[Adrenal cortical carcinoma in children: a clinicopathological analysis of 25 cases].

Objective: To investigate the clinicopathological features, diagnosis and differential diagnosis of adrenal cortical carcinoma (ACC) in children. Methods: Twenty-five children with ACC diagnosed in the Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China from March 2014 to August 2022 were retrospectively analyzed. The related literature was reviewed. Results: A total of 25 children with ACC were collected, including 11 males and 14 females, with a male to female ratio of 1.0∶1.3. The patient ages ranged from 8 months to 14 years (median, 4 years). Eighteen cases with clinical data had functional tumors (18/22, 81.8%) presenting with virilization or precocious puberty (15/18), symptoms related to hypercortisolism (8/18) or endocrine symptoms mixed with both (5/18), while 3 cases (3/22, 13.6%) had unknown clinical data. The clinical manifestations of four patients with nonfunctional tumors were an abdominal mass and/or abdominal pain, walking instability and others. Grossly, the average maximum diameter of the tumor was 9.4 cm. Most of the tumors were nodular and partially encapsuled. The cut surfaces were gray or gray brown, soft with hemorrhage. Histologically, the tumor cells were diffusely distributed, separated by a vascular-rich network. The tumor cells were large, with distinct nucleoli, abundant eosinophilic or clear cytoplasm, and round or oval nuclei. The mitotic index was high, and atypical mitoses were common. Necrosis, calcification, capsule invasion or/and venous invasion were present. In some cases, the tumor invaded the surrounding soft tissues or kidneys. Immunohistochemically, the tumor cells were diffusely positive for syn and SF1 and focally positive for α-inhibin, Melan A and Calretinin, but negative for CgA. Ki-67 proliferation index ranged from 2%-90%. TP53 gene status was examined in 7 cases, in which mutations were detected in 4 cases. Follow-up data was obtained in 21 patients, among whom 18 received chemotherapy and 3 received radiotherapy. Distant metastasis occurred in 13 patients. Median progression-free survival (PFS) was 11.2 months and median overall survival (OS) was 54.7 months. Patients aged less than 5 years had a better prognosis for OS (P<0.05) than the older ones (≥5 years), but a similar PFS (P>0.05). Male patients and Ki-67 proliferation index <15% had a better prognosis tendency for OS, but there was no statistically significant difference (P>0.05). Conclusions: ACC in children is a rare, often functional tumor associated with Li-Fraumeni genetic syndrome and has a poor prognosis. Diagnosis and differential diagnosis require a combination of morphological, phenotypic and clinical analysis.

[Multiple primary tumors in children: a clinicopathological analysis of four cases].

Objective: To investigate the clinicopathological features of children with metachronous or synchronous primary tumors and to identify related genetic tumor syndromes. Methods: The clinicopathological data of 4 children with multiple primary tumors diagnosed in the Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China from 2011 to 2023 were collected. The histological, immunophenotypic and molecular characteristics were examined using H&E staining, immunohistochemical staining, PCR, Sanger sequencing and next-generation sequencing (NGS). The patients were followed up. Results: Case 1 was an 8-year-old boy with the adrenal cortical carcinoma, and 5 years later a poorly differentiated gastric adenocarcinoma was detected. Case 2 was a 2-year-old boy, presented with a left ventricular choroid plexus carcinoma, and a hepatoblastoma was detected 8 months later. Case 3 was a 9-month-old girl, diagnosed with renal rhabdoid tumor first and intracranial atypical teratoid/rhabdoid tumor (AT/RT) 3 months later. Case 4 was a 7-year-old boy and had a sigmoid colon adenocarcinoma 3 years after the diagnosis of a glioblastoma. The morphology and immunohistochemical features of the metachronous or synchronous primary tumors in the 4 cases were similar to the corresponding symptom-presenting/first-diagnosed tumors. No characteristic germ line mutations were detected in cases 1 and 2 by relevant molecular detection, and the rhabdoid tumor predisposition syndrome was confirmed in case 3 using NGS. Case 4 was clearly related to constitutional mismatch repair deficiency as shown by the molecular testing and clinical features. Conclusions: Childhood multiple primary tumors are a rare disease with histological morphology and immunophenotype similar to the symptom-presenting tumors. They are either sporadic or associated with a genetic (tumor) syndrome. The development of both tumors can occur simultaneously (synchronously) or at different times (metachronously). Early identification of the children associated with genetic tumor syndromes can facilitate routine tumor screening and early treatment.

[Efficacy and safety of neoadjuvant chemotherapy combined with PD-1 antibody for esophageal squamous cell carcinoma in the real world].

