Conserved transcription factors NRZ1 and NRM1 regulate NLR receptor-mediated immunity.

Plant innate immunity mediated by the nucleotide-binding leucine-rich repeat (NLR) class of immune receptors plays an important role in defense against various pathogens. Although key biochemical events involving NLR activation and signaling have been recently uncovered, we know very little about the transcriptional regulation of NLRs and their downstream signaling components. Here, we show that the Toll-Interleukin 1 receptor homology domain containing NLR (TNL) gene N (Necrosis), which confers resistance to Tobacco mosaic virus, is transcriptionally induced upon immune activation. We identified two conserved transcription factors, N required C3H zinc finger 1 (NRZ1) and N required MYB-like transcription factor 1 (NRM1), that activate N in an immune responsive manner. Genetic analyses indicated that NRZ1 and NRM1 positively regulate coiled-coil domain-containing NLR- and TNL-mediated immunity and function independently of the signaling component Enhanced Disease Susceptibility 1. Furthermore, NRZ1 functions upstream of NRM1 in cell death signaling, and their gene overexpression induces ectopic cell death and expression of NLR signaling components. Our findings uncovered a conserved transcriptional regulatory network that is central to NLR-mediated cell death and immune signaling in plants.

Evaluation of supercritical fluid chromatography coupled to tandem mass spectrometry for the analysis of pesticide residues in grain.

A supercritical fluid chromatography-tandem mass spectrometry (SFC-MS/MS) technique was developed for the rapid and simultaneous detection of nine pesticides (carbendazim, isoprocarb, paclobutrazol, isoprothiolane, flusilazole, quinalphos, piperonylbutoxide, propargite, and bioresmethrin) in rice, wheat, and maize. The cereal samples were extracted with a solution of 0.5% acetic acid in acetonitrile and purified using quick, easy, cheap, effective, rugged, and safe method. The samples were characterized using multi-reaction monitoring and quantified with the external standard method. Excellent linearities (R2  > 0.9991) and limits of quantification (0.4-40.0 µg/kg) were established for all nine pesticides. Satisfactory pesticide recovery rates (62.2%-107.4%) were obtained at three standard concentrations (50, 100, and 200 µg/kg), with relative standard deviations in the range of 2.1%-14.3%. The results confirmed that the proposed method was suitable for the routine detection of these pesticides in grain samples. Compared with high-performance liquid chromatography-MS/MS, the overall test run time and the amount of solvent required were reduced by 66% and 90%, respectively, when SFC-MS/MS was applied. Therefore, the use of SFC-MS/MS permits a shorter run time and affords greater analytical efficiency, such that it is both economical and environmentally sustainable.

Vimentin and tumor-stroma ratio for neoadjuvant chemoradiotherapy response prediction in locally advanced rectal cancer.

Vimentin expression in tumor tissues and the tumor-stroma ratio (TSR) have been demonstrated as strong prognostic factors for cancer patients, but whether they are predictive markers of neoadjuvant chemoradiotherapy (nCRT) outcome in locally advanced rectal cancer (LARC) patients is poorly understood. This study aimed to explore the predictive significance of vimentin and TSR combined for nCRT response in LARC patients. Imaging mass cytometry (IMC) was performed to determine the association of vimentin and TSR with nCRT response in six LARC patients [three achieved pathological complete response (pCR), three did not]. Immunohistochemistry (IHC) for vimentin and TSR on biopsy tissues before nCRT and logistic regression analysis were performed to further evaluate their predictive value for treatment responses in a larger patient cohort. A trend of decreased vimentin expression and increased TSR in the pCR group was revealed by IMC. In the validation group, vimentin [odds ratio (OR) 0.260, 95% confidence interval (CI) 0.102-0.602, p = 0.002] and TSR (OR 4.971, 95% CI 1.933-15.431, p = 0.002) were associated with pCR by univariate analysis. Patients in the vimentin-low/TSR-low or vimentin-high/TSR-high (OR 5.211, 95% CI 1.248-35.582, p = 0.042) and vimentin-low/TSR-high groups (OR 11.846, 95% CI 3.197-77.079, p = 0.001) had significantly higher odds of pCR. By multivariate analysis, only the combination of vimentin and TSR was an independent predictor for nCRT response (OR 9.324, 95% CI 2.290-63.623, p = 0.006). Our study suggested that the combined assessment of vimentin and TSR can provide additive significance and may be a promising indicator of nCRT response in LARC patients.

