Risk factors for recurrent wheezing after bronchiolitis.

BACKGROUND: This study aimed to determine whether there was an association between certain factors in patients with bronchiolitis and recurrent wheezing in childhood. METHOD: In 2021 we tracked children hospitalized for bronchiolitis at Chengdu Women's and Children's Central Hospital in 2017. The patients were classified into recurrent wheezing group (RWG) and non-recurrent wheezing group (NRWG). Possible risk factors including maternal age, school-age siblings, allergic history, atopic dermatitis, allergic rhinitis, atopic family history, severity of the condition, duration of hospitalization, nasopharyngeal secretions culture, blood eosinophil counts, FeNO and skin prick test were compared between the two groups. Continuous variables were analyzed by independent sample t-test for normal distribution and Mann-Whitney U-test for non-normal distribution. Categorical variables were tested using chi-square tests. Multifactor analysis was conducted by stepwise logistics regression analysis. RESULTS: In total 167 participants were included, of which 26 and 141 were in RWG and NRWG respectively. In RWG children represented higher maternal age (P = 0.02) and greater probability of allergic history, atopic dermatitis, allergic rhinitis, atopic family history (odds ratio [OR] = 4.0,3.7, 7.8, 10.9 respectively, P < 0.01). However, school-age siblings, severity of the condition, duration of hospitalization, blood eosinophil counts, fractional exhaled nitric oxide and skin prick test results seemed unrelated to recurrent wheezing. In the subgroup analysis of nasopharyngeal secretion culture, there were more Moraxella catarrhalis-positive in RWG(P = 0.043). Atopic dermatitis, allergic rhinitis and atopic family history were identified as independent risk factors for recurrent wheezing. CONCLUSION: Some children with bronchiolitis will develop recurrent wheezing, and the risk factors are allergic history, Moraxella catarrhalis infection or colonization, atopic dermatitis, allergic rhinitis and atopic family history; the latter three are independent risk factors.

Identifying a sphenoid sinus fungus ball using a nomogram model.

BACKGROUND: Sphenoid sinus fungus ball (SSFB) is a rare entity and usually presents with non-specific symptoms. SSFB could potentially lead to serious orbital and intracranial complications. Computed tomography (CT) scan is usually the first imaging test of the diagnostic workup in patients with specific clinical symptoms. This study aimed to compare the clinical characteristics and CT features between SSFB and unilateral (non-fungus ball) chronic sphenoid rhinosinusitis (USRS) and help differentiate between these two most common inflammatory diseases of the sphenoid sinus. METHODS: By retrospective database review, 66 patients with a histopathologic diagnosis of isolated SSFB were recruited for analysis. Fifty-four patients who underwent endoscopic sinus surgery with clinical and histopathological diagnoses of USRS were enrolled as the control group. Clinical characteristics and CT features were evaluated. RESULTS: Headache, rhinorrhoea, nasal obstruction, postnasal dripping, and hyposmia were the most common symptoms in both groups. In the univariate analysis, older age, lower white blood cell counts, irregular surface, bony dehiscence, lateral wall sclerosis, and intralesional hyperdensity (IH) were significant predictors for SSFB. Older age, irregular surface, and IH remained statistically significant in the multivariate analysis. Based on the results of the regression analysis, a nomogram for predicting the probability of SSFB was plotted. CONCLUSIONS: We developed a nomogram model as a novel preoperative diagnostic tool for identifying SSFB according to the predictors both in clinical characteristics and on CT features. This could help the clinicians in predicting the probability of SSFB, to reduce ineffective or delayed treatment and occurrence of complications.

Deep Underground Laboratory Measurement of

The ^{13}C(α,n)^{16}O reaction is the main neutron source for the slow-neutron-capture process in asymptotic giant branch stars and for the intermediate process. Direct measurements at astrophysical energies in above-ground laboratories are hindered by the extremely small cross sections and vast cosmic-ray-induced background. We performed the first consistent direct measurement in the range of E_{c.m.}=0.24 to 1.9 MeV using the accelerators at the China Jinping Underground Laboratory and Sichuan University. Our measurement covers almost the entire intermediate process Gamow window in which the large uncertainty of the previous experiments has been reduced from 60% down to 15%, eliminates the large systematic uncertainty in the extrapolation arising from the inconsistency of existing datasets, and provides a more reliable reaction rate for the studies of the slow-neutron-capture and intermediate processes along with the first direct determination of the alpha strength for the near-threshold state.

