EPAS1 prevents telomeric damage-induced senescence by enhancing transcription of TRF1, TRF2, and RAD50.

Telomeres are nucleoprotein structures located at the end of each chromosome, which function in terminal protection and genomic stability. Telomeric damage is closely related to replicative senescence in vitro and physical aging in vivo. As relatively long-lived mammals based on body size, bats display unique telomeric patterns, including the up-regulation of genes involved in alternative lengthening of telomeres (ALT), DNA repair, and DNA replication. At present, however, the relevant molecular mechanisms remain unclear. In this study, we performed cross-species comparison and identified EPAS1, a well-defined oxygen response gene, as a key telomeric protector in bat fibroblasts. Bat fibroblasts showed high expression of EPAS1, which enhanced the transcription of shelterin components TRF1 and TRF2, as well as DNA repair factor RAD50, conferring bat fibroblasts with resistance to senescence during long-term consecutive expansion. Based on a human single-cell transcriptome atlas, we found that EPAS1 was predominantly expressed in the human pulmonary endothelial cell subpopulation. Using in vitro-cultured human pulmonary endothelial cells, we confirmed the functional and mechanistic conservation of EPAS1 in telomeric protection between bats and humans. In addition, the EPAS1 agonist M1001 was shown to be a protective compound against bleomycin-induced pulmonary telomeric damage and senescence. In conclusion, we identified a potential mechanism for regulating telomere stability in human pulmonary diseases associated with aging, drawing insights from the longevity of bats.

Transcutaneous Electrical Acupoints Stimulation Improves Spontaneous Voiding Recovery After Laparoscopic Cholecystectomy: A Randomized Clinical Trial.

BACKGROUND: Facilitating the recurrence of spontaneous voiding is considered to be a way to prevent urinary retention after surgery, which is of great importance in cholecystectomy. This study aimed to assess the effect of transcutaneous electrical acupoint stimulation (TEAS) on spontaneous voiding recovery after laparoscopic cholecystectom. METHODS: Participants who underwent elective laparoscopic cholecystectomy were randomly assigned to either the TEAS group or the sham group. Active TEAS or sham TEAS at specific acupuncture points was conducted intraoperatively and postoperatively. The primary outcome was the recovery speed of spontaneous voiding ability after surgery and secondary outcomes included postoperative urinary retention (POUR), voiding dysfunction, pain, anxiety and depression, and early recovery after surgery. RESULTS: A total of 1,948 participants were recruited and randomized to TEAS (n = 975) or sham (n = 973) between August 2018 and June 2020. TEAS shortens the time delay of the first spontaneous voiding after laparoscopic cholecystectomy (5.6 h [IQR, 3.7-8.1 h] in the TEAS group vs 7.0 h [IQR, 4.7-9.7 h] in the sham group) (p < 0.001). The TEAS group experienced less POUR (p = 0.020), less voiding difficulty (p < 0.001), less anxiety and depression (p < 0.001), reduced pain (p = 0.007), and earlier ambulation (p = 0.01) than the sham group. CONCLUSIONS: Our results showed that TEAS is an effective approach to accelerate the recovery of spontaneous voiding and reduce POUR which facilitates recovery for patients after laparoscopic cholecystectomy.

Acute retinal necrosis following dexamethasone intravitreal implant (Ozurdex®) administration in an immunocompetent adult with a history of HSV encephalitis: a case report.

