p53 deficiency mediates cisplatin resistance by upregulating RRM2 and crotonylation of RRM2K283 through the downregulation of SIRT7.

p53 deficiency plays a crucial role in chemotherapy resistance through various biological events, including posttranslational modifications (PTMs). Recently, lysine crotonylation (Kcr) has been shown to play a vital role in cancer progression. However, the global p53-regulated crotonylome and the function of these altered Kcr proteins after p53 deficiency remain unclear. In this study, we used a SILAC-based quantitative crotonylome to identify 3,520 Kcr in 1924 crotonylated proteins in response to p53 knockout. We found that increased crotonylation of RRM2 at K283 (RRM2K283Cr) in the presence of p53 deficiency promoted HCT116 cell resistance to cisplatin. We discovered that SIRT7 could be the decrotonylase of RRM2 and was downregulated after p53 knockout, resulting in increased RRM2K283Cr. Mechanistically, p53 deficiency inhibited cell apoptosis by upregulating RRM2 protein expression and RRM2K283Cr-mediated cleaved-PARP1 and cleaved-caspase3 expression, and SIRT7 was downregulated to upregulate crotonylation of RRM2 upon p53 deficiency. In conclusion, our results indicated that p53 deficiency plays a malignant role in colon cancer resistance to cisplatin therapy by regulating RRM2 protein and RRM2K283Cr expression. Our findings provide a novel therapeutic target against p53-deficient cancer.

Nutrient requirements determined by grain yield and protein content to optimize N, P, and K fertilizer management in China.

Nutrient requirement for crop growth, defined as the amount of nutrient that crops take up from soil to produce a specific grain yield, is a key parameter in determining fertilizer application rate. However, existing studies primarily focus on identifying nitrogen (N), phosphorus (P), and potassium (K) requirements solely in relation to grain yield, neglecting grain protein content, a crucial index for wheat grain quality. Addressing this gap, we conducted multi-site, multi-cultivar, and multi-year field trials across three ecological regions of China from 2016 to 2020 to elucidate variations in nutrient requirements for grain yield and grain protein. The research findings revealed that wheat grain yield ranged from 4.1 to 9.3 Mg ha-1 (average 6.9 Mg ha-1) and grain protein content ranged from 98 to 157 g kg-1 (average 127 g kg-1) across the three regions. Notably, the N requirement exhibited a nonlinear correlation with the wheat grain yield but a linear increase with increasing grain protein, while the P and K requirements positively correlated with grain yield and protein content. Regression models were formulated to determine the nutrient requirements (MENR), enabling the prediction of N, P, and K requirements for leading cultivars with varying grain yields and protein contents. Implementing nutrient requirements based on MENR projections resulted in substantial reductions in fertilizer rates: 22.0 kg ha-1 N (10.7 %), 9.9 kg ha-1 P (20.2 %), and 8.1 kg ha-1 K (16.3 %). This translated to potential savings of 0.4 Mt. N, 0.23 Mt. P, and 0.17 Mt. K, consequently mitigating 5.5 Mt. CO2 greenhouse-gas emission and yielding an economic benefit of 0.8 billion US$ annually in China. These findings underscore the significance of considering grain yield and protein content in estimating nutrient requirements for fertilizer recommendations to realize high-yielding, high-protein wheat production, and minimize overfertilization and associated environmental risks.

Recurrent, Severe Coital Headaches Associated With Bilateral Carotid Artery Aneurysms and the Effect of Endovascular Treatment.

Headaches are one of the most common chief complaints in the outpatient setting. Distinguishing between benign and life-threatening headaches can be difficult, particularly in the setting of a pre-existing history of headaches. Here, we present a 41-year-old female with a past medical history of migraines and uterine leiomyoma status post hysterectomy about nine months ago who presented to the clinic for severe coital headaches and worsening migraines starting eight months ago. Computer tomography angiogram (CTA) head and neck demonstrated bilateral para-ophthalmic internal carotid artery (ICA) aneurysms (right, 7.5, left 6 mm). A diagnostic cerebral angiogram (DSA) was subsequently done and confirmed the CTA findings. The patient underwent left and right flow-diverting stent placement two and four months later, respectively. One week after the right ICA stent placement, her headaches had improved to one to two times per week. At six months after the stent placement, she resumed her normal sex life and her migraines returned to baseline. Our case suggests that recurrent severe coital headaches are associated with bilateral carotid artery aneurysms. Thus, while assessing a patient with recurrent coital headaches, it is important to have a wide arsenal of differentials to rule out possibly catastrophic causes.

