Evaluating the efficacy of percutaneous puncture biopsy guided by contrast-enhanced ultrasound for peripheral pulmonary lesions.

BACKGROUND: The incidence and mortality of lung cancer have increased annually. Accurate diagnosis can help improve therapeutic efficacy of interventions and prognosis. Percutaneous lung biopsy is a reliable method for the clinical diagnosis of lung cancer. Ultrasound-guided percutaneous lung biopsy technology has been widely promoted and applied in recent years. AIM: To investigate the diagnostic value of contrast-enhanced ultrasound (CEUS)-guided percutaneous biopsy in peripheral pulmonary lesions. METHODS: We retrospectively collected data on 237 patients with peripheral thoracic focal lesions who underwent puncture biopsy at Wuxi People's Hospital. The patients were randomly divided into two groups: The CEUS-guided before lesion puncture group (contrast group) and conventional ultrasound-guided group (control group). Analyze the diagnostic efficacy of the puncture biopsy, impact of tumor size, and number of puncture needles and complications were analyzed and compared between the two groups. RESULTS: Accurate pathological results were obtained for 92.83% (220/237) of peripheral lung lesions during the first biopsy, with an accuracy rate of 95.8% (113/118) in the contrast group and 89.9% (107/119) in the control group. The difference in the area under the curve (AUC) between the contrast and the control groups was not statistically significant (0.952 vs 0.902, respectively; P > 0.05). However, when the lesion diameter ≥ 5 cm, the diagnostic AUC of the contrast group was higher than that of the control group (0.952 vs 0.902, respectively; P < 0.05). In addition, the average number of puncture needles in the contrast group was lower than that in the control group (2.58 ± 0.53 vs 2.90 ± 0.56, respectively; P < 0.05). CONCLUSION: CEUS guidance can enhance the efficiency of puncture biopsy of peripheral pulmonary lesions, especially for lesions with a diameter ≥ 5 cm. Therefore, CEUS guidance has high clinical diagnostic value in puncture biopsy of peripheral focal lung lesions.

Tamoxifen resistance-related ceRNA network for breast cancer.

Background: Tamoxifen (TMX) is one of the most widely used drugs to treat breast cancer (BC). However, acquired drug resistance is still a major obstacle to its application, rendering it crucial to explore the mechanisms of TMX resistance in BC. This aims of this study were to identify the mechanisms of TMX resistance and construct ceRNA regulatory networks in breast cancer. Methods: GEO2R was used to screen for differentially expressed mRNAs (DEmRNAs) leading to drug resistance in BC cells. MiRTarbase and miRNet were used to predict miRNAs and lncRNAs upstream, and the competing endogenous RNA (ceRNA) regulatory network of BC cell resistance was constructed by starBase. We used the Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA) to analyze the expression and prognostic differences of genes in the ceRNA network with core axis, and qRT-PCR was used to further verify the above conclusions. Results: We found that 21 DEmRNAs were upregulated and 43 DEmRNA downregulated in drug-resistant BC cells. DEmRNAs were noticeably enriched in pathways relevant to cancer. We then constructed a protein-protein interaction (PPI) network based on the STRING database and defined 10 top-ranked hub genes among the upregulated and downregulated DEmRNAs. The 20 DEmRNAs were predicted to obtain 113 upstream miRNAs and 501 lncRNAs. Among them, 7 mRNAs, 22 lncRNAs, and 11 miRNAs were used to structure the ceRNA regulatory network of drug resistance in BC cells. 4 mRNAs, 4 lncRNAs, and 3 miRNAs were detected by GEPIA and the Kaplan-Meier plotter to be significantly associated with BC expression and prognosis. The differential expression of the genes in BC cells was confirmed by qRT-PCR. Conclusion: The ceRNA regulatory network of TMX-resistant BC was successfully constructed and confirmed. This will provide an important resource for finding therapeutic targets for TMX resistance, where the discovery of candidate conventional mechanisms can aid clinical decision-making. In addition, this resource will help discover the mechanisms behind this type of resistance.

ID2 inhibits lung adenocarcinoma cell malignant behaviors by inhibiting the activation of the PI3K/AKT/mTOR signaling pathway.