Objective: To evaluate the efficacy and safety of neoadjuvant chemotherapy combined with programmed death-1 (PD-1) antibody in operable, borderline or potentially resectable locally advanced esophageal squamous cell carcinoma(ESCC) in the real world. Methods: The study retrospectively analyzed 28 patients with operable or potentially resectable locally advanced ESCC patients treated with preoperative chemotherapy combined with PD-1 inhibitor in Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School from April 2020 to March 2021. According to the clinical TNM staging system of the 8th edition of the American Joint Committee on Cancer, there were 1, 15, 10, 1 and 1 case of stage Ⅱ, Ⅲ, ⅣA, ⅣB and unknown stage respectively. The treatment was two cycle of dual drug chemotherapy regimen including taxane plus platinum or fluorouracil combined with PD-1 antibody followed by tumor response assessment and surgery if the patient was eligible for resection. Results: Of the 28 patients, 1, 2, 3 and 4 cycles of chemotherapy combined with PD-1 antibody treatment completed in 1, 21, 5, and 1 patient, respectively. Objective response rate (ORR) was 71.4% (20/28), and disease control rate (DCR) was 100% (28/28). The incidence of adverse events exceeding grade 3 levels was 21.4% (6/28), including 3 neutropenia, 1 leukopenia, 1 thrombocytopenia and 1 immune hepatitis. There was no treatment-related death. Of the 23 patients underwent surgery, R0 resection rate was 87.0% (20/23), 13 patients had down staged to the T1-2N0M0 I stage, the pCR rate was 17.3% (4/23), and the pCR rate of primary tumor was 21.7% (5/23). Four patients received definitive chemoradiotherapy. One patient rejected surgery and other treatment after achieved PR response. Conclusion: Neoadjuvant chemotherapy combined PD-1 inhibitor is safe and has high efficacy in operable, borderline or potentially resectable locally advanced ESCC, and it is a promising regimen.

[Phenotypic and genotypic characteristics of Escherichia coli causing bloodstream and abdominal co-infection].

Objective: To analyze the phenotypic and genotypic characteristics of Escherichia coli causing bloodstream and abdominal co-infection (CoECO), and provide clues for empirical antibiotics treatment. Methods: The strains of Escherichia coli isolated from blood and abdominal samples in the Department of Laboratory Medicine of the First Medical Center of the PLA General Hospital from 2010 to 2020 were retrospectively analyzed. Mass spectrometer was used to identify all of the strains and the minimum inhibitory concentration (MIC) were detected by VITEK 2 Compact. All isolates were sequenced by 2×150 bp double terminal sequencing strategy on the HiSeq X Ten sequencer (Illumina). After the genome sequence was spliced, the single nucleotide polymorphism (SNP) analysis of the strain sequence was performed using kSNP3 software to clarify the homologous relationship between strains. If the strains isolated from two different parts had high homology, they were regarded as the same strain and the case was with CoECO infection. Meanwhile, the multilocus sequence type (MLST) was determined using PubMLST website and resistant genes were screened by CARD website. Results: A total of 70 cases of CoECO infection were screened, including 45 males and 25 females, and aged (59.2±16.3) years old. The 70 CoECO isolates belonged to 35 sequence types (STs). The most prevalent STs included ST38 (n=6), ST 405 (n=6), ST 1193 (n=6) and ST131 (n=5), and other ST types contained less than 5 strains. The homologous relationship among strains was relatively scattered, presenting a sporadic trend as a whole, and only a few strains had a small-scale outbreak. The CoECO isolates showed significantly resistance to ampicillin (91.4%, 64/70), ampicillin/sulbactam (74.3%, 5 2/70), ceftriaxone (72.9%, 51/70), ciprofloxacin (71.4%, 50/70) and levofloxacin (71.4%, 50/70), and high-sensitivity to piperacillin/tazobactam, carbapenems and amikacin. The most prevalent resistant gene was tet (A/B) (70%, 49/70), followed by blaTEM (58.6%, 41/70), sul1 (55.7%, 40/70), sul2 (54.3%, 38/70), blaCTX-M-14(25.7%, 18/70), blaCTX-M-15(17.1%, 13/70), blaCTX-M-55(15.7%, 11/70), blaCTX-M-64/65(5.7%, 4/70), blaCTX-M-27(4.3%, 3/70), mcr-1 (4.3%, 3/70), blaNDM-5(2.9%, 2/70). Conclusions: CoECO is distributed dispersedly and has no obvious advantage clone. No genotype with obvious advantages was found. Although the strain has a high resistance rate to some antibacterial drugs, the proportion of carrying resistant genes is low, and it has a high sensitivity to some first-line antibacterial drugs.

[Primary adrenal NK/T cell lymphoma: a clinicopathologic analysis of six cases].