Hypercholesterolemia Is Associated With Dysregulation of Lipid Metabolism and Poor Prognosis in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Hypercholesterolemia is frequently diagnosed in patients with primary biliary cholangitis (PBC). However, its association with the prognosis and lipid metabolism is unknown. In this study, we aimed to investigate the prognostic value of baseline total cholesterol (TC) levels in PBC and characterized the associated lipid metabolism. METHODS: Five hundred and thirty-one patients with PBC without prior cirrhosis-related complications were randomly divided into the derivation and validation cohorts at a ratio of 7:3. Complete clinical data were obtained and analyzed. The endpoints were defined as liver-related death, liver transplantation, and cirrhosis-related complications. Lipidomics was performed in 89 patients and 28 healthy controls. RESULTS: Baseline TC was independently associated with poor liver-related outcomes, and adjusted C-statistics were 0.80 (95% confidence interval [CI]: 0.74-0.85) and 0.88 (95% CI: 0.78-0.91) in the derivation and validation cohorts, respectively. The predictive ability of TC for disease outcomes was stable over time and comparable with the Globe score. The 200 mg/dL cut-off optimally divided patients into low- and high-TC groups. A combination of TC and Globe score provided a more accurate stratification of patients into risk subgroups. Lipidomics indicated an up-regulation of lipid families in high-TC patients. Pathway analysis of 66 up-regulated lipids revealed the dysregulation of glycerophospholipid and sphingolipid metabolism in high-TC patients, which were associated with poor liver-related outcomes. CONCLUSIONS: Our results indicate that patients with PBC having baseline TC levels above 200 mg/dL have unique lipidome characteristics and are at a higher risk of poor liver-related outcomes.

Molecular mechanisms involved in the destabilization of two types of R3-R4 tau fibrils associated with chronic traumatic encephalopathy by Fisetin.

Chronic traumatic encephalopathy is a neurodegenerative tauopathy pathologically characterized by fibrillary tau aggregates in the depth of sulci. Clearing fibrous tau aggregates is considered a promising strategy in the treatment of CTE. Fisetin (FS), a natural polyphenolic small molecule, was confirmed to disassociate the tau filaments in vitro. However, the molecular mechanisms of FS in destabilizing the CTE-related R3-R4 tau fibrils remain largely unknown. In this study, we compared the atomic-level structural differences of the two types of CTE-related R3-R4 tau fibrils and explored the influence and molecular mechanisms of FS on the two types of fibrils by conducting multiple molecular dynamics (MD) simulations. The results reveal that the type 1 fibril displays higher structural stability than the type 2 fibril, with a lower root-mean-square-fluctuation value and higher ß-sheet structure probability. FS can destabilize both types of fibrils by decreasing the ß-sheet structure content, interrupting the mainchain H-bond network, and increasing the solvent accessible surface area and ß7-ß8 angle of the fibrils. H-bonding, π-π stacking and cation-π are the common interactions driving FS molecules binding on the two types of fibrils, while the hydrophobic interaction occurs only in the type 2 fibril. Due to the relatively short simulation time, our study captures the early molecular mechanisms. However, it does provide beneficial information for the design of drugs to prevent or treat CTE.

Atomic insights into the inhibition of R3 domain of tau protein by epigallocatechin gallate, quercetin and gallic acid.

