Photodynamic-Assisted Electrochemiluminescence Enhancement toward Advanced BODIPY for Precision Diagnosis of Parkinson.

Nowadays, signal enhancement is imperative to increase sensitivity of advanced ECL devices for expediting their promising applications in clinic. In this work, photodynamic-assisted electrochemiluminescence (PDECL) device was constructed for precision diagnosis of Parkinson, where an advanced emitter was prepared by electrostatically linking 2,6-dimethyl-8-(3-carboxyphenyl)4,4'-difluoroboradiazene (BET) with 1-butyl-3-methylimidazole tetrafluoroborate ([BMIm][BF4]). Specifically, protoporphyrin IX (PPIX) can trigger the photodynamic reaction under light irradiation with a wavelength of 450 nm to generate lots of singlet oxygen (1O2), showing a 2.43-fold magnification in the ECL responses. Then, the aptamer (Apt) was assembled on the functional BET-[BMIm] for constructing a "signal off" ECL biosensor. Later on, the PPIX was embedded into the G-quadruplex (G4) of the Apt to magnify the ECL signals for bioanalysis of α-synuclein (α-syn) under light excitation. In the optimized surroundings, the resulting PDECL sensor has a broad linear range of 100.0 aM ∼ 10.0 fM and a low limit of detection (LOD) of 63 aM, coupled by differentiating Parkinson patients from normal individuals according to the receiver operating characteristic (ROC) curve analysis of actual blood samples. Such research holds great promise for synthesis of other advanced luminophores, combined with achieving an early clinical diagnosis.

Paclitaxel liposome (Lipusu) based chemotherapy combined with immunotherapy for advanced non-small cell lung cancer: a multicenter, retrospective real-world study.

BACKGROUND: Paclitaxel liposome (Lipusu) is known to be effective in non-small cell lung cancer (NSCLC) as first-line treatment. This study aimed to evaluate the effectiveness and safety of paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor in patients with advanced NSCLC. METHODS: In this multicenter, retrospective, real-world study, patients with advanced NSCLC who were administered paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor in three centers (Peking University People's Hospital as the lead center) in China between 2016 and 2022 were included. Progression-free survival (PFS), overall survival (OS), objective response rate, disease control rate, and adverse events (AEs) were evaluated. RESULTS: A total of 49 patients were included, with 33 (67.3%) receiving paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor as first-line treatment. There were 34 patients (69.4%) diagnosed with squamous cell carcinoma and 15 (30.6%) with adenocarcinoma. The median follow-up was 20.5 (range: 3.1-41.1) months. The median PFS and OS of all patients were 9.7 months (95% confidence interval [CI], 7.0-12.4) and 30.5 months (95% CI, not evaluable-not evaluable), respectively. Patients with squamous cell carcinoma and adenocarcinoma had median PFS of 11 months (95%CI, 6.5-15.5) and 9.3 months (95%CI, 7.0-12.4), respectively. The median PFS was 9.9 months (95%CI, 7.1-12.7) in patients who received the combined regimen as first-line treatment. Treatment-related AEs of any grade were observed in 25 (51.0%) patients, and AEs of grade 3 or worse were observed in nine patients (18.4%). The most common treatment-related AEs were myelosuppression (14.3%) and fever (10.2%). CONCLUSIONS: Paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor prolonged the PFS in advanced NSCLC with acceptable safety, which was worthy of clinical application.

Prognostic value of GLIM-defined malnutrition in combination with hand-grip strength or gait speed for the prediction of postoperative outcomes in gastric cancer patients with cachexia.