Application of Anlotinib Combined With Neoadjuvant Chemotherapy in Primary EWS/PNET of Lung: A Case Report.

Primary pulmonary EWS/PNET(PPES) is extremely rare and is associated with a poor prognosis. Tumor angiogenesis plays an important role in tumor, so it has become a hot topic in molecular targeted therapy. Anlotinib is a new oral small molecular multi-targeted receptor tyrosine kinase (RTK) inhibitor. This report describes a 20 year-old man with PPES. After 4 neoadjuvant chemotherapy cycles (VACwith alternating IE) combined with anlotinib, the left total pneumonectomy was performed. Then maintenance anlotinib monotherapy was continued, no sign of recurrence to date as an outcome. To our knowledge, this is the first demonstration of anlotinib combined with neoadjuvant chemotherapy efficacy in PPES.

Early-life infections in association with the development of atopic dermatitis in infancy and early childhood: a nationwide nested case-control study.

BACKGROUND: Microbial dysbiosis has been implicated in the development of atopic dermatitis (AD). The risk of development of AD following early-life infections remains unclear. OBJECTIVE: To investigate the impact of early-life infections on AD development. METHODS: This population-based nested case-control study was conducted using the Taiwan's National Health Insurance Research Database. A total of 5454 AD patients and 16 362 control subjects without AD were identified, for the period 1997 to 2013. Demographic characteristics, comorbidities and maternal factors were compared. Adjusted odds ratio (aOR) was calculated to examine the associations between early-life infections and subsequent AD by conditional stepwise logistic regression analysis. RESULTS: Mean age was 2.6 ± 2.9 years in both groups. Overall infections (41.8% vs. 28.9%) before the diagnosis of AD were more common in AD patients than in control subjects (P < 0.001). Infectious diseases [aOR, 1.40; 95% confidence interval (CI), 1.29-1.51], skin infections (aOR, 1.55; 95% CI, 1.40-1.71) and systemic antibiotic exposure (aOR 1.67, 95% CI 1.55-1.79) before AD diagnosis were independently associated with AD development on multivariate analyses. These results were consistent across observation periods (0-1, 1-2 and >2 years after birth) and sensitivity analyses after redefining the index date as 3 or 6 months before the date of AD diagnosis. Other independent risk factors included asthma, allergic rhinitis, intussusception and neonatal hyperbilirubinemia. No association with subsequent AD was found for maternal age at delivery, Caesarean delivery or prenatal antibiotic exposure. CONCLUSION: Infections in early life are associated with AD development in infancy and early childhood.

[A multicenter randomized controlled study of bismuth-containing quadruple therapy followed by Jing-Hua-Wei-Kang in the treatment of patients newly diagnosed with Helicobacter pylori infection and dyspepsia].

