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.

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.

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.

BACKGROUND On March 2022, the United States Food and Drug Administration(FDA) announced the approval of radiolabeled drug lutetium Lu 177 vipivotide tetraxetan for treatment of adult patients with prostate specific membrane antigen(PSMA)-positive metastatic castration-resistant prostate cancer who have been treated with androgen-receptor pathway inhibition and taxane-based chemotherapy. As PSMA is barely expressed on non-prostatic tissue, it has a very low background accumulation in healthy tissue, consequently, avoiding severe adverse drug reaction of lutetium Lu 177 vipivotide tetraxetan. A multicenter phase Ⅲ VISION study(NCT 03511664) showed that about 30% of patients with evaluable disease at baseline demonstrated an overall response with lutetium Lu 177 vipivotide tetraxetan plus standard care, compared to only 2% in the control arm. The high efficacy and mild adverse drug reaction of lutetium Lu 177 vipivotide tetraxetan cause opportunities for the healthcare systems and represent an important next step towards novel oncotherapy, but also cause great challenges in its clinical use due to lack of practical experience. Currently, data on the large sample and real-world comprehensive safety of lutetium Lu 177 vipivotide tetraxetan are still limited. Therefore, it is necessary to employ data mining algorithms to seek out the potential adverse event signals of lutetium Lu 177 vipivotide tetraxetan by post-marketing monitoring. METHODS FDA Adverse Event Reporting System(FAERS) is a publicly available, voluntary, and spontaneous reporting database. In the present study, the adverse events reported from the second quarter of 2022 to the fourth quarter of 2022 with lutetium Lu 177 vipivotide tetraxetan from FAERS were retrospectively analyzed. Seven types of datasets, including patient demographic and administrative information(DEMO), drug information(DRUG), therapy start dates and end dates for reported drugs(THER), adverse event results(OUTC), adverse event sources(PRSP), coded for the adverse events(REAC), and indications for use/diagnosis(INDI) were used. The reports of lutetium Lu 177 vipivotide tetraxetan were identified using generic name(LUTETIUM LU-177 VIPIVOTIDE TETRAXETAN in prod_ai column) and trade name(PLUVICTO in drug name column) in the DRUG dataset. The adverse event reports with the role_cod as the primary suspected(PS) were chose. Next, the report characteristics, demographic characteristics and onset time of lutetium Lu 177 vipivotide tetraxetan-associated adverse events were analyzed. The adverse events were coded using preferred terms(PT) derived from the standardized Medical Dictionary for Regulatory Activities 25.1(MedDRA), which contained 27 system organ classes(SOCs). Four algorithms, including reporting odds ratio(ROR), proportional reporting ratio(PRR), Bayesian confidence propagation neural network(BCPNN) and multi-item gamma Poisson shrinker(MGPS) were used to detect the signals. All the four data mining algorithms were based on the disproportionality analysis. An adverse event signal was detected only when it conformed to all of the four algorithms criteria simultaneously. RESULTS A total of 634 reports associated with lutetium Lu 177 vipivotide tetraxetan were considered. As a whole, the number of reports had increased gradually month-on-month, and 568(89.6%) reports occurred in the United States. The most common age and body weight groups were 61-80 years(75.4%) and 61-80 kg(50.9%), respectively. Most reports occurred within 30 d after administration of lutetium Lu 177 vipivotide tetraxetan, accounting for 41.5%. Based on 4 algorithms of ROR, PRR, BCPNN and MGPS, six effective signals at the PT level were detected, including anaemia(PT: 10002034), thrombocytopenia(PT: 10043554), laboratory test abnormal(PT: 10023547), platelet count decreased(PT: 10035528), full blood count decreased(PT: 10017413) and dry mouth(PT: 10013781). CONCLUSION When using lutetium Lu 177 vipivotide tetraxetan, it is important to strengthen clinical monitoring within one month and pay attentions to laboratory results including complete blood cell and platelet count. This study might provide powerful support for clinical monitoring of lutetium Lu 177 vipivotide tetraxetan.