Lung cancer is the most common cancer and one of the main causes of cancer-related deaths, presenting in most cases as metastatic disease. Given the frequent gene mutation and/or signaling deregulation in lung adenocarcinoma, identifying novel factors or agents that target these signaling pathways may be promising strategies for lung adenocarcinoma therapy. Herein, we identified inhibitor of DNA binding 2 (ID2) as an aberrantly downregulated gene in lung adenocarcinoma. ID2 overexpression not only suppressed the viability, colony formation ability, and migration ability of lung adenocarcinoma cells but also decreased the protein levels of N-cadherin, MMP2, MMP9 and the phosphorylation levels of AKT and mTOR. The effects of PI3K/AKT/mTOR signaling agonist on lung adenocarcinoma cells were opposite to those of ID2 overexpression, partially reversing the effects of ID2 overexpression. In these experimental tissue samples, ID2 protein levels and mRNA expression were also down-regulated compared with those in adjacent non-cancerous tissues. Altogether, these findings indicated that ID2 exerts its tumor-suppressive effects on the malignant behavior of lung adenocarcinoma cells by inhibiting the activation of the PI3K/AKT/mTOR signaling pathway. Restoration of ID2 expression in lung adenocarcinoma cells may improve the therapeutic efficacy of lung adenocarcinoma therapies.

Pathogens and Pathogenesis in Wheezing Diseases in Children Under 6.

Few studies have comprehensively assessed the roles of cytokine production in wheezing pathogenesis. Therefore, we undertook this study to determine the association between wheezing episodes and cytokines, and to provide further information on this topic. Firstly, we retrospectively collected I176 children, including 122 subjects with first wheezing and 54 subjects with recurrent wheezing, to analyze the etiology and clinical characteristics of children with wheezing diseases. Then, we collected 52 children with wheezing diseases and 25 normal controls to detect the expression of interferon-γ (IFN-γ), interleukin-4 (IL-4), IFN-γ/IL-4, IL-17A, IL-17E, IgE, matrix metalloproteinase-3 (MMP-3), and MMP-9 in serum or plasma. The results showed that boys under 3 years old with history of allergies were more likely to develop wheezing diseases. In our cohort, M. pneumoniae caused a greater proportion of wheezing in children than expected. The expression of IgE [18.80 (13.65-31.00) vs. 17.9 (10.15-21.60)], IL-4 [24.00 (24.00-48.00) vs. 23.00 (9.50-27.00)], IFN-γ [70.59 (41.63-116.46) vs. 49.83 (29.58-81.74)], MMP3 [53.40 (20.02-128.2) vs. 30.90 (13.80-50.95)], MMP9 [148.10 (99.30-276.10) vs. 122.10 (82.20-162.35)], IL-17A [80.55 (54.46-113.08) vs. 61.11 (29.43-93.87)], and IL-17E [1.75 (0.66-2.77) vs. 1.19 (0.488-2.1615)] were significantly increased in the wheezing group (p<0.05) compared to normal controls, while the level of IFN-γ/IL-4 had no significant difference between the two groups (1.24 ± 1.88 vs 0.68 ± 0.74, p>0.05). There was altered cytokine production in children with wheezing diseases which was quite similar to asthma pathogenesis. Sex, age, pathogen infection, and inflammation in our study were also risk factors for wheezing diseases.

Tuberous sclerosis complex with skin lesions as the initial presentation: A case report and multidisciplinary discussion. / 1例以皮肤损害为首发症状的结节性硬化症并多学科讨论.

We reported a case of tuberous sclerosis complex with facial angiofibroma as the initial presentation and conducted a multidisciplinary discussion. The patient, a young female, was admitted to the Department of Dermatology for cosmetic purpose. After the examination, she was found to have multiple system involvement, including a large renal angiomyolipoma pressing on the liver. She never had any subjective symptom. After consultation by the multidisciplinary team of tuberous sclerosis complex, the patient was treated with everolimus orally and followed up regularly. It is suggested that dermatologists should pay attention to the systemic involvement of patients with tuberous sclerosis complex. Early intervention can prolong the life of patients and improve their life quality. Multidisciplinary collaboration for lifelong disease management is the key to enhance the diagnosis and treatment for tuberous sclerosis complex and enhance the prognosis of patients.

Programmable Biosensors Based on RNA-Guided CRISPR/Cas Endonuclease.

