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Zhuo Chen, Zhengkui Jiang, Wenzhou Zhang, Baoxia He The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou 450008, People’s Republic of China Background: The application of the oral targeted therapeutic agent sorafenib provides new hope for patients suffering from advanced stages of hepatocellular carcinoma (HCC), but the prognosis of such patients remains poor due to the rapid development of the multidrug resistance process in cancer pathogenesis. The present work evaluated whether copine-III, a novel cancer regulator encoded by the CPNE3 gene, would be a potential indicator of sorafenib resistance in HCC treatment.Materials and methods: The endogenous expression of copine-III in clinical specimens was examined by quantitative polymerase chain reaction. Copine-III siRNA was transfected into HCC cells to downregulate copine-III expression. The effect of copine-III on sorafenib’s antitumor activation was identified by in vitro and in vivo experiments (MTT, Transwell, and flow cytometry as well as a nude mice model).Results: High levels of copine-III in clinical specimens are related to poor prognosis of advanced HCC patients on sorafenib treatment. Infection of Ad-siCPNE3 significantly decreased the endogenous expression of copine-III and enhanced the susceptibility of MHCC97-H cells to sorafenib: the IC50 value decreased from 1.15±0.11 to 0.25±0.05 μmol/L. Moreover, silencing copine-III enhanced the effect of sorafenib on apoptosis, in vitro invasion/migration, and subcutaneous or intrahepatic growth of MHCC97-H cells in nude mice.Conclusion: Copine-III is a novel potential indicator of prognosis for patients who received sorafenib for advanced HCC treatment. Keywords: hepatocellular carcinoma, CPNE3, copine-III, molecular targeted agent, sorafenib-resistance

Objectives: Lack of physical activity has a critical effect on the physical and mental health of adolescents. This study examined the influence of family adversities on the longitudinal changes in physical inactivity among adolescents during the coronavirus disease 2019 (COVID-19) pandemic., Methods: The study used multi-wave data from the Korean Children and Youth Panel Survey, including 2590 Korean adolescents aged 12-14 years. The longitudinal trajectory of physical inactivity among adolescents and the effects of related factors were estimated using a latent growth modeling method., Results: Our results revealed a significant increase in physical inactivity among adolescents over time. At the onset of the pandemic, approximately one-seventh of Korean middle schoolers reported a lack of physical activity. However, 3 years later, during the quarantine, nearly one-fifth of these adolescents reported a significant increase in their physical inactivity. Initially, low level parental education was predictive of adolescents' physical inactivity, but this effect diminished over time, becoming statistically insignificant by the end of the 3-year period. Moreover, the increase in physical inactivity over the 3 years was significantly influenced by parental rejection., Conclusions: These findings suggest that adolescents who experience parental rejection are more likely to report an increase in sedentary behaviors in contexts such as the COVID-19 pandemic.

Precise regulation of Type I interferon signaling is crucial for combating infection and cancer while avoiding autoimmunity. Type I interferon signaling is negatively regulated by USP18. USP18 cleaves ISG15, an interferon-induced ubiquitin-like modification, via its canonical catalytic function, and inhibits Type I interferon receptor activity through its scaffold role. USP18 loss-of-function dramatically impacts immune regulation, pathogen susceptibility, and tumor growth. However, prior studies have reached conflicting conclusions regarding the relative importance of catalytic versus scaffold function. Here, we develop biochemical and cellular methods to systematically define the physiological role of USP18. By comparing a patient-derived mutation impairing scaffold function (I60N) to a mutation disrupting catalytic activity (C64S), we demonstrate that scaffold function is critical for cancer cell vulnerability to Type I interferon. Surprisingly, we discovered that human USP18 exhibits minimal catalytic activity, in stark contrast to mouse USP18. These findings resolve human USP18's mechanism-of-action and enable USP18-targeted therapeutics., Competing Interests: VJ, HW, CWL, DRH, KL, ECR, MY, ZKJ, EC, YX, JS, BY, AG, PL, ACG, VF, PDW, and FW are current or former employees of Pfizer and may own Pfizer stock. BMK and APF receive research funding from Pfizer. This work was supported by Pfizer, and APF and BMK are funded by the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science (CIFMS), China (grant nr - 2018-I2M-2-002)., (© 2024 Pfizer Inc.)