BACKGROUND: Dexamethasone intravitreal implants (0.7 mg) (Ozurdex®, Allergan Inc., Madison, NJ) are FDA approved for managing macular oedema (ME) of retinal vein occlusion (RVO). The major complications associated with intravitreal Ozurdex® implant include increased intraocular pressure and cataract progression. In regard to the occurrence of retinal complications, we report an unusual intravitreal Ozurdex® implantation-related acute retinal necrosis (ARN). CASE PRESENTATION: A 45-year-old immunocompetent woman with a history of encephalitis presented with photophobia, redness, floaters, and rapidly decreased vision in her left eye. Three and six months ago, she received two doses of intravitreal Ozurdex® implant for ME of RVO. Clinical evaluation, including slit-lamp biomicroscopy, retinal photography, and fluorescein angiography, revealed anterior chamber cells, granulomatous keratic precipitates, cells in the vitreous, optic disc oedema, occlusive retinal vasculitis, scattered retinal haemorrhages, one quadrant of peripheral white areas with retinal necrosis, optic disc and vessels fluorescein staining, and retinal nonperfusion zones. All the above clinical manifestations showed an ARN. Herpes simplex virus was detected in the aqueous and vitreous humour by quantitative polymerase chain reaction testing. Intravenous acyclovir 500 mg tid for 7 days followed by oral valcyclovir was immediately performed for ARN. At 4 months, the patient's condition improved without retinal detachment, and the best-corrected visual acuity remained stable at 0.3. CONCLUSIONS: ARN might represent a risk of Ozurdex® administration.

The epidemiology of paediatric Mycoplasma pneumoniae pneumonia in North China: 2006 to 2016.

Paediatric Mycoplasma pneumoniae pneumonia (MPP) is a major cause of community-acquired pneumonia in China. Data on epidemiology of paediatric MPP from China are little known. This study retrospectively collected data from June 2006 to June 2016 in Beijing Children's Hospital, Capital Medical University of North China and aims to explore the epidemiological features of paediatric MPP and severe MPP (SMPP) in North China during the past 10 years. A total of 27 498 paediatric patients with pneumonia were enrolled. Among them, 37.5% of paediatric patients had MPP. In this area, an epidemic took place every 2-3 years at the peak, and the positive rate of MPP increased during these peak years over time. The peak age of MPP was between the ages of 6 and 10 years, accounting for 75.2%, significantly more compared with other age groups (χ2 = 1384.1, P < 0.0001). The epidemics peaked in September, October and November (χ2 = 904.9, P < 0.0001). Additionally, 13.0% of MPP paediatric patients were SMPP, but over time, the rate of SMPP increased, reaching 42.6% in 2016. The mean age of paediatric patients with SMPP (6.7 ± 3.0 years old) was younger than that of patients with non-SMPP (7.4 ± 3.2 years old) (t = 3.60, P = 0.0001). The prevalence of MPP and SMPP is common in China, especially in children from 6 to 10 years old. Paediatric patients with SMPP tend to be younger than those with non-SMPP. MPP outbreaks occur every 2-3 years in North China. September, October and November are the peak months, unlike in South China. Understanding the epidemiological characteristics of paediatric MPP can contribute to timely treatment and diagnosis, and may improve the prognosis of children with SMPP.

Clinical and genetic characteristics of Chinese pediatric patients with chronic granulomatous disease.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare disease in China, and very little large-scale studies have been conducted to date. We aimed to investigate the clinical and genetic features of CGD in Chinese pediatric patients. METHODS: Pediatric patients with CGD from Beijing Children's Hospital, Capital Medical University, China, were enrolled from January 2006 to December 2016. RESULTS: A total of 159 pediatric patients with CGD were enrolled. The median age of clinical onset was 1.4 months, and 73% (116/159) had clinical onset symptoms before the 1 year of age. The most common site of invasion was the lungs. The lymph nodes, liver, and skin were more frequently invaded in X-linked (XL) CGD patients than in autosomal recessive (AR) CGD patients (P < 0.05). Approximately 64% (92/144) of the pediatric patients suffered from abnormal response to BCG vaccination. The most frequent pathogens were Aspergillus and Mycobacterium tuberculosis. Gene analysis indicated that 132 cases (89%, 132/147) harbored CYBB pathogenic variants, 7 (5%, 7/147) carried CYBA pathogenic variants, 4 (3%, 4/147) had NCF1 pathogenic variants, and 4 (3%, 4/147) had NCF2 pathogenic variants. The overall mortality rate in this study was 43%, particularly the patients were males, with CYBB mutant and did not receive HSCT treatment. CONCLUSIONS: Chronic granulomatous disease is a rare disease affecting Chinese children; however, it is often diagnosed at a later age, and thus, the mortality rate is relatively high. The prevalence and the severity of disease in XL-CGD are higher than AR-CGD.