Inhibiting tau protein aggregation has become a prospective avenue for the therapeutic development of tauopathies. The third microtubule-binding repeat (R3) domain of tau is confirmed as the most aggregation-favorable fragment of the whole protein. As dimerization is the first step of the aggregation of tau into amyloid fibrils, impeding the dimerization of the R3 domain is critical to prevent the full-length tau aggregation. Natural polyphenol small molecules epigallocatechin gallate (EGCG), quercetin (QE) and gallic acid (GA) are proven to inhibit the aggregation of the full-length recombinant tau (For EGCG and QE) or the R3 domain (For GA) of tau in vitro. However, the underlying molecular mechanisms of the inhibitive effects on the R3 domain of tau remain largely unknown. In this study, we conducted numerous all-atom molecular dynamics simulations on R3 dimers with and without EGCG, QE or GA, respectively. The results reveal that all three molecules can effectively decrease the ß structure composition of the R3 dimer, induce the dimer to adopt loosely-packed conformations, and weaken interchain interactions, thus impeding the dimerization of the R3 peptide chains. The specific preferentially binding sites for the three molecules exhibit similarities and differences. Hydrophobic, π-π stacking and hydrogen-bonding interactions collectively drive EGCG, QE and GA respectively binding on the R3 dimer, while QE also binds with the dimer through cation-π interaction. Given the incurable nature of tauopathies hitherto, our research provides helpful knowledge for the development of drugs to treat tauopathies.

Prognostic significance of liver stiffness in patients with primary biliary cholangitis: validation of Baveno VII criteria.

BACKGROUND: The role of liver stiffness measurements (LSM) in patients with primary biliary cholangitis (PBC) remains to be further elucidated. AIMS: To clarify the prognostic role of LSM and to validate the "novel concepts" proposed by the Baveno VII Working Group. METHODS: An analysis of the prognostic significance of LSM was performed involving 672 patients. RESULTS: LSM and ΔLSM/ΔT were independent risk factors for liver decompensation, liver transplantation, or liver-related death (primary outcomes, p < 0.001, both). A rule of 5 kPa for LSM (10-15-20 kPa) could be used to denote progressively higher relative risks of primary outcomes. Patients with LSM < 10 kPa have a negligible 3-year risk of primary outcomes (< 1%). Cut-off values of 10 and 15 kPa can be used to classify PBC patients into low-, medium-, and high-risk groups. A clinically significant decrease in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially reduced risk of primary outcomes (p < 0.05, all), which can be defined as a decrease in LSM of > - 20% associated with LSM < 20 kPa or any decrease to LSM < 10 kPa. A clinically significant increase in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially raised risk of primary outcomes (p < 0.05, all), which can be defined as an increase in LSM of ≥ + 20% or any increase to LSM ≥ 15 kPa. CONCLUSIONS: LSM can be used to monitor disease progression and predict long-term prognosis in patients with PBC.

A dual-mode green emissive fluorescent probe for real-time detection of doxycycline in milk using a smartphone sensing platform.

Real-time quantitative analysis of tetracyclines is urgently needed to provide consumers with early warning of potential risks. Herein, we report a dual-mode green emissive fluorescent probe, which refers to the liquid mode and the solid mode of electrospun films doped with nitride-doped carbon nanosheets (NCNSs) for real-time detection of doxycycline (DOX). Highly fluorescent NCNSs were prepared by low-temperature solid treatment of urea and sodium citrate. With the addition of DOX, the green emission intensity of NCNSs at 475 nm can be obviously reduced. Method validation exhibited a good linear relationship in 0.05-150 µM between the fluorescence quenching of NCNSs and the concentration of DOX with a limit of detection (LOD) of 0.0127 µM. Furthermore, the immobilization of NCNSs in PAN carriers forming electrospun films stabilizes the green fluorescence of NCNSs. Additionally, electrospun films integrated into a smartphone were developed for real-time detection of DOX with LOD of 0.285 µM. Additionally, DOX in milk was monitored with satisfactory recoveries. Therefore, the integration of the smartphone and electrospun film provides a promising and convenient method for real-time identification of DOX in food analysis.

Fenofibrate normalizes alkaline phosphatase and improves long-term outcomes in patients with advanced primary biliary cholangitis refractory to ursodeoxycholic acid / El fenofibrato normaliza la fosfatasa alcalina y mejora los resultados a largo plazo en pacientes con colangitis biliar primaria avanzada refractaria al ácido ursodesoxicólico