Lung cancer remains a leading cause of cancer-related death, but scientists have made great strides in developing new treatments recently, partly owing to the use of genetically engineered mouse models (GEMMs). GEMM tumors represent a translational model that recapitulates human disease better than implanted models because tumors develop spontaneously in the lungs. However, detection of these tumors relies on in vivo imaging tools, specifically micro-Computed Tomography (micro-CT or µCT), and image analysis can be laborious with high inter-user variability. Here we present a deep learning model trained to perform fully automated segmentation of lung tumors without the interference of other soft tissues. Trained and tested on 100 3D µCT images (18,662 slices) that were manually segmented, the model demonstrated a high correlation to manual segmentations on the testing data (r 2 =0.99, DSC=0.78) and on an independent dataset (n = 12 3D scans or 2328 2D slices, r 2 =0.97, DSC=0.73). In a comparison against manual segmentation performed by multiple analysts, the model (r 2 =0.98, DSC=0.78) performed within inter-reader variability (r 2 =0.79, DSC=0.69) and close to intra-reader variability (r 2 =0.99, DSC=0.82), all while completing 5+ hours of manual segmentations in 1 minute. Finally, when applied to a real-world longitudinal study (n = 55 mice), the model successfully detected tumor progression over time and the differences in tumor burden between groups induced with different virus titers, aligning well with more traditional analysis methods. In conclusion, we have developed a deep learning model which can perform fast, accurate, and fully automated segmentation of µCT scans of murine lung tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

This study aimed to examine the role played by the physical literacy and mindfulness in the health-related quality of life (QoL) of college students. In early 2022, 24,236 college students from three universities in southern China were recruited in the study. R software and the lavvan package was utilized to build the structural equation model. The measurement model was composed of three latent factors (physical literacy, mindfulness, and quality of life) and 16 observed variables in total. The results of the measurement model indicated goodness fit with p > .05 in Chi-square result, and GFI = .92. In addition, the comparative fit index (.92), Tucker-Lewis index (.91), root-mean-square error of approximation (.07), and root of mean square residual (.11) were in accord with the cutoff model-fit criteria. The results confirm that physical literacy and mindfulness can play a significant and positive role in the structural equation model of quality of life. In addition, this study provides initial evidence that mindfulness and physical literacy could potentially buffer declines in student QoL during the COVID-19 pandemic. Moreover, this study is the first to develop a structural equation model of QoL with multiple indicators, making it a strong addition to existing research on QoL during a pandemic., (© 2024. The Author(s).)

Background: Although there are many studies on the prognostic factors of left ventricular myocardial noncompaction (LVNC), the determinants are varied and not entirely consistent. This study aimed to build predictive models using radiomics features and machine learning to predict major adverse cardiovascular events (MACEs) in patients with LVNC., Methods: In total, 96 patients with LVNC were included and randomly divided into training and test cohorts. A total of 105 cine cardiac magnetic resonance (CMR)-derived radiomics features and 35 clinical characteristics were extracted. Five different oversampling algorithms were compared for selection of the optimal imbalanced processing. Feature importance was assessed with extreme gradient boosting (XGBoost). We compared the performance of 5 machine learning classification methods with different sample:feature ratios to determine the optimal hybrid classification strategy. Subsequently, radiomics, clinical, and combined radiomics-clinical models were developed and compared., Results: The machine learning pipeline included an adaptive synthetic (ADASYN) algorithm for imbalanced processing, XGBoost feature selection with a sample:feature ratio of 10, and support vector machine (SVM) modeling. The areas under the receiver operating characteristic curves (AUCs) of the radiomics model, clinical model, and combined model in the validation cohort were 0.87 (sensitivity 83.33%, specificity 64.29%), 0.65 (sensitivity 16.67%, specificity 78.57%), and 0.92 (specificity 33.33%, sensitivity 100.00%), respectively. The radiomics model performed similarly to the clinical and combined models (P=0.124 and P=0.621, respectively). The performance of the combined model was significantly better than that of the clinical model (P=0.003)., Conclusions: The machine learning-based cine CMR radiomics model performed well at predicting MACEs in patients with LVNC. Adding radiomics features offered incremental prognostic value over clinical factors alone., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-372/coif). The authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

KRAS is one of the most commonly mutated oncogenes in lung, colorectal, and pancreatic cancers. Recent clinical trials directly targeting KRAS G12C presented encouraging results for a large population of non-small cell lung cancer (NSCLC), but resistance to treatment is a concern. Continued exploration of new inhibitors and preclinical models is needed to address resistance mechanisms and improve duration of patient responses. To further enable the development of KRAS G12C inhibitors, we present a preclinical framework involving translational, non-invasive imaging modalities (CT and PET) and histopathology in a conventional xenograft model and a novel KRAS G12C knock-in mouse model of NSCLC. We utilized an in-house developed KRAS G12C inhibitor (Compound A) as a tool to demonstrate the value of this framework in studying in vivo pharmacokinetic/pharmacodynamic (PK/PD) relationship and anti-tumor efficacy. We characterized the Kras G12C-driven genetically engineered mouse model (GEMM) and identify tumor growth and signaling differences compared to its Kras G12D-driven counterpart. We also find that Compound A has comparable efficacy to sotorasib in the Kras G12C-driven lung tumors arising in the GEMM, but like observations in the clinic, some tumors inevitably progress on treatment. These findings establish a foundation for evaluating future KRAS G12C inhibitors that is not limited to xenograft studies and can be applied in a translationally relevant mouse model that mirrors human disease progression and resistance., (©2023 The Authors; Published by the American Association for Cancer Research.)