Objective: To investigate the clinicopathologic features of primary adrenal NK/T cell lymphoma (PANKL). Methods: Six cases of PANKL were collected at Henan Provincial People's Hospital from January 2000 to December 2021. The clinicopathologic features including morphology, immunophenotype, treatment and prognosis were retrospectively analyzed, and relevant literature was reviewed. Results: There were two males and four females. The median age was 63 years (ranged from 57 to 68 years). The tumors involved bilateral adrenal glands in 4 cases and unilateral adrenal gland in 2 cases. The main clinical symptom was low back pain without obvious cause. Serum lactate dehydrogenase (LDH) is elevated in five cases. The imaging feature was rapidly enlarging mass initially confined to unilateral/bilateral adrenal glands. Morphologically, the lymphoid cells were mainly medium-sized with a diffuse growth pattern. Coagulative necrosis and nuclear fragmentation were common. Angioinvasion was seen. Immunophenotypically, the neoplastic cells were positive for CD3, CD56 and TIA-1 while CD5 was negative in 5 cases. All cases were positive for EBER by in situ hybridization with more than 80% proliferative activity by Ki-67. Four cases received chemotherapy, one case underwent surgery, and one case underwent surgery with chemotherapy. Follow-up was done in 5 cases; one case was lost to follow-up. Three patients died with a median survival of 11.6 months (3-42 months). Conclusions: PANKL is rare with highly aggressive clinical presentation and poor prognosis. Accurate diagnosis entails correlation of histomorphology, immunohistochemistry, EBER in situ hybridization and clinical history.

[The preliminary study of Neuroform EZ stent in the treatment of severe intracranial atherosclerotic stenosis].

Objective: To evaluate the safety and clinical efficacy of Neuroform EZ stent in the treatment of severe intracranial atherosclerotic stenosis (ICAS). Methods: A total of 36 patients with severe ICAS receiving Neuroform EZ stent angioplasty were retrospectively analyzed at Beijing Anzhen Hospital from July 2018 to January 2020. Digital subtraction angiography (DSA) before endovascular intervention confirmed the diagnosis. Follow-up information was reviewed by neurologists at 30 days and 6 months after the procedure. The primary endpoints were transient ischemic attack (TIA), ischemic or hemorrhagic stroke and death caused by any reason within 30 days. Results: The overall technical success rate was 100%. The median stenosis rate was reduced from 93.6%±4.5% to 18.8%±11.2% (t=37.36,P<0.001).Primary endpoint event was not reported. During follow-up, one patient developed TIA and no death or ischemic stroke was observed. No in-stent restenosis at six months occurred. Conclusion: Neuroform EZ stent is safe and effective in patients with severe ICAS. However, perspective studies need to be operated for further validation via long-term follow-up.

[Clinicopathological features of mature T/NK cell lymphoma with aberrant CD20 or CD79α expression].

Objective: To investigate the clinicopathological characteristics and prognosis of mature T/NK cell lymphomas with aberrant CD20 or CD79α expression. Methods: A retrospective analysis of 641 cases of mature T/NK cell lymphoma diagnosed from January 2014 to December 2020 was performed, and 14 cases of CD20-positive and one case of CD79α-positive mature T/NK-cell lymphoma were identified. Histological examination, immunohistochemical characterization, in situ hybridization for Epstein-Barr virus encoded early RNA (EBER), and PCR testing for immunoglobulin and T cell receptor (TCR) gene rearrangements were performed. Clinicopathological characteristics of these lymphomas were analyzed. Results: There were 13 males and 2 females, with a median age of 56 years. There were 8 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), 3 cases of extranodal NK/T-cell lymphoma, nasal type (ENKTCL), 2 cases of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) and 2 cases of angioimmunoblastic T-cell lymphoma (AITL). Twelve cases were stage Ⅲ or Ⅳ lymphomas. The prognosis was overall poor. The histology, immunophenotype and TCR gene rearrangement were not significantly different from the corresponding types of lymphoma. Ki-67 proliferation index was over 70% in all cases. The expression of CD20 or CD79α was weak and heterogeneous. All 15 case of Ig gene rearrangement were polyclonal. Conclusions: Mature T/NK cell lymphoma with abnormal expression of CD20 or CD79α is rare, commonly found in advanced stage, and associated with poor prognosis. The expression of CD20 or CD79α in these cases is weaker than the corresponding mature T/NK cell lymphomas, while its proliferation index is higher. Histomorphology, extensive immunoprofiling and molecular detection are required for accurate diagnosis.

[Clinicopathological features and BRAF V600E and MYD88 L265P mutation status of nodal marginal zone lymphoma].

Objective: To investigate the clinicopathological features as well as BRAF V600E and MYD88 L265P mutation status of nodal marginal zone B cell lymphoma (NMZL). Methods: Thirty-two cases of NMZL were diagnosed from September 2009 to February 2021 at the Henan Provincial People's Hospital and Peking University School of Basic Medical Sciences. The clinicopathologic characteristics were obtained and analyzed. BRAF V600E and MYD88 L265P mutation status were identified using PCR and Sanger sequencing, respectively. Results: There were 20 males and 12 females patients with a median age of 69 years (ranging 36-82 years). The most prevalent clinical manifestation was multiple lymph nodes enlargement in head and neck (22/32, 68.8%), followed by inguinal (12/32, 37.5%), axillary (11/32, 34.4%), mediastinum (5/32, 15.6%) and retroperitoneal lymph nodes (4/32, 12.5%). Most of the patients were in Ann Arbor stage Ⅰ/Ⅱ (21 cases). The morphologic features included diffuse (24/32, 75.0%), nodular (5/32, 15.6%), interfollicular (2/32,6.3%) and perifollicular (1/32,3.1%) types. The tumor cells showed monocyte-like, centrocyte-like, small lymphocyte-like and plasma cell-like differentiation. Immunophenotyping revealed diffuse expression of CD20 in all tumor cells, whereas CD43 (11/32, 34.4%), bcl-2 (20/32, 62.5%), MNDA (13/32, 40.6%) and CD5 (2/32, 6.3%) were partially expressed. Ki-67 proliferation index varied from 10% to 40%. BRAF V600E mutation was found in two cases (2/32, 6.3%), but MYD88 L265P mutation was not detected. Eighteen patients survived and three died at the end of follow-up period which ranged 6 to 110 months. Conclusions: The morphologic features of NMZL varies across individuals, it should be differentiated from various B-cell lymphomas; however immunological biomarkers with high specificity for NMZL are still lacking. No MYD88 L265P mutation is found in NMZL. Some cases may harbor BRAF V600E mutation and yet the prevalence remains indeterminate; further researches are warranted.

