Chuanzhitongluo capsule improves cognitive impairment in mice with chronic cerebral hypoperfusion via the cholinergic anti-inflammatory pathway.

Vascular cognitive impairment (VCI) has become a common disease-causing cognitive deficit in humans, second only to Alzheimer's Disease (AD). Chuanzhitongluo capsule (CZTL) is a Traditional Chinese Medicine (TCM) preparation known for its effective protection against cerebral ischemia. However, its potential to ameliorate VCI remains unclear. This study aimed to investigate the cognitive improvement effects of CZTL in a mouse model of VCI. Chronic cerebral hypoperfusion (CCH) was induced in mice by bilateral common carotid artery stenosis (BCAS) to simulate the pathological changes associated with VCI. Spatial learning and memory abilities were assessed using the Morris Water Maze (MWM). RNA sequencing (RNA-Seq) was employed to identify differentially expressed genes (DEGs) in the hippocampus. Levels of inflammatory factors were measured through enzyme-linked immunosorbent assay (ELISA), while immunofluorescence (IF) determined the expression intensity of target proteins. Western Blot (WB) confirmed the final action pathway. Results indicated that CZTL significantly improved the spatial learning and memory abilities of CCH mice, along with alterations in gene expression profiles in the hippocampus. It also reduced neuroinflammation in the hippocampus and upregulated the choline acetyltransferase (ChAT) and α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR), which are in synaptic plasticity and neuronal development. Moreover, CZTL inhibited the NF-κB signaling pathway. In conclusion, CZTL may alleviate neuroinflammation induced by CCH and improve cognitive impairment in CCH mice by regulating the cholinergic anti-inflammatory pathway (CAIP) involving ChAT/α7nAChR/NF-κB.

Clinical analysis of 2790 children with retinoblastoma: a single-center experience in China.

BACKGROUND: In this study, we aimed to analyze the clinical characteristics and prognosis of children with retinoblastoma (RB) in a single center in China with a large sample collection spanning 17 years. METHODS: The clinical data of 2790 children with RB treated in Beijing Tongren Hospital from 2005 to 2021 were collected, and a retrospective analysis was conducted. RESULTS: The median age of the participants was 28.3 months. There were 3624 affected eyes, 12.4% of which were in groups A-C, 67.1% in groups D-E and 16.2% were not specified. The primary symptom observed in most cases was a white pupil, accounting for 66.5%, followed by strabismus (12.8%). The median follow-up time was 59.7 months. The enucleation rate was 71.3% (703/986) in a single left eye and 72.5% (702/968) in a single right eye. The overall survival (OS) rate was 95.8% (2444/2552) because 237 patients dropped out, and 109 died. Kaplan‒Meier survival analysis showed that the median survival time (MST) was 125.92 months [95% confidence interval (CI) = 124.83-127.01]. Cox multivariate survival analysis showed that trilateral RB (P = 0.017), metastasis site (P = 0.001), and combined distant tissue metastasis (P = 0.001) were independent prognostic factors for RB. The OS of 44 cases of familial RB was 93.2% (41/44), with an MST of 80.62 months (95% CI = 67.70-93.54). CONCLUSIONS: The timing of eye protection treatment and enucleation should be comprehensively judged to avoid worsening prognosis due to operation time delay. More importantly, the promotion and popularization of diagnosis and treatment technologies are necessary to further improve RB prognosis.

Correlation between ARID1B gene mutation (p.A460, p.V215G) and prognosis of high-risk refractory neuroblastoma.

In a few reports, ARID1B/A mutation was found in neuroblastoma. We analyzed the clinical characteristics, clinical efficacy, and prognosis of three children with high-risk refractory neuroblastoma (NB) with somatic ARID1B gene mutation. The whole exon sequencing results showed that there were involved in transcription, DNA synthesis, and repair of ARID1B gene mutations. All mutation sites were located in the promoter region of the exon: ARID1B (p.A460) mutation was found in cases 1 and 2, and ARID1B (p.V215G) mutation was found in cases 1 and 3. The nucleic acid site of ARID1B (p.A460) mutation was c.1379 (exon1) C > G, and the nucleic acid site of ARID1B (p.V215G) mutation was c.644 (exon1) T > G. The meningeal metastasis in case 1 turned negative after 4 cycles of intrathecal injection combined with chemotherapy. However, the child died of agranulocytosis combined with sepsis during the 5th cycle of chemotherapy. Case 2 achieved complete remission (CR). Case 3 achieved CR after chemotherapy, surgery, metaiodobenzylguanidine, and 3F-8 (Naxitamab) immunotherapy after the initial diagnosis. The mediastinum and lymph node metastasis occurred during the 6-month observation period after stopping treatment. He achieved very good partial remission after individualized chemotherapy and surgical treatment. ARID1B is a component protein of the SWI/SNF chromatin-remodeling complex that participates in the occurrence of a variety of tumors by regulating DNA repair and synthesis. ARID1B nucleic acid mutation (p.A460, p.V215G) in the promoter region of three children may contribute to the poor prognosis of NB children.