Clinicopathological parameters predicting recurrence of pT1N0 esophageal squamous cell carcinoma.

AIM: To identify the clinicopathological characteristics of pT1N0 esophageal squamous cell carcinoma (ESCC) that are associated with tumor recurrence. METHODS: We reviewed 216 pT1N0 thoracic ESCC cases who underwent esophagectomy and thoracoabdominal two-field lymphadenectomy without preoperative chemoradiotherapy. After excluding those cases with clinical follow-up recorded fewer than 3 mo and those who died within 3 mo of surgery, we included 199 cases in the current analysis. Overall survival and recurrence-free survival were assessed by the Kaplan-Meier method, and clinicopathological characteristics associated with any recurrence or distant recurrence were evaluated using univariate and multivariate Cox proportional hazards models. Early recurrence (≤ 24 mo) and correlated parameters were assessed using univariate and multivariate logistic regression models. RESULTS: Forty-seven (24%) patients had a recurrence at 3 to 178 (median, 33) mo. The 5-year recurrence-free survival rate was 80.7%. None of 13 asymptomatic cases had a recurrence. Preoperative clinical symptoms, upper thoracic location, ulcerative or intraluminal mass macroscopic tumor type, tumor invasion depth level, basaloid histology, angiolymphatic invasion, tumor thickness, submucosal invasion thickness, diameter of the largest single tongue of invasion, and complete negative aberrant p53 expression were significantly related to tumor recurrence and/or recurrence-free survival. Upper thoracic tumor location, angiolymphatic invasion, and submucosal invasion thickness were independent predictors of tumor recurrence (Hazard ratios = 3.26, 3.42, and 2.06, P < 0.001, P < 0.001, and P = 0.002, respectively), and a nomogram for predicting recurrence-free survival with these three predictors was constructed. Upper thoracic tumor location and angiolymphatic invasion were independent predictors of distant recurrence. Upper thoracic tumor location, angiolymphatic invasion, submucosal invasion thickness, and diameter of the largest single tongue of invasion were independent predictors of early recurrence. CONCLUSION: These results should be useful for designing optimal individual follow-up and therapy for patients with T1N0 ESCC.

Lepidic and micropapillary growth pattern and expression of Napsin A can stratify patients of stage I lung adenocarcinoma into different prognostic subgroup.

Histologic categories and related growth pattern proposed by IASLC/ATS/ERS classification has been reported to be prognostically important in lung adenocarcinoma. Thyroid transcription factor-1 (TTF1) and Napsin A have been investigated as potential prognostic parameters with conflicting results. A total of 211 cases with stage I lung adenocarcinoma were analyzed according to the IASLC/ATS/ERS classification with slight modifications. Expression levels of TTF1 and Napsin A were evaluated by immunohistochemistry. In univariate analyses, we found female sex (p=0.009), lepidic growth pattern (P=0.011) and lack of micropapillary pattern (P=0.048) were favorable predictor significantly associated with disease-free survival (DFS). Lack of mitosis (P=0.044) and Napsin A expression (P=0.031) were favorable predictors for overall survival (OS). Tumors with a maximum diameter≤2 cm had both longer DFS (P=0.008) and OS (P=0.020). Negative TTF1 expression indicated increased risk of death, but failure in statistical significance (P=0.215). After multivariate analysis, histologic subtype, tumor size and gender were identified as independent predictor for DFS (RR: 0.343, 3.697, 0.494; P=0.006, 0.029, 0.019), no feature was found as an independent predictor for overall survival (P>0.05). To conclude, lepidic growth pattern, female sex and tumor size≤2 cm are independent favorable predictors for tumor recurrence, tumors with more than 5% percentage of lepidic growth pattern will have a better prognosis than absence, in early-stage lung adenocarcinoma.

[Analysis of clinicopathological features of intestinal neuroendocrine neoplasms].