Effects of the circadian rhythm on milk composition in dairy cows: Does day milk differ from night milk?

Metabolism in most organisms can show variations between the day and night. These variations may also affect the composition of products derived from livestock. The aim of the present study was to investigate the difference in composition between the day milk and night milk of dairy cows. Ten multiparous Holstein cows (milk yield = 25.2 ± 5.00 kg/d) were randomly selected during mid lactation. Milk samples were collected at 0500 h ("night milk") and 1500 h ("day milk") and analyzed to determine their composition. Mid-infrared spectroscopy was used to analyze macronutrient content of milk. Metabolomics and lipidomics were used to detect and analyze small molecules and fatty acids, respectively. An automatic biochemical analyzer and ELISA kits were used to determine biochemical indicators, as well as antioxidant and immune parameters in the milk. Though milk fat, protein, lactose, and total milk solids were not different between day milk and night milk, small molecules, metabolites and lipids, and hormones and cytokines differed between day milk and night milk. Regarding biochemical and immune-related indicators, the concentrations of malondialdehyde, HSP70, and HSP90 in night milk were lower than that in day milk. However, interferon-γ levels were higher in night milk. Additionally, night milk was naturally rich in melatonin. Lipidomics analyses showed that the levels of some lipids in night milk were higher than those in day milk. Metabolomics analyses identified 36 different metabolites between day milk and night milk. Higher concentrations of N-acetyl-d-glucosamine, cis-aconitate, and d-sorbitol were observed in day milk. However, the other 33 metabolites analyzed, including carbohydrates, lipids, AA, and aromatic compounds, showed lower concentrations in day milk than in night milk. The present findings show that the composition of night milk differs considerably from that of day milk. Notable changes in the circadian rhythm also altered milk composition. These results provide evidence to support the strategic use and classification of day milk and night milk.

Mucin 5AC is significantly upregulated in exosomes from the nasal lavage fluid and may promote the expression of COX-2, VEGF and MMP-9: an implication in nasal polyp pathogenesis.

BACKGROUND: Exosomes are critical mediators of intercellular communication and could be involved in many human diseases; however, little is known about the role of exosomes in nasal polyps (NP). METHODS: Exosomes in nasal lavage fluids (NLF) were isolated by ultracentrifugation. Exosome identity was validated by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and specific exosomal markers. The exosome proteome was revealed by LC-MS/MS, and the expression of the candidate exosomal protein, mucin 5AC, was confirmed by Western blot analysis and immunohistochemistry (IHC). Cellular uptake of the exosomes was monitored by fluorescence confocal microscopy and the ensuing effects on COX-2, VEGF and MMP-2/MMP-9 were determined by Western blotting, ELISA and gelatin zymography, respectively. RESULTS: Mass spectrometry analysis and subsequent verification by Western blotting identified that mucin 5AC was significantly upregulated in exosomes from NLFs of NP patients. Moreover, the expression of mucin 5AC was increased in the tissue specimens of the NP patients. Functional assays suggest that the mucin 5 AC-enriched exosomes could be effectively taken up by chronic rhinosinusitis without NP (CRSsNP)-derived fibroblasts, the control cells, resulting in a significant increase in the expression of COX-2, VEGF and MMP-9. CONCLUSIONS: Mucin 5AC, the major airway mucin, cannot only be carried and transferred by nasal exosomes, but may also promote tissue remodeling and angiogenesis and thus could be a potential therapeutic target of NP.

[Efficacy and safety of PD-1 inhibitor combined with chemotherapy in the primary treatment of phase â ¢/â £ extranodal nasal-type natural killer/T cell lymphoma].