Boson sampling is a computational problem, which is commonly believed to be a representative paradigm for attaining the milestone of quantum advantage. So far, massive efforts have been made to the experimental large-scale boson sampling for demonstrating this milestone, while further applications of the machines remain a largely unexplored area. Here, we investigate experimentally the efficiency and security of a cryptographic one-way function that relies on coarse-grained boson sampling, in the framework of a photonic boson-sampling machine fabricated by a femtosecond laser direct writing technique. Our findings demonstrate that the implementation of the function requires moderate sample sizes, which can be over 4 orders of magnitude smaller than the ones predicted by the Chernoff bound; whereas for numbers of photons n≥3 and bins d∼poly(m,n), the same output of the function cannot be generated by nonboson samplers. Our Letter is the first experimental study that deals with the potential applications of boson sampling in the field of cryptography and paves the way toward additional studies in this direction.

Background: The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mainly infects the upper respiratory tract. This study aimed to determine whether the probability of pulmonary infection and the cycle threshold (Ct) measured using the fluorescent polymerase chain reaction (PCR) method were related to pulmonary infections diagnosed via computed tomography (CT)., Aim: To analyze the chest CT signs of SARS-CoV-2 Omicron variant infections with different Ct values, as determined via PCR., Methods: The chest CT images and PCR Ct values of 331 patients with SARS-CoV-2 Omicron variant infections were retrospectively collected and categorized into low (< 25), medium (25.00-34.99), and high (≥ 35) Ct groups. The characteristics of chest CT images in each group were statistically analyzed., Results: The PCR Ct values ranged from 13.36 to 39.81, with 99 patients in the low, 155 in the medium, and 77 in the high Ct groups. Six abnormal chest CT signs were detected, namely, focal infection, patchy consolidation shadows, patchy ground-glass shadows, mixed consolidation ground-glass shadows, subpleural interstitial changes, and pleural changes. Focal infections were less frequent in the low Ct group than in the medium and high Ct groups; these infections were the most common sign in the medium and high Ct groups. Patchy consolidation shadows and pleural changes were more frequent in the low Ct group than in the other two groups. The number of patients with two or more signs was greater in the low Ct group than in the medium and high Ct groups., Conclusion: The chest CT signs of patients with pulmonary infection caused by the Omicron variants of SARS-CoV-2 varied depending on the Ct values. Identification of the characteristics of Omicron variant infection can help subsequent planning of clinical treatment., Competing Interests: Conflict-of-interest statement: The authors state that there are no conflicts of interest to report., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The relationship of left atrial (LA) strain to high-risk heart failure (HF) events in patients with left ventricular myocardial noncompaction (LVNC) remains to be thoroughly investigated., Purpose: To evaluate the LA performance in patients with LVNC, and to investigate the prognostic value of LA phasic strain on high-risk HF events, and its influencing factors., Study Type: Retrospective., Population: A total of 95 LVNC patients (74 with LA enlargement [LAE] and 21 without LAE) and 50 healthy controls., Field Strength/sequence: A 3.0 T, balanced steady-state free-precession cine imaging., Assessment: LA longitudinal strains were measured by cardiac MRI feature tracking technique. LA volume index (LAVI) and LA ejection fraction (LAEF) were calculated. Their intraobserver and interobserver reproducibility were evaluated. The primary outcome was high-risk HF events, a composite of first HF hospitalization, hospitalization for worsening HF and death from HF., Statistical Tests: Student's t/Mann-Whitney U, one-way analysis of variance/Kruskal-Wallis, Chi-squared, receiver operating characteristic, Kaplan-Meier, log-rank, Cox regression, Pearson and Spearman correlation and linear regression analyses were performed. The significance threshold was set at P < 0 .05., Results: LAEF and LA longitudinal strains decreased in LVNC patients irrespective of the presence of LAE. During a median follow-up of 32.17 months, high-risk HF occurred in 13 (13.68%) patients. Patients with increased LAVI, decreased LAEF and decreased LA longitudinal strain had significantly higher risks of high-risk HF events. In patients with LVNC, LA reservoir strain (εs) was independently associated with high-risk HF (hazard ratio = 23.208 [95% CI: 2.993-179.967]). LV global longitudinal strain (LV GLS) (β = -1.783 [95% CI: -2.493 to -1.073]) was significantly and independently associated with εs. Intraobserver and interobserver reproducibility was excellent for LAVI, LAEF, and LA strain., Conclusion: In patients with LVNC, εs was an independent predictor for high-risk HF events. LV GLS was an independent determinant of εs in LVNC., Evidence Level: 4 TECHNICAL EFFICACY: Stage 4., (© 2022 International Society for Magnetic Resonance in Medicine.)