Chuanzhitongluo regulates microglia polarization and inflammatory response in acute ischemic stroke.

BACKGROUND AND PURPOSE: Chuanzhitongluo (CZTL), a traditional Chinese medicine mixture, is used in the recovery period of acute ischemic stroke (AIS), and effectively improves the prognosis of AIS patients. This study aims to evaluate whether CZTL regulates microglia polarization and inflammatory response to reduce brain damage in the acute phase of AIS. METHODS: A mouse model of AIS was prepared by the photochemical method. Cerebral infarct volume was detected by 2,3,5-Triphenyltetrazolium chloride (TTC) staining. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to assess neuronal apoptosis. Gene expression profile change was explored by Gene chip. Inflammatory factors were analyzed by Protein microarray. The Immunofluorescence double-labeling assay was executed to elucidate the effects of CD16+ / Iba-1+ and CD206+ / Iba-1+ in the peripheral area of cerebral ischemia. RESULTS: Results revealed that CZTL treatment alleviated the neurological impairment, reduced cerebral infarct volume, and inhibited neuronal apoptosis. CZTL altered gene expression profiles, which indicate that CZTL may be involved in regulating neuroinflammation. CZTL restrained inflammatory responses by down-regulated pro-inflammatory cytokines expression and enhanced anti-inflammatory cytokines level. Further experiments demonstrated that CZTL inhibited the activation of NLRP3 inflammasome, which decreasing the inflammatory response. In addition, CZTL promoted the transformation of microglia from M1 to M2 phenotype. CONCLUSIONS: These results indicate that CZTL alleviates neuroinflammation and brain damage after AIS in mice, which may be mediated by modulating microglia polarization.

Corrigendum: The Effects of rs405509 on APOEε4 Non-carriers in Non-demented Aging.

[This corrects the article DOI: 10.3389/fnins.2021.677823.].

Clinical Characteristics and Image Manifestations of a Rare Retinoblastoma with a Bone Metastasis.

Purpose: Retinoblastoma (RB) is the most common intraocular malignancy in infancy and childhood. This study evaluated the clinical and imaging features, treatment, and prognosis of patients with recurrent RB with limb bone metastases and without central nervous system involvement. Patients and Methods: The clinical data of five patients with RB with limb bone metastases who were diagnosed at the Department of Pediatrics in Beijing Tongren Hospital between January 2015 and January 2021 were analyzed retrospectively. Results: Three males and two females were included (seven eyes: four group E and one each of group D, C, and B). The most common symptom was pain. Three patients had bone marrow and lymph node metastases. Three patients had single and two had multiple skeletal lesions. The main bones that were involved were the femur, humerus, talus, and ulna. The simultaneous involvement of the bone marrow and cortex was also observed. Serum neuron-specific enolase (NSE) levels were significantly elevated in four cases and slightly elevated in one case; primary intravenous chemotherapy resulted in a decrease in NSE levels and the gradual resolution of the bone lesions. Two patients died at the time of follow-up and three were in complete remission. The results of the statistical analysis showed that anterior chamber invasion was correlated with prognosis, and there was significant difference in the decrease in the serum NSE levels after intravenous chemotherapy. Conclusion: Regular lifelong follow-up of patients with RB is warranted to identify bone metastases earlier. Anterior chamber invasion may be a risk factor. The simultaneous involvement of the bone marrow and cortex is characteristic manifestations in images of RB with bone metastases. Multidisciplinary treatment especially intravenous chemotherapy is useful, at least at the beginning.

Correlation between Family RB1 Gene Pathogenic Variant with Clinical Features and Prognosis of Retinoblastoma under 5 Years Old.