BACKGROUND: Cancer cachexia is associated with impaired functional and nutritional status and worse clinical outcomes. Global Leadership Initiative in Malnutrition (GLIM) consensus recommended the application of GLIM criteria to diagnose malnutrition in patients with cachexia. However, few previous study has applied the GLIM criteria in patients with cancer cachexia. METHODS: From July 2014 to May 2019, patients who were diagnosed with cancer cachexia and underwent radical gastrectomy for gastric cancer were included in this study. Malnutrition was diagnosed using the GLIM criteria. Skeletal muscle index was measured using abdominal computed tomography (CT) images at the third lumbar vertebra (L3) level. Hand-grip strength and 6-meters gait speed were measured before surgery. RESULTS: A total of 356 patients with cancer cachexia were included in the present study, in which 269 (75.56%) were identified as having malnutrition based on the GLIM criteria. GLIM-defined malnutrition alone did not show significant association with short-term postoperative outcomes, including complications, costs or length of postoperative hospital stays. The combination of low hand-grip strength or low gait speed with GLIM-defined malnutrition led to a significant predictive value for these outcomes. Moreover, low hand-grip strength plus GLIM-defined malnutrition was independently associated with postoperative complications (OR 1.912, 95% CI 1.151-3.178, P = 0.012). GLIM-defined malnutrition was an independent predictive factor for worse OS (HR 2.310, 95% CI 1.421-3.754, P = 0.001) and DFS (HR 1.815, 95% CI 1.186-2.779, P = 0.006) after surgery. The addition of low hand-grip strength or low gait speed to GLIM-defined malnutrition did not increase its predictive value for survival. CONCLUSION: GLIM-defined malnutrition predicted worse long-term survival in gastric cancer patients with cachexia. Gait speed and hand-grip strength added prognostic value to GLIM-defined malnutrition for the prediction of short-term postoperative outcomes, which could be incorporated into preoperative assessment protocols in patients with cancer cachexia.

Pan-cancer analysis of NUP155 and validation of its role in breast cancer cell proliferation, migration, and apoptosis.

NUP155 is reported to be correlated with tumor development. However, the role of NUP155 in tumor physiology and the tumor immune microenvironment (TIME) has not been previously examined. This study comprehensively investigated the expression, immunological function, and prognostic significance of NUP155 in different cancer types. Bioinformatics analysis revealed that NUP155 was upregulated in 26 types of cancer. Additionally, NUP155 upregulation was strongly correlated with advanced pathological or clinical stages and poor prognosis in several cancers. Furthermore, NUP155 was significantly and positively correlated with DNA methylation, tumor mutational burden, microsatellite instability, and stemness score in most cancers. Additionally, NUP155 was also found to be involved in TIME and closely associated with tumor infiltrating immune cells and immunoregulation-related genes. Functional enrichment analysis revealed a strong correlation between NUP155 and immunomodulatory pathways, especially antigen processing and presentation. The role of NUP155 in breast cancer has not been examined. This study, for the first time, demonstrated that NUP155 was upregulated in breast invasive carcinoma (BRCA) cells and revealed its oncogenic role in BRCA using molecular biology experiments. Thus, our study highlights the potential value of NUP155 as a biomarker in the assessment of prognostic prediction, tumor microenvironment and immunotherapeutic response in pan-cancer.

N6-methyladenosine-induced miR-182-5p promotes multiple myeloma tumorigenesis by regulating CAMK2N1.

Methyltransferase like 3 (METTL3) has been reported to promote tumorigenesis of multiple myeloma (MM), however, the molecular mechanism still needs further research. The N6-methyladenosine (m6A) level in tissues or cells was measured by m6A kit and dot blot assay. The mRNA and protein expression were detected by quantitative real-time PCR (RT-qPCR) and Western blot, respectively. The cell counting kit-8 and colony formation assay were used to detect the cell proliferation. Coimmunoprecipitation (Co-IP) experiment verified the binding of two proteins. The luciferase reporter experiment demonstrated the targeted binding of miR-182-5p and CaMKII inhibitor 1 (CAMK2N1). More importantly, tumor growth was measured in xenograft mice. Our data showed that the expression of METTL3 was significantly increased in MM patients' samples and MM cells. METTL3 overexpression promoted MM cells proliferation, and METTL3 knockdown inhibited MM cells proliferation. Mechanically, METTL3-dependent m6A participated in DiGeorge syndrome critical region 8 (DGCR8)-mediated maturation of pri-miR-182. Upregulation of miR-182-5p further enhanced the promoting proliferation effect of METTL3 overexpression on MM cells. Moreover, the luciferase reporter gene experiment proved that miR-182-5p targetedly regulated CAMK2N1 expression. Xenograft tumor in nude mice further verified that METTL3 promoted MM tumor growth through miR-182/CAMK2N1 signal axis. In summary, the METTL3/miR-182-5p/CAMK2N1 axis plays an important role in MM tumorigenesis, which may provide a new target for MM therapy.