Quantum-correlated biphoton states play an important role in quantum communication and processing, especially considering the recent advances in integrated photonics. However, it remains a challenge to flexibly transport quantum states on a chip, when dealing with large-scale sophisticated photonic designs. The equivalence between certain aspects of quantum optics and solid-state physics makes it possible to utilize a range of powerful approaches in photonics, including topologically protected boundary states, graphene edge states, and dynamic localization. Optical dynamic localization allows efficient protection of classical signals in photonic systems by implementing an analogue of an external alternating electric field. Here, we report on the observation of dynamic localization for quantum-correlated biphotons, including both the generation and the propagation aspects. As a platform, we use sinusoidal waveguide arrays with cubic nonlinearity. We record biphoton coincidence count rates as evidence of robust generation of biphotons and demonstrate the dynamic localization features in both spatial and temporal space by analyzing the quantum correlation of biphotons at the output of the waveguide array. Experimental results demonstrate that various dynamic modulation parameters are effective in protecting quantum states without introducing complex topologies. Our Letter opens new avenues for studying complex physical processes using photonic chips and provides an alternative mechanism of protecting communication channels and nonclassical quantum sources in large-scale integrated quantum optics.

Objectives: To systematically quantify the diagnostic accuracy and identify potential covariates affecting the performance of artificial intelligence (AI) in diagnosing orthopedic fractures., Methods: PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for studies on AI applications in diagnosing orthopedic fractures from inception to September 29, 2021. Pooled sensitivity and specificity and the area under the receiver operating characteristic curves (AUC) were obtained. This study was registered in the PROSPERO database prior to initiation (CRD 42021254618)., Results: Thirty-nine were eligible for quantitative analysis. The overall pooled AUC, sensitivity, and specificity were 0.96 (95% CI 0.94-0.98), 90% (95% CI 87-92%), and 92% (95% CI 90-94%), respectively. In subgroup analyses, multicenter designed studies yielded higher sensitivity (92% vs. 88%) and specificity (94% vs. 91%) than single-center studies. AI demonstrated higher sensitivity with transfer learning (with vs. without: 92% vs. 87%) or data augmentation (with vs. without: 92% vs. 87%), compared to those without. Utilizing plain X-rays as input images for AI achieved results comparable to CT (AUC 0.96 vs. 0.96). Moreover, AI achieved comparable results to humans (AUC 0.97 vs. 0.97) and better results than non-expert human readers (AUC 0.98 vs. 0.96; sensitivity 95% vs. 88%)., Conclusions: AI demonstrated high accuracy in diagnosing orthopedic fractures from medical images. Larger-scale studies with higher design quality are needed to validate our findings., Key Points: • Multicenter study design, application of transfer learning, and data augmentation are closely related to improving the performance of artificial intelligence models in diagnosing orthopedic fractures. • Utilizing plain X-rays as input images for AI to diagnose fractures achieved results comparable to CT (AUC 0.96 vs. 0.96). • AI achieved comparable results to humans (AUC 0.97 vs. 0.97) but was superior to non-expert human readers (AUC 0.98 vs. 0.96, sensitivity 95% vs. 88%) in diagnosing fractures., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Irrigation regimes should be chosen to maximize crop yield and water use efficiency. To realize high yield and efficient water use with the appropriate furrow irrigation regime, the effects of two regimes (alternate furrow irrigation and conventional furrow irrigation) and three lower soil moisture limits (60, 70, and 80%) were studied on winter wheat yield and water consumption using a multi-level fuzzy comprehensive evaluation method. The results show that under the two regimes, alternate furrow irrigation and conventional furrow irrigation, when the lower limit of the soil moisture is 70%, the harvest index (0.45 and 0.39, respectively) and crop water productivity of winter wheat (1.86 and 1.90 kg m -3 , respectively) are highest. The comprehensive fuzzy evaluation model considers multiple measures, including yield, harvest indices, irrigation volume, total water consumption, and crop water productivity - the index values are highest at the 70% condition, which are 0.3468 and 0.3432, respectively. Therefore, it can be concluded that a moderate water deficit is conducive to saving water resources and improving water use efficiency. In conclusion, a multi-level and multi-factor indices system of furrow irrigation regime was constructed based on ensuring winter wheat production. Conventional furrow irrigation is recommended in areas with sufficient irrigation water, while alternating furrow irrigation, which can reduce the total amount of irrigation required, is suitable for areas with water shortages., Competing Interests: Conflict of interest: Authors state no conflicts of interest., (© 2022 Xiao-Hang Li et al., published by De Gruyter.)