OBJECTIVE: To analyze the clinicopathological features of intestinal neuroendocrine neoplasms. METHODS: The clinicopathological features of 114 patients with intestinal neuroendocrine neoplasms treated in our hospital from April 1999 to March 2011 were retrospectively reviewed, including tumor location, histological classification, muscle invasion, metastasis and clinical data. Immunohistochemical SP staining was applied to examine the expression of 15 markers in the tumor specimens. RESULTS: The male:female ratio of the patients was 1.33, and most of the tumors were located in the rectum of polypoid type. The positive rate of immunohistochemical staining of Syn expression was 97.4%, NSE 95.6%, PGP9.5 84.2%, CD56 75.4%, CD57 72.8%, CgA 43.0%, S100 36.0%, Syn combined with CgA 99.1%, and the two marker Syn and CgA combined with any one of CD56, CD57 or PGP9.5 reached to 100%. The 5-years survival rates of G1, G2 were 98.9% and 76.9%, respectively, and the overall 5-year survival rate of intestinal neuroendocrine neoplasms was 92.9%. Two of the 7 cases of poor differentiated neuroendocrine carcinoma died after operation, another 2 of them lost to follow up. Others were still alive during the follow-up. Among the 3 patients with small cell carcinoma, two survived for 8 to 24 months after operation, and one lost to follow up. Two cases of mixed adenoneuroendocrine carcinoma (MANEC) were still surviving during the follow-up. Different histological types of intestinal neuroendocrine neoplasms were significantly different in sex, primary tumor site, pathological type, tumor size, types of combined tumors, pT stage, aggressive nervous and vascular invasion, and metastasis (all P < 0.05). Single factor analysis of the intestinal neuroendocrine neoplasms indicated that tumor size (Z = -6.334, P < 0.001), histological classification (χ(2) = 31.175, P < 0.001) and muscle invasion (χ(2) = 63.567, P < 0.001) were associated with metastasis of intestinal neuroendocrine neoplasms. Logistic analysis showed that muscle invasion was the main behavior risk factor of this tumor (OR = 1.827, P < 0.05). CONCLUSIONS: Intestinal neuroendocrine neoplasms usually occur in males, and the most common involved organ is the rectum. Their histological types are related to the prognosis, and the depth of invasion is an important metastasis factor of intestinal neuroendocrine neoplasms. Of the neuroendocrine makers, the combination of CgA and Syn shows a higher diagnostic sensitivity.

[Analysis of HER2 status in breast carcinoma using fully automated HER2 staining and fluorescence in-situ hybridization technology].

OBJECTIVE: To determine human epidermal growth factor receptor 2 (HER2) status in breast carcinoma by the techniques of a fully automated immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), to compare the concordance of protein expression with gene amplification and to explore the optimization in process quality control. METHODS: A prospective study of invasive breast cancer specimens excised between May 2009 and April 2011 at the Cancer Hospital, Chinese Academy of Medical Sciences was conducted by automated IHC staining with the new 4B5 rabbit monoclonal antibody and FISH. An evaluation was performed according to the ASCO/CAP guidelines (2007) and Chinese guidelines (2009). The gene amplification status of 740 cases were detected by FISH. RESULTS: A total of 2420 cases of breast invasive ductal carcinoma without pre-operation therapy were tested by automated IHC. 551 cases (22.8%) were scored as positive (3+), 664 cases (27.4%) as equivocal (2+), and 1205 cases (49.8%) as negative (1+/0). Gene amplification was detected in 98.0% (242/247) HER2 protein expression positive (3+) cases and in 13.6% (53/389) equivocal (2+) cases. One of 247 (0.4%) HER2 expression 3+ cases and 5 of 389 (1.3%) HER2 expression 2+ cases were equivocal for gene amplification. No gene amplification was detected in expression negative (1+/0) cases by FISH (0/104). The overall concordance between IHC and FISH was 98.6% [(242 + 104)/(247 + 104)]. CONCLUSIONS: There is a high concordance rate between automated IHC with 4B5 rabbit monoclonal antibody and FISH results for assessing the HER2 gene amplification status in surgically-excised breast cancer specimens, suggesting that automated IHC with 4B5 antibody can provide a reliable method to detect HER2 overexpression for eligibility of HER2 targeted therapy.