Cardio-oncology in China.

OPINION STATEMENT: Cardio-oncology is going under rapid development in various areas across an increasing number of provinces in China. However there are still a myriad of challenges that need to be overcome in order to ensure its gradual and consistent expansion. The Cardio-Oncology Knowledge Transfer Model (KTM) forms the basis to allow exponential development of effective cardio-oncology services. This would ensure the implementation of precision-based practice while dynamically evolving cardio-oncology to integrate both Western and Chinese medical practices to become an official clinical sub-speciality in its own right in China, for the ultimate benefit of the patient.

Synthesis and evaluation of highly potent HBV capsid assembly modulators (CAMs).

Chronic hepatitis B virus (HBV) infection remains a major global health burden. It affects more than 290 million individuals worldwide and is responsible for approximately 900,000 deaths annually. Anti-HBV treatment with a nucleoside analog in combination with pegylated interferon are considered first-line therapy for patients with chronic HBV infection and liver inflammation. However, because cure rates are low, most patients will require lifetime treatment. HBV Capsid Assembly Modulators (CAMs) have emerged as a promising new class of compounds as they can affect levels of HBV covalently closed-circular DNA (cccDNA) associated with viral persistence. SAR studies around the core structure of lead HBV CAM GLP-26 (Fig. 1B) was performed and led to the discovery of non-toxic compound 10a displaying sub-nanomolar anti-HBV activity. Advanced toxicity and cellular pharmacology profiles of compounds 10a were also established and the results are discussed herein.

The Effects of Angiosome Morphology on Choke Vessels and Flap Necrosis in a Rat Multiterritory Perforator Flap.

BACKGROUND: Although the angiosome concept has been proposed for a long time, very few studies have been done on its morphology. Our study investigated the effects of angiosome morphology on choke vessels and flap necrosis in a rat multiterritory perforator flap. METHODS: Seventy-two male Sprague-Dawley rats were randomly divided into 3 groups (n = 24/group). The flap contained the right iliolumbar, posterior intercostal, and thoracodorsal angiosomes (TDAVs), termed angiosomes I, II, and III, respectively. Only the posterior intercostal artery and iliolumbar vein were preserved in group 1, whereas only the posterior intercostal artery and vein were preserved in group 2, and only the posterior intercostal artery and thoracodorsal vein were preserved in group 3. Distances from angiosome II to angiosome I (II-I), angiosome II to angiosome III (II-III), angiosome I to the caudal side of the flap (I-caudal), and angiosome III to the cranial side of the flap (III-cranial) were measured. Arteriography, flap necrosis, average microvascular density, and vascular endothelial growth factor expression were evaluated. RESULTS: The II-I distance was significantly greater than that of II-III (3.853 ± 0.488 versus 3.274 ± 0.433 cm, P = 0.012), whereas the distance of I-caudal resembled that of III-cranial (1.062 ± 0.237 versus 0.979 ± 0.236 cm, P = 0.442). The iliolumbar and posterior intercostal angiosomes were multidirectional, whereas the TDAV was craniocaudal and unidirectional. Seven days after the operation, the choke arteries had transformed into true anastomotic arteries. Flap necrosis was lowest in group 3, followed by group 2, and highest in group 1 (10.5% ± 2.4% versus 18.3% ± 3.5% versus 25.5% ± 4.6%, P < 0.01), whereas group 3 showed the highest microvascular density and vascular endothelial growth factor expression, in contrast to groups 2 and 1, with the lowest. CONCLUSIONS: The choke vessel adjacent to the craniocaudal and unidirectional TDAV significantly blocked venous return. Increasing venous return may reduce the necrosis.