Background Aims: Chimeric antigen receptor (CAR) T-cell therapy can be associated with significant toxicities. CAR-engineered natural killer (NK) cells provide a safer alternative while maintaining anti-tumor effects. Activated NK (aNK) cells are a clinical-grade cellular product obtained from the NK-92 cell line that have demonstrated both safety and potent cytotoxicity toward a wide range of cancers in phase 1 trials. Genetically engineered variants of aNK cells expressing a high-affinity Fc receptor (haNK) or co-expressing a CAR (t-haNK) are currently in phase 1/2 clinical trials. A key factor in the efficacy of cellular immunotherapies is biodistribution and tumor infiltration, which affect the local effector:target ratio. The chemokines CCL19 and CCL21 can drive recruitment of CCR7 receptor-expressing immune cells to secondary lymphoid organs., Methods: Since NK-92 cells do not spontaneously express CCR7, clinical-grade aNK cells were transfected with a non-viral vector containing the CCR7 receptor, an anti-CD19 CAR and a high-affinity CD16 Fc receptor., Results: CCR7-engineered CD19 t-haNK showed significant migration in vitro toward K562 cells engineered to secrete CCL19. This observation was confirmed in a NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mouse model in which subcutaneous tumors of CCL19-expressing K562 cells displayed a higher number of infiltrating CCR7&#95;CD19 t-haNK cells than CCR7-negative CD19 t-haNK cells. In NSG mice inoculated either intravenously or subcutaneously with CCL19-secreting Raji cells, treatment with CCR7&#95;CD19 t-haNK improved survival and tumor control compared with CD19 t-haNK or vehicle., Conclusions: Expression of CCR7 receptor by off-the-shelf t-haNK cells improves their homing toward lymph node chemokines both in vitro and in vivo, resulting in superior tumor control., Competing Interests: Declaration of Competing Interest MIL, HK and LB are employed by ImmunityBio, Inc (formerly NantKwest, Inc). All authors own stocks and/or stock options in ImmunityBio, Inc. NTS, HK and LB are inventors of PCT/US2018/044842 (patent pending)., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Mangrove actinomycetia are considered one of the promising sources for discovering novel biologically active compounds. Traditional bioactivity- and/or taxonomy-based methods are inefficient and usually result in the re-discovery of known metabolites. Thus, improving selection efficiency among strain candidates is of interest especially in the early stage of the antibiotic discovery program. In this study, an integrated strategy of combining phylogenetic data and bioactivity tests with a metabolomics-based dereplication approach was applied to fast track the selection process. A total of 521 actinomycetial strains affiliated to 40 genera in 23 families were isolated from 13 different mangrove soil samples by the culture-dependent method. A total of 179 strains affiliated to 40 different genera with a unique colony morphology were selected to evaluate antibacterial activity against 12 indicator bacteria. Of the 179 tested isolates, 47 showed activities against at least one of the tested pathogens. Analysis of 23 out of 47 active isolates using UPLC-HRMS-PCA revealed six outliers. Further analysis using the OPLS-DA model identified five compounds from two outliers contributing to the bioactivity against drug-sensitive A. baumannii . Molecular networking was used to determine the relationship of significant metabolites in six outliers and to find their potentially new congeners. Finally, two Streptomyces strains (M22, H37) producing potentially new compounds were rapidly prioritized on the basis of their distinct chemistry profiles, dereplication results, and antibacterial activities, as well as taxonomical information. Two new trioxacarcins with keto-reduced trioxacarcinose B, gutingimycin B ( 16 ) and trioxacarcin G ( 20 ), together with known gutingimycin ( 12 ), were isolated from the scale-up fermentation broth of Streptomyces sp. M22. Our study demonstrated that metabolomics tools could greatly assist classic antibiotic discovery methods in strain prioritization to improve efficiency in discovering novel antibiotics from those highly productive and rich diversity ecosystems.