Retinoblastoma (RB) is the most common primary intraocular malignant tumor in infants and the prototype of human hereditary tumors. Its occurrence and development are closely related to the pathogenic variant of tumor suppressor RB1 gene. We aim to analyze the characteristics of RB1 gene pathogenic variant and clinical phenotype in retinoblastoma patients and their relatives. Children with RB were recruited from August 2007 to November 2017. QT-PCR, probing, and gene sequencing were used to analyze the sequence of RB1 gene in RB children, their parents, or grandparents with a clear history of illness. The SPSS20.0 software was used to analyze the correlation between polymorphisms of RB1 gene and the incidence and prognosis of the enrolled children and relatives. 40 RB children (20 males and 20 females) were recruited, unilateral RB accounted for 52.5% (21/40), bilateral RB accounted for 42.5% (17/40), and trilateral RB accounted for 5.0% (2/40). 6 patients had a clear family history (15.0%, 6/40). It had been verified that 19 probands (47.5%) have RB1 gene pathogenic variants (11 frameshift and 8 missense pathogenic variants), of which germline inheritance accounted for 47.4% (9/19) and nongermline heredity accounted for 52.6% (10/19). Pathogenic variants of 10 nucleic acid sites without reported were found, among which c.2455C>G (p.L819V) was confirmed to have heterozygous pathogenic variants in both a bilateral RB patient and his mother with unilateral RB. Family genetic high-risk factors, bilateral/trilateral RB, >12-month-onset RB have a higher proportion of RB1 gene pathogenic variant than children with no family history, unilateral RB, and ≤12-month (P = 0.021, 0.001,0.034). The proportion of pedigree inheritance of infantile retinoblastoma with bilateral disease is high. There was a certain proportion of RB1 gene pathogenic variant in 3-5-year-old children with bilateral RB, even if they had no family genetic history. Therefore, the detection of RB1 gene pathogenic variant should not only focus on infants but also on the phenotype of RB1 gene pathogenic variant in children over 3 years old with bilateral eye disease.

Clinical features and imaging manifestations of retinoblastoma with hepatic metastasis.

Clinical data of five patients with hepatic metastases of retinoblastoma were analyzed retrospectively (two had bilateral tumors three had unilateral intraocular tumors). On computed tomography, multiple and single low-density foci were observed. Four patients had tumor remission, and one showed no response after chemotherapy. Three patients who underwent enucleation were at high risk for extensive choroidal invasion. Central nervous system and bone metastases occurred in all five patients. Neuron-specific enolase and lactate dehydrogenase levels were significantly elevated in all patients. Two patients died (not from hepatic metastasis). Three patients (one with tumor progression and two with shorter courses) are continuing treatment.

The Effects of rs405509 on APOEε4 Non-carriers in Non-demented Aging.

BACKGROUND: There is evidence that the T allele of rs405509 located in the apolipoprotein E (APOE) promotor region is a risk factor for Alzheimer's disease (AD). However, the effect of the T/T allele on brain function in non-demented aging is still unclear. METHODS: We analyzed the effects of the rs405509 T/T allele on cognitive performances using multiple neuropsychological tests and local brain function using resting-state functional magnetic resonance imaging (rs-fMRI). RESULTS: Significant differences were found between T/T carriers and G allele carriers on general cognitive status, memory, and attention (p < 0.05). Rs-fMRI analyses demonstrated decreased amplitude of low frequency fluctuation (ALFF) in the right middle frontal gyrus, decreased percent amplitude of fluctuation (PerAF) in the right middle frontal gyrus, increased regional homogeneity (ReHo) in the right cerebellar tonsil and decreased ReHo in the right putamen, and decreased degree centrality (DC) in the left middle frontal gyrus (p < 0.05, corrected). Furthermore, significant correlations were found between cognitive performance and these neuroimaging changes (p < 0.05). CONCLUSION: These findings suggest that T/T allele may serve as an independent risk factor that can influence brain function in different regions in non-demented aging.

Case Analysis of 14 Children with Malignant Rhabdoid Tumor of the Kidney.

