As a new strategy for the application of sacubitril/valsartan (LCZ696) in patients with CKD, much evidence showed that it improved the prognosis of patients with CKD. This review summarizes the efficacy and safety of sacubitril/valsartan in physiology, pathology, pharmacology and clinical application by searching Wanfang, CNKI, PubMed and other databases for related articles on the application of sacubitril/valsartan in CKD patients. Although LBQ657, the active product of sacubitril, has a high drug accumulation in patients with moderate, severe renal injury, and ESRD, it is not cleared in hemodialysis, and has very little eliminated in peritoneal dialysis, which does not affect its safety. Compared with angiotensin converting enzyme inhibitor and angiotensin receptor blocker drugs, LCZ696 could increase the blood pressure control rate, improve cardiac function, slow down the decline of glomerular filtration rate, and significantly improve cardiovascular outcomes without more adverse events. Sacubitril/valsartan can be used in all levels of CKD patients complicated with hypertension and/or heart failure, with reliable safety and tolerance.

Objective To investigate the expression of Midkine(MDK)in cholangiocarcinoma(CCA)and its value in predicting the prognosis of CCA,as well as the potential mechanism of the effect of MDK on the progression of CCA.Methods The data of CCA samples were obtained from TCGA database to analyze the difference in the expression of MDK between cancer tissue and paracancerous tissue and its association with clinical features,and the data collected from GEO database and 11 CCA patients who underwent surgical resection in The Fifth Medical Center of Chinese PLA General Hospital from June 2018 to September 2021 were used for validation.STRING and Cytoscape were used to construct a protein-protein interaction network,and gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were used to investigate the biological functions and tumor-related pathways involving MDK-related genes.In addition,TIMER and TISIDB databases were used to analyze the correlation between MDK expression and immune cell infiltration in CCA tissue.The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups,and the Fisher's exact test was used for comparison of categorical data between two groups.The Kaplan-Meier method was used to plot survival curves,and the Log-rank test was used for comparison between groups.The Spearman correlation analysis was used to investigate the correlation between two variables.Results The expression level of MDK in cancer tissue and paracancerous tissue of CCA patients was compared based on TCGA database,and the results of the non-paired and paired analyses showed that the expression level of MDK in CCA tumor tissue was significantly higher than that in paracancerous tissue(P<0.001).Transcriptome sequencing was performed for the tumor tissue and its corresponding paracancerous tissue from 11 CCA patients,and the results showed that the expression level of MDK in CCA tumor tissue was significantly higher than that in corresponding paracancerous tissue(P<0.01).High expression of MDK was associated with lymph node metastasis(P=0.045)and vascular invasion(P=0.044).Survival analysis showed that compared with the CCA patients with low MDK expression,the CCA patients with high MDK expression had significantly shorter overall survival time(χ2=5.30,P=0.028)and disease-specific survival time(χ2=6.25,P=0.019).The GO and KEGG enrichment analyses showed that the 30 MDK-related genes were closely associated with ubiquitin-mediated proteolysis and affected the prognosis of CCA patients.The TIMER analysis showed that the expression level of MDK was positively correlated with the infiltration of B cells(r=0.356,P=0.035 6)and dendritic cells(r=0.409,P=0.014 7)in tumor microenvironment of CCA;the TISIDB analysis showed that the expression level of MDK was positively correlated with CXCL16(r=0.465,P=0.004 67)and was negatively correlated with CXCL12(r=-0.389,P=0.019 7)and CXCR5(r=-0.393,P=0.018 5),and it was also negatively correlated with the immune checkpoint regulators VTCN1(r=-0.393,P=0.018 3),LTA(r=-0.380,P=0.022 7),and PVR(r=-0.350,P=0.037 3).Conclusion High expression of MDK is associated with poor prognosis in CCA patients,and MDK has the potential of being used as a molecular marker for predicting the prognosis of CCA.MDK may promote the development and progression of CCA by regulating ubiquitin-mediated proteolysis and the infiltration of B cells and dendritic cells.