Palladium nanospheres-embedded metal-organic frameworks to enhance the ECL efficiency of 2,6-dimethyl-8-(3-carboxyphenyl)4,4'-difluoroboradiazene in aqueous solution for ultrasensitive Cu2+ detection.

Nowadays, organic emitters suffer from insufficient electrochemiluminescence (ECL) efficiency in aqueous solutions, and their practical applications are severely restricted in the bio-sensing field. In this work, palladium nanospheres-embedded metal-organic frameworks (Pd@MOFs) were exploited to enhance the ECL efficiency of 2,6-dimethyl-8-(3-carboxyphenyl)4,4'-difluoroboradiazene (BET) prepared by a one-pot method in aqueous environment. First, the Pd@MOFs were generated via in situ reduction of Pd nanospheres anchored onto the MOFs, and fabricated by orderly coordination of palladium chloride (PdCl2) with 1,2,4,5-benzenetetramine (BTA) tetrahydrochloride. Then, the influence of protons on the ECL response of BET was studied in detail to obtain stronger ECL emission using potassium persulfate (K2S2O8) as co-reactant in aqueous environment. As a result, a 1.47-fold ECL efficiency enlargement of BET/K2S2O8 was harvested at the Pd@MOFs/GCE, where Ru(bpy)32+ behaved as a standard. Based on the fact that the ECL signals of the BET-covered Pd@MOFs modified glassy carbon electrode (simplified as BET/Pd@MOFs/GCE) can be quenched by Cu2+, the as-built ECL sensor showed a wide linear range (1.0-100.0 pM) and a limit of detection (LOD) as low as 0.12 pM. Hence, such research offers huge potential to promote the development of organic emitters in ECL biosensors and environmental monitoring.

Quantifying the energy landscape in weakly and strongly disordered frictional media.

We investigate the "roughness" of the energy landscape of a system that diffuses in a heterogeneous medium with a random position-dependent friction coefficient α(x). This random friction acting on the system stems from spatial inhomogeneity in the surrounding medium and is modeled using the generalized Caldira-Leggett model. For a weakly disordered medium exhibiting a Gaussian random diffusivity D(x) = kBT/α(x) characterized by its average value ⟨D(x)⟩ and a pair-correlation function ⟨D(x1)D(x2)⟩, we find that the renormalized intrinsic diffusion coefficient is lower than the average one due to the fluctuations in diffusivity. The induced weak internal friction leads to increased roughness in the energy landscape. When applying this idea to diffusive motion in liquid water, the dissociation energy for a hydrogen bond gradually approaches experimental findings as fluctuation parameters increase. Conversely, for a strongly disordered medium (i.e., ultrafast-folding proteins), the energy landscape ranges from a few to a few kcal/mol, depending on the strength of the disorder. By fitting protein folding dynamics to the escape process from a metastable potential, the decreased escape rate conceptualizes the role of strong internal friction. Studying the energy landscape in complex systems is helpful because it has implications for the dynamics of biological, soft, and active matter systems.

Multiarmed DNA jumper and metal-organic frameworks-functionalized paper-based bioplatform for small extracellular vesicle-derived miRNAs assay.

Small extracellular vesicle-derived microRNAs (sEV-miRNAs) have emerged as promising noninvasive biomarkers for early cancer diagnosis. Herein, we developed a molecular probe based on three-dimensional (3D) multiarmed DNA tetrahedral jumpers (mDNA-Js)-assisted DNAzyme activated by Na+, combined with a disposable paper-based electrode modified with a Zr-MOF-rGO-Au NP nanocomplex (ZrGA) to fabricate a novel biosensor for sEV-miRNAs Assay. Zr-MOF tightly wrapped by rGO was prepared via a one-step method, and it effectively aids electron transfer and maximizes the effective reaction area. In addition, the mechanically rigid, and nanoscale-addressable mDNA-Js assembled from the bottom up ensure the distance and orientation between fixed biological probes as well as avoid probe entanglement, considerably improving the efficiency of molecular hybridization. The fabricated bioplatform achieved the sensitive detection of sEV-miR-21 with a detection limit of 34.6 aM and a dynamic range from100 aM to 0.2 µM. In clinical blood sample tests, the proposed bioplatform showed results highly consistent with those of qRT-PCRs and the signal increased proportionally with the NSCLC staging. The proposed biosensor with a portable wireless USB-type analyzer is promising for the fast, easy, low-cost, and highly sensitive detection of various nucleic acids and their mutation derivatives, making it ideal for POC biosensing.