OBJECTIVE: This study aims to summarize the clinical features and prognoses of the malignant rhabdoid tumor of the kidney (MRTK) in children. It further aims to analyze the high-risk factors affecting MRTK prognosis. METHODS: Clinical data from 14 children with MRTK treated in Paediatrics of Beijing Tongren Hospital from January 2010 to December 2019, along with the high-risk factors affecting prognosis, were retrospectively analyzed. RESULTS: There were 14 children with MRTK included in the study, with a median onset age of 13 (3-46) months. Thirteen patients had distant metastases, the most common site for metastases being inside the lung. A comprehensive treatment protocol combined with chemotherapy was mainly applied during the surgery. A surgical resection of primary tumors was performed on 13 (13/14) patients, and all 14 children received chemotherapy with ifosfamide + carboplatin + etoposide, ifosfamide + etoposide, and vincristine + pirarubicin + cyclophosphamide regimens, alternately. Three patients received radiotherapy and two received oral targeted drugs after partial response. The median follow-up was after 16.5 months (3-53 months) and the four-year overall survival (OS) was 41.8%. In children aged ≤24 months and children aged >24 months, the two-year OS was 67.2% and 100% (χ2 = 108.998, P<0.05), respectively. In children with Ki 67 > 70% and children with Ki 67 < 70%, the two-year OS was 52.6% and 86.9% (χ2 = 8.544, P = 0.003), respectively. In children with distant metastases and children without distant metastasis, the two-year OS was 70% and 100% (χ2 = 14.239, P<0.05), respectively. CONCLUSION: The most common MRTK distant metastasis site is the lung. Risk factors for poor MRTK prognoses include an age of <24 months, Ki 67 > 70%, and distant metastases.

Case report: Delayed retinoblastoma relapse in a lymph node after 9 years of complete remission.

Retinoblastoma (RB) is the most common primary intraocular malignancy of childhood. Recurrence of RB often occurs within 6 months to 1 year after the end of treatment. Orbital tissue is the most common site of recurrence in children who have undergone enucleation; other sites include the central nervous system, bone, bone marrow, lymph nodes, and other organs. Here, we describe an adolescent girl who presented with RB recurrence and metastasis in a distant lymph node after 9 years of complete remission. The tumor was an incidental finding during a routine examination and was misdiagnosed as lymphadenitis. After histopathologic examination of an aspiration biopsy sample, the correct diagnosis of recurrent metastatic RB was made. Systemic chemotherapy and surgical excision were provided; the patient remained tumor-free during the 6-month follow-up period. RB often relapses within 1 year after treatment; orbital tissue is the most common site of recurrence. However, our patient's case was unique in terms of delayed relapse and the presence of a single metastatic site; these findings may provide new insights into the behavior of RB. Furthermore, this case report indicates the need for lifelong follow-up of children with RB. Oncologists should be vigilant when treating patients with a history of RB, because complete remission does not mean complete safety; long-term recurrence and metastasis may occur. Lifelong follow-up is necessary for children with RB. Complete remission might be achieved after active and standardized treatment.

Clinical characteristics, treatment and prognosis of children with unilateral retinoblastoma and intracranial segment of Retrobulbar optic nerve invasion.

BACKGROUND: To analyze the clinical characteristics, treatment and prognosis of children with unilateral retinoblastoma (RB) and intracranial segment of retrobulbar optic nerve invasion. METHODS: A total of 14 children with unilateral RB and intracranial segment of retrobulbar optic nerve invasion were enrolled in this retrospective study from January 2009 to December 2018. Clinical characteristics, treatment and prognosis were collected and analyzed. Survival curves were calculated by Kaplan-Meier method. RESULTS: Of 14 cases, there were 7 male and 7 female, ranging in age from 22.85 to 121.97 months (median, 41.03 months). Seventy-one percent of patients came from first-tier cities in China and effected in the left eye. Magnetic resonance imaging (MRI) results indicated that all patients presented with thickened and enhanced optic nerve and intracranial segment of optic nerve invasion. Nine patients received comprehensive therapeutic regimen (chemotherapy, eye enucleation, radiotherapy and intrathecal therapy). The patients were followed up to December 2019, with a median follow-up of 20.6 months. The median disease specific survival was 48.99 ± 8.62 months, and the overall survival (OS) rate was 64.3%. Radiotherapy and comprehensive therapeutic regimen had significant impact on survival time (all p < 0.05). CONCLUSIONS: The overall prognosis of unilateral RB patients with intracranial segment of retrobulbar optic nerve invasion was poor. Chemotherapy and surgical treatment were necessary, but more attention should be paid to radiotherapy and intrathecal therapy for improving prognosis.

MicroRNA-185 suppresses pancreatic cell proliferation by targeting transcriptional coactivator with PDZ-binding motif in pancreatic cancer.