Objective:To investigate the characteristics of the CD8+T cells infiltration from the 4 sub-types in medulloblastoma(MB),to analyze the relationship between CD8+T cells infiltration and prog-nosis,to study the function of C-X-C motif chemokine ligand 11(CXCL11)and its receptor in CD8+T cells infiltration into tumors and to explore the potential mechanism,and to provide the necessary clinico-pathological basis for exploring the immunotherapy of MB.Methods:In the study,48 clinical MB sam-ples(12 cases in each of 4 subtypes)were selected from the multiple medical center from 2012 to 2019.The transcriptomics analysis for the tumor of 48 clinical samples was conducted on the NanoString Pan-Cancer 10360?Panel(NanoString Technologies).Immunohistochemistry(IHC)staining of formalin-fixed,paraffin-embedded sections from MB was carried out using CD8 primary antibody to analyze diffe-rential quantities of CD8+T cells in the MB four subtypes.Through bioinformatics analysis,the relation-ship between CD8+T cells infiltration and prognosis of the patients and the expression differences of various chemokines in the different subtypes of MB were investigated.The expression of CXCR3 receptor on the surface of CD8+T cells in MB was verified by double immunofluorescence staining,and the under-lying molecular mechanism of CD8+T cells infiltration into the tumor was explored.Results:The charac-teristic index of CD8+T cells in the WNT subtype of MB was relatively high,suggesting that the number of CD8+T cells in the WNT subtype was significantly higher than that in the other three subtypes,which was confirmed by CD8 immunohistochemical staining and Gene Expression Omnibus(GEO)database analysis by using R2 online data analysis platform.And the increase of CD8+T cells infiltration was posi-tively correlated with the patient survival.The expression level of CXCL11 in the WNT subtype MB was significantly higher than that of the other three subtypes.Immunofluorescence staining showed the presence of CXCL11 receptor,CXCR3,on the surface of CD8+T cells,suggesting that the CD8+T cells might be attracted to the MB microenvironment by CXCL11 through CXCR3.Conclusion:The CD8+T cells infiltrate more in the WNT subtype MB than other subtypes.The mechanism may be related to the activation of CXCL11-CXCR3 chemokine system,and the patients with more infiltration of CD8+T cells in tumor have better prognosis.This finding may provide the necessary clinicopathological basis for the regulatory mechanism of CD8+T cells infiltration in MB,and give a new potential therapeutic target for the future immunotherapy of MB.

Objective:To investigate the clinicopathological characteristics, immunophenotypes, molecular features, and differential diagnosis of BAP1 mutated clear cell renal cell carcinoma (CCRCC) for better understanding this entity.Methods:Clinical data, histological morphology, immunophenotypes and molecular characteristics of 18 BAP1 mutated CCRCC cases diagnosed at the Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China from January 2020 to December 2022 were analyzed. The patients were followed up.Results:There were 17 males and 1 female patients, aged from 39 to 72 years, with an average age of 56.3 years. Sixteen patients with primary CCRCC were followed up for an average of 24 months, 7 patients had metastases occurred from 4 to 22 months postoperatively. Thirteen of the 16 patients were alive at the time of the last follow-up while 3 patients died 12, 15, and 20 months after the surgery, respectively. One patient underwent retroperitoneal mass resection, but had lung metastasis 32 months after surgery. One case received cervical tumor resection and died at 22 months after the surgery. Characteristic CCRCC regions were identified in 11 of the 18 cases. The tumor cells were arranged in papillary, alveolar, and large nest patterns. Abundant lymphoid tissue, necrosis, and psammoma bodies were seen. Tumor cells showed abundant eosinophilic cytoplasm, and sometimes exhibited rhabdoid differentiation. Round eosinophilic globules were located in the cytoplasm and extracellular matrix. There were 9 cases with WHO/International Society of Urological Pathology grade 3, and 9 cases with grade 4. PAX8 (18/18), carbonic anhydrase 9 (CA9, 16/18), CD10 (18/18), and vimentin (18/18) were positive in the vast majority of tumors.TFE3 was expressed in 5 cases, with strong expression in only 1 case. Eighteen cases were all positive for P504s. Twelve cases harbored a BAP1 mutation combined with von Hippel-Lindau (VHL) mutation, and 2 cases had mutations in BAP1, VHL and PBRM1 simultaneously. SETD2 mutation was not found in any of the cases.Conclusions:BAP1 mutated CCRCC contained papillary, alveolar, and large nest patterns, eosinophilic cytoplasm, high-grade nucleoli, and collagen globules, with P504s positivity. In practical work, when encountering CCRCC containing these features, pathologists should consider the possibility of BAP1 mutations and conduct related molecular tests.