The data of 9 patients with stage Ⅲ/Ⅳ extranodal nasal-type natural killer/T cell lymphoma from August 2019 to August 2020 in People's Hospital of Zhengzhou University was retrospectively analyzed. All the patients were treated with the programmed cell death-1 (PD-1) inhibitor combined with P-GemoX-DEX (gemcitabine+oxaliplatin+dexamethasone+peraspartase) regimen as the first-line treatment. After 4 cycles of treatment, positron emission tomography/computed tomography (PET/CT) was used to evaluate the curative effect, and adverse reactions were also observed. The median follow-up time was 7 months. The overall response rate, complete and partial remission rate was 9/9, 6/9 and 3/9, respectively. The main adverse event was hematological toxicity, with 6 cases of grade Ⅰ/Ⅱ neutropenia, and no immune-related adverse events were reported.

[Extranodal nasal type natural killer/T-cell lymphoma of the digestive system: a clinicopathological study of thirteen cases].

Objective: To investigate the clinicopathological features, and diagnostic and differential diagnostic characteristics of extranodal nasal type natural killer/T-cell lymphoma (ENKTCL) of the digestive system. Methods: Thirteen cases of ENKTCL in the digestive system were collected at the Henan Provincial People's Hospital, Zhengzhou, China, from August 2000 to August 2020. The histopathological, immunohistochemical and in situ hybridization features were analyzed, as well as those of T-cell receptor (TCR) gene rearrangement in some cases. The patients were followed up. Results: There were 11 males and 2 females. The age ranged from 28 to 80 years (median=53 years). Seven cases were present in the colorectum, and 3 cases were present in the small intestine. The other three cases were in stomach, gallbladder and liver (one case each). The main clinical symptoms were fever, and abdominal pain, often accompanied by fatigue, diarrhea, hematochezia, elevated serum albumin, elevated lactate dehydrogenase, and increased peripheral blood EB virus DNA copy. Histologically, the tumor accompanied by a heavy admixture of inflammatory cells (small lymphocytes, plasma cells and histiocytes). There was diffuse dense tumor cell infiltrate, with prominent coagulative necrosis. The lymphomatous infiltrate had angiocentric and angio-necrotic changes. Immunohistochemically, lymphoid cells expressed CD3 in all cases. Some of them showed weakened/absent other T cell markers, while all of them expressed CD56 except 1 case. A few of the cases showed CD4-/CD8+ killer T cell phenotypes. In situ hybridization showed EB virus encoded RNA (EBER) was positive in all cases. Clonal TCR gene rearrangement was not detected in all 7 cases tested. The median survival time was 9 months. Conclusions: ENKTCL of the digestive system is extremely rare. It often predisposes the patients to acute abdomen such as perforation of the gastrointestinal tract. The treatment outcomes are dismal, and the prognosis is poor. Clinical and imaging studies are often non-specific. It is also easy to be misdiagnosed as non-specific ulcers. Combined with immunohistochemistry, in situ hybridization and TCR gene rearrangement analysis and better understanding of this tumor's clinicopathological characteristics can help improve its diagnosis and early treatment.

Barriers to early diagnosis and treatment of severely immunosuppressed patients with HIV-1 infection: A quantitative and qualitative study.

OBJECTIVES: To explore the barriers to early diagnosis of HIV infection and timely initiation of antiretroviral therapy (ART). METHODS: We assessed the annual number and proportion of ART-naïve people living with HIV infection (PLWH) with severe immunosuppression in Shenzhen, China, from 2008 to 2019. Selected ART-naïve PLWHs with severe immunosuppression who were seeking treatment for the first time in the hospital in 2019 were subjected to an in-depth interview. RESULTS: The proportion of severely immunosuppressed, ART-naïve PLWH decreased from 36.73% in 2008 to 8.94% in 2015, and then plateaued at approximately 10% from 2015 to 2019. Overall, 55 patients, 70% of whom were men who had sex with men, participated in the qualitative interviews. Ten of them delayed treatment after diagnosis, with a median [interquartile range (IQR)] interval of 5.83 (3.98-8.54) years between diagnosis and ART. More than 80% of the patients reported casual sexual contact within a median period of 6 years and with a median (IQR) of nine (4-20) casual sex partners. The major barriers to HIV testing and diagnosis included lack of knowledge about HIV and high-risk behaviours, low awareness about HIV testing, and resistance to HIV testing. The major barriers to ART initiation included lack of knowledge about the importance of ART and change of national ART eligibility policy, and HIV-related stress. CONCLUSIONS: The number of PLWHs with severe immunosuppression who seek treatment remains high in Shenzhen, China. Thus, current HIV-related care programmes targeting access to early diagnosis and treatment need to be improved.

[Neuroprotective effect of ginsenoside Rb-1 on a rat model of Alzheimer's disease].