Background: Although patients with advanced liver disease have been included in studies evaluating fibrates for the treatment of primary biliary cholangitis (PBC), the frequency of biochemical responses and adverse effects for this group of patients was not reported separately and comprehensively. Aims: to evaluate the efficacy and safety of additional fenofibrate therapy in patients with advanced and ursodeoxycholic acid (UDCA)-refractory PBC. Methods: Patients were analyzed retrospectively to determine the clinical therapeutic effects of UDCA with additional fenofibrate therapy versus continued UDCA monotherapy. The liver transplantation (LT)-free survival and the alkaline phosphatase (ALP) normalization rates were estimated using Cox regression analyses and Kaplan–Meier plots with inverse probability of treatment weighting (IPTW). Results: A total of 118 patients were included: 54 received UDCA alone and 64 received UDCA in combination with fenofibrate therapy. In the fenofibrate and UDCA groups, 37% and 11% of patients with advanced and UDCA-refractory PBC, respectively, achieved ALP normalization (P=0.001). Additional fenofibrate therapy improved both LT-free survival and ALP normalization rate after IPTW (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.07–0.75, P=0.015; and HR: 11.66, 95% CI: 5.02–27.06, P=0.001, respectively). These effects were supported by parallel changes in the rates of liver decompensation and histologic progression, and the United Kingdom (UK)-PBC and Globe risk scores. (AU)

Antecedentes: Aunque los pacientes con enfermedad hepática avanzada se han incluido en los estudios que evalúan los fibratos para el tratamiento de la colangitis biliar primaria, la frecuencia de las respuestas bioquímicas y los efectos adversos para este grupo de pacientes no se informó por separado y de forma exhaustiva. Objetivos: Evaluar la eficacia y la seguridad del tratamiento adicional con fenofibrato en pacientes con colangitis biliar primaria avanzada y refractaria al ácido ursodesoxicólico. Métodos: Se analizaron los pacientes de forma retrospectiva para determinar los efectos terapéuticos clínicos del ácido ursodesoxicólico con terapia adicional de fenofibrato frente a la monoterapia continuada con ácido ursodesoxicólico. La supervivencia sin trasplante de hígado y las tasas de normalización de la fosfatasa alcalina se estimaron mediante análisis de regresión de Cox y gráficos de Kaplan-Meier con ponderación de la probabilidad inversa del tratamiento. Resultados: Se incluyeron un total de 118 pacientes: 54 recibieron ácido ursodesoxicólico solo y 64 recibieron ácido ursodesoxicólico en combinación con el tratamiento con fenofibrato. En los grupos de fenofibrato y ácido ursodesoxicólico, 37 y 11% de los pacientes con colangitis biliar primaria avanzada y refractaria al ácido ursodesoxicólico, respectivamente, lograron la normalización de la fosfatasa alcalina (p=0,001). El tratamiento adicional con fenofibrato mejoró tanto la supervivencia libre de trasplante de hígado como la tasa de normalización de la fosfatasa alcalina tras la ponderación de la probabilidad inversa del tratamiento (cociente de riesgos: 0,23, intervalo de confianza del 95% [IC 95%]: 0,07-0,75, p=0,015; y cociente de riesgos: 11,66, IC 95%: 5,02–27,06, p=0,001, respectivamente). (AU)

Unsupervised adaptive coded illumination Fourier ptychographic microscopy based on a physical neural network.

Fourier Ptychographic Microscopy (FPM) is a computational technique that achieves a large space-bandwidth product imaging. It addresses the challenge of balancing a large field of view and high resolution by fusing information from multiple images taken with varying illumination angles. Nevertheless, conventional FPM framework always suffers from long acquisition time and a heavy computational burden. In this paper, we propose a novel physical neural network that generates an adaptive illumination mode by incorporating temporally-encoded illumination modes as a distinct layer, aiming to improve the acquisition and calculation efficiency. Both simulations and experiments have been conducted to validate the feasibility and effectiveness of the proposed method. It is worth mentioning that, unlike previous works that obtain the intensity of a multiplexed illumination by post-combination of each sequentially illuminated and obtained low-resolution images, our experimental data is captured directly by turning on multiple LEDs with a coded illumination pattern. Our method has exhibited state-of-the-art performance in terms of both detail fidelity and imaging velocity when assessed through a multitude of evaluative aspects.

Measuring the Residual Levels of Fenpyroximate and Its Z-Isomer in Citrus Using Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry and Assessing the Related Dietary Intake Risks.

