Multisensory Logic of Infant-Directed Aggression by Males.

Newborn mice emit signals that promote parenting from mothers and fathers but trigger aggressive responses from virgin males. Although pup-directed attacks by males require vomeronasal function, the specific infant cues that elicit this behavior are unknown. We developed a behavioral paradigm based on reconstituted pup cues and showed that discrete infant morphological features combined with salivary chemosignals elicit robust male aggression. Seven vomeronasal receptors were identified based on infant-mediated activity, and the involvement of two receptors, Vmn2r65 and Vmn2r88, in infant-directed aggression was demonstrated by genetic deletion. Using the activation of these receptors as readouts for biochemical fractionation, we isolated two pheromonal compounds, the submandibular gland protein C and hemoglobins. Unexpectedly, none of the identified vomeronasal receptors and associated cues were specific to pups. Thus, infant-mediated aggression by virgin males relies on the recognition of pup's physical traits in addition to parental and infant chemical cues.

NeuroD1-GPX4 signaling leads to ferroptosis resistance in hepatocellular carcinoma.

Cell death resistance is a hallmark of tumor cells that drives tumorigenesis and drug resistance. Targeting cell death resistance-related genes to sensitize tumor cells and decrease their cell death threshold has attracted attention as a potential antitumor therapeutic strategy. However, the underlying mechanism is not fully understood. Recent studies have reported that NeuroD1, first discovered as a neurodifferentiation factor, is upregulated in various tumor cells and plays a crucial role in tumorigenesis. However, its involvement in tumor cell death resistance remains unknown. Here, we found that NeuroD1 was highly expressed in hepatocellular carcinoma (HCC) cells and was associated with tumor cell death resistance. We revealed that NeuroD1 enhanced HCC cell resistance to ferroptosis, a type of cell death caused by aberrant redox homeostasis that induces lipid peroxide accumulation, leading to increased HCC cell viability. NeuroD1 binds to the promoter of glutathione peroxidase 4 (GPX4), a key reductant that suppresses ferroptosis by reducing lipid peroxide, and activates its transcriptional activity, resulting in decreased lipid peroxide and ferroptosis. Subsequently, we showed that NeuroD1/GPX4-mediated ferroptosis resistance was crucial for HCC cell tumorigenic potential. These findings not only identify NeuroD1 as a regulator of tumor cell ferroptosis resistance but also reveal a novel molecular mechanism underlying the oncogenic function of NeuroD1. Furthermore, our findings suggest the potential of targeting NeuroD1 in antitumor therapy.

EphB2-dependent prefrontal cortex activation promotes long-range social approach and partner responsiveness.

Social behavior starts with dynamic approach prior to the final consummation. The flexible processes ensure mutual feedback across social brains to transmit signals. However, how the brain responds to the initial social stimuli precisely to elicit timed behaviors remains elusive. Here, by using real-time calcium recording, we identify the abnormalities of EphB2 mutant with autism-associated Q858X mutation in processing long-range approach and accurate activity of prefrontal cortex (dmPFC). The EphB2-dependent dmPFC activation precedes the behavioral onset and is actively associated with subsequent social action with the partner. Furthermore, we find that partner dmPFC activity is responsive coordinately to the approaching WT mouse rather than Q858X mutant mouse, and the social defects caused by the mutation are rescued by synchro-optogenetic activation in dmPFC of paired social partners. These results thus reveal that EphB2 sustains neuronal activation in the dmPFC that is essential for the proactive modulation of social approach to initial social interaction.

Mitochondrial DNA: cellular genotoxic stress sentinel.

High copy number, damage prone, and lean on repair mechanisms are unique features of mitochondrial DNA (mtDNA) that are hard to reconcile with its essentiality for oxidative phosphorylation, the primary function ascribed to this maternally inherited component of our genome. We propose that mtDNA is also a genotoxic stress sentinel, as well as a direct second messenger of this type of cellular stress. Here, we discuss existing evidence for this sentinel/effector role through the ability of mtDNA to escape the confines of the mitochondrial matrix and activate nuclear DNA damage/repair responses via interferon-stimulated gene products and other downstream effectors. However, this arrangement may come at a cost, leading to cancer chemoresistance and contributing to inflammation, disease pathology, and aging.