Objective: To investigate the protective mechanism of ginsenoside Rb-1 on the brain in a rat model of Alzheimer's disease. Methods: Fifty-six male Sprague-Dawley rats were randomly divided into control group, model group, low-dose Rb-1 group (Rb-1: 25 mg•kg(-1)•d(-1)) and high-dose Rb-1 group (Rb-1:50 mg•kg(-1)•d(-1)). Morris water maze was designed to observe the changes of learning and memory ability in rats. Flow cytometry was used to detect the apoptosis of hippocampal neurons. Immunohistochemistry and Western blot were employed to detect the expression levels of apoptosis-related genes (p53, Bax, cytochrome C (Cyto C), Caspase-3 and caspase-9) and anti-oxidative stress-associated genes (nuclear Factor-E2-related factor 2 (Nrf2), kelch-like ECH-associated protein 1 (keap-1), heme oxygenase 1(HO-1) and NADPH quinone dehydrogenase 1 (NQO1)).The activities of catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were detected by relevant kits. ANOVA and Tukey-Kramer test were used for statistical analysis. Results: The learning and memory ability of rats in the model group was lower than that of the control group (P<0.01).The learning and memory ability of rats in the high-dose Rb-1 treatment group was significantly higher than that of the model group [(80±8) s vs (100±11) s, t=5.390, P<0.01]. The expression levels of apoptosis-related genes (p53, Bax, Cyto C, caspase-3 and caspase-9) in the model group were significantly higher than those in the control group (P<0.01), while the expression levels of these genes in low-dose and high-dose Rb-1 groups were significantly lower than those of the model group (P<0.01). The expression levels of Nrf2, HO-1 and NQO1 genes in the model group were significantly lower than those in the control group (P<0.05), while the expression of these genes in low-dose and high-dose Rb-1 groupswere significantly higher than those of the model group (P<0.01). The activities of CAT, GSH-Px and SOD in the model group were lower than those in the control group (P<0.01), however the activities of CAT, GSH-Px and SOD in low-dose and high-dose Rb-1 groups were higher than those of model group (P<0.05). Conclusions: Both low-dose and high-dose Rb-1 have protective effect on memory and cognitive function of Alzheimer's disease rats by reducing the damage and apoptosis of hippocampal neurons, down-regulating the expression levels of p53, Bax, Cyto C, caspase-3 and caspase-9, up-regulating the expression of Nrf2, HO-1 and NQO1 genes, and increasing the activities of CAT, GSH-Px and SOD. Moreover, the protective effect of Rb-1 on rat brain may be dose-dependent.

[Long-term outcomes of Bryan artificial cervical disc replacement for degenerative cervical spondylosis].

Objective: To compare the long-term clinical effect and imaging results of Bryan artificial cervical disc replacement (ACDR) and anterior cervical discectomy and fusion (ACDF) and to explore whether ACDR can reduce the occurrence of postoperative adjacent segment degeneration (ASD) in the treatment of degenerative cervical spondylosis. Methods: It was a retrospective study. Total of 60 patients with degenerative cervical spondylosis, who had received operations by Bryan ACDR (n=27) and ACDF (n=33) in the Third Hospital of Hebei Medical University between January 2005 and December 2009 were enrolled in this study. The Japanese Orthopedic Association (JOA) scores, neck disability index (NDI), visual analogue scale (VAS), Odom's scale, cervical range of motion (ROM), surgical segment ROM, heterotopic ossification (HO) and ASD were used to evaluate the clinical and radiologic results. The indices abovementioned were compared between the two groups. Results: The VAS, NDI and JOA scores at each follow-up node in both ACDR and ACDF group were all significantly improved when compared with those before operation (all P<0.05), but there was no significant differences between the two groups (all P>0.05). Of all, 88.9%(24/27) of patients in ACDR group and 84.8%(28/33) of patients in ACDF group achieved excellent or good results, however, there was no significant difference in Odom's scale between the two groups (P>0.05). At the last follow-up, the cervical ROM in ACDR group was 43.2°±8.8°, which was slightly lower than that before operation (45.7°±10.4°), the difference was not statistically significant (t=0.954, P=0.345); the surgical segment ROM in ACDR group was 5.9°±3.6°, which was significantly reduced when compared with that before operation (8.8°±3.4°, t=3.043, P<0.01). However at the last follow-up, the cervical ROM in ACDF group was 36.4°±8.4°, which was significantly reduced when compared with that before operation (43.9°±11.1°), the difference was statistically significant (t=3.095, P<0.01). Although, there was no significant difference in the cervical ROM between the two groups before operation (t=0.643, P=0.523), and the difference was statistically significant at the last follow-up (t=3.054, P<0.01). At the last follow-up, the incidence of HO in ACDR group was 92.6%, and the high-grade HO was 37.0%. The incidence of ASD in ACDR group was 39.5%, which was much lower than that in ACDF group (61.1%, χ(2)=4.462, P=0.035). Conclusion: At minimum follow-up of 10 years, Bryan ACDR achieves a satisfactory clinical effect consistent with ACDF. In terms of advantages, ACDR could maintain the ROM of cervical and retain the ROM of the surgical segment, which reduces the occurrence of ASD by preserving motion.

[Efficacy comparison of primary percutaneous coronary intervention by drug-coated balloon angioplasty or drug-eluting stenting in acute myocardial infarction patients with de novo coronary lesions].