Tumor Regression upon Intratumoral and Subcutaneous Dosing of the STING Agonist ALG-031048 in Mouse Efficacy Models.

Stimulator of interferon genes (STING) agonists have shown potent anti-tumor efficacy in various mouse tumor models and have the potential to overcome resistance to immune checkpoint inhibitors (ICI) by linking the innate and acquired immune systems. First-generation STING agonists are administered intratumorally; however, a systemic delivery route would greatly expand the clinical use of STING agonists. Biochemical and cell-based experiments, as well as syngeneic mouse efficacy models, were used to demonstrate the anti-tumoral activity of ALG-031048, a novel STING agonist. In vitro, ALG-031048 is highly stable in plasma and liver microsomes and is resistant to degradation via phosphodiesterases. The high stability in biological matrices translated to good cellular potency in a HEK 293 STING R232 reporter assay, efficient activation and maturation of primary human dendritic cells and monocytes, as well as long-lasting, antigen-specific anti-tumor activity in up to 90% of animals in the CT26 mouse colon carcinoma model. Significant reductions in tumor growth were observed in two syngeneic mouse tumor models following subcutaneous administration. Combinations of ALG-031048 and ICIs further enhanced the in vivo anti-tumor activity. This initial demonstration of anti-tumor activity after systemic administration of ALG-031048 warrants further investigation, while the combination of systemically administered ALG-031048 with ICIs offers an attractive approach to overcome key limitations of ICIs in the clinic.

Automated whole-slide images assessment of immune infiltration in resected non-small-cell lung cancer: towards better risk-stratification.

BACKGROUND: High immune infiltration is associated with favourable prognosis in patients with non-small-cell lung cancer (NSCLC), but an automated workflow for characterizing immune infiltration, with high validity and reliability, remains to be developed. METHODS: We performed a multicentre retrospective study of patients with completely resected NSCLC. We developed an image analysis workflow for automatically evaluating the density of CD3+ and CD8+ T-cells in the tumour regions on immunohistochemistry (IHC)-stained whole-slide images (WSIs), and proposed an immune scoring system "I-score" based on the automated assessed cell density. RESULTS: A discovery cohort (n = 145) and a validation cohort (n = 180) were used to assess the prognostic value of the I-score for disease-free survival (DFS). The I-score (two-category) was an independent prognostic factor after adjusting for other clinicopathologic factors. Compared with a low I-score (two-category), a high I-score was associated with significantly superior DFS in the discovery cohort (adjusted hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.33-0.86; P = 0.010) and validation cohort (adjusted HR, 0.57; 95% CI 0.36-0.92; P = 0.022). The I-score improved the prognostic stratification when integrating it into the Cox proportional hazard regression models with other risk factors (discovery cohort, C-index 0.742 vs. 0.728; validation cohort, C-index 0.695 vs. 0.685). CONCLUSION: This automated workflow and immune scoring system would advance the clinical application of immune microenvironment evaluation and support the clinical decision making for patients with resected NSCLC.

Inhibition of TRPA1 reduces airway inflammation and hyperresponsiveness in mice with allergic rhinitis.