FormulationAI: a novel web-based platform for drug formulation design driven by artificial intelligence.

Today, pharmaceutical industry faces great pressure to employ more efficient and systematic ways in drug discovery and development process. However, conventional formulation studies still strongly rely on personal experiences by trial-and-error experiments, resulting in a labor-consuming, tedious and costly pipeline. Thus, it is highly required to develop intelligent and efficient methods for formulation development to keep pace with the progress of the pharmaceutical industry. Here, we developed a comprehensive web-based platform (FormulationAI) for in silico formulation design. First, the most comprehensive datasets of six widely used drug formulation systems in the pharmaceutical industry were collected over 10 years, including cyclodextrin formulation, solid dispersion, phospholipid complex, nanocrystals, self-emulsifying and liposome systems. Then, intelligent prediction and evaluation of 16 important properties from the six systems were investigated and implemented by systematic study and comparison of different AI algorithms and molecular representations. Finally, an efficient prediction platform was established and validated, which enables the formulation design just by inputting basic information of drugs and excipients. FormulationAI is the first freely available comprehensive web-based platform, which provides a powerful solution to assist the formulation design in pharmaceutical industry. It is available at https://formulationai.computpharm.org/.

Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial.

BACKGROUND: Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. METHODS: In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon's two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. RESULTS: Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6-51.9) and 90.3% (56/62, 95% CI, 80.1-96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8-not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7-94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. CONCLUSIONS: Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04401800).

FBXO22 Mediates the NGF/TRKA Signaling Pathway in Bone Metastases in Prostate Cancer.

Prostate cancer (PC) is a malignancy with high morbidity and mortality. Bone metastasis is the main driver of short survival time and difficulties in the treatment and prevention of PC. The goal of this study was to explore the biological function of E3 ubiquitin ligase F-box only protein 22 (FBXO22) in PC metastasis and its specific regulation mechanism. According to transcriptome sequencing, FBXO22 was overexpressed in PC tissues (versus adjacent tissues) and bone tissues (versus biopsied bone tissues without bone metastases). Fbxo22 down-regulation reduced bone metastases and macrophage M2 polarization in mice. FBXO22 was down-regulated in macrophages, and polarization was observed by flow cytometry. Macrophages were co-cultured with PC cells and osteoblasts to assess PC cell and osteoblast activity. FBXO22 knockdown restored osteoblast capacity. FBXO22 ubiquitinated and degraded Krüppel-like factor 4 (KLF4), which regulated the nerve growth factor (NGF)/tropomyosin receptor kinase A pathway by repressing NGF transcription. Silencing of KLF4 mitigated the metastasis-suppressing properties of FBXO22 knockdown, whereas NGF reversed the metastasis-suppressing properties of KLF4 in vitro and in vivo. Cumulatively, these data indicate that FBXO22 promotes PC cell activity and osteogenic lesions by stimulating macrophage M2 polarization. It also degrades KLF4 in macrophages and promotes NGF transcription, thereby activating the NGF/tropomyosin receptor kinase A pathway.

Hybrid integrated optical chaos circuits with optoelectronic feedback.

A chip-scale chaotic laser system with optoelectronic delayed feedback is proposed and analyzed by numerical simulation. This chip eliminates the need for bulky delay components such as long optical fibers, free propagation and external cavities, relying solely on internal devices and waveguides to achieve feedback delay. This approach simplifies integration, maintaining a compact chip size. According to the results, the chip-scale system exhibits rich dynamics, including periodicity, quasi-periodicity, and chaotic states. Chaos resembling Gaussian white noise is achieved with picosecond-level delay time, highlighting the complexity of chip-scale signals. Furthermore, time delay signature (TDS) concealment is enhanced with a short delay comparable to the inverse bandwidth τ, albeit at a cost of sacrificing chaotic signal complexity. Applying the photonic integrated circuits to practical applications, 1 Gbps back-to-back communication transmission is feasible. Results demonstrate low bit error rates (BERs) for authorizers (<10-6) and high BERs for eavesdroppers (>10-2), ensuring communication confidentiality and chaotic synchronization. Lastly, preliminary experiments validate the feasibility. Our theoretical work has demonstrated the feasibility of hybrid integrated optical chaos circuits with optoelectronic feedback based on photonic wire bonding, which can provide a stable and flexible integrated chaos source.