Objective: To compare the safety profile, angiographic and clinical outcomes between drug-coated balloon(DCB) only strategy versus drug eluting stent(DES) implantation in primary percutaneous coronary intervention(PCI) for acute myocardial infarction(AMI) patients. Methods: A total of 380 AMI patients who underwent primary PCI in Beijing Chaoyang Hospital from January 2016 to May 2019 were enrolled. They were allocated into DEB group(n=180) or DES group(n=200). The Primary endpoint was the major adverse cardiac events(MACE) in hospital and within 3 months after discharge, the composite event of cardiac death, non-fatal myocardial infarction(MI), target vessel revascularization(TVR) and in stent thrombosis. The secondary endpoints included: (1)TIMI blood flow grade and myocardial perfusion grade (TMP grade) of infarct-related vessels before and after PCI. (2)The degree of ST segment resolution(STR) between half hour and two hours after PCI, and STR was represented by percentage of summed ST-segment reduction between baseline and post-PCI. Using the most significant lead of ST segment elevation, calculating the rate of decline in the ST segment after treatment; or the most significant lead of the ST segment depression, to calculate the rate of recovery in the ST segment after treatment. STR<50% was defined as incomplete STR. (3)The occurrence of coronary artery dissection during operation. (4)The peak value of myocardial enzymes. (5)The incidence of bleeding in hospital and within 3 months after discharge. The inverse probability weighting method based on propensity score (IPTW) was used to compare the effects of the two treatments on MACE occurrence in the logistic regression model. Results: There was no significant difference in sex, age, risk factors of coronary heart disease, type and site of AMI, interventional therapy data(P>0.05) between the two groups. The ratio of bifurcation lesions in DCB group was significantly higher than that in DES group, and the diameter of the DCB was smaller while the length was longer than that of DES (all P<0.05). One death occurred in each group during hospitalization. Compared with the DES group, the incidence of MI ï¼»2.8%(5/180) vs. 0.5% (1/200), P=0.10ï¼½ and TVR ï¼»2.8%(5/180) vs. 0.5%(1/200), P=0.10ï¼½ in the DCB group during hospitalization showed an increasing trend, and were mostly associated with delayed coronary dissection. The incidence of MACE was similar between the two groups (3.3%(6/180) and 1.0%(2/200), P=0.15) during hospitalization. There was no MACE occurred in the two groups within 3 months after discharge. There was no significant difference between the two groups in TIMI grade, TMP grade, incomplete STR rate and peak value of myocardial enzyme (all P>0.05). The incidence of coronary artery dissection was significantly higher in DCB group than in DES group (8.3%(15/180) and 3.0%(6/200), P=0.02), but most of them were type B or A dissection and did not need special treatment. There was no significant difference in bleeding event between the two groups(P=0.91). Logistic regression analysis showed that there was no difference in the risk of MACE during hospitalization between DES and DCB groups for AMI patients receiving PCI (compared with DCB, OR=0.35, 95%CI 0.08-1.43, P=0.13). Conclusions: The initial safety and efficacy profiles of DCB are similar with those of DES for the AMI patients during PCI. The study highlights that the incidence of coronary dissection (type A or B) is higher post DCB treatment than post DES, but it does not affect blood flow. However, the incidence of in-hospital MI due to delayed coronary dissection trends to be higher post DCB. So we should pay close attention to the risk of delayed coronary dissection after DCB in AMI patients with de novo lesion.

[Brain protection strategy and effectivity in pulmonary thromboendarterectomy].

Objective: To summarize the experience and effectivity of brain protection in 25 patients who suffered from chronic thromboembolic pulmonary hypertension (CTEPH) and received pulmonary thromboendarterectomy (PTE) under deep hypothermic circulatory arrest. Methods: Retrospective analysis of 25 PTE surgeries in our center from December 2016 to August 2018. All cases were completed underdeep hypothermic circulatory arrest. Standard brain protections were strictly executed, including: balanced and controlled extracorporeal circulation cooling, cerebral oxygen saturation (rSO(2)) monitoring, strictly control of circulatory arrest time, and etc. The neurological adverse events during the perioperative period were recorded and statistically analyzed, and the intelligence level and cognitive function of the patients were evaluated by MMSE scale and MoCA scale before surgery and discharge. Results: All the 25 patients successfully completed the surgery, and 1 patient (4%) died of postoperative infection. The mean pulmonary arterial pressure decreased from (52.9±16.7) mmHg before surgery to (23.6±8.1) mmHg immediately after surgery (t=10.01, P<0.01), and(20.7±7.9) mmHg at 3 months follow-up (t=10.73, P<0.01). Pulmonary vascular resistance decreased from 975.4 (788.6-1 292.8) dyn·s·cm(-5) to 376.1 (283.6-565.5) dyn·s·cm(-5) (Z=5.34, P<0.01). Neurological complications occurred in 3 patients during the perioperative period, including 2 patients with hypoxic encephalopathy, and 1 patient with cerebral hemorrhage. All 3 patients fully recovered before discharge. Univariate analysis showed that the duration of rSO(2)<40% and the maximum decrease rate of rSO(2) from baseline were significantly correlated with postoperative neurological damage. Multivariate analysis showed only time of rSO(2)<40% was significantly correlated with postoperative neurological damage. There was no significant difference in MMSE and MoCA score before and after surgery (P>0.05). Conclusions: Adequate brain protection measures are essential to reduce the neurological complications of PTE surgery. Real-time intraoperative monitoring of rSO(2) and strict control of circulatory arrest time can further reduce the occurrence of neurological damage.