Objective: To investigate the Helicobacter pylori (H. pylori) eradication rate and improvement of dyspepsia in patients who were newly diagnosed with H. pylori infection and dyspepsia and treated by bismuth-containing quadruple therapy followed by Jing-Hua-Wei-Kang(JHWK). Methods: Patients who were newly diagnosed with dyspepsia and H. pylori infection and treated in 16 medical centers in China between December 1, 2017 and September 30, 2019 were randomly divided into two groups. The experimental group received bismuth-containing quadruple therapy (esomeprazole+amoxicillin+furazolidone+colloidal bismuth pectin capsule, 14 days), followed by JHWK (30 days), and the course of treatment was 44 days in total. In the control group, the administration regimen was bismuth-containing quadruple therapy (esomeprazole+amoxicillin+furazolidone+colloidal bismuth pectin capsule, 14 days). The main outcome measure was H. pylori eradication rate, while the secondary outcome measures were dyspepsia symptom changes and adverse events during the treatment and the 1st month after treatment. Results: A total of 1 054 patients were included in the study. There were 522 cases enrolled in the experimental group, including 224(42.91%) men and 298(57.09%) women, and the age was 53(26, 73) years old; 532 cases enrolled in the control group, including 221(41.54%) men and 311(58.46%) women, and the age was 46(22, 71) years old. Based on PP analysis, it was found that the H. pylori eradication rate in the experimental group was significantly higher than those in the control group (93.85% vs 87.88%, P=0.001). In the group of all enrolled patients, the symptom dyspepsia after H. pylori eradication was significantly improved compared with that before treatment [4(4, 7) vs 15(10, 22), P<0.001], so was the superior and middle abdominal pain [1(1, 4) vs 4(1, 8), P<0.001], the postprandial fullness [1(1, 4) vs 4(4, 9), P<0.001], the early satiety [1(1, 1) vs 4(1, 4), P<0.001], and the heartburn [1(1, 1) vs 1(1, 4), P<0.001]. The symptom dyspepsia after treatment was significantly improved compared with that before treatment in the experimental, the control groups, the successful and the unsuccessful H. pylori eradication groups. The superior and middle abdominal pain after treatment was signifcantly improved than that before treatment [1(1, 2) vs 1(1, 4), P<0.001], so were the postprandial fullness [1(1, 3) vs 1(1, 4), P=0.002] and the dyspepsia[4(4, 7) VS 7(4, 10), P<0.001]. There was no statistically significant difference in the incidence of adverse events between the experimental group and the control group (1.34% vs 0.38%, P=0.09). Conclusions: Compared with bismuth-containing quadruple therapy, bismuth-containing quadruple therapy followed by JHWK significantly improves the H. pylori eradication rate without increasing the incidence of adverse events. H. pylori eradication therapy can improve symptoms of patients with H. pylori infection and dyspepsia.

[Cognitive and gait dysfunction in the elderly caused by age-related cerebral small vessel disease and idiopathic normal pressure hydrocephalus: a case series of three patients].

Three cases with age-related cerebral small vessel disease and normal pressure hydrocephalus in the Department of Neurology of Sun Yat-sen University were retrospectively reviewed. All the patients exhibited gait disturbance, cognitive impairment and urinary incontinence. Meanwhile, the Craniocerebral imaging demonstrated cerebral small vessel disease and communicating hydrocephalus. The cerebralspinal fluid (CSF) Aß42 levels decreased, and apolipoprotein E (APOE) genotypes were ε3/ε4,ε3/ε3,ε2/ε3, respectively. After treatment in an all-cause individualized manner, the symptoms of 3 patients were stable or improved.

Enhanced O-succinyl-l-homoserine production by recombinant Escherichia coli ΔIJBB*TrcmetL/pTrc-metAfbr -Trc-thrAfbr -yjeH via multilevel fermentation optimization.

AIMS: Constructing a strain with high yield of O-succinyl-l-homoserine (OSH) and improving the titre through multilevel fermentation optimization. METHODS AND RESULTS: OSH high-yielding strain was first constructed by deleting the thrB gene to block the threonine biosynthesis. Single-factor experiment was carried out, where a Plackett-Burman design was used to screen out three factors (glucose, yeast and threonine) from the original 11 factors that affected the titre of OSH. The Box-Behnken response surface method was used to optimize the fermentation conditions. Through gene editing and medium optimization, the titre of OSH increased from 7·20 to 8·70 g l-1 in 500 ml flask. Furthermore, the fermentation process and fed-batch fermentation conditions including pH, temperature, feeding strategy and feeding medium were investigated and optimized. Under the optimal conditions, the titre of OSH reached 102·5 g l-1 , which is 5·6 times higher than before (15·6 g l-1 ). CONCLUSIONS: O-succinyl-l-homoserine fermentation process was established and the combination of response surface methodology and metabolic pathway analysis effectively improved the titre of OSH. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, the titre of OSH reached the needs for industrial production and the metabolic pathway of OSH was demonstrated for further optimization.

Long noncoding RNA NNT-AS1 functions as an oncogene in breast cancer via repressing ZFP36 expression.