Discussion on Improvement of the Incidence of Complications After the Application of Self-Management and Continuous Nursing in Children with Primary Nephrotic Syndrome.

Objective: To analyze the effects of self-management and continuous nursing on improving the incidence of complications in children with primary nephrotic syndrome. Methods: A retrospective analysis of 80 cases of children with primary nephrotic syndrome treated in our hospital from January 2019 to October 2022 was conducted. The patients were divided into a control group and an observation group, with 40 cases in each group. The control group received routine nursing, while the observation group received self-management and continuous nursing. After different nursing measures were taken in the two groups, the incidence of complications, the total satisfaction rate of patients' parents, quality of life scores, and the urinary albumin excretion rate before and after nursing between the two groups were analyzed. Results: (1) In comparison to the control group, the observation group had a lower incidence of complications (gastrointestinal discomfort, hypoglycemia, and abnormal liver function) (P < .05). (2) In comparison to the control group, the observation group had a higher total satisfaction rate of the patients' parents after nursing (P < .05). (3) Compared to the control group, the observation group reported higher quality of life scores (psychological function, spiritual vitality, and somatic function) after nursing (P < .05). (4) Compared to the control group, the observation group revealed higher self-management ability scores after nursing (P < .05). (5) After nursing, the urinary albumin excretion rate in the observation group was lower than that in the control group (P < .05). (6) In terms of disease recurrence rate after 1 month and 2 months of nursing, the observation group reported was lower rate of disease recurrence compared to the control group (P < .05). Conclusion: The application values of self-management and continuous nursing in children with primary nephrotic syndrome are significant.

Forensic Identification and Evaluation of 25 Obstetric Brachial Plexus Palsy Medical Damage Cases.

OBJECTIVES: To analyze the high risk factors of obstetric brachial plexus palsy (OBPP), and to explore how to evaluate the relationship between fault medical behavior and OBPP in the process of medical damage forensic identification. METHODS: A retrospective analysis was carried out on 25 cases of medical damage liability disputes related to OBPP from 2017 to 2021 in Beijing Fayuan Judicial Science Evidence Appraisal Center. The shortcomings of hospitals in birth weight assessment, delivery mode selection, labor process observation and shoulder dystocia management, and the causal relationship between them and the damage consequences of the children were summarized. RESULTS: Fault medical behavior was assessed as the primary cause in 2 cases, equal cause in 10 cases, secondary cause in 8 cases, minor cause in 1 case, no causal relationship in 1 case, and unclear causal force in 3 cases. CONCLUSIONS: In the process of forensic identification of OBPP, whether medical behaviors fulfill diagnosis and treatment obligations should be objectively analyzed from the aspects of prenatal evaluation, delivery mode notification, standardized use of oxytocin, standard operation of shoulder dystocia, etc. Meanwhile, it is necessary to fully consider the objective risk of different risk factors and the difficulty of injury prevention, and comprehensively evaluate the causal force of fault medical behavior in the damage consequences.

N6-methyladenosine in hematological malignancies: a concise review.

PURPOSE OF REVIEW: Hematological malignancies are a kind of systemic cancers mostly related to abnormal differentiation of blood stem cells. Because of the poor prognosis, chemotherapy resistance and common recurrence, new mechanisms and treatment therapies are looking forward to be discovered. RECENT FINDINGS: Over the years, epigenetic abnormalities have been known to act a key part in occurrence and development of hematological tumors. In the internal modifications on long noncoding eukaryotic mRNA, there is a common type called N6-methyladenosine that can change the expression of target genes and participate in the translation, degradation and splicing of mRNA. M6A is related to a wealth of cancers, such as HNRNPA2B1's elevation in multiple myeloma, METTLE3's elevation in acute myeloid leukemia and lung cancer. Immune cells, playing a significant role in hematological cancers, can also be regulated by m6A. SUMMARY: In the review, we summarized the recent progress on hematological malignancies associating with m6A and immune cells, which may offer a new road for the treatment of them.

Arterial remodeling: the role of mitochondrial metabolism in vascular smooth muscle cells.