Investigation on the monolithically integrated chaotic optical transmitting chip based on parallel EAMs.

Chaotic optical communication ensures information security at the physical layer. However, the monolithic integration of lasers and lithium niobate Mach-Zehnder modulators remains a challenge, limiting the progress of integrated chaotic optical communication systems based on an electro-optic feedback. Here, we propose the monolithically integrated chaotic optical transmitting chip based on the parallel EAMs and validate its performance from the perspectives of phase portraits, fast Fourier transform (FFT), probability density function (PDF), largest Lyapunov exponents, and bifurcation. The results demonstrate the feasibility of the chip, which is beneficial for the miniaturization and integration of the system.

Abnormal Degraded Tapetum 1 (ADT1) is required for tapetal cell death and pollen development in rice.

The timely degradation of tapetum, the innermost somatic anther cell layer in flowering plants, is critical for pollen development. Although several genes involved in tapetum development have been characterized, the molecular mechanisms underlying tapetum degeneration remain elusive. Here, we showed that mutation in Abnormal Degraded Tapetum 1 (ADT1) resulted in overaccumulation of Reactive Oxygen Species (ROS) and abnormal anther development, causing earlier tapetum Programmed Cell Death (PCD) and pollen abortion. ADT1 encodes a nuclear membrane localized protein, which is strongly expressed in the developing microspores and tapetal cells during early anther development. Moreover, ADT1 could interact with metallothionein MT2b, which was related to ROS scavenging and cell death regulation. These findings indicate that ADT1 is required for proper timing of tapetum PCD by regulating ROS homeostasis, expanding our understanding of the regulatory network of male reproductive development in rice.

Machine learning-based coronary artery calcium score predicted from clinical variables as a prognostic indicator in patients referred for invasive coronary angiography.

OBJECTIVES: Utilising readily available clinical variables, we aimed to develop and validate a novel machine learning (ML) model to predict severe coronary calcification, and further assessed its prognostic significance. METHODS: This retrospective study enrolled patients who underwent coronary CT angiography and subsequent invasive coronary angiography. Multiple ML algorithms were used to train the models for predicting severe coronary calcification (cardiac CT-measured coronary artery calcium [CT-CAC] score ≥ 400). The ML-based CAC (ML-CAC) score derived from the ML predictive probability was stratified into quartiles for prognostic analysis. The primary endpoint was a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: Overall, 5785 patients were divided into training (80%) and test sets (20%). For clinical practicability, we selected the nine-feature support vector machine model with good and satisfactory performance regarding both discrimination and calibration based on five repetitions of the 10-fold cross-validation in the training set (mean AUC = 0.715, Brier score = 0.202), and based on the test in the test set (AUC = 0.753, Brier score = 0.191). In the test set cohort (n = 1137), the primary endpoint was observed in 50 (4.4%) patients during a median 2.8 years' follow-up. The ML-CAC system was significantly associated with an increased risk of the primary endpoint (adjusted hazard ratio for trend 2.26, 95% CI 1.35-3.79, p = 0.002). There was no significant difference in the prognostic value between the ML-CAC and CT-CAC systems (C-index, 0.67 vs. 0.69; p = 0.618). CONCLUSION: ML-CAC score predicted from clinical variables can serve as a novel prognostic indicator in patients referred for invasive coronary angiography. CLINICAL RELEVANCE STATEMENT: In patients referred for invasive coronary angiography who have not undergone preoperative CT-measured coronary artery calcium scoring, machine learning-based coronary artery calcium score assessment can serve as an alternative for predicting the prognosis. KEY POINTS: • The coronary artery calcium (CAC) score, a solid prognostic indicator, can be predicted using non-CT methods. • We developed a machine learning (ML)-CAC model utilising nine clinical variables to predict severe coronary calcification. • The ML-CAC system offers significant prognostic value in patients referred for invasive coronary angiography.