Highly infectious illnesses caused by pathogens constitute severe threats to public health and lead to global economic loss. The use of robust and programmable clustered regularly interspaced short palindromic repeat and CRISPR-associated protein (CRISPR-Cas) systems, repurposed from genome-engineering applications has markedly improved traditional nucleic acid detection for precise identification, independently enabling rapid diagnostics of multiplex biomarker with genetic and mutation related to tumors, and microbial pathogens. In this review, we delineate the utility of the current CRISPR-Cas enzyme as biosensors by which these effector toolkits achieve recognition, signaling amplification, and finally, accurate detection. Additionally, we discuss the details of the dominance and hurdles related to expanding this revolutionary technology into an effective and convenient contraption crucial for improving the rational redesign to CRISPR/Cas biosensing. Overall, this review provides an insight into the current status of rapid and POC diagnostic systems by CRISPR/Cas tools.

[Effects of heavy metal cadmium on Caulerpa lentillifera based on transcriptome analysis]. / 基于转录组分析重金属镉对长茎葡萄蕨藻的影响.

With the acceleration of industrialization, the toxic effect of heavy metal cadmium (Cd) pollution has become prominent. In order to explore the molecular mechanism of the physiological regulation of Caulerpa lentillifera under Cd stress, we analyzed the transcriptome of Cd-stressed (Hcd2+) algae tissues using RNA-Seq. A total of 702 differentially expressed genes (DEGs) were screened between the control and Hcd2+ groups, out of which 257 genes were up-regulated and 445 genes were down-regulated in the Hcd2+ group. We conducted functional annotation and enrichment analysis of the obtained DEGs. The results showed that various biological functions of C. lentillifera were affected under Cd2+stress, which eventually showed growth inhibition. Results of GO enrichment analysis showed that the production and removal of reactive oxygen species (ROS) in C. lentillifera were out of balance and caused oxidative damage such as DNA damage. Results of KEGG enrichment analysis showed that many photosynthesis-related pathways were inhibited, indicating that Cd2+ stress led to disorder of photosynthetic reaction of C. lentillifera.

ß-Cyclodextrin-grafted hyaluronic acid as a supramolecular polysaccharide carrier for cell-targeted drug delivery.

ß-Cyclodextrin (ß-CD) was grafted onto hyaluronic acid (HA) in a single step to generate a supramolecular biopolymer (HA-ß-CD) that was explored for targeted drug delivery applications. Along with its excellent biocompatibility, the prepared HA-ß-CD exhibits not only exceptionally high loading capacity for the model drugs doxorubicin and Rhodamine B through the formation of inclusion complexes with the ß-CD component, but also the capability of targeted drug delivery to cancerous cells with a high level of expression of CD44 receptors, attributable to its HA component. The polymer can release the drug under slightly acidic conditions. With all its attributes, HA-ß-CD may be a promising cancer-cell-targeting drug carrier.

The role of peripheral type 2 innate lymphoid cells in bronchiolitis.

Our aim was to detect type 2 innate lymphoid cells (ILC2s)-related cytokines of infants with bronchiolitis by using Elisa, Liquidchip technology and RT-PCR and investigated its correlation with bronchiolitis. We recruited 26 infants with bronchiolitis and 20 healthy infants as control from Xiangya Hospital. Compared to the control group, the serum levels of interleukin-5 (IL-5) [41.99 (21.11) vs 25.70 (19.64)], IL-9 [27.04 (37.51) vs 8.30 (0.54)], IL-13 [184.05 (132.81) vs 121.75 (176.13)], IL-33 [83.70 (46.69) vs 11.23 (55.31)] and thymic stromal lymphopoietin (TSLP) [31.42 (5.41) vs 28.76 (2.56)] were significantly increased in infants with bronchiolitis (P < 0.05), while the level of IgE had no significant difference between the two groups [19.05 (14.15) vs 14.85 (20.2), P > 0.05]. The mRNA expression of IL-17RB (9.83 ± 0.35 vs 9.19 ± 0.58), TSLP (16.98 ± 2.12 vs 15.07 ± 2.25), retinoid acid receptor related orphan receptor α (7.18 ± 0.71 vs 5.46 ± 1.09) and trans-acting T-cell-specific transcription factor 3 (4.86 ± 0.66 vs 4.19 ± 0.90) were significantly increased in infants with bronchiolitis versus the control group (P < 0.05), while there was no statistical significance for suppression of tumorigenicity 2 (5.59 ± 0.68 vs 5.41 ± 0.87, P > 0.05). Our findings suggested that ILC2s possibly play a specific role in immunopathology of bronchiolitis.

Zhidai Decoction Inhibits Cervical Cancer through Regulation of Vaginal Microbiota.