Breast cancer is one of the most common cancers in women. This study focuses on the effects of Long non-coding RNAs (lncRNAs) NNT-AS1 on breast cancer cell growth and metastasis. Fifty-six pairs of breast cancer (BC) tissues and matched paracarcinoma tissues were obtained. The BC cell lines and normal human breast cell line were employed. NNT-AS1 in BC cells was knocked down by shRNA. Cell counting kit-8 assay (CCK-8), colony formation assay, cell cycle analysis, cell apoptosis analysis, cound healing assay, Transwell assay, cioinformatics analysis, Western blot analysis and Xenograft model were used. Quantitative real-time polymerase chain reaction (qRT-PCR) assay indicated that expression of NNT-AS1 was obviously upregulated in breast cancer tissues compared with adjacent tissues (n=56). Knockdown of NNT-AS1 could attenuate breast cancer cell viability, proliferation, invasion and migration, as well as promote cell apoptosis and induce cell cycle arrest at G0/G1 phase. ZFP36 was directly combined with NNT-AS1, and silencing of ZFP36 could rescue tumor suppression role by downregulating NNT-AS1 on cell proliferation and metastasis. Knockdown of NNT-AS1 could suppress cell growth and metastasis via interacting with ZFP36 in vivo. This study demonstrated that knockdown of NNT-AS1 had tumor-suppressive effect on breast cancer progression and metastasis via interacting with ZFP36 in vitro and in vivo, which provides a new insight into the treatment and prognosis evaluation of breast cancer.

[Correlation of vasogenic white matter lesions and retinal vascular network parameters].

Objective: To investigate the correlation of vasogenic white matter lesions with retinal vascular network parameters using fully automatic retinal image analysis of fundus photographs. Methods: A total of 106 patients with cerebral small vessel disease who were hospitalized in Department of Neurology, the First Affiliated Hospital of Sun Yat-sen University during March and October 2015, and were able to undertake cerebral MRI and fundus photography in a sitting position were included. They were divided into two groups (mild or moderate-severe) according to the Fazekas scores of periventricular white matter lesions and deep white matter lesions shown by MRI. The clinical data and retinal vascular network parameters were compared between mild and moderate-severe groups. Results: According to the severity of periventricular white matter lesions, Logistic regression analysis showed that after adjusting baseline information, decreased asymmetry index of artery (OR=1.71, 95%CI 1.02-2.88, P<0.05)was associated with periventricular white matter lesions. As for deep white matter lesions, Logistic regression analysis showed that after adjusting baseline information, decreased central retinal artery equivalent(OR=5.19, 95%CI 1.06-25.44, P<0.05), decreased asymmetry index of artery (OR=2.96, 95%CI 1.42-6.17, P<0.05), decreased asymmetry index of venule (OR=2.99, 95%CI 1.48-6.02, P<0.05) and increased central retinal vein equivalent (OR=0.14, 95%CI 0.03-0.67, P<0.05) were associated with deep white matter lesions. Conclusions: White matter lesions of different places could be contributed to different pathological process. Therefore, the early diagnosis and observation of them are applicable to different retinal vascular network parameters.

T-cell factor-4 and MHC upregulation in pigs receiving a live attenuated classical swine fever virus (CSFV) vaccine strain with interferon-gamma adjuvant.

The effect of co-administration of interferon (IFN)-γ in pigs undergoing vaccination with an attenuated strain (LPC) of classical swine fever virus (CSFV) was investigated. Unvaccinated pigs demonstrated pyrexia and died 7-9 days after challenge with virulent CSFV. Pigs receiving the attenuated vaccine remained healthy after virus challenge, except for mild, transient pyrexia, whereas pigs receiving IFN-γ simultaneously with the vaccine demonstrated normal body temperatures after virus challenge. Examination by nested RT-PCR revealed greater viral load in the spleens of the pigs vaccinated with the attenuated CSFV, compared with those that had additionally received IFN-γ. Expression of major histocompatibility complex (MHC) class I and MHC class II molecules was upregulated in the spleens of the IFN-γ treated vaccinated pigs, demonstrated by immunohistochemistry. Based on Western blot analysis, anti-CSFV IgG2 antibodies were elevated in vaccinated pigs by co-administration of IFN-γ (IFN-γ(Hi): P < 0.01; IFN-γ(Lo): P <0.05). By employing the suppression subtractive hybridization technique, RT-PCR, in situ hybridization, and immunohistochemistry, T-cell factor-4 (Tcf-4) mRNA and protein expression were found to be upregulated in the spleens of vaccinated pigs that had received IFN-γ. This study suggests involvement of Tcf-4 in IFN-γ-mediated immune regulation following CSFV vaccination.

Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells.

Hepatoma exhibits a series of heterogeneous subpopulations in its cell surface markers, tumorigenicity, invasion and metastatic capability. We previously demonstrated that the CD133(-)/EpCAM(-) hepatoma subpopulation was more metastatic than its counterpart; however, the controlling mechanisms are unexplored. The present study aimed to delineate the significance of aberrant hedgehog (Hh) signaling in the mediation of metastases. Fluorescence-activated cell sorting-enriched CD133(-)/EpCAM(-) (double negative, DN), Huh-7 cells underwent a transwell selection for metastatic cells (transwell-selected, TS). The TS cells displayed much greater metastatic activity as evidenced by an increased invasion rate, extremely upregulated expression of matrix metalloproteinase (MMP)-1/2/9 genes compared with DN and double-positive (DP) subpopulations. In contrast to DP cells, TS cells lost E-cadherin and were all vimentin-positive as shown by immunocytochemistry. There was a transitional increase in Gli-1/2 gene expression levels from DP, DN to TS subpopulations, which was consistent with elevated Gli-1/2 or Twist-1 protein levels in the nuclear fraction. Furthermore, truncated Gli-1 (tGli-1), which transactivates molecules involved in metastasis, was detected in the highly invasive Huh-7 cell subpopulation, but not in less metastatic hepatoma cells or normal hepatocytes. The enhanced metastatic features with increased expression of MMPs as well as the presence of twist and snail genes in TS Huh-7 cells were reversed by LDE225, a potent Smoothened antagonist. In conclusion, the highly metastatic capability of a unique TS subpopulation was highly attributed to significant epithelial-mesenchymal transition, enhanced Hh activity and aberrant occurrence of a tGli-1 variant, which appears to be responsible for the highly invasive behavior.

Overexpression of miR-98 inhibits cell invasion in glioma cell lines via downregulation of IKKε.

OBJECTIVE: MicroRNAs (miRNAs) function as negative regulators for the expression of genes involved in cancer metastasis. The aim of this study was to investigate the potential role of miR-98 in gliomas and validate its regulatory mechanism. PATIENTS AND METHODS: Cell viability assays are used to measure proliferation of cell. mRNA expression is measured by qRT-PCR. Western blot analysis is used to measure protein expression. RESULTS: Functional studies showed that miR-98 overexpression inhibited glioma migration and invasion, but had no effect on the cell viability. An enhanced green fluorescent protein reporter assay, quantitative RT-PCR, and a western blot analysis confirmed that miR-98 suppressed the expression of IκB kinase (IKKε) by directly targeting its 3'-untranslated region, also, the NF-κB p65 nuclear translocation and matrix metalloproteinase (MMP)-9 expression were significantly arrested in glioma cells treated with miR-98 mimics. Accordingly, the overexpression of IKKε or NF-κB p65 can restore cell migration and invasion after being inhibited by miR-98, and can restore NF-κB p65 nuclear translocation as well as increase MMP-9 expression. CONCLUSIONS: These findings demonstrated that miR-98 functions as a tumor suppressor in gliomas. Furthermore, miR-98 may act as a potential therapeutic biomarker for glioma patients.

A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways.