Functionalization of the Octahydro-Binaphthol Skeleton: A Universal Strategy for Directly Constructing D-A Type Axially Chiral Biphenyl Luminescent Molecules.

D-A type axially chiral biphenyl luminescent molecules are directly constructed through ingenious functionalization of the octahydro-binaphthol skeleton without optical resolution. The circularly polarized organic light-emitting diodes based on them display remarkable circularly polarized electroluminescence emission, a high luminance of >10 000 cd m-2, a maximum external quantum efficiency of 6.6%, and an extremely low-efficiency roll-off. This work provides a universal strategy for developing efficient and diverse axially chiral biphenyl emitters.

Advances in uremic toxin detection and monitoring in the management of chronic kidney disease progression to end-stage renal disease.

Patients with end-stage kidney disease (ESKD) rely on dialysis to remove toxins and stay alive. However, hemodialysis alone is insufficient to completely remove all/major uremic toxins, resulting in the accumulation of specific toxins over time. The complexity of uremic toxins and their varying clearance rates across different dialysis modalities poses significant challenges, and innovative approaches such as microfluidics, biomarker discovery, and point-of-care testing are being investigated. This review explores recent advances in the qualitative and quantitative analysis of uremic toxins and highlights the use of innovative methods, particularly label-mediated and label-free surface-enhanced Raman spectroscopy, primarily for qualitative detection. The ability to analyze uremic toxins can optimize hemodialysis settings for more efficient toxin removal. Integration of multiple omics disciplines will also help identify biomarkers and understand the pathogenesis of ESKD, provide deeper understanding of uremic toxin profiling, and offer insights for improving hemodialysis programs. This review also highlights the importance of early detection and improved understanding of chronic kidney disease to improve patient outcomes.

Global brain network modularity dynamics after local optic nerve damage following noninvasive brain stimulation: an EEG-tracking study.

Tightly connected clusters of nodes, called communities, interact in a time-dependent manner in brain functional connectivity networks (FCN) to support complex cognitive functions. However, little is known if and how different nodes synchronize their neural interactions to form functional communities ("modules") during visual processing and if and how this modularity changes postlesion (progression or recovery) following neuromodulation. Using the damaged optic nerve as a paradigm, we now studied brain FCN modularity dynamics to better understand module interactions and dynamic reconfigurations before and after neuromodulation with noninvasive repetitive transorbital alternating current stimulation (rtACS). We found that in both patients and controls, local intermodule interactions correlated with visual performance. However, patients' recovery of vision after treatment with rtACS was associated with improved interaction strength of pathways linked to the attention module, and it improved global modularity and increased the stability of FCN. Our results show that temporal coordination of multiple cortical modules and intermodule interaction are functionally relevant for visual processing. This modularity can be neuromodulated with tACS, which induces a more optimal balanced and stable multilayer modular structure for visual processing by enhancing the interaction of neural pathways with the attention network module.

Maternal cardiovascular health in early pregnancy and the risk of congenital heart defects in offspring.

BACKGROUND: Congenital heart disease (CHD) is the predominant birth defect. This study aimed to explore the association between maternal cardiovascular health (CVH) and the CHD risk in offspring. METHODS: We used the prospective data from the Fujian Birth Cohort Study, collected from March 2019 to December 2022 on pregnant women within 14 weeks of gestation. Overall maternal CVH was assessed by seven CVH metrics (including physical activity, smoking, sleep duration, body mass index, blood pressure, total cholesterol, and fasting plasma glucose), with each metric classified as ideal, intermediate or poor with specific points. Participants were further allocated into high, moderate and low CVH categories based on the cumulative CVH score. The association with offspring CHD was determined with log-binominal regression models. RESULTS: A total of 19810 participants aged 29.7 (SD: 3.9) years were included, with 7846 (39.6%) classified as having high CVH, 10949 (55.3%) as having moderate CVH, and 1015 (5.1%) as having low CVH. The average offspring CHD rate was 2.52%, with rates of 2.35%, 2.52% and 3.84% across the high, moderate and low CVH categories, respectively (P = 0.02). Adjusted relative risks (RRs) of having offspring CHD were 0.64 (95% CI: 0.45-0.90, P = 0.001) for high CVH and 0.67 (95% CI: 0.48-0.93, P = 0.02) for moderate CVH compared to low CVH. For individual metrics, only ideal total cholesterol was significantly associated with lower offspring CHD (RR: 0.73, 95% CI: 0.59-0.83, P = 0.002). CONCLUSIONS: Pregnant women of high or moderate CVH categories in early pregnancy had reduced risks of CHD in offspring, compared to those of low CVH. It is important to monitor and improve CVH during pre-pregnancy counseling and early prenatal care.