This study was conducted to investigate whether a transient receptor potential ankyrin 1 (TRPA1) antagonist (HC-030031) can reduce airway inflammation and hyperresponsiveness in a murine allergic rhinitis (AR) model. BALB/c mice were sensitized and challenged by ovalbumin (OVA) to induce AR. HC-030031 or vehicle was administrated to mice via intraperitoneal injection prior to OVA challenges. Nose-scratching events, histopathologic alterations of the airways, and bronchial hyperresponsiveness (BHR) were assessed. Differential cells and proinflammatory cytokines in the nasal lavage (NAL) and bronchoalveolar lavage (BAL) fluid were measured. Expressions of TRPA1 in nasal mucosa were examined by immunohistochemistry. TRPA1-expressing vagal neurons were labeled by immunofluorescent staining. HC-030031-treated AR mice had markedly reduced type-2 inflammation in nasal mucosa and ameliorated-nose-scratching events than AR mice received vehicle. HC-030031 treatment also dramatically reduced leucocyte numbers and IL-8 level in the BAL fluid, inhibited lower airway remodeling and fibrosis, and nearly abolished BHR. HC-0300031 treatment significantly inhibited the upregulated number of TRPA1 expressing nasal epithelial cells and TRPA1 expressing sensory neurons, leading to downregulation of SP in both upper and lower airways. Targeting TRPA1 may represent a promising strategy for treating AR and AR-related asthma.

A deep learning quantified stroma-immune score to predict survival of patients with stage II-III colorectal cancer.

BACKGROUND: Profound heterogeneity in prognosis has been observed in colorectal cancer (CRC) patients with intermediate levels of disease (stage II-III), advocating the identification of valuable biomarkers that could improve the prognostic stratification. This study aims to develop a deep learning-based pipeline for fully automatic quantification of immune infiltration within the stroma region on immunohistochemical (IHC) whole-slide images (WSIs) and further analyze its prognostic value in CRC. METHODS: Patients from two independent cohorts were divided into three groups: the development group (N = 200), the internal (N = 134), and the external validation group (N = 90). We trained a convolutional neural network for tissue classification of CD3 and CD8 stained WSIs. A scoring system, named stroma-immune score, was established by quantifying the density of CD3+ and CD8+ T-cells infiltration in the stroma region. RESULTS: Patients with higher stroma-immune scores had much longer survival. In the development group, 5-year survival rates of the low and high scores were 55.7% and 80.8% (hazard ratio [HR] for high vs. low 0.39, 95% confidence interval [CI] 0.24-0.63, P < 0.001). These results were confirmed in the internal and external validation groups with 5-year survival rates of low and high scores were 57.1% and 78.8%, 63.9% and 88.9%, respectively (internal: HR for high vs. low 0.49, 95% CI 0.28-0.88, P = 0.017; external: HR for high vs. low 0.35, 95% CI 0.15-0.83, P = 0.018). The combination of stroma-immune score and tumor-node-metastasis (TNM) stage showed better discrimination ability for survival prediction than using the TNM stage alone. CONCLUSIONS: We proposed a stroma-immune score via a deep learning-based pipeline to quantify CD3+ and CD8+ T-cells densities within the stroma region on WSIs of CRC and further predict survival.

Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth.

The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells' adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients.

MTOR suppresses autophagy-mediated production of IL25 in allergic airway inflammation.

INTRODUCTION: Airway epithelial cells are recognised as an essential controller for the initiation and perpetuation of asthmatic inflammation, yet the detailed mechanisms remain largely unknown. This study aims to investigate the roles and mechanisms of the mechanistic target of rapamycin (MTOR)-autophagy axis in airway epithelial injury in asthma. METHODS: We examined the MTOR-autophagy signalling in airway epithelium from asthmatic patients or allergic mice induced by ovalbumin or house dust mites, or in human bronchial epithelial (HBE) cells. Furthermore, mice with specific MTOR knockdown in airway epithelium and autophagy-related lc3b-/- mice were used for allergic models. RESULTS: MTOR activity was decreased, while autophagy was elevated, in airway epithelium from asthmatic patients or allergic mice, or in HBE cells treated with IL33 or IL13. These changes were associated with upstream tuberous sclerosis protein 2 signalling. Specific MTOR knockdown in mouse bronchial epithelium augmented, while LC3B deletion diminished allergen-induced airway inflammation and mucus hyperproduction. The worsened inflammation caused by MTOR deficiency was also ameliorated in lc3b-/- mice. Mechanistically, autophagy was induced later than the emergence of allergen-initiated inflammation, particularly IL33 expression. MTOR deficiency increased, while knocking out of LC3B abolished the production of IL25 and the eventual airway inflammation on allergen challenge. Blocking IL25 markedly attenuated the exacerbated airway inflammation in MTOR-deficiency mice. CONCLUSION: Collectively, these results demonstrate that allergen-initiated inflammation suppresses MTOR and induces autophagy in airway epithelial cells, which results in the production of certain proallergic cytokines such as IL25, further promoting the type 2 response and eventually perpetuating airway inflammation in asthma.