Arterial remodeling is a common pathological basis of cardiovascular diseases such as atherosclerosis, vascular restenosis, hypertension, pulmonary hypertension, aortic dissection, and aneurysm. Vascular smooth muscle cells (VSMCs) are not only the main cellular components in the middle layer of the arterial wall but also the main cells involved in arterial remodeling. Dedifferentiated VSMCs lose their contractile properties and are converted to a synthetic, secretory, proliferative, and migratory phenotype, playing key roles in the pathogenesis of arterial remodeling. As mitochondria are the main site of biological oxidation and energy transformation in eukaryotic cells, mitochondrial numbers and function are very important in maintaining the metabolic processes in VSMCs. Mitochondrial dysfunction and oxidative stress are novel triggers of the phenotypic transformation of VSMCs, leading to the onset and development of arterial remodeling. Therefore, pharmacological measures that alleviate mitochondrial dysfunction reverse arterial remodeling by ameliorating VSMCs metabolic dysfunction and phenotypic transformation, providing new options for the treatment of cardiovascular diseases related to arterial remodeling. This review summarizes the relationship between mitochondrial dysfunction and cardiovascular diseases associated with arterial remodeling and then discusses the potential mechanism by which mitochondrial dysfunction participates in pathological arterial remodeling. Furthermore, maintaining or improving mitochondrial function may be a new intervention strategy to prevent the progression of arterial remodeling.

Myofascial release for the treatment of pain and dysfunction in patients with chronic mechanical neck pain: Systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To explore the effects of myofascial release (MFR) on pain and dysfunction in individuals with chronic mechanical neck pain (MNP). DATA SOURCES: PubMed, Embase, Medline, Wiley Online Library, Web of Science, CNKI, VIP, WanFang Data, and the Cochrane Library were searched until 12 September 2022. REVIEW METHODS: This study was registered in PROSPERO (CRD42022302485). Methodological quality was assessed using Cochrane risk of bias assessment, and the quality of the evidence followed the GRADE recommendation. The outcomes pain, cervical mobility (Flexion, Extension, Rotation, lateral flexion), trapezius and suboccipital pressure pain thresholds (PPT), neck disability index (NDI), and adverse effects were extracted. RESULTS: After screening of 346 studies, 13 studies and 601 participants met the inclusion criteria. All studies were of moderate methodological quality. Compared with the control group, the participants in the MFR group showed significantly greater improvements trapezius PPT SMD 0.41 (95% CI 0.11-0.72), suboccipital PPT SMD 0.47 (95% CI 0.21-0.72), respectively. The differences were not significant to support the MFR treatment on pain, flexion, extension, rotation, lateral flexion angle, and NDI. None of the studies reported any adverse events. CONCLUSION: This systematic review suggests that MFR is an effective treatment for the improvement of PPT of trapezius and suboccipital muscle in patients with chronic MNP. However, there is low to moderate evidence and may change over time.

A cross-sectional study on the tea consumption effects of ankle-brachial index.

OBJECTIVES: This thesis aims to explore the relationship between tea consumption and ankle-brachial index (ABI) and further studies the relationship between tea consumption and lower extremity atherosclerosis. METHODS: This is a cross-sectional, epidemiological survey of 17,373 subjects selected from the staff of Kailuan Group who had come to Kailuan General Hospital for a health examination from January 2016 to December 2017. Tea consumption was obtained by questionnaires. ABI was measured using an automated analyzer. The other data, such as age, gender, body mass index (BMI), and so on, was collected on the same day of the health examination results. The relationship between tea drinking habits and ABI was studied using logistic regression and multivariate linear regression analysis. RESULTS: Among the 17,373 analyzed subjects, the difference in age, gender, BMI, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), uric acid (UA), C-reactive protein (CRP), fasting blood-glucose (Fbg), and ABI was statistically significant in the tea-drinking group and the nontea-drinking group (p < 0.05). Multiple logistic regression models revealed that tea consumption was a positive predictor for ABI (odds ratio (OR) = 0.782, confidence interval (CI), 0.615-0.994) (p < 0.05). Multivariate linear regression analysis of the ABI value showed that frequent tea-drinking has a positive correlation with the ABI value (p < 0.05). CONCLUSIONS: The higher tea consumption is significantly associated with higher ABI which means less risk for lower extremity atherosclerosis.