Cervical cancer is one of the top lethal malignancies among women worldwide. The current treatment methods have so many drawbacks that new treatment methods need to be developed. Zhidai Decoction (ZDD) is an effective traditional Chinese herbal formulation for gynecological diseases. Its main effect is controlling abnormal leucorrhea which is a typical early clinical manifestation of cervical cancer. However, how ZDD directly affects cervical cancer has not been addressed. In this study, we established a mouse cervical cancer U14 cell subcutaneous transplantation tumor model and took an early intervention with ZDD to evaluate the antitumor effect of ZDD. In addition, we also investigated the regulatory effects of ZDD on the vaginal microbiota using 16S rRNA analysis in this study. Our results showed that ZDD can significantly improve systemic symptoms and reduce vaginal secretions of tumor-bearing mice. Compared with the CCM group (the cervical cancer model group), in the ZDD-treated group, the tumor inhibitory rate was 37.90%, the average daily food intake of mice was increased to 5.27 ± 0.74 g (P < 0.05), and the survival time was obviously prolonged to 21 days (P < 0.05). Analysis of the sequencing results of 16S rRNA showed that the main microbial genera of the CCM group were Pasteurella (27.20%) and Helicobacter (18.50%), while those in the ZDD group were Staphylococcus (13.22%) and Lactobacillus (4.68%). It revealed that ZDD has the effect of regulating the vaginal microbiota of cervical cancer, especially in increasing the relative abundance of Lactobacillus and Staphylococcus and decreasing the relative abundance of Pasteurella and Helicobacter. The analysis also showed that ZDD could adjust microbiota structure, species abundance, and community compositions of vaginal microbiota. In conclusion, ZDD displayed inhibitory effect on cervical cancer, and it might be based on restoring the balance of vaginal microbiota. Furthermore, our conclusion supports the promotion of ZDD in the early treatment of cervical cancer.

[Cyanosis for more than 4 years in a girl aged 4 years and 3 months].

A girl, aged 4 years and 3 months, presented with cyanosis of the lips shortly after birth. She then experienced shortness of breath after activity 1 year ago and acrocyanosis 3 months ago, with obvious acropachy and toe deformity. Laboratory examinations revealed an increase in hemoglobin (178 g/L) and a reduction in arterial partial pressure of oxygen (37.7 mm Hg). Plain and contrast-enhanced CT scans of the lungs showed a large area of dense shadow and multiple nodules with clear boundaries in the right lower lung, as well as thickening of the arteries and dilatation of the veins in the right lower lung. Magnetic resonance angiography of the pulmonary artery showed large arteriovenous malformation in the lung. The child was diagnosed with congenital pulmonary arteriovenous fistula and was given interventional embolization of the pulmonary arterial fistula. The child was followed up at 3 months after surgery. The symptoms of shortness of breath and cyanosis disappeared, and activity tolerance, heart rate, hemoglobin, red blood cell count, and transcutaneous oxygen saturation all returned to normal.

Gene polymorphisms in VEGFA and COL2A1 are associated with response to inhaled corticosteroids in children with asthma.

Aim: The purpose of this study was to investigate the involvement of single-nucleotide polymorphisms in VEGFA, TBX21 and COL2A1 in the response to inhaled corticosteroids in asthmatic children. Subjects & methods: Children with mild-to-moderate asthma were enrolled in the study. The SEQUENOM MassARRAY method was used to sequence 27 SNP genotypes. By ranking the data from smallest to largest, we could infer whether the change in distribution of forced expiratory volume in one second/forced vital capcacity (FEV1/FVC) and fractional exhaled nitric oxide differed between genotype groups. Results:VEGFA rs3025039 T allele carriers had a smaller change in FEV1 than CC carriers (p = 0.040), and in COL2A1 rs3809324, the frequency of T allele carriers was lower than that of GG carriers (p = 0.048). rs3025039 was also associated with changes in FEV1/FVC (p = 0.016). Conclusion:VEGFA and COL2A1 polymorphisms are significantly associated with the response to inhaled corticosteroids in asthmatic children.

Fusion of multiple heterogeneous networks for predicting circRNA-disease associations.