Measurement of the distance between tumor micro-foci and gross tumor in rectal cancer pathological specimens: implication on margin distance of clinical target volume treated with high-dose radiotherapy for rectal cancer.

PURPOSE: To measure the micro-foci distance away from gross tumor and to provide reference to create the clinical target volume (CTV) margin for boost radiotherapy in rectal adenocarcinoma. METHODS: Twenty-eight rectal cancer surgical specimens of only total mesorectal excision were collected. The pathological specimens were retrospectively measured, and the nearest distance between the tumor micro-foci and gross tumor was microscopically measured. The "in vivo-in vitro" retraction factor was calculated as the ratio of the deepest thickness laterally and the vertical height superior/inferiorly of the rectal tumor measured in MRI and those measured in immediate pathological specimens. The retraction factor during pathological specimen processing was calculated as the distance ratio before and after dehydration in the lateral, superior, and inferior sides by the "knot marking method." The distances of tumor micro-foci were individually corrected with these two retraction factors. RESULTS: The mean "in vivo-in vitro" tumor retraction factors were 0.913 peripherally and 0.920 superior/inferiorly. The mean tumor specimen processing retraction factors were 0.804 peripherally, 0.815 inferiorly, and 0.789 superiorly. Of 28 patients, 14 cases (50.0%) had 24 lateral micro-foci, 8 cases (28.6%) had 13 inferior micro-foci, and 7 cases (25.0%) had 19 superior micro-foci. The 95th percentiles of the micro-foci distance for 28 patients were 6.44 mm (peripheral), 5.54 mm (inferior), and 5.42 mm (superior) after retraction correction. CONCLUSION: The micro-foci distances of 95% of rectal adenocarcinoma patients examined were within 6.44 mm peripherally, 5.54 mm inferiorly, and 5.42 mm superiorly. These findings provide reference to set the boost radiotherapy CTV margin for rectal cancer.

Risk-stratified Approach for Never- and Ever-Smokers in Lung Cancer Screening: A Prospective Cohort Study in China.

Rationale: Over 40% of lung cancer cases occurred in never-smokers in China. However, high-risk never-smokers were precluded from benefiting from lung cancer screening as most screening guidelines did not consider them. Objectives: We sought to develop and validate prediction models for 3-year lung cancer risks for never- and ever-smokers, named the China National Cancer Center Lung Cancer models (China NCC-LCm2021 models). Methods: 425,626 never-smokers and 128,952 ever-smokers from the National Lung Cancer Screening program were used as the training cohort and analyzed using multivariable Cox models. Models were validated in two independent prospective cohorts: one included 369,650 never-smokers and 107,678 ever-smokers (841 and 421 lung cancers), and the other included 286,327 never-smokers and 78,469 ever-smokers (503 and 127 lung cancers). Measurements and Main Results: The areas under the receiver operating characteristic curves in the two validation cohorts were 0.698 and 0.673 for never-smokers and 0.728 and 0.752 for ever-smokers. Our models had higher areas under the receiver operating characteristic curves than other existing models and were well calibrated in the validation cohort. The China NCC-LCm2021 ⩾0.47% threshold was suggested for never-smokers and ⩾0.51% for ever-smokers. Moreover, we provided a range of threshold options with corresponding expected screening outcomes, screening targets, and screening efficiency. Conclusion: The construction of the China NCC-LCm2021 models can accurately reflect individual risk of lung cancer, regardless of smoking status. Our models can significantly increase the feasibility of conducting centralized lung cancer screening programs because we provide justified thresholds to define the high-risk population of lung cancer and threshold options to adapt different configurations of medical resources.