This study included 20 patients with hematological diseases who developed Pneumocystis jirovecii pneumonia (PJP) after receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) from April 2014 to October 2022 at Peking University People’s Hospital. The 20 patients comprised 13 males (65.0% ) and seven females (35.0% ), with a median age of 34 (19-60) years. Eleven cases (55.0% ) of acute myeloid leukemia, four cases (20.0% ) of acute lymphocytic leukemia, two cases (10.0% ) of myelodysplastic syndrome, one case (5.0% ) of chronic myelomonocytic leukemia, one case (5.0% ) of non-Hodgkin lymphoma, and one case (5.0% ) of aplastic anemia were analyzed. Three cases (15.0% ) of HLA-identical sibling hematopoietic stem cell transplantation, three cases (15.0% ) of matched unrelated donor hematopoietic stem cell transplantation, and 14 cases (70.0% ) of haploid hematopoietic stem cell transplantation were identified. The median onset time of PJP was 353 (74-1121) days after transplantation. The clinical symptoms mainly included fever, cough, expectoration, and dyspnea. All patients presented signs of infection based on the CT scan, including bilateral diffuse ground-glass opacities, patchy shadows, and solid nodules. Nine patients (45.0% ) required respiratory support via nasal catheter oxygen inhalation, while seven patients (35.0% ) required ventilator-assisted breathing. Seven (35.0% ) severe infections and 13 (65.0% ) mild to moderate infections were recorded. Moreover, eight patients (40.0% ) were complicated with human cytomegalovirus infection, whereas two patients were complicated with EB virus infection. Furthermore, all 20 patients received treatment with compound sulfamethoxazole (standard dose, 11 cases; low dose, 9 cases). Furthermore, 19 patients survived and one patient died.

Objective:To summarize the clinical features associated with respiratory syncytial virus (RSV) infection in patients following the hematopoietic stem cell transplant (HSCT) and exploring the risk factors for death.Methods:Patients who had RSV infection after undergoing HSCT from October 2023 to January 2024 in the hematology department of Peking University People’s Hospital were enrolled in the study. The clinical characteristics of the participating patients were summarized. The clinical characteristics of the surviving and the dying patients were compared, and the risk factors of death were analyzed by binary logistic regression.Results:Among the 43 RSV-positive HSCT patients, 20 (46.5%) were hypoxemic, six (14.0%) were admitted to the ICU for further treatment, four (9.3%) required tracheal intubation assisted ventilation, and seven patients (16.3%) died. A comparison of the clinical features of the surviving patients and the deceased patients demonstrated that the deceased patients had a lower PLT when infected with RSV [74.5 (8.0-348.0) ×10 9/L vs 15.0 (10.0-62.0) ×10 9/L, P=0.003], a higher incidence of simultaneous bacterial infections (85.7% vs 41.7%, P=0.046), and a higher rate of hematological recurrence (71.4% vs 13.9%, P=0.004). Hematological recurrence ( OR=15.500, 95% CI 2.336-102.848, P=0.005), influenza A viral infection ( OR=14.000, 95% CI 1.064-184.182, P=0.045), and low PLT at the time of RSV infection ( OR=0.945, 95% CI 0.894-0.999, P=0.048) were the factors associated with death following HSCT. Conclusion:Patients infected with RSV after undergoing HSCT have a poor prognosis, and active prevention and treatment of RSV in the autumn and winter requires urgent attention.