Clinicopathological analysis of 156 patients with angiomyolipoma originating from different organs.

Angiomyolipoma (AML) is a benign mesenchymal tumor composed of variable proportions of adipose tissue, spindle and epithelioid smooth muscle cells and abnormal thick-walled blood vessels. Approximately one-third of epithelioid AML (EAML) cases have been reported to have metastasis. Thus, it would be of interest to identify the adverse pathological parameters correlated with outcome. However, few studies have been conducted on large numbers of samples. The aim of this study was to highlight the clinicopathological features of AML and the morphological features of EAML, which were correlated with malignant behaviors in patients from a single institutional series analysis. One hundred and fifty-six consecutive AMLs, correlating with pathological characteristics, were analyzed between 1981 and 2010. The Chi-square test was performed to clarify the significance of the clinicopathological factors among the regular and epithelioid subtypes with or without atypia. The two organs most commonly involved were the kidney (77%, 120/156) and liver (14%, 22/156). Of the 156 AMLs, EAMLs (17.3%, 27/156) had more marked mitosis, hemorrhage and multinucleated giant cells compared with the regular AMLs (82.7%, 129/156). The 11 EAMLs with atypia (40.7%, 11/27) had more nucleoli and mitotic cells compared with the 16 EAMLs without atypia (59.3%, 16/27; p<0.05). Follow-up results of 79% of cases (124/156) were obtained, and of these, only one kidney AML (0.8%, 1/124) presented with liver metastasis one year after nephrectomy. This sizeable single institutional AML series analysis revealed that the kidney and liver were the two most commonly involved organs, and most of the cases presented a benign clinical course. Few EAMLs were malignant, although adverse features including atypical mitotic figures, blood vessel invasion and tumor embolus may be significant in predicting malignant behavior.

[Comparison of histopathologic changes and expression of biomarkers in breast carcinoma before and after neoadjuvant chemotherapy].

OBJECTIVE: To investigate the relationship between the pathologic responses and histologic type, grade, the expression of ER, PR and HER2 and their changes in breast carcinoma before and after neoadjuvant chemotherapy (NAC). METHODS: Two-hundred and nine cases of breast cancer with NAC were analyzed and clinical, pathologic data were evaluated based on the Miller and Payne ( MP) grading system. The expression of ER, PR and HER2 in the cancers before and after NAC were detected by immunohistochemistry (MaxVision method). SPSS 15.0 software was used to conduct statistical analysis. RESULTS: (1) Pathologic responses to the NAC were graded as MP1 (14 cases), MP2 (35 cases), MP3 (106 cases), MP4 (36 cases) and MP5 (18 cases); (2) The expression of ER in core needle biopsy had related negatively to the pathologic response (chi2 = 33.083, P = 0.001). However, the histologic type, grade, ER and PR status, and HER2 expression in surgically-removed specimens had not related to the pathologic response (P>0.05); (3) After NAC, the pathologic type and grade changed in 6. 8% (9/132) and 34.9% (30/86) of the cases, and the rates of changes in the expression of ER, PR and HER2 were 42.4% (75/177), 55.4% (98/177) and 26.6% (46/173) , respectively. Only the expression of HER2 had significant difference between before and after neoadjuvant chemotherapy (P = 0.049). The changes in other data had no relationship with the pathologic response (P>0.05). CONCLUSIONS: Analysis of core needle biopsy can provide important information to predict the pathologic responses to the NAC. The pathologic appearance, grade, ER, PR and HER2 in breast carcinoma may change after NAC. It is necessary to examine the histologic type, grade and the expression of ER, PR and HER2 after NAC once more.

[Clinical features of 3 cases with acute interstitial pneumonia in children].