Rapid identification of chemical compositions in callicarpa kwangtungensis Chun by ultra-high-performance liquid chromatography with Q Exactive hybrid quadrupole orbitrap high-resolution accurate mass spectrometry.

Callicarpa kwangtungensis Chun is a traditional Chinese medicine that has various therapeutic effects. Despite its wide use in Chinese medicine, the study is still quite limited, especially its chemical compositions. In this research, an ultra-high-pressure liquid chromatography coupled with Q Exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry tandem mass spectrometry method was utilized to analyze its chemical compositions for the first time. As a result, a total of 124 compounds, including 20 phenylethanoid glycosides, 31 flavonoids, 36 organic acids, 26 terpenoids and 11 phenols, were identified or tentatively characterized in 30 min. Among them, 49 compounds, including 5 phenylethanoid glycosides, 12 flavonoids, 16 organic acids, 12 terpenoids, and 4 phenols, were identified in Callicarpa kwangtungensis Chun for the first time. Besides, the fragmentation pathways were also discussed. This research established a rapid and reliable method to analyze the chemical compositions of complicated herb without the process of isolation, and provide abundant information on the chemical material basis for further bioactivity and quality control studies.

Cough in hypereosinophilic syndrome: case report and literature review.

BACKGROUND: Cough and airway eosinophilic inflammation has not been highlighted in hypereosinophilic syndrome (HES). CASE PRESENTATION: We report 2 further cases and reviewed the clinical features and treatment of HES present with cough from the literature. Both cases were middle age male, presenting with chronic cough, airway eosinophilic inflammation and hyper eosinophilia who have been previous misdiagnosed as cough-variant asthma and failed anti-asthma treatment. PDGFRA fusion gene was confirmed in one case, but not in the other case. Both had evidence of myeloproliferative features. The tyrosine kinase inhibitor, imatinib, resulted in complete resolution of eosinophilia and cough. By searching PubMed, we found 8 HES cohorts of 411 cases between 1975 and 2013, where the incidence of cough was 23.11%. Sixteen case reports of HES presented with cough as predominant or sole symptom, with nine male patients with positive PDGFRA fusion gene, who responded well to imatinib. Six of seven patients, who tested negative for the PDGFRA, responded to systemic glucocorticoids. CONCLUSIONS: Cough and airway eosinophilic inflammation is common in some HES patients. PDGFRA+ HES patients present with chronic cough respond well to imatinib. Our case reports indicate that PDGFRA negative HES patients may respond to imatinib as well.

IL-17F, rather than IL-17A, underlies airway inflammation in a steroid-insensitive toluene diisocyanate-induced asthma model.

Steroid insensitivity constitutes a major problem for asthma management. Toluene diisocyanate (TDI) is one of the leading allergens of asthma that induces both T-helper Th2 and Th17 responses, and is often associated with poor responsiveness to steroid treatment in the clinic.We sought to evaluate the effects of inhaled and systemic steroids on a TDI-induced asthma model and to find how interleukin (IL)-17A and IL-17F function in this model. BALB/c mice were exposed to TDI for generating an asthma model and were treated with inhaled fluticasone propionate, systemic prednisone, anti-IL-17A, anti-IL-17F, recombinant IL-17A or IL-17F.Both fluticasone propionate and prednisone showed no effects on TDI-induced airway hyperresponsiveness (AHR), bronchial neutrophilia and eosinophilia, and epithelial goblet cell metaplasia. TDI-induced Th2 and Th17 signatures were not suppressed by fluticasone propionate or prednisone. Treatment with anti-IL-17A after TDI exposure led to increased AHR, aggravated mucus production and airway eosinophil recruitment, accompanied by amplified Th2 responses, whereas anti-IL-17F ameliorated TDI-induced AHR and airway neutrophilia, with decreased Th17 responses. Recombinant IL-17A and IL-17F showed opposite effects to the monoclonal antibodies.IL-17A and IL-17F exert distinct biological effects during airway inflammation of a TDI-induced asthma model, which is unresponsive to both inhaled and systemic steroids.

Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans.

Background: Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5'-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. Objectives: To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Methods: Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. Results: The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC50 = 1.79 µM), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. Conclusions: The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients.

Uncontrolled asthma phenotypes defined from parameters using quantitative CT analysis.

OBJECTIVE: Asthma is a heterogeneous disease with diverse clinical phenotypes that have been identified via cluster analyses. However, the classification of phenotypes based on quantitative CT (qCT) is poorly understood. The study was conducted to investigate CT determination of uncontrolled asthma phenotypes. METHODS: Sixty-five patients with uncontrolled asthma (37 with severe asthma, 28 with non-severe asthma) underwent detailed clinical, laboratory, and pulmonary function tests, as well as qCT analysis. Twenty-five healthy subjects were also included in this study and underwent clinical physical examinations, pulmonary function tests, and low-dose CT scans. RESULTS: The mean lumen area/body surface area ratio was smaller in patients with severe uncontrolled asthma compared with that in healthy subjects (9.84 mm2 [SD, 2.57 mm2], 11.96 mm2 [SD, 3.09 mm2]; p = 0.026). However, the percentage of mean wall area (WA) was greater (64.39% [SD, 2.55%], 62.09% [SD, 3.81%], p = 0.011). Air trapping (measured based on mean lung density and VI-856 [%] on expiratory scan) was greater in patients with severe uncontrolled asthma than in those with non-severe uncontrolled asthma and was higher in all patients with uncontrolled asthma than that in healthy subjects (all p < 0.001). Three CT-determined uncontrolled asthma phenotypes were identified. Cluster 1 had mild air trapping with or without proximal airway remodeling. Cluster 2 had moderate air trapping with or without proximal airway remodeling. Cluster 3 had severe air trapping with proximal airway remodeling. CONCLUSIONS: There was obvious air trapping and proximal airway remodeling in patients with severe uncontrolled asthma. The three CT-determined uncontrolled asthma phenotypes might reflect underlying mechanisms of disease in patient stratification and in the different stages of disease development. KEY POINTS: • Obvious air trapping and proximal airway remodeling were present in patients with severe uncontrolled asthma. • CT air trapping indices showed a good correlation with disease duration, total IgE, atopy, and OCS and ICS doses, and were even more strongly correlated with clinical lung function. • Three CT-determined uncontrolled asthma phenotypes were identified, which might reflect underlying mechanisms of disease in patient stratification and in the different stages of disease development.

Biomarker screening for antenatal depression in women who underwent caesarean section: a matched observational study with plasma Lipidomics.