Circular RNAs (circRNAs) are a newly identified type of non-coding RNA (ncRNA) that plays crucial roles in many cellular processes and human diseases, and are potential disease biomarkers and therapeutic targets in human diseases. However, experimentally verified circRNA-disease associations are very rare. Hence, developing an accurate and efficient method to predict the association between circRNA and disease may be beneficial to disease prevention, diagnosis, and treatment. Here, we propose a computational method named KATZCPDA, which is based on the KATZ method and the integrations among circRNAs, proteins, and diseases to predict circRNA-disease associations. KATZCPDA not only verifies existing circRNA-disease associations but also predicts unknown associations. As demonstrated by leave-one-out and 10-fold cross-validation, KATZCPDA achieves AUC values of 0.959 and 0.958, respectively. The performance of KATZCPDA was substantially higher than those of previously developed network-based methods. To further demonstrate the effectiveness of KATZCPDA, we apply KATZCPDA to predict the associated circRNAs of Colorectal cancer, glioma, breast cancer, and Tuberculosis. The results illustrated that the predicted circRNA-disease associations could rank the top 10 of the experimentally verified associations.

Epigallocatechin-3-gallate-induced vascular normalization in A549-cell xenograft-bearing nude mice: therapeutic efficacy in combination with chemotherapy.

PURPOSE: Large-scale studies have revealed that appropriate antiangiogenic treatment enables the recovery of the normal structure and function of solid tumor vessels. Epigallocatechin-3-gallate (EGCG), a natural extract of green tea, has multiple effects on angiogenesis. However, normalization of blood vessels due to natural ingredients has not yet been reported. Therefore, we examined the microvasculature, microenvironment, and efficacy of EGCG combined with chemotherapy in a xenograft model. METHODS: We treated A549 cell (human lung adenocarcinoma cell line) xenograft-bearing nude mice with EGCG in vivo. CD31, αSMA, and collagen IV were labeled and detected using quantum-dot double-labeled immunofluorescence to measure microvessel density, microvessel pericyte-coverage index, and collagen IV expression. Vessel-perfusion function was determined by lectin injection, permeability by Evans blue extravasation, interstitial fluid pressure using the wick-in-needle technique, and hypoxia levels using a polarographic electrode and immunohistochemical pimonidazole labeling. Cisplatin concentration in tumor tissue was detected using graphite-furnace atomic absorption spectrophotometry. Xenograft mice were randomized into five groups: treated with saline, cisplatin, EGCG, EGCG + cisplatin on day 1, or EGCG + cisplatin during the vascular normalization window. Tumor-growth delay and tumor-suppression rate were measured to evaluate tumor growth. RESULTS: EGCG treatment in vivo caused temporary changes, including transient depression of microvessel density, microvessel pericyte-coverage index, and collagen IV expression, transient elevation of vessel perfusion and permeability, and decreased interstitial fluid pressure and hypoxia. During vascular normalization, pretreatment with EGCG increased cisplatin concentration in tumor tissue compared with treatment with cisplatin only. Tumor-growth delay after treatment in the five groups during the vascular normalization window was 6.3±1.51, 7.5±1.57, 8.3±1.79, 12.1±1.35, and 15.4±1.99 days, indicating synergistic EGCG-cisplatin effects, especially during the vascular normalization window (P<0.01). CONCLUSION: EGCG-induced vascular normalization in human lung adenocarcinoma may be a novel modality for enhancing chemotherapy effects.

[Liver dysfunction for 8 years with hypertension for 1 week in an 8-year-old girl].

A girl, aged 8 years, developed jaundice and liver dysfunction in the neonatal period, with congenital glaucoma diagnosed on day 5 after birth, hypertension and unusual facies (broad forehead, hypertelorism and deep-set eyes). Cholestasis was the main type of liver dysfunction. Cardiac macrovascular CTA showed stenosis at the abdominal aorta and the beginning of the bilateral renal arteries. Whole exon sequencing revealed a heterozygous frameshift mutation, c.1485delC (absence of cytosine), in exon 12 of the JAG1gene. The girl was diagnosed with Alagille syndrome and was given transaminase-lowering, cholagogic and antihypertensive treatment with multiple drugs. There were significant reductions in serum levels of alanine aminotransferase, aspartate aminotransferase and total bile acid, but blood pressure fluctuated between 102-140 mm Hg/53-89 mm Hg. After renal artery angiography and balloon dilatation angioplasty, the girl was given oral administration of antihypertensive drugs, and blood pressure was controlled at a level of 110-120 mm Hg/60-80 mm Hg. The rare disease Alagille syndrome should be considered when a child has refractory hypertension with the involvement of multiple systems, especially liver dysfunction with cholestasis as the main manifestation. Genetic causes should be analyzed for a early diagnosis.