Ergodic Measure and Potential Control of Anomalous Diffusion.

In statistical mechanics, the ergodic hypothesis (i.e., the long-time average is the same as the ensemble average) accompanying anomalous diffusion has become a continuous topic of research, being closely related to irreversibility and increasing entropy. While measurement time is finite for a given process, the time average of an observable quantity might be a random variable, whose distribution width narrows with time, and one wonders how long it takes for the convergence rate to become a constant. This is also the premise of ergodic establishment, because the ensemble average is always equal to the constant. We focus on the time-dependent fluctuation width for the time average of both the velocity and kinetic energy of a force-free particle described by the generalized Langevin equation, where the stationary velocity autocorrelation function is considered. Subsequently, the shortest time scale can be estimated for a system transferring from a stationary state to an effective ergodic state. Moreover, a logarithmic spatial potential is used to modulate the processes associated with free ballistic diffusion and the control of diffusion, as well as the minimal realization of the whole power-law regime. The results presented suggest that non-ergodicity mimics the sparseness of the medium and reveals the unique role of logarithmic potential in modulating diffusion behavior.

Modularized Enzymatic Tandem Reaction for tsRNA Detection.

tRNA-derived small RNA (tsRNA) has emerged as a new biomarker for early diagnosis and prognosis prediction of breast cancer. Like the detection of other small non-coding RNAs, the traditional DNA circuit could be used for the tsRNA detection. However, the highly coupling DNA strands in the circuit increase the difficulty of design and could raise a false-positive signal. Here, we demonstrated a versatile modularized enzymatic tandem reaction, namely, reverse-transcribed nicking exponential truncation (RT-NExT). This enzymatic reaction was constructed by cohesive modules, which can work independently or in assembly. Each module could amplify and initiate the downstream module. The RT-NExT reaction could detect 10-18 M ts-66 or ts-86 within 10 min and exhibited excellent consistency to the qRT-PCR when measuring the tsRNA expression level of breast cancer or healthy patients. RT-NExT provides an appealing detection strategy for further research on the clinical diagnosis with tsRNAs.

ABIN1 Inhibits Inflammation through Necroptosis-Dependent Pathway in Ulcerative Colitis.

Background: Ulcerative colitis (UC) is characterized by chronic, recurrent intestinal inflammation and intestinal epithelial injury including a wide range of epithelial cell death, ulcers, crypt abscesses, and the formation of fibrosis. The intestinal barrier dysfunction runs through the whole process of the occurrence and development of UC. A recent study revealed that an ubiquitin binding protein ABIN1 played a role in tissue homeostasis and autoimmunity diseases which involved in the anti-inflammatory response of intestinal epithelia cells. However, the roles of ABIN1 in ulcerative colitis pathogenesis remain unclear. Methods: The mRNA and protein expression level of ABIN1 and necroptosis-associated genes (RIPK1, RIPK3, and MLKL) were conducted to investigate the relationship between ABIN1 and necroptosis in clinical UC specimens. Subsequently, the dextran sodium sulfate (DSS)-induced mice colitis model was used to verify the ABIN1 function in vivo. Furthermore, we established ABIN1 gain and loss function assay in CACO-2 to confirm the mechanism in UC in vitro. Results: We found that ABIN1, RIPK1, RIPK3, and MLKL were upregulated in UC sample and DSS-induced colitis. Upon TNF-α stimulation in the intestinal epithelia cell line, overexpression of ABIN1 significantly inhibits necroptosis in the intestinal inflammation model along with the reduction expression of pro-inflammatory cytokines such as IL1B, IL6, IL8, and TNF-α. Blocking RIPK1 by Nec-1s in vivo and in vitro dramatically alleviated the colitis and cell death which shares the same phenotype with ABIN1 overexpression. Conclusion: Hence, the dysregulation of ABIN1 may relate to the uncontrolled necroptosis and inflammation in UC, and negatively regulate the occurrence and process of ulcerative colitis. ABIN1 activation may be considered a therapeutic strategy for UC.

Coexistence of ergodicity and nonergodicity in the aging two-state random walks.