Fenpyroximate is an efficient, broad-spectrum phenoxypyrazole acaricide which is used for controlling various mites. In this study, we measured the levels of terminal fenpyroximate residues in citrus fruits, and estimated the dietary intake risks posed by fenpyroximate. To this end, a QuEChERS analytical method was used in combination with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to determine the residual levels of fenpyroximate and its Z-isomer (Z-fenpyroximate) in citrus fruits collected from 12 fields under good agricultural practices (GAPs). The average recoveries of fenpyroximate in whole fruits and citrus flesh were 104-110% and 92-109%, respectively, with corresponding RSDs of 1-4% and 1-3%. The average recoveries of Z-fenpyroximate were 104-113% and 90-91%, respectively, with RSDs of 1-2% in both cases. Each limit of quantification (LOQ) was 0.01 mg kg-1. Fifteen days after application with 56 mg kg-1, the terminal residues of fenpyroximate in whole fruits and citrus flesh were <0.010-0.18 mg kg-1 and <0.010-0.063 mg kg-1, respectively; the corresponding values for total fenpyroximate (the sum of fenpyroximate and Z-fenpyroximate) were <0.020-0.19 and <0.020-0.053 mg kg-1. The levels of terminal fenpyroximate residues in citrus fruit were less than the maximum residue limits (MRLs) specified in all the existing international standards. In addition, the risk quotients RQc and RQa were both less than 100%, indicating that the long-term and short-term dietary intake risks posed to Chinese consumers by fenpyroximate in citrus fruit are both acceptable after a 15-day harvest interval.

Destabilization mechanism of R3-R4 tau protofilament by purpurin: a molecular dynamics study.

The accumulation of tau protein aggregates is a common feature observed in many neurodegenerative diseases. However, the structural characteristics of tau aggregates can vary among different tauopathies. It has been established that the structure of the tau protofilament in Chronic traumatic encephalopathy (CTE) is similar to that of Alzheimer's disease (AD). In addition, a previous study found that purpurin, an anthraquinone, could inhibit and disassemble the pre-formed 306VQIVYK311 isoform of AD-tau protofilament. Herein, we used all-atom molecular dynamic (MD) simulation to investigate the distinctive features between CTE-tau and AD-tau protofilament and the influence of purpurin on CTE-tau protofilament. Our findings revealed notable differences at the atomic level between CTE-tau and AD-tau protofilaments, particularly in the ß6-ß7 angle and the solvent-accessible surface area (SASA) of the ß4-ß6 region. These structural disparities contributed to the distinct characteristics observed in the two types of tau protofilaments. Our simulations substantiated that purpurin could destabilize the CTE-tau protofilament and decrease ß-sheet content. Purpurin molecules could insert the ß4-ß6 region and weaken the hydrophobic packing between ß1 and ß8 through π-π stacking. Interestingly, each of the three rings in purpurin exhibited unique binding preferences with the CTE-tau protofilament. Overall, our study sheds light on the structural distinctions between CTE-tau and AD-tau protofilaments, as well as the destabilizing mechanism of purpurin on CTE-tau protofilament, which may be helpful to the development of drugs to prevent CTE.

Reversible cerebral vasoconstriction syndrome after levonorgestrel-releasing intrauterine device placement-Case report.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is a disease characterized by reversible multifocal narrowing of the cerebral arteries with clinical manifestations that typically include thunderclap headache and occasionally brain edema, stroke, or seizure. The exact pathophysiology of RCVS is not well known. CASE: A 46-year-old female with history of episodic migraine presented with 1-month duration of worsening headaches that had become more severe over the past 2 weeks. The headaches were episodic and thunderclap in onset and aggravated by physical exertion or emotional situations. A neurological examination was unremarkable including initial head computed tomography (CT). A CT angiogram of the head showed multifocal stenosis in the right anterior cerebral artery, bilateral middle cerebral arteries, and right posterior cerebral artery. Cerebral angiogram confirmed the CT angiogram findings. A repeated CT angiogram a few days later showed improvement in the multifocal cerebral arterial stenosis. Lumbar puncture and autoimmune workup were not suggestive of neuroinflammatory etiology. She had one generalized tonic-clonic seizure during her second day of hospitalization. The patient's thunderclap onset headaches resolved in 1 week after she was managed with blood pressure control and pain medication. She denied any illicit drug use or any new medications other than the placement of a levonorgestrel-releasing intrauterine device (IUD) about 6 weeks prior to her presentation. CONCLUSIONS: Our case suggests a possible link between RCVS and levonorgestrel-releasing IUDs.

