pathway. In transgenic mice expressing this system in hepatocytes, biotin-induced elevations in plasma ACBP/DBI concentrations prevented anorexia induced by CRS or chemotherapeutic agents including cisplatin, doxorubicin, and paclitaxel. ACBP/DBI reversed the CRS or cisplatin-induced increase in plasma lipocalin-2 concentrations and the hypothalamic activation of anorexigenic melanocortin 4 receptors, for which lipocalin-2 is an agonist. Daily intravenous injections of recombinant ACBP/DBI protein or subcutaneous implantation of osmotic pumps releasing recombinant ACBP/DBI mimicked the orexigenic effects of the chemical-genetic system. In conclusion, the supplementation of extracellular and peripheral ACBP/DBI might constitute a viable strategy for treating anorexia.

SnoRNA U50A mediates everolimus resistance in breast cancer through mTOR downregulation.

Breast cancer remains the most prevalent cancer in women globally, posing significant challenges in treatment due to the inevitable development of resistance to targeted therapies like everolimus, an mTOR inhibitor. While several mechanisms of resistance have been proposed, the role of snoRNAs in this context remains inadequately explored. Our study unveils a novel connection between snoRNAs and everolimus resistance, focusing on the snoRNA U50A. We discovered that U50A negatively regulates mTOR signaling by transcriptionally downregulating mTOR gene expression, which consequently leads to decreased sensitivity to everolimus treatment. Through RNA sequencing, gene set enrichment analyses, and experimental validations, we established that U50A overexpression in breast cancer cells results in mTOR downregulation and subsequently, everolimus desensitization. Clinical results further supported our findings, showing a higher prevalence of everolimus resistance in tumors with elevated U50A expression. Moreover, our results suggest that U50A's effect on mTOR is mediated through the suppression of the transcription factors c-Myc, with a notable impact on cancer cell viability under everolimus treatment. This study not only highlights the complex role of snoRNAs in cancer drug resistance but also proposes U50A as a potential biomarker for predicting everolimus efficacy in breast cancer treatment.