Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. Methods: We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). Results: We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. Conclusions PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. Methods: We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). Results: We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. Conclusions PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

Background: Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. Methods: We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). Results: We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. Conclusions PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

ObjectiveTo investigate the dynamic trajectories of prognostic scores and key clinical indicators in hepatitis B virus-related acute-on-chronic liver failure （HBV-ACLF） patients without liver cirrhosis， to clarify their association with outcomes， and to provide new evidence for individualized prognostic assessment. MethodsA prospective study was conducted for the data of 154 non-cirrhotic HBV-ACLF patients who attended Beijing YouAn Hospital of Capital Medical University from January 2016 to December 2023， including prognostic scores and key biochemical indicators on Days 3， 7， 14， 21， and 28 of the disease course. According to the outcome of patients at 1 year， they were divided into death/liver transplantation group with 43 patients， liver cirrhosis group with 23 patients， and non-liver cirrhosis group with 88 patients， and the trajectory heterogeneity of different outcome subgroups was analyzed. A one-way analysis of variance was used for comparison of normally distributed continuous data among the three groups； the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data among the three groups； the Wilcoxon test was used between two groups. the chi-square test was used for comparison of categorical data between groups. The mean and its 95% confidence interval （CI） were calculated for each indicator at difference time points； the linear interpolation method was used to connect the means at adjacent time points and construct the group-specific longitudinal trend curve； the 95%CI was visualized using the semi-transparent ribbon area， with the transparency parameter （α=0.2） optimized to enhance the visual discrimination of overlapping intervals across multiple groups. A linear mixed-effects model was used to compare the longitudinal changing trend of each indicator between the patients with different outcomes； likelihood ratio was used to evaluate the significance of the interaction effect between time and group， and in case of the significant interaction effect， the slope based on the estimated marginal mean was used for comparison between two groups. ResultsThere were significant differences between the three groups in the incidence rates of ascites and grade Ⅲ — Ⅳ hepatic encephalopathy， MELD score， MELD-Na score， CLIF-C ACLF score， COSSH-ACLF Ⅱ score， total bilirubin （TBil）， international normalized ratio （INR）， alpha-fetoprotein， blood sodium， alanine aminotransferase， and procalcitonin at the baseline（all P0.05）. The analysis of dynamic trajectories showed that the death/liver transplantation group had high levels of prognostic scores and the biochemical parameters of TBil and INR （TBil400 μmol/L， INR2.5）， as well as a low level of platelet count （PLT） （100×10⁹/L）. The non-liver cirrhosis group had rapid improvements in indicators， with TBil200 μmol/L， INR1.5， and PLT100×10⁹/L by day 28， while the liver cirrhosis group showed a trend of recovery， with TBil200 μmol/L， INR2.0， and PLT 100×10⁹/L on day 28， with significant global heterogeneity in the temporal trends of the above indicators across the three groups （all P0.01）. ConclusionDynamic monitoring of prognostic scores and key clinical indicators can effectively stratify the 1-year outcomes of non-cirrhotic patients with HBV-ACLF. Patients with poor prognosis were typically characterized by INR 2.5 and TBil 400 μmol/L. Among those who survived beyond 1 year， individuals who subsequently progressed to cirrhosis were frequently identified by the presence of INR 1.5， TBil 200 μmol/L， and PLT 100×10⁹/L at day 28.

Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

AIM:To investigate the effect of icari-in on renal fibrosis and injury in hypertension through Cx32-Nox4 signaling pathway.METHODS:Models of hypertensive nephropathy(HN)were es-tablished in spontaneously hypertensive rats(SHRs).The experiment was divided into 4 groups:normal control group(WKY rats),model group(SHR),icariin 10 mg·kg-1·d-1 group(icariin once dai-ly),icariin 30 mg·kg-1·d-1 group(icariin once daily),n=10.The expression of fibrosis-related proteins was detected in vivo.NRK-52E cells exposed to An-gⅡ were selected to observe the effects of icariin on kidney injury.Extracellular matrix(ECM)levels,including α-smooth muscle actin(α-SMA),collagenⅠ(Col-Ⅰ)and fibronectin(FN)expression were mea-sured by Western blot and immunohistochemistry.The expressions of oxidative stress markers includ-ing superoxide dismutase(SOD)and malondialde-hyde(MDA)were determined by the test kit.RE-SULTS:Icariin reduced renal fibrosis in SHR rats in vivo.Icariin down-regulated the expression of α-SMA,FN,and Col-Ⅰ and protected hypertension-damaged kidney tissue from progressive fibrosis(P＜0.05).Icariin increased the total SOD activity and decrease the MDA level in kidney and serum of SHR rats(P＜0.05).In addition,icariin increased the expression of Cx32 and decreased the expression of Nox4 in the kidneys of SHR rats(P＜0.05).Icariin had a protective effect on AngⅡ-mediated NRK-52E cell damage and fibrosis.CONCLUSION:Icariin can improve renal tubulointerstitial fibrosis and delay the progression of HN.Renal protection may be at-tributed to the regulation of oxidative stress medi-ated by the Cx32-Nox4 signaling pathway.

Orthostatic hypotension (OH) is a common cardiovascular symptom,divided into neurogenic and non-neurogenic categories according to pathophysiology,both of which are associated with impaired quality of life and potential adverse outcomes.Due to the complex influential factors,diagnosis and treatment often require multidisciplinary cooperation and individualization.But domestic doctors pay little attention to the diagnosis and treatment of OH.This consensus,co-authored by experts from relevant professional fields including cardiology,neurology and psychology,systematically describes the concept,pathophysiology,classification and clinical characteristics of OH.The recommendations on the diagnosis,evaluation and treatment of OH were put forward to improve the attention of clinicians to OH and their ability of diagnosis and treatment.

Antipsychotics, lithium preparations can cause a variety of renal side effects, most of which occur insidiously. The paper reports a 46-year-old female patient developing fatigue and soft paresis after taking lithium carbonate for 17 years. Laboratory tests showed hypokalemia, distal renal tubular acidosis (dRTA), and renal calculus. After discontinuation of lithium carbonate, partial remission of hypokalemia and dRTA were observed. Combined with literature review, in addition to dRTA, the renal side effects of lithium preparations also include acute toxic kidney injury, nephrogenic diabetes insipidus and various glomerulopathy.

Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders (NDDs) that exhibit delayed speech development, intellectual disability, and congenital abnormalities. The etiology of NDDs is unclear. Here we found that FOXP4 and N-cadherin are expressed in the nuclei and apical end-feet of radial glial cells (RGCs), respectively, in the mouse neocortex during early gestation. Knockdown or dominant-negative inhibition of Foxp4 abolishes the apical condensation of N-cadherin in RGCs and the integrity of neuroepithelium in the ventricular zone (VZ). Inhibition of Foxp4 leads to impeded radial migration of cortical neurons and ectopic neurogenesis from the proliferating VZ. The ectopic differentiation and deficient migration disappear when N-cadherin is over-expressed in RGCs. The data indicate that Foxp4 is essential for N-cadherin-based adherens junctions, the loss of which leads to periventricular heterotopias. We hypothesize that FOXP4 variant-associated NDDs may be caused by disruption of the adherens junctions and malformation of the cerebral cortex.
Mice ; Animals ; Ependymoglial Cells/physiology* ; Cadherins ; Neurons/metabolism* ; Cerebral Cortex/metabolism* ; Cell Differentiation ; Cell Movement