[Progress and prospects of clinical cell therapy for liver cirrhosis and liver cancer].

The treatment options for liver cancer and liver cirrhosis are limited. Cell therapy (immune cells, stem cells) can significantly improve the therapeutic effect by actively regulating body's immunity. In addition, when choosing different methods of cell therapy, clinicians should also fully consider the adverse reactions associated with cell therapy. This article reviews the progress of cells therapy in clinical trials of liver cancer and liver cirrhosis, including therapeutic mechanism, advantages, disadvantages and limitations.

[Effect of thrombus aspiration during primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction].

Objective: To investigate the effect of thrombus aspiration during primary percutaneous coronary intervention (PPCI) in patients with ST-segment elevation myocardial infarction (STEMI). Methods: This retrospective study included 321 STEMI patients who underwent PPCI at Beijing Chaoyang hospital from January 2013 to March 2014. Patients were divided into the PPCI group (189 cases) and the PPCI plus thrombus aspiration group (132 cases). Baseline and perioperative clinical data, procedural characteristics were collected, and primary endpoint events including all-cause death, re-myocardial infarction, and coronary revascularization and secondary endpoint events including cardiac death, recurrent angina, target lesion revascularization, and stent thrombosis were recorded during the follow-up. Results: There were no significant difference between PPCI group and PPCI plus aspiration group in age ((59.8±12.5) years old vs. (58.3±14.4) years old, P=0.060) and male ratio (82.5% (156/189) vs. 82.6% (109/132), P=0.993). The number of disease vessels (1.59±0.81 vs. 1.47±0.70, P=0.039) and the prevalence of left anterior descending as infarction related artery (52.3% (69/132) vs. 38.6% (73/189), P=0.022) were significantly higher in the PPCI plus aspiration group than that in the PPCI group.The symptom onset time (3.0 (2.0,4.8) hours vs. 4.0 (2.0,7.0) hours, P=0.027) and myocardial ischemia time (3.9 (2.7,6.2) hours vs. 4.7 (2.9,7.9) hours, P=0.022) were significantly in the PPCI plus aspiration group than in the PPCI group. The percent of thrombolysis in myocardial infarction (TIMI) thrombosis score≥ grade 4 (92.4% (122/132) vs. 75.1% (142/189), P<0.001)and postoperative TIMI flow grade 3 (70.5% (93/132) vs. 60.8% (115/189), P=0.003) was significantly higher in the PPCI plus aspiration group than in the PPCI group. The PPCI group patients were followed up for (31.6±7.5) months, and PPCI plus aspiration group patients were followed up for (32.2±6.7) months (P=0.466). During the follow-up period, there was no significant difference in the incidence of primary endpoint events between the PPCI plus aspiration group and the PPCI group (17.1% (22/129) vs. 16.9% (31/184), P=0.962). Recurrent angina was more frequent in the PPCI plus aspiration group than in the PPCI group (25.6% (33/129) vs. 16.3% (30/184), P=0.044). There was no significant difference in cardiac death (3.1% (4/129) vs. 3.3% (6/184), P=1.000), target lesion revascularization (3.9% (5/129) vs. 3.3% (6/184), P=0.765), and stent thrombosis (3.1% (4/129) vs. 2.7% (5/184), P=1.000) between the PPCI plus aspiration group and the PPCI group. Multivariate Cox regression analysis showed that the number of diseased vessels (RR=1.901, 95%CI 1.217-2.970, P=0.005) and postoperative TIMI flow grade (RR=0.455, 95%CI 0.221-0.934, P=0.032) were the risk factors for coronary revascularization after PPCI. The number of diseased vessels was a risk factor for major endpoint events after PPCI (RR=1.421, 95%CI 1.017-1.986, P=0.040). Conclusion: The incidence of clinical events is similar in patients with STEMI treated with PPCI alone or PPCI plus aspiration.

[Development and Optimization of Therapeutic Analogues of Anti-TNFα Antibody Infliximab].

Previously, we have reported the crystal structures of Fab fragment of Infliximab in complex with TNFα. The structurally identified epitope on TNFα revealed the mechanism of TNFα inhibition by partially overlapping with the TNFα-receptor interface and the possibility to optimize the binding affinity. In this study, we launched a screen of a phage display library to isolate novel anti-TNFα antibodies based on the infliximab epitope. To develop novel anti-TNFα antibodies, structural analysis, the phage display antibody isolation, step by step antibody optimization, CDR residues random mutagenesis, and binding affinity characterization were performed. One of the novel antibodies generated on the backbone of infliximab, Inf3D6, has the superior binding affinity to TNFα, thus, demonstrating the potential for structure guided optimization for improvement of existing antibody-based therapeutics.