Glycosylation inactivation is one of the important macrolide resistance mechanisms. The accumulated evidences attributed glycosylation inactivation to a glucosylation modification at the inactivation sites of macrolides. Whether other glycosylation modifications lead to macrolides inactivation is unclear. Herein, we demonstrated that varied glycosylation modifications could cause inactivation of midecamycin, a 16-membered macrolide antibiotic used clinically and agriculturally. Specifically, an actinomycetic glycosyltransferase (GT) OleD was selected for its glycodiversification capacity towards midecamycin. OleD was demonstrated to recognize UDP-D-glucose, UDP-D-xylose, UDP-galactose, UDP-rhamnose and UDP- N -acetylglucosamine to yield corresponding midecamycin 2'- O -glycosides, most of which displayed low yields. Protein engineering of OleD was thus performed to improve its conversions towards sugar donors. Q327F was the most favorable variant with seven times the conversion enhancement towards UDP- N -acetylglucosamine. Likewise, Q327A exhibited 30% conversion enhancement towards UDP-D-xylose. Potent biocatalysts for midecamycin glycosylation were thus obtained through protein engineering. Wild OleD, Q327F and Q327A were used as biocatalysts for scale-up preparation of midecamycin 2'- O -glucopyranoside, midecamycin 2'- O -GlcNAc and midecamycin 2'- O -xylopyranoside. In contrast to midecamycin, these midecamycin 2'- O -glycosides displayed no antimicrobial activities. These evidences suggested that besides glucosylation, other glycosylation patterns also could inactivate midecamycin, providing a new inactivation mechanism for midecamycin resistance. Cumulatively, glycosylation inactivation of midecamycin was independent of the type of attached sugar moieties at its inactivation site.

One new virginiamycin derivative, 'beilunmycin' ( 1 ), and three known virginiamycin antibiotics, 16-hydroxy-virginiamycin M1 ( 2 ), virginiamycin M2 ( 3 ), and virginiamycin M1 ( 4 ), were isolated from the culture of a mangrove-derived endophytic Streptomyces sp. 2BBP-J2. The structures were characterized on the basis of their spectroscopic data, and the absolute configuration of 1 was established by ECD calculations. Compounds 1 - 4 exhibited antibacterial activities against Gram-positive bacteria, with MIC values in the range of 0.5-16 μg/ml. All the compounds demonstrated strong protein translation-stalling activity, with minimal concentrations detected with pDualrep2 in the range of 1.9-5.9 nmol.

In oncology research, while xenograft tumor models are easily visualized and humane endpoints can be clearly defined, metastatic tumor models are often based on more subjective clinical observations as endpoints. This study aimed at identifying objective non-invasive criteria for predicting imminent distress and mortality in metastatic lung tumor-bearing mice. BALB/c and C57BL/6 mice were inoculated with CT26 or B16F10 cells, respectively. The mice were housed in Vium smart cages to continuously monitor and stream respiratory rate and locomotion for up to 28 days until scheduled euthanasia or humane endpoint criteria were met. Body weight and body temperature were measured during the study. On days 11, 14, 17 and 28, lungs of subsets of animals were microCT imaged in vivo to assess lung metastasis progression and then euthanized for lung microscopic evaluations. Beginning at day 21, most tumor-bearing animals developed increased respiratory rates followed by decreased locomotion 1-2 days later, compared with the baseline values. Increases in respiratory rate did not correlate to surface tumor nodule counts or lung weight. Body weight measurement did not show significant changes from days 14-28 in either tumor-bearing or control animals. We propose that increases in respiratory rate (1.3-1.5 X) can be used to provide an objective benchmark to signal the need for increased clinical observations or euthanasia. Adoption of this novel humane endpoint criterion would allow investigators time to collect tissue samples prior to spontaneous morbidity or death and significantly reduce the distress of mice in the terminal stages of these metastatic lung tumor models., Competing Interests: The authors have declared that no competing interests exist.