Inhibitive and Destructive Mechanisms of Chronic Traumatic Encephalopathy-Related R3-R4 Tau Peptide Chains and Protofibril by Epigallocatechin Gallate: Evidence from Molecular Dynamics Simulation.

Chronic traumatic encephalopathy (CTE), a unique tauopathy, is pathologically associated with the aggregation of hyperphosphorylated tau protein into fibrillar aggregates. Inhibiting tau aggregation and disaggregating tau protofibril might be promising strategies to prevent or delay the development of CTE. Newly resolved tau fibril structures from deceased CTE patients' brains show that the R3-R4 fragment of tau forms the core of the fibrils and the structures are distinct from other tauopathies. An in vitro experiment finds that epigallocatechin gallate (EGCG) can effectively inhibit human full-length tau aggregation and disaggregate preformed fibrils. However, its inhibitive and destructive effects on the CTE-related R3-R4 tau and the underlying molecular mechanisms remain elusive. In this study, we performed extensive all-atom molecular dynamics simulations on the CTE-related R3-R4 tau dimer/protofibril with and without EGCG. The results reveal that EGCG could reduce the ß-sheet structure content of the dimer, induce the dimer to form loosely packed conformations, and impede the interchain interactions, thus inhibiting the further aggregation of the two peptide chains. Besides, EGCG could reduce the structural stability, decrease the ß-sheet structure content, reduce the structural compactness, and weaken local residue-residue contacts of the protofibril, hence making the protofibril disaggregated. We also identified the dominant binding sites and pivotal interactions. EGCG preferentially binds with hydrophobic, aromatic, and positively/negatively charged residues of the dimer, while it tends to bind with polar, hydrophobic, aromatic, and positively charged residues of the protofibril. Hydrophobic, hydrogen-bonding, π-π stacking, and cation-π interactions synergistically drive the binding of EGCG on both the dimer and the protofibril, but anion-π interaction only exists in the interaction of EGCG with the dimer. Our work unravels EGCG's inhibitive and destructive effects on the CTE-related R3-R4 tau dimer/protofibril and the underlying molecular mechanisms, which provides useful implications for the design of drugs to prevent or delay the progression of CTE.

NSRGRN: a network structure refinement method for gene regulatory network inference.

The elucidation of gene regulatory networks (GRNs) is one of the central challenges of systems biology, which is crucial for understanding pathogenesis and curing diseases. Various computational methods have been developed for GRN inference, but identifying redundant regulation remains a fundamental problem. Although considering topological properties and edge importance measures simultaneously can identify and reduce redundant regulations, how to address their respective weaknesses whilst leveraging their strengths is a critical problem faced by researchers. Here, we propose a network structure refinement method for GRN (NSRGRN) that effectively combines the topological properties and edge importance measures during GRN inference. NSRGRN has two major parts. The first part constructs a preliminary ranking list of gene regulations to avoid starting the GRN inference from a directed complete graph. The second part develops a novel network structure refinement (NSR) algorithm to refine the network structure from local and global topology perspectives. Specifically, the Conditional Mutual Information with Directionality and network motifs are applied to optimise the local topology, and the lower and upper networks are used to balance the bilateral relationship between the local topology's optimisation and the global topology's maintenance. NSRGRN is compared with six state-of-the-art methods on three datasets (26 networks in total), and it shows the best all-round performance. Furthermore, when acting as a post-processing step, the NSR algorithm can improve the results of other methods in most datasets.

Effectiveness of Fenofibrate in Treatment-Naive Patients With Primary Biliary Cholangitis: A Randomized Clinical Trial.