The aim of the present study was to compare the expression of transcriptional coactivator with the PDZ-binding motif (TAZ) in pancreatic cancer (PC) patients, and to investigate the regulation mechanisms of TAZ in the proliferation of PC. PC tissues and matched peritumoral tissues, pancreatic juice and serum were collected from PC patients who underwent pancreatectomy between June 2012 and December 2015 at the Affiliated Hospital of Qingdao University (Qingdao, China). Pancreatic juice and serum were collected from patients with chronic pancreatitis as a control. The levels of taz mRNA expression in the samples were examined by reverse-transcription quantitative polymerase chain reaction, and the protein expression of TAZ was assessed by western blot analysis and ELISA. MicroRNAs (miRNAs) that regulate TAZ expression were also predicted by bioinformatics analysis and validated by dual luciferase reporter and rescue assays. In addition, the proliferation of PC cells was evaluated after transfection with TAZ small interfering RNA (siRNA) or its upstream miRNA agomir. Expression of TAZ was significantly increased in the PC tissues, pancreatic juice and serum of PC patients at the mRNA and protein levels compared with controls (P<0.05). Furthermore, TAZ was predicted and verified to be a target of miRNA (miR)-185, and miR-185 and TAZ were inversely expressed in samples from PC patients (P<0.05). In addition, TAZ siRNA or agomiR-185 transfection significantly inhibited human pancreatic adenocarcinoma cell proliferation (P<0.05). However, overexpression of TAZ in the agomiR-185 group rescued the inhibition (P<0.05). Finally, the expression of TAZ effector proteins, namely ankyrin repeat domain-containing protein and cysteine-rich 61, were upregulated in PC tissues (P<0.05), but repressed following transfection of PC cells with agomiR-185 (P<0.05). Thus, miR-185 may regulate the proliferation of PC by targeting TAZ, making it a promising diagnostic marker for PC.

Neuroglobin protects cardiomyocytes against apoptosis and cardiac hypertrophy induced by isoproterenol in rats.

Neuroglobin (Ngb) is well known as a physiological role in oxygen homeostasis of neurons and perhaps a protective role against hypoxia and oxidative stress. In this study, we found that Ngb is expressed in rat heart tissues and it is related to isoproterenol induced cardiac hypertrophy. Moreover, overexpression or knock-down of Ngb influences the expression of hypertrophic markers ANP and BNP and the ratio of hypertrophic cells in rat H9c2 myoblasts when isoproterenol treatment. The Annexin V-FITC/PI Staining, Western blot and qPCR analysis showed that the involvement in p53-mediated apoptosis of cardiomyocytes of Ngb is might be the mechanism. This protein could prevent the cells against ROS and POS-induced apoptosis not only in nervous systems but also in cardiomyocytes. From the results, it is concluded that Ngb is a promising protectant in the cardiac hypertrophy, it may be a candidate target to cardiac hypertrophy for clinic treatment.

[Effects of large dose of Astragalus membranaceus on the dendritic cell induction of peripheral mononuclear cell and antigen presenting ability of dendritic cells in children with acute leukemia].

OBJECTIVE: To explore the effects of large dose of Astragalus membranaceus (Astragalus) on the dentritic cell (DC) induction in vitro and augumentation by peripheral mononuclear cell (MNC) and on antigen presenting ability of DC in children with acute leukemia. METHODS: Forty-four children with acute leukemia in complete remission stage were divided into two groups. Twenty patients in the Astragalus (90 g daily) group were treated with large dose of Astragalus (90 g daily) based on conventional chemotherapy for one month, while 24 patients in the control group received chemotherapy alone. MNC were extracted from peripheral blood by wall-sticking method and cultured with such cell factors as interleukin-4, gramulocyte macrophage colony stimulating factor, tumor necrosis factor-alpha for 7-8 days. Phenotype of DC was assayed by flow cytometry and antigen presenting ability of them was assayed by mixed lymphocyte reaction. RESULTS: There was no morphological difference in MNC induced DC between the two groups. The average number of DC in Astragalus group and control group was 4.4 x 10(6) / 2.5 x 10(6) MNC and 2.6 x 10(6) / 2.5 x 10(6) MNC, respectively, showing significant difference (P < 0.001). DC in Astragalus group could stimulate the proliferation of allogeneic lymphocytes strongly, showing significant difference when compared with that in the control group (P < 0.001). Conclusion Large dose of Astragalus could increase the DC induction of MNC and enhance the antigen presenting ability of DC in acute leukemia patients.