Neuroblastoma (NB) is the most common extracranial neoplasm in children. In NB, loss of p53 function is largely due to cytoplasmic sequestration rather than mutation. Ubiquitin-conjugating enzyme E2 N (UBE2N), also known as Ubc13, is an E2 ubiquitin-conjugating enzyme that promotes formation of monomeric p53 that results in its cytoplasmic translocation and subsequent loss of function. Therefore, inhibition of UBE2N may reactivate p53 by promoting its nuclear accumulation. Here, we show that NSC697923, a novel UBE2N inhibitor, exhibits potent cytotoxicity in a panel of NB cell lines evidenced by its ability to induce apoptosis. In p53 wild-type NB cells, NSC697923 induced nuclear accumulation of p53, which led to its increased transcriptional activity and tumor suppressor function. Interestingly, in p53 mutant NB cells, NSC697923 induced cell death by activating JNK pathway. This effect was reversible by blocking JNK activity with its selective inhibitor, SP600125. More importantly, NSC697923 impeded cell growth of chemoresistant LA-N-6 NB cell line in a manner greater than conventional chemotherapy drugs doxorubicin and etoposide. NSC697923 also revealed in vivo antitumor efficacy in NB orthotopic xenografts. Taken together, our results suggest that UBE2N is a potential therapeutic target in NB and provide a basis for the rational use of UBE2N inhibitors like NSC697923 as a novel treatment option for NB patients.

miR-1207-5p and miR-1266 suppress gastric cancer growth and invasion by targeting telomerase reverse transcriptase.

hTERT is the catalytic subunit of the telomerase complex. Elevated expression of hTERT is associated with the expansion and metastasis of gastric tumor. In this study, we aimed to identify novel tumor suppressor miRNAs that restrain hTERT expression. We began our screen for hTERT-targeting miRNAs with a miRNA microarray. miRNA candidates were further filtered by bioinformatic analysis, general expression pattern in different cell lines, gain-of-function effects on hTERT protein and the potential of these effects to suppress hTERT 3' untranslated region (3'UTR) luciferase activity. The clinical relevance of two miRNAs (miR-1207-5p and miR-1266) was evaluated by real-time RT-PCR. The effects of these miRNAs on cell growth, cell cycle and invasion of gastric cancer cells were measured with CCK-8, flow cytometry and transwell assays. Finally, the ability of these miRNAs to suppress the transplanted tumors was also investigated. Fourteen miRNAs were identified using a combination of bioinformatics and miRNA microarray analysis. Of these fourteen miRNAs, nine were expressed at significantly lower levels in hTERT-positive cell lines compared with hTERT-negative cell lines and five could downregulate hTERT protein expression. Only miR-1207-5p and miR-1266 interacted with the 3' UTR of hTERT and the expression levels of these two miRNAs were significantly decreased in gastric cancer tissues. These two miRNAs also inhibited gastric tumor growth in vitro and in vivo. Altogether, miR-1207-5p and miR-1266 were determined to be hTERT suppressors in gastric cancer, and the delivery of these two miRNAs represents a novel therapeutic strategy for gastric cancer treatment.

USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis.

Neuroblastoma (NB) is a common pediatric cancer and contributes to more than 15% of all pediatric cancer-related deaths. Unlike adult tumors, recurrent somatic mutations in NB, such as tumor protein 53 (p53) mutations, occur with relative paucity. In addition, p53 downstream function is intact in NB cells with wild-type p53, suggesting that reactivation of p53 may be a viable therapeutic strategy for NB treatment. Herein, we report that the ubiquitin-specific protease 7 (USP7) inhibitor, P22077, potently induces apoptosis in NB cells with an intact USP7-HDM2-p53 axis but not in NB cells with mutant p53 or without human homolog of MDM2 (HDM2) expression. In this study, we found that P22077 stabilized p53 by inducing HDM2 protein degradation in NB cells. P22077 also significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) in NB cells with an intact USP7-HDM2-p53 axis. Moreover, P22077 was found to be able to sensitize chemoresistant LA-N-6 NB cells to chemotherapy. In an in vivo orthotopic NB mouse model, P22077 significantly inhibited the xenograft growth of three NB cell lines. Database analysis of NB patients shows that high expression of USP7 significantly predicts poor outcomes. Together, our data strongly suggest that targeting USP7 is a novel concept in the treatment of NB. USP7-specific inhibitors like P22077 may serve not only as a stand-alone therapy but also as an effective adjunct to current chemotherapeutic regimens for treating NB with an intact USP7-HDM2-p53 axis.