The two-state stochastic phenomenon is observed in various systems and is attracting more interest, and it can be described by the two-state random walk (TSRW) model. The TSRW model is a typical two-state renewal process alternating between the continuous-time random walk state and the Lévy walk state, in both of which the sojourn time distributions follow a power law. In this paper, by discussing the statistical properties and calculating the ensemble averaged and time averaged mean squared displacement, the ergodic property and the ultimate diffusive behavior of the aging TSRW is studied. Results reveal that because of the two-state intermittent feature, ergodicity and nonergodicity can coexist in the aging TSRW, which behave as the time scalings of the time averages and ensemble averages not being identically equal. In addition, we find that the unique state occupation mechanism caused by the diverging mean of the sojourn times of one state, determines the aging TSRW's ultimate diffusive behavior at extremely large timescales, i.e., instead of the term with the larger diffusion exponent, the diffusion is surprisingly characterized by the term with the smaller one, which is distinctly different from previous conclusions and known results. At last, we note that the Lévy walk with rests model which also displays aging and ergodicity breaking, can be generalized by the TSRW model.

Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans.

Furmonertinib was designed for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation. In this study, we investigated the metabolic disposition and mass balance in humans and tissue distribution in rats. After a single oral administration of 97.9 µCi/81.5 mg [14C]-furmonertinib mesylate to six healthy male volunteers, the absorption process of furmonertinib was fast with a tmax of total plasma radioactivity at 0.75 h. Afterward, furmonertinib was extensively metabolized, with the parent drug and active metabolite AST5902 accounting for 1.68% and 0.97% of total radioactivity in plasma. The terminal t1/2 of total radioactivity in plasma was as long as 333 h, suggesting that the covalent binding of drug-related substances to plasma proteins was irreversible to a great extent. The most abundant metabolites identified in feces were desmethyl metabolite (AST5902), cysteine conjugate (M19), and parent drug (M0), which accounted for 6.28%, 5.52%, and 1.38% of the dose, respectively. After intragastric administration of 124 µCi/9.93 mg/kg [14C]-furmonertinib to rats, drug-related substances were widely and rapidly distributed in tissues within 4 h. The concentration of total radioactivity in the lung was 100-fold higher than that in rat plasma, which could be beneficial to the treatment of lung cancer. Mass balance in humans was achieved with 77.8% of the administered dose recovered in excretions within 35 days after administration, including 6.63% and 71.2% in urine and feces, respectively. In conclusion, [14C]-furmonertinib is completely absorbed and rapidly distributed into lung tissue, extensively metabolized in humans, presented mostly as covalent conjugates in plasma, and slowly eliminated mostly via fecal route.

Genome-wide association study of 7661 Chinese Han individuals and fine-mapping major histocompatibility complex identifies HLA-DRB1 as associated with IgA vasculitis.

BACKGROUND: Immunoglobulin-A vasculitis (IgAV) is an immune-related systemic vasculitis with an unclear etiology. Genetic predisposition is now considered to be closely associated with the development of the disease, and it is essential to reveal the relationship between them. To explore the role of heredity in the disease, we performed a genome-wide association study (GWAS) of 496 IgAV cases and 7165 controls using an Illumina Infinium Global Screening Array chip. METHODS: In the first stage of analysis, a significant correlation between the major histocompatibility complex (MHC) and IgAV was observed. Subsequently, human leukocyte antigen (HLA) analysis was conducted using a new large-scale Han-MHC reference panel. Fine mapping of IgAV risk in the MHC region indicated that two amino acid positions, 120 and 11, of HLA-DRB1 and three potential HLA alleles (HLA-DRB1∗04, HLA-DRB1∗16, and HLA-DRB1∗16:02) were significantly associated. RESULTS: Further stepwise conditional analysis demonstrated that 3 amino acid positions (120, 26, 96) of HLA-DRB1 and 6 HLA-DRB1 alleles (HLA-DRB1*04, HLA-DRB1*16, HLA-DRB1*01, HLA-DRB1*12:02, HLA-DRB1*10, and HLA-DRB1*15:02) were independent signals. Among them, the most significant signal was HLA-DRB1 amino acid Ser120 (OR = 1.59, p = 3.19 × 10-8 ); no independent signal in the MHC region except for HLA-DRB1 was found. CONCLUSIONS: Our study confirms that the pathogenesis of IgAV has a genetic component and that HLA-DRB1 is strongly associated with susceptibility to IgAV.