Unlike the majority of cancers, survival for lung cancer has not shown much improvement since the early 1970s and survival rates remain low. Genetically engineered mice tumor models are of high translational relevance as we can generate tissue specific mutations which are observed in lung cancer patients. Since these tumors cannot be detected and quantified by traditional methods, we use micro-computed tomography imaging for longitudinal evaluation and to measure response to therapy. Conventionally, we analyze microCT images of lung cancer via a manual segmentation. Manual segmentation is time-consuming and sensitive to intra- and inter-analyst variation. To overcome the limitations of manual segmentation, we set out to develop a fully-automated alternative, the Mouse Lung Automated Segmentation Tool (MLAST). MLAST locates the thoracic region of interest, thresholds and categorizes the lung field into three tissue categories: soft tissue, intermediate, and lung. An increase in the tumor burden was measured by a decrease in lung volume with a simultaneous increase in soft and intermediate tissue quantities. MLAST segmentation was validated against three methods: manual scoring, manual segmentation, and histology. MLAST was applied in an efficacy trial using a Kras/Lkb1 non-small cell lung cancer model and demonstrated adequate precision and sensitivity in quantifying tumor growth inhibition after drug treatment. Implementation of MLAST has considerably accelerated the microCT data analysis, allowing for larger study sizes and mid-study readouts. This study illustrates how automated image analysis tools for large datasets can be used in preclinical imaging to deliver high throughput and quantitative results., Competing Interests: All authors are or were full- or part-time employees of Pfizer, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background and Aims: Previous studies have suggested that aggressive hydration with lactated ringer solution are one of the protective factors in preventing post endoscopic retrograde cholangiopancreatography (post-ERCP). We conducted a systematic review and meta-analysis to examine the efficacy aggressive hydration with lactated Ringer solution in preventing PEP., Methods: All published and unpublished articles on aggressive hydration with lactated ringer solution in those underwent ERCP procedure for any reasons were screened for eligibility. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. This paper doesn't need the IRB approval., Results: Seven RCTs met the inclusion criteria. Meta-analysis indicates that aggressive hydration with lactated Ringer solution were associated with lower PEP rate.[odds ratio (OR) 0.29; 95% confidence interval (CI) 0.18-0.48]; lower incidence of hyperamylasemia (OR 0.49; 95% CI 0.35, 0.69) and lower risk of pain (OR 0.28; 95% CI 0.10-0.81). The association between aggressive hydration with lactated Ringer solution and incidence of moderate severity PEP were unclear (OR 0.57; 95% CI 0.22, 1.45). Sensitivity analyses also showed that omitting 1 study from analysis of PEP rate could reduce the heterogeneity but did not change the conclusion of this meta-analysis. A cumulating meta-analysis was performed statistically which showed a stable result of overall incidence of PEP., Conclusions: Aggressive hydration with lactated Ringer solution was a protective factor in reducing the overall incidence of PEP, hyperamylasemia and risk of abdominal pain.

IL13Rα2 is a cell surface tumor antigen that is overexpressed in multiple tumor types. Here, we studied biodistribution and targeting potential of an anti-IL13Rα2 antibody (Ab) and anti-tumor activity of anti-IL13Rα2-antibody-drug conjugate (ADC). The anti-IL13Rα2 Ab was labeled with fluorophore AF680 or radioisotope 89 Zr for in vivo tracking using fluorescence molecular tomography (FMT) or positron emission tomography (PET) imaging, respectively. Both imaging modalities showed that the tumor was the major uptake site for anti-IL13Rα2-Ab, with peak uptake of 5-8% ID and 10% ID/g as quantified from FMT and PET, respectively. Pharmacological in vivo competition with excess of unlabeled anti-IL13Rα2-Ab significantly reduced the tumor uptake, indicative of antigen-specific tumor accumulation. Further, FMT imaging demonstrated similar biodistribution and pharmacokinetic profiles of an auristatin-conjugated anti-IL13Rα2-ADC as compared to the parental Ab. Finally, the anti-IL13Rα2-ADC exhibited a dose-dependent anti-tumor effect on A375 xenografts, with 90% complete responders at a dose of 3 mg/kg. Taken together, both FMT and PET showed a favorable biodistribution profile for anti-IL13Rα2-Ab/ADC, along with antigen-specific tumor targeting and excellent therapeutic efficacy in the A375 xenograft model. This work shows the great potential of this anti-IL13Rα2-ADC as a targeted anti-cancer agent.

More than 50% of colorectal cancer (CRC) deaths are attributed to metastasis, and the liver is the most common distant metastatic site of CRC. The molecular mechanisms underlying CRC liver metastasis are very complicated and remain largely unknown. Accumulated evidence has shown that non-coding RNAs (NcRNAs) play critical roles in tumor development and progression. Here we reviewed the roles and underlying mechanisms of NcRNAs in CRC liver metastasis.

CD8-expressing T cells are the main effector cells in cancer immunotherapy. Treatment-induced changes in intratumoral CD8 + T cells may represent a biomarker to identify patients responding to cancer immunotherapy. Here, we have used a 89 Zr-radiolabeled human CD8-specific minibody ( 89 Zr-Df-IAB22M2C) to monitor CD8 + T-cell tumor infiltrates by PET. The ability of this tracer to quantify CD8 + T-cell tumor infiltrates was evaluated in preclinical studies following single-agent treatment with FOLR1-T-cell bispecific (TCB) antibody and combination therapy of CEA-TCB (RG7802) and CEA-targeted 4-1BB agonist CEA-4-1BBL. In vitro cytotoxicity assays with peripheral blood mononuclear cells and CEA-expressing MKN-45 gastric or FOLR1-expressing HeLa cervical cancer cells confirmed noninterference of the anti-CD8-PET-tracer with the mode of action of CEA-TCB/CEA-4-1BBL and FOLR1-TCB at relevant doses. In vivo , the extent of tumor regression induced by combination treatment with CEA-TCB/CEA-4-1BBL in MKN-45 tumor-bearing humanized mice correlated with intratumoral CD8 + T-cell infiltration. This was detectable by 89 Zr-IAB22M2C-PET and γ-counting. Similarly, single-agent treatment with FOLR1-TCB induced strong CD8 + T-cell infiltration in HeLa tumors, where 89 Zr-Df-IAB22M2C again was able to detect CD8 tumor infiltrates. CD8-IHC confirmed the PET imaging results. Taken together, the anti-CD8-minibody 89 Zr-Df-IAB22M2C revealed a high sensitivity for the detection of intratumoral CD8 + T-cell infiltrates upon either single or combination treatment with TCB antibody-based fusion proteins. These results provide further evidence that the anti-CD8 tracer, which is currently in clinical phase II, is a promising monitoring tool for intratumoral CD8 + T cells in patients treated with cancer immunotherapy. SIGNIFICANCE: Monitoring the pharmacodynamic activity of cancer immunotherapy with novel molecular imaging tools such as 89 Zr-Df-IAB22M2C for PET imaging is of prime importance to identify patients responding early to cancer immunotherapy., (©2020 American Association for Cancer Research.)