OBJECTIVE: Acute interstitial pneumonia (AIP) is a rare lung interstitial disease in children. This study was conducted to understand the clinical features of the AIP in children. METHOD: The data of the three cases with AIP admitted to our hospital from March 2008 to November 2009 were reviewed. Of the 3 cases, 2 were male, one was female. Their age ranged from 1 year and 4 months to 10 years. The clinical manifestation, pulmonary function test and the high resolution computed tomography (HRCT) and pathology of the lung were studied retrospectively. Tissue specimens of the lung were obtained by video-assisted thoracoscopic biopsy. Viral etiologic examinations for the respiratory syncytial virus, adenovirus, influenza virus, parainfluenza viruses, EB virus, cytomegalovirus, enterovirus and herpes simplex virus were performed. The IgM antibody to Mycoplasma pneumoniae in the serum was also detected. RESULT: All the 3 cases rapidly developed respiratory failure of unknown origin, none of these cases had failure of any other organs. All three cases had cough and dyspnea. No case had the rales and digital clubbing. The examinations for viruses, bacteria and Mycoplasma pneumoniae infection were all negative. No evidence for the diagnosis of connective tissue disease was obtained. The HRCT of the chest showed diffuse alveolar consolidation, air bronchogram and ground glass appearance in the bilateral lungs, and the traction-associated bronchiectasis in areas. All the three cases had the histological proof of diffuse alveolar damage by the biopsy. All the three cases were treated with CPAP and corticosteroid. Two cases were treated with corticosteroid in early stage of the disease, the condition of these cases were improved obviously. The third case was treated with high-dose steroid pulse therapy days, the condition of this case was improved slightly in a month. One year follow-up showed that case 1 and case 2 had no hypoxemia and the HRCT of the chest showed obvious improvement. The pulmonary function of case 2 had restrictive deficiency. CONCLUSION: AIP has a rapidly progressive clinical course leading to respiratory failure. The HRCT of the chest showed alveolar consolidation and ground glass-like change. The pathology of the lung includes diffuse alveolar damage. The prognosis of the AIP in children may be improved by the treatment with respiratory assistance and corticosteroids.

Expressions of the γ2 chain of laminin-5 and secreted protein acidic and rich in cysteine in esophageal squamous cell carcinoma and their relation to prognosis.

Previous studies have shown that the expressions of the γ2 chain of laminin-5 and secreted protein acidic and rich in cysteine (SPARC) play important roles in oncogenesis and the development of carcinoma. To assess the expressions of laminin-5 γ2 chain and SPARC in esophageal squamous cell carcinoma (SCC), and to clarify the prognostic significance of the expressions of laminin-5 γ2 chain and SPARC in esophageal SCC, we detected the expressions of laminin-5 γ2 chain and SPARC in cancer tissue and corresponding normal mucosa from 116 patients with advanced (stages II-IV) esophageal SCC using the tissue microarray-based immunohistochemistry and analyzed the correlation of the expressions with clinicopathologic characteristics and survival. We found that in normal esophageal tissues, laminin-5 γ2 chain was expressed in the basement membrane, whereas in esophageal SCC tissues, laminin-5 γ2 chain was expressed in the cytoplasm of carcinoma cells, with a positive rate of 72.4%. SPARC was not detected in normal esophageal mucosa, but was expressed in stromal fibroblasts in 84.6% of esophageal SCC cases and in cancer cells in 7.8% of esophageal SCC cases. There was a significant correlation between laminin-5 γ2 chain and stromal SPARC expression in esophageal SCC (Spearman's rho=0.423, P<0.001). The expressions of both laminin-5 γ2 chain and stromal SPARC were correlated with survival (P=0.032 and P=0.034, respectively). In stage-II esophageal SCC, the expression of laminin-5 γ2 chain was significantly correlated with survival (P=0.023), while the expression of SPARC was not significantly correlated with survival (P=0.154). Patients with elevated levels of laminin-5 γ2 chain and SPARC expressions had a poorer prognosis than did those lacking elevated levels of laminin-5 γ2 chain expression and/or elevated levels of SPARC expression (P=0.001). In stage-II esophageal SCC, patients with elevated levels of laminin-5 γ2 chain and SPARC expressions had a poorer prognosis (P<0.001). These results suggest that laminin-5 γ2 chain and SPARC may play roles in the progression of esophageal SCC and their simultaneous expression is correlated with poorer prognosis, especially in patients with stage-II SCC.