BACKGROUND: Antenatal depression is a prevalent mental disorder in women who have undergone caesarean section, and it often presages adverse postoperative outcomes. Because of the lack of a laboratory-based diagnostic strategy, antenatal depression is mainly determined by a psychologist's subjective judgment based on a structured clinical interview for established diagnostic criteria. However, the diagnostic accuracy rate for depression by non-psychiatrists is relatively low. Thus, this study aimed to use lipidomics to identify potential biomarkers related to antenatal depression in women who have undergone caesarean section. METHODS: The study was designed as a matched prospective observational study. Singleton pregnant women scheduled to receive elective caesarean section, were screened for eligibility. Women diagnosed with major antenatal depression were matched with non-antenatal depression controls in terms of age (±1 year) and BMI (±1 kg/m2), and blood samples of the included matched pairs were collected. Subsequently, lipidomics of the plasma samples were performed using Ultra Performance Liquid Chromatography-mass spectrometry analysis to explore the differentially expressed lipids in women with or without antenatal depression. RESULTS: In total, 484 pregnant women were screened; 66 subjects were recruited, including 33 subjects with major antenatal depression and 33 matched controls without antenatal depression. Thirty-five differentially expressed lipid metabolites were identified (P < 0.05). The area under the receiver operating characteristic curve of these lipid metabolites was 0.7 or larger; the area under curve for cholesterol sulfate was 0.823 (95% CI: 0.716-0.930), and that of PC (18:2 (2E, 4E)/0:0) was 0.778 (95%CI: 0.662-0.895). In the conditional logistic stepwise regression analysis, cholesterol sulfate (P = 0.009) and PC (18:2 (2E, 4E)/0:0) (P = 0.035) were also identified as effective predictive risk factors for antenatal depression. CONCLUSIONS: Women who had undergone caesarean section and experienced antenatal depression presented a significantly differentially expressed profile of plasma lipidomics compared to those who did not experience antenatal depression. Cholesterol sulfate and PC (18:2 (2E, 4E)/0:0) may be effective and specific lipidic biomarkers for the prediction of antenatal depression. TRIAL REGISTRATION: China Clinical Trial Registration Center registration number: ChiCTR1800016230 ; date of registration: 21/05/2018.

Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study.

BACKGROUND Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. METHODS We conducted a randomized, double-blind, clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. RESULTS A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents × hours per milliliter, respectively (P≤0.001). The time to nondetectability on polymerase-chain-reaction assay (P<0.001), the peak viral load (P≤0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose--viral clearance was accelerated (P≤0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. CONCLUSIONS In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. (Funded by Alios BioPharma; ClinicalTrials.gov number, NCT02094365.).

Transumbilical laparoendoscopic single-site radical prostatectomy and cystectomy with the aid of a transurethral port: a feasibility study.

OBJECTIVE: To describe the surgical technique and report early outcomes of transurethral assisted laparoendoscopic single-site (LESS) radical prostatectomy (RP) and LESS radical cystectomy (RC) in a single institution. MATERIALS AND METHODS: Between December 2014 and March 2016, a total of 114 LESS RPs and RCs were performed, comprising 68 LESS RPs, 38 LESS RCs with cutaneous ureterostomy (CU) and eight LESS RCs with orthotopic ileal neobladder (OIN). Access was achieved via a single-port, with four channels placed through a transumblical incision. After the apex of prostate was separated from the urethra, a self-developed port ('Zhu's port') was inserted through the urethra to facilitate resection of prostate and urethrovesical anastomosis. The peri-operative and postoperative data were collected and analysed retrospectively. Patients were followed up postoperatively for evidence of long-term side effects. RESULTS: All the procedures were completed successfully. No conversion to conventional laparoscopic surgery was necessary. For LESS RP, the average operating time was 152 min. Estimated blood loss was 117 mL. The mean hospital stay was 16.4 days after surgery. For LESS RC with CU and LESS RC with OIN, the mean operating times were 215 and 328 min, mean estimated blood loss was 175 and 252 mL, and mean hospital stay was 9.4 and 18.2 days, respectively. Six patients required blood transfusion (5.26%). Intra-operative complications occurred in two patients (1.75%), and postoperative complications in nine (7.89%). Fourteen out of 68 (20.6%) patients who underwent LESS RP had positive surgical margins. Follow-up ranged from 10 to 30.6 months. In the prostate cancer cases, good urinary control was observed in 35.3%, 97.1% and 100% of patients at 1, 6 and 12 months after the operation, respectively, while biochemical recurrence was observed in 11.8% patients. In the bladder cancer cases, two patients had local recurrence and two patients had distant metastasis. CONCLUSION: Our results showed that LESS RP and LESS RC are feasible and safe with the aid of a transurethral port. Operating through the transurethral port might overcome the challenges posed by the single-port laparoscopic approach.