Expression of recombinant tachyplesin I in Pichia pastoris.

The development of antibiotic-resistant bacteria has become a major public health problem, prompting the search for alternative solutions. Tachyplesin I (TP-I) is an antimicrobial peptide, which exhibits potent and broad-spectrum activities against bacteria, fungi, viruses, and tumor cells. However, limited amounts of TP-I produced in horseshoe crab restrict its large-scale use. In order to solve this problem, a eukaryotic expression system of Pichia pastoris with high TP-I expression was constructed by gene engineering. To achieve high expression of TP-I, 74 amino acid-long peptide (4TP-1) was designed containing 4 copies of TP-I, and specific cleavage sites for pancreatic elastase (-Ala↓ or -Gly↓) and carboxypeptidase A (cleaves C terminal amino acid); these cleavage sites for enzymes were located between the four copies of TP-I. The gene sequence for the designed peptide was synthesized taking into consideration codon preferences for P. pastoris, and cloned into the highly efficient expression vector pGAPZα B. Host Pichia pastoris strain GS115 cells were transfected by the constructed expression vector pGAPZα B-4tp-I by electroporation. Tricine-SDS-PAGE electrophoresis was carried out to detect the expression of target peptides in the fermentation medium. This analysis showed a protein band of 3.3 kDa, identical to that of chemically synthesized TP-I, verifying that successful synthesis and secretion of TP-I by genetically engineered P. pastoris. The concentration of TP-I in the fermentation broth was 27.24-29.53 mg/L. High-resolution mass spectrometry analysis documented that the TP-I monomer had the same molecular weight, 2262.85, as the designed 17-amino acid sequence. The recombinant TP-I peptide displayed different levels of bactericidal activity against Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa, and Staphylococcus aureus. Thus, the present study demonstrated the feasibility of achieving high levels of expression of TP-I in P. pastoris.

KATZLGO: Large-Scale Prediction of LncRNA Functions by Using the KATZ Measure Based on Multiple Networks.

Aggregating evidences have shown that long non-coding RNAs (lncRNAs) generally play key roles in cellular biological processes such as epigenetic regulation, gene expression regulation at transcriptional and post-transcriptional levels, cell differentiation, and others. However, most lncRNAs have not been functionally characterized. There is an urgent need to develop computational approaches for function annotation of increasing available lncRNAs. In this article, we propose a global network-based method, KATZLGO, to predict the functions of human lncRNAs at large scale. A global network is constructed by integrating three heterogeneous networks: lncRNA-lncRNA similarity network, lncRNA-protein association network, and protein-protein interaction network. The KATZ measure is then employed to calculate similarities between lncRNAs and proteins in the global network. We annotate lncRNAs with Gene Ontology (GO) terms of their neighboring protein-coding genes based on the KATZ similarity scores. The performance of KATZLGO is evaluated on a manually annotated lncRNA benchmark and a protein-coding gene benchmark with known function annotations. KATZLGO significantly outperforms state-of-the-art computational method both in maximum F-measure and coverage. Furthermore, we apply KATZLGO to predict functions of human lncRNAs and successfully map 12,318 human lncRNA genes to GO terms.

ß­blockers inhibit the viability of breast cancer cells by regulating the ERK/COX­2 signaling pathway and the drug response is affected by ADRB2 single­nucleotide polymorphisms.

The ß2­adrenergic receptor (ß2­AR, encoded by the ADRB2 gene) is a member of the G­protein­coupled receptor superfamily that can be stimulated by catecholamines. Studies in vivo and in vitro have confirmed that ß­blockers (ß­AR antagonists) exert antitumor effects on various tumors. Furthermore, ADRB2 single­nucleotide polymorphisms (SNPs) have been identified to alter the expression and conformation of ß2­AR, which may alter the ß­blocker drug response. The aim of the present study was to investigate the effect of ß­blockers on triple­negative breast cancer cells and determine whether ADRB2 SNPs affect the response to ß­blocker drugs. Propranolol and ICI 118,551 significantly inhibited the viability of MDA­MB­231 cells, arrested cell cycle progression at G0/G1 and S phase and induced cell apoptosis. Western blot analysis indicated that the phosphorylation levels of extracellular­signal­regulated kinase (ERK)1/2 and the expression levels of cyclo­oxygenase 2 (COX­2) were significantly decreased following ß­blocker treatment. Four haplotypes, which comprised ADRB2 SNPs rs1042713 and rs1042714, were transfected into 293 cells. After 24 and 48 h of transfection, ADRB2 mRNA expression was significantly decreased in mutant groups compared with the wild­type group. The ADRB2 SNPs exerted no effect on cell viability, but did affect the drug response of ICI 118,551. Furthermore, ADRB2 SNPs also affected the regulatory function of ICI 118,551 on the ERK/COX­2 signaling pathway. Collectively, propranolol and ICI 118,551 inhibited the viability of MDA­MB­231 cells by downregulating the ERK/COX­2 signaling pathway and inducing apoptosis. The results of the present study indicated that SNPs rs1042713 and rs1042714 of ADRB2 affected the response to ICI 118,551, and the underlying molecular mechanism was elucidated.