INTRODUCTION: Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease, and patients with inadequate response to ursodeoxycholic acid (UDCA) treatment show reduced long-term survival. Recent studies have shown that fenofibrate is an effective off-label therapy for PBC. However, prospective studies on biochemical response including the timing of fenofibrate administration are lacking. This study is aimed to evaluate the efficacy and safety of fenofibrate in UDCA treatment-naive patients with PBC. METHODS: A total of 117 treatment-naive patients with PBC were recruited from the Xijing Hospital for a 12-month randomized, parallel, and open-label clinical trial. Study participants were assigned to receive either UDCA standard dose (UDCA-only group) or fenofibrate at a daily dose of 200 mg in addition to UDCA (UDCA-Fenofibrate group). RESULTS: The primary outcome was biochemical response percentage in patients according to the Barcelona criterion at 12 months. In the UDCA-Fenofibrate group, 81.4% (69.9%-92.9%) of patients achieved the primary outcome and 64.3% (51.9%-76.8%) in the UDCA-only group achieved the primary outcome ( P = 0.048). There was no difference between the 2 groups in noninvasive measures of liver fibrosis and biochemical markers other than alkaline phosphatase at 12 months. Creatinine and transaminases levels in the UDCA-Fenofibrate group increased within the first month, then returned to normal, and remained stable thereafter until the end of the study, even in patients with cirrhosis. DISCUSSION: In this randomized clinical trial in treatment-naive patients with PBC, the combination of fenofibrate and UDCA resulted in a significantly higher biochemical response rate. Fenofibrate seemed to be well-tolerated in patients.

Fenofibrate normalizes alkaline phosphatase and improves long-term outcomes in patients with advanced primary biliary cholangitis refractory to ursodeoxycholic acid.

BACKGROUND: Although patients with advanced liver disease have been included in studies evaluating fibrates for the treatment of primary biliary cholangitis (PBC), the frequency of biochemical responses and adverse effects for this group of patients was not reported separately and comprehensively. AIMS: to evaluate the efficacy and safety of additional fenofibrate therapy in patients with advanced and ursodeoxycholic acid (UDCA)-refractory PBC. METHODS: Patients were analyzed retrospectively to determine the clinical therapeutic effects of UDCA with additional fenofibrate therapy versus continued UDCA monotherapy. The liver transplantation (LT)-free survival and the alkaline phosphatase (ALP) normalization rates were estimated using Cox regression analyses and Kaplan-Meier plots with inverse probability of treatment weighting (IPTW). RESULTS: A total of 118 patients were included: 54 received UDCA alone and 64 received UDCA in combination with fenofibrate therapy. In the fenofibrate and UDCA groups, 37% and 11% of patients with advanced and UDCA-refractory PBC, respectively, achieved ALP normalization (P=0.001). Additional fenofibrate therapy improved both LT-free survival and ALP normalization rate after IPTW (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.07-0.75, P=0.015; and HR: 11.66, 95% CI: 5.02-27.06, P=0.001, respectively). These effects were supported by parallel changes in the rates of liver decompensation and histologic progression, and the United Kingdom (UK)-PBC and Globe risk scores. During the follow-up period, serum levels of ALP and aminotransferase decreased significantly, while total bilirubin, albumin, platelet, serum creatinine, and estimated glomerular filtration rate remained stable in fenofibrate-treated participants. No fenofibrate-related significant adverse events were observed in our cohort. CONCLUSIONS: Additional fenofibrate therapy significantly improved LT-free survival and ALP normalization in patients with advanced and UDCA-refractory PBC. Furthermore, adding-on fenofibrate therapy appeared to be safe and well tolerated in this population.

Detection of novel variant and functional study in a Chinese family with nonsyndromic oligodontia.

OBJECTIVES: To investigate the pathogenic gene of a patient with nonsyndromic oligodontia, and analyze its possible pathogenic mechanism. SUBJECTS AND METHODS: The variant was detected by whole exome sequencing (WES) and Sanger sequencing in a family with oligodontia. Bioinformatic and structural analyses were used to analyze variant. Functional studies including western blotting and immunofluorescent analyses and luciferase reporter assay were conducted to explore the functional effects. RESULTS: We identified a novel frameshift variant of PAX9 (c.491-510delGCCCT-ATCACGGCGGCGGCC, p.P165Qfs*145) outside the DNA-binding domain causing an autosomal-dominant nonsyndromic oligodontia in a Chinese family. Bioinformatic and structural analyses revealed that the variant is pathogenic and conserved evolutionarily, and the changes might affect protein stability or folding. Functional studies demonstrate dramatically reduced ability in activating transcription activity of BMP4 promoter and a marked decrease in protein production, as evaluated by western blotting and immunofluorescent analyses. CONCLUSIONS: We found a novel frameshift variant of PAX9 causing nonsyndromic oligodontia in a Chinese family. Our findings indicate that frameshift variants cause loss of function of PAX9 protein during the patterning of the dentition and the subsequent tooth agenesis, providing new molecular insights into the role of frameshift variant of PAX9 and broaden the pathogenic spectrum of PAX9 variants.