Pressure-induced high-temperature superconductivity retained without pressure in FeSe single crystals.

To raise the superconducting-transition temperature (Tc) has been the driving force for the long-sustained effort in superconductivity research. Recent progress in hydrides with Tcs up to 287 K under pressure of 267 GPa has heralded a new era of room temperature superconductivity (RTS) with immense technological promise. Indeed, RTS will lift the temperature barrier for the ubiquitous application of superconductivity. Unfortunately, formidable pressure is required to attain such high Tcs. The most effective relief to this impasse is to remove the pressure needed while retaining the pressure-induced Tc without pressure. Here, we show such a possibility in the pure and doped high-temperature superconductor (HTS) FeSe by retaining, at ambient pressure via pressure quenching (PQ), its Tc up to 37 K (quadrupling that of a pristine FeSe at ambient) and other pressure-induced phases. We have also observed that some phases remain stable without pressure at up to 300 K and for at least 7 d. The observations are in qualitative agreement with our ab initio simulations using the solid-state nudged elastic band (SSNEB) method. We strongly believe that the PQ technique developed here can be adapted to the RTS hydrides and other materials of value with minimal effort.

Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial).

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

The Analysis of Serum Klotho Protein Level and Related Gene Polymorphism in Osteoporotic Fracture of Elderly Patients with Osteoporosis.

Objective: Klotho protein level are reported to play important roles in the osteoporosis. To investigate the correlation between serum Klotho protein level and related gene (Klotho G395-A gene) polymorphism and osteoporotic fracture in elderly patients with osteoporosis. Methods: A total of 62 elderly patients with osteoporosis admitted to the Department of Orthopedics of our hospital from January 2021 to June 2022 were included in the study group. Another 62 elderly patients without osteoporosis who underwent a physical examination at the same time were selected as the control group. Patients in the study group were divided into group A (n = 23, osteoporotic fracture) and group B (n = 39, osteoporotic fracture) according to the occurrence of osteoporotic fracture. Serum Klotho protein level was detected in all patients, and its related gene (Klotho G395-A gene) polymorphism was analyzed. After fasting in the morning (fasting for more than 8 hours), 3-5 ml venous blood was collected and immediately placed in a centrifuge tube. Serum was separated and serum Klotho protein level was measured by enzyme-linked immunosorbent assay kit. Polymorphism typing was performed by Taqman allele-specific hybridization analysis. At the same time, general information (gender, age, body mass index, systolic blood pressure, diastolic blood pressure, glycated glucose protein, low-density lipoprotein cholesterol, bone mineral density) was collected. The differences in general data, serum Klotho protein level and Klotho G395-A gene polymorphism between the study group and the control group were analyzed. Spearman analysis was used to analyze the correlation between general data, serum Klotho protein level and Klotho G395-A gene and osteoporotic fracture. Logistic analysis was used to analyze the independent risk factors of osteoporotic fracture. Results: There was no significant difference of the sex, systolic blood pressure (SBP), diastolic blood pressure (DBP), Klotho G395-A genotype GG and alleles A and G between the study group and the control group. There was significant difference of body mass index (BMI), glycated glucose protein, low-density lipoprotein cholesterol (LDL-C), bone mineral density, serum Klotho protein level and Klotho G395-A genotype AA and AG were between the study group and the control group. Gender, age, glycated glucose protein and Klotho G395-A genotype AA were positively correlated with osteoporotic fracture (P < .05), while bone mineral density was negatively correlated with osteoporotic fracture (P < .05). There was no correlationship between the serum Klotho protein level and the incidence of osteoporotic fracture (P > .05). Logistic analysis showed that age, bone mineral density and Klotho G395-A genotype AA were independent risk factors for osteoporotic fracture. Conclusion: The level of serum Klotho protein and related gene polymorphisms are both related to osteoporotic fracture in elderly patients with osteoporosis. It is significant to reduce the incidence of osteoporotic fractures. In future, more experiments are needed to explore the underlying mechanism.