Glucocorticoids Modulate Th1 and Th2 Responses in Asthmatic Mouse Models by Inhibition of Notch1 Signaling.

BACKGROUND: Notch1 has been linked to the pathogenesis of asthma due to its contribution on Th1/Th2 imbalance. γ-Secretase inhibitor (GSI) acts as an effective blocker of Notch1 signaling. Glucocorticoids (GCs) are the most effective anti-inflammatory drugs for asthma. The present study investigated the involvement of the Notch1 pathway in the anti-inflammatory effect of GCs and its association with Th1/Th2 balance. METHODS: The asthma model was established in BALB/c mice by sensitization with ovalbumin (OVA). Dexamethasone (DEX; 1 mg/kg) and/or GSI (0.03 mg/kg) was orally or intranasally administrated. RESULTS: Compared to the OVA-sensitized mice, the administration of DEX and/or GSI significantly ameliorated the airway inflammation infiltration, goblet cell metaplasia, and airway hyper-responsiveness. The expression of IL-4 and IL-13, as well as the ratios of eosinophils and lymphocytes, were significantly decreased, whereas IFN-γ and IL-2 levels were significantly increased in bronchoalveolar lavage fluid after the administration of DEX and GSI. The expressions of the Notch1/NICD1 pathway were decreased after DEX and/or GSI administration in lung tissues, especially in CD4+ T cells. Also, a reduction of GATA3 and elevation of T-bet levels were correlated with the upregulation of Th1/Th2 ratios in lung tissues. CONCLUSIONS: Through the inhibition of Notch1 signaling, both GSI and GCs could regulate Th1/Th2 balance involved in allergic airway inflammation in OVA-induced asthma.

Report of 12 cases with tracheobronchial mucormycosis and a review.

OBJECTIVES: Tracheobronchial mucormycosis is a rare and invasive pulmonary mucormycosis involving the tracheobronchial tree. DATA SOURCE: At a 3500-bed tertiary care center. STUDY SELECTION: This was a retroactive study of 12 cases of tracheobronchial mucormycosis diagnosed in our hospital, and 48 cases that were previously reported in the English literature. RESULTS: Rhizopus was the predominant species of pathogen (66.7%). Primary bronchus was the most frequently involved location (38.2%), and upper lobes (51% of cases) were a predilection. Obstructive necrosis and mucosal necrosis were the most common pathological forms (40% and 34.5%, respectively). Fever (59.3%), cough (59.3%), dyspnea (40.7%) and hemoptysis (30.5%) were the most common symptoms. 51.4% patients had rales, 40% had moist rales and 28.6% had negative physical findings. Ninety-five percent patients had immunosuppressive diseases. Diabetes mellitus (66.7%), diabetes ketoacidosis (21.7%), corticosteroid therapy (20%) and kidney insufficiency (18.3%) were the most common predisposing factors. 13.2% had neutropenia which was mostly among the non-diabetic patients (P = .006). Endobronchial lesion of 23.2% had imaging reports with 33.9% exhibiting single mass. Pathological diagnosis of 76.7% used the transbronchial biopsy. The most frequent antifungal therapies were intravenous amphotericin B (79.7%), surgery (33.3%) and surgery combined with amphotericin B therapy (28.3%). Overall in-hospital mortality was 52.5%, with hemoptysis (P = .017), dyspnea at presentation (P = .022) and angioinvasion (P = .03) as independent risk prognostic factors. In contrast, surgery (P = .003) was an independent protection prognostic factor. CONCLUSIONS: Tracheobronchial mucormycosis is a rare but severe disease with high mortality because of its nonspecific clinical presentations and variable predisposing factors.