Prediction and evaluation of high-risk patients with primary biliary cholangitis receiving ursodeoxycholic acid therapy: an early criterion.

BACKGROUND AND AIMS: Current treatment guidelines recommend ursodeoxycholic acid (UDCA) as the first-line treatment for new-diagnosed primary biliary cholangitis (PBC) patients. However, up to 40% patients are insensitive to UDCA monotherapy, and evaluation of UDCA response at 12 months may result in long period of ineffective treatment. We aimed to develop a new criterion to reliably identify non-response patients much earlier. METHODS: Five hundred sixty-nine patients with an average of 59 months (Median: 53; IQR:32-79) follow-up periods were randomly divided into either the training (70%) or the validation cohort (30%). The efficiency of different combinations of total bilirubin (TBIL), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) threshold values to predict outcomes was assessed at 1, 3 or 6 month after the initiation of UDCA therapy. The endpoints were defined as adverse outcomes, including liver-related death, liver transplantation and complications of cirrhosis. Adverse outcome-free survival was compared using various published criteria and a proposed new criterion. RESULTS: A new criterion of evaluating UDCA responses at 1 month was established as: ALP ≤ 2.5 × upper limit of normal (ULN) and AST ≤ 2 × ULN, and TBIL ≤ 1 × ULN (Xi'an criterion). The 5 year adverse outcome-free survival rate of UDCA responders, defined by Xi'an criterion, was 97%, which was significantly higher than that of those non-responders (64%). An accurate distinguishing high-risk patients' capacity of Xi'an criterion was confirmed in both early and late-stage PBC. CONCLUSIONS: Xi'an criterion has a similar or even higher ability to distinguish high-risk PBC patients than other published criteria. Xi'an criterion can facilitate early identification of patients requiring new therapeutic approaches.

Efficacy and safety of fenofibrate addition therapy in patients with cirrhotic primary biliary cholangitis with incomplete response to ursodeoxycholic acid.

Fenofibrate (FF) has shown potential benefits in patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid (UDCA). However, the efficacy and safety of FF in patients with cirrhosis remain unclear. To evaluate the efficacy and safety of additional FF therapy in patients with PBC-related cirrhosis with an incomplete response to UDCA, we conducted a retrospective analysis comparing the clinical results of additional FF therapy and continued UDCA monotherapy. A total of 59 patients were included; 27 cases underwent UDCA monotherapy and 32 cases underwent UDCA combined with FF therapy. A significant difference in alkaline phosphatase (ALP) normalization was achieved in the FF group compared to the UDCA group (37% vs. 11%, respectively; p = 0.020). Additional FF therapy was an independent risk factor for ALP normalization (hazard ratio, 7.679; 95% confidence interval, 2.059-28.633; p = 0.003). Hepatic deterioration was experienced by 40% versus 48% (p = 0.562) while 11% vs. 37% (p = 0.111) experienced liver-related mortality or liver transplantation in the FF and UDCA groups, respectively. Compared to UDCA monotherapy, additional FF therapy was associated with lower United Kingdom (UK)-PBC risk score and surrogate serum indices of liver fibrosis. After 12 months of add-on FF therapy, median ALP level and UK-PBC risk score decreased 35% and 52% from baseline (p = 0.001 and 0.210, respectively). Serum aminotransferase, triglyceride, and cholesterol decreased progressively, while total bilirubin, serum creatinine, blood urea, estimated glomerular filtration rate, aspartate aminotransferase-to-platelet ratio index, and fibrosis-4 index remained stable in FF-treated cirrhotic cases during follow-up. No significant adverse effects associated with additional FF therapy were observed in our cohort. Conclusion: Additional FF therapy was associated with higher ALP normalization rates and lower UK-PBC risk scores in patients with cirrhotic PBC with an incomplete response to UDCA. In addition, FF therapy seemed safe and well tolerated with a low frequency of adverse effects in patients with cirrhosis.