Objective:To explore the prognostic impact of different intracranial radiotherapy modalities in patients with a limited number (≤10) of brain metastases from small cell lung cancer (SCLC-BM).Methods:The data of 143 cases with SCLC-BM that received intracranial radiotherapy at the First Affiliated Hospital of Bengbu Medical University in 2019-2022 were analyzed. The patients were grouped by radiotherapy modalities: whole brain radiotherapy (WBRT, 58 cases), WBRT combined with simultaneous integrated boost (WBRT+ SIB, 53 cases), and WBRT combined with sequential integrated boost (WBRT+ SEB, 32 cases). The overall survival (OS) and intracranial progression-free survival (IPFS) were calculated using the Kaplan-Meier method, and the Cox proportional hazard model was used for prognostic analysis.Results:In the whole group, the median OS and IPFS were 11.9 and 9.9 months, and the 1-, 2-, and 3-year survival rates were 49.7%, 15.3%, and 2.9%, respectively. The difference in OS among patients in the WBRT+ SIB, WBRT+ SEB, and WBRT groups was not significant (median OS: 13.0 months vs. 12.5 months vs. 11.2 months, P>0.05). The WBRT+ SIB and WBRT+ SEB groups were preferred over the WBRT group in terms of IPFS (median IPFS: 11.7 months vs. 10.4 months vs. 8.1 months, χ2=21.69, P<0.001). For patients with few brain metastases (≤3) analyzed separately, the WBRT+ SIB and WBRT+ SEB groups were preferred over the WBRT group in terms of OS and IPFS (median OS: 14.4 months vs. 13.7 months vs. 11.5 months, χ2=8.72, P=0.013; median IPFS: 12.6 months vs. 10.4 months vs. 8.9 months, χ2=12.37, P=0.002). Evaluation of the central nervous system as well as hematological acute radiological reactions reaching grade 2 and above showed no significant differences among the three groups ( P>0.05). Multivariate analysis showed that subsequent chemotherapy, targeted therapy, and immunotherapy were common independent influencing factors for patients′ OS and IPFS. Body mass index (BMI) level was an independent influencing factor for patients′ OS, and the number of brain metastases, lymph node metastasis, and radiotherapy modality were independent influencing factors for patients′ IPFS. Conclusions:BMI level and subsequent treatment (chemotherapy, targeted therapy, and immunotherapy) are independent influencing factors for patients' prognosis. WBRT+ SIB and WBRT+ SEB modalities are associated with increased IPFS.

Objective:To observe any effect of an enriched environment (EET) on cognitive functioning and sonic hedgehog (SHH) signaling in rats modeling cerebral ischemia.Methods:Sixty adult male Sprague-Dawley rats were randomly divided into a blank control group, a model group and a training group. A model of cerebral ischemia was established in the model and training groups by thread thrombus. The training group was given an EET. After 7 and 14 days, the rats′ cognition was tested using the Morris water maze and the platform jumping test. Apoptosis of brain cells in the hippocampus was detected by using TUNEL staining, and the expression of SHH, Gli2 and PTCH1 proteins in the hippocampus were measured using qRT-PCRs, western blotting and immunohistochemistry.Results:After 14 days the average escape latency in the Morris water maze test had shortened more in the training group than in the model group, while the average swimming speed, the number of platform crossings and the time spent in the quadrant had increased significantly more. They also received fewer electric shocks and spent significantly less time on the platform in the platform jumping test on average. Apoptosis in the hippocampus after 14 days was significantly less in the training group with significantly greater expression of SHH and Gli2 protein and significantly less PTCH1 protein expression.Conclusion:An EET can significantly improve cognition after cerebral ischemia, at least in rats. Its mechanism may be related to enhanced activation of the SHH signaling pathway.

Objective:To identify the potential intracranial inflammation in neuromyelitis optica spectrum disorders(NMOSD) patients without supratentorial MRI lesions using quantitative susceptibility mapping (QSM).Methods:Seventy NMOSD patients and 35 age- and gender-matched healthy controls (NC) underwent QSM, 3D-T 1, diffusion MRI from Beijing Tiantan Hospital during June 2019 to June 2021. Susceptibility was compared among NMOSD patients with acute attack (ANMOSD), NMOSD patients in chronic phase (CNMOSD) and NC. The correlation between susceptibility in several brain regions and the cerebrospinal fluid levels of inflammatory makers were analyzed. Results:NMOSD patients showed different susceptibility in several brain regions including bilateral hippocampus, precuneus, right cuneus, putamen, superior parietal and inferior temporal ( P<0.001) and the posr-hoc showed it is higher than normal. Compared to CNMOSD patients, the ANMOSD patients showed increased susceptibility in the cuneus (0.009 ± 0.004 vs. 0.005 ± 0.004, P<0.05). There was significant positive correlations between susceptibility and CSF levels of sTREM2 which reflect the active of microglial cells ( r = 0.494, P<0.05). Conclusions:Despite the absence of supratentorial lesions on MRI, increased susceptibility suggests underlying inflammation in the cerebral cortex in both patients with ANMOSD and CNMOSD, and some of them are obviously related to inflammatory markers in CSF. QSM sequence can be used to explore the potential inflammation in NMOSD patients without obvious supratentorial lesions.

Objective:To analyze the immunology-related risk factors for short-term prognosis in patients with demyelinating diseases of central nervous system, and to evaluate their predictive value.Methods:From January 2012 to October 2022 in Beijing Tiantan Hospital of Capital Medical University and General Hospital of Tianjin Medical University, the clinical data of 362 patients with demyelinating diseases of central nervous system were analyzed, including neuromyelitis optic spectrum disease (NMOSD) 181 cases, multiple sclerosis (MS) 129 cases, anti-myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) 38 cases, acute disseminated encephalomyelopathy (ADEM) 14 cases. According to the expanded disability status scale (EDSS) score at discharge, the patients were divided into good prognosis group (EDSS≤3 scores, 267 cases) and poor prognosis group (EDSS>3 scores, 95 cases). The clinical data, admission severity (admission EDSS score), treatment, autoantibodies and immunoglobulin level and serum inflammatory factor level were compared between two groups. Multivariate Logistic regression was used to analyze the independent risk factors of short-term prognosis in patients with demyelinating diseases of central nervous system; and the predictive efficacy was evaluated by receiver operating characteristic (ROC) curve.Results:Compared with the good prognosis group, the admission EDSS score in the poor prognosis group was significantly higher: 2.5 (1.5) scores vs. 6.5 (3.5) scores. The positive rates of autoimmune disease-related antibody, systemic autoantibody, anti-nuclear antibody, anti-extractable nuclear antigen antibody, thyroid peroxidase antibody and thyroid globulin antibody were significantly higher: 89.5% (85/95) vs. 59.6% (159/267), 75.8% (72/95) vs. 52.1% (139/267), 65.3% (62/95) vs. 38.6% (103/267), 42.1% (40/95) vs. 23.2% (62/267), 40.0% (38/95) vs. 19.1% (51/267) and 42.1% (40/95) vs. 19.9% (53/267). The serum IgM was significantly lower: 0.84 (0.78) g/L vs. 1.00 (0.75) g/L. The serum tumor necrosis factor-α, interleukin-2 receptor and cerebrospinal fluid IgG were significantly higher: 8 055 (3 118) pg/L vs. 6 830 (3 515) pg/L, 348 (175) kU/L vs. 314 (146) kU/L and 47.50 (46.50) g/L vs. 33.00 (24.00) g/L. And there were statistical differences ( P<0.01 or <0.05). Multivariate Logistic regression analysis result showed that the admission EDSS score and anti-nuclear antibody positive were the independent risk factors of short-term prognosis in patients with demyelinating diseases of central nervous system ( OR = 5.034 and 6.942, 95% CI 3.289 to 7.705 and 2.250 to 21.422, P<0.01). ROC curve analysis result showed that the area under the curve of anti-nuclear antibody positive combined with admission EDSS score predicted the short-term prognosis in patients with demyelinating diseases of central nervous system was 0.972, with a sensitivity of 90.5%, and a specificity of 92.5%. Conclusions:The admission EDSS score and anti-nuclear antibody positive are the independent risk factors for poor prognosis in patients with demyelinating diseases of central nervous system. And the combination of two indexes can better predict the short-term prognosis.