Colorectal cancer (CRC) is one of the most common malignancies with a dismal prognosis. Indeterminate pulmonary nodules (IPNs) are lung nodules with uncertain nature, generally defined as a noncalcified nodule smaller than 10 mm in diameter or solid nodule no greater than 20 mm at maximum diameter without malignant character. With the widespread use of preoperative staging computed tomography (CT) of the chest and follow-up CT, IPNs are frequently detected in patients with CRC, which makes diagnosis more controversial. Generally, progression to pulmonary metastasis from IPNs is rare. Thus, no further interventions were needed for IPNs in CRC patients. A second reviewing of scans with IPNs by both clinicians and experienced thoracic radiologists may help to obtain a more accurate diagnosis.

Objective: To develop a predicting model for tumor resistance to neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal cancer (LARC) by using pre-treatment apparent diffusion coefficient (ADC) image-derived radiomics features., Method: A total of 89 patients with LARC were randomly assigned into training (N = 66) and testing cohorts (N = 23) at the ratio of 3:1. Radiomics features were derived from manually determined tumor region of pre-treatment ADC images. Random forest algorithm was used to determine the most relevant features and then to construct a predicting model for identifying resistant tumor. Stability and diagnostic performance of the random forest model was evaluated with the testing cohort., Results: The top 10 most relevant features (entropy mean , inverse variance, energy mean , small area emphasis, ADC min , ADC mean , sdGa02, small gradient emphasis, age, and size) were determined from clinical characteristics and 133 radiomics features. In the prediction of resistant tumor of the testing cohort, the random forest model constructed based on these most relevant features achieved an area under the receiver operating characteristic curve of 0.83, with the highest accuracy of 91.3%, a sensitivity of 88.9%, and a specificity of 92.8%., Conclusion: The random forest classifier based on radiomics features derived from pre-treatment ADC images have the potential to predict tumor resistance to NCRT in patients with LARC, and the use of predicting model may facilitate individualized management of rectal cancer.

Smoking is the biggest risk factor for lung cancer. Smokers have a much higher chance of developing lung tumors with a worse survival rate; however, non-smokers also develop lung tumors. A number of questions remain including the underlying difference between smoker and non-smoker lung cancer patients and the involvement of genetic and epigenetic processes in tumor development. The present study analyzed the mutation data of 100 non-small cell lung cancer (NSCLC) patients, 12 non-smokers, 48 ex-smokers and 40 smokers, from Tracking Non-Small Cell Lung Cancer Evolution through Therapy Consortium. A total of 68 genes exhibited different mutation patterns across non-smokers, ex-smokers and smokers. A number of these 68 genes encode membrane proteins with biological regulation, metabolic process, and response to stimulus functions. For each group of patients, the top 10 most frequently mutated genes were selected and their oncogenetic tree inferred, which reflected how the genes evolve during tumor genesis. By comparing the oncogenetic trees of non-smokers and smokers, it was identified that in non-smokers, the mutation of epidermal growth factor receptor (EGFR) was an early genetic alteration event and EGFR was the key driver, but in smokers, the mutation of titin (TTN) was more important. Based on network analysis, TTN can interact with spectrin α erythrocytic 1 through calmodulin 2 and troponin C1. These genetic differences during tumorigenesis of non-smoker and smoker lung cancer patients provided novel insights into the effects of smoking on the evolutionary trajectory of non-small cell lung cancer and may prove helpful for targeted therapy of different lung cancer subtypes., (Copyright: © Yu et al.)

A Gram-stain-positive, aerobic, motile, non-spore-forming and rod-shaped actinobacterium, designated strain 4Q3S-7 T , was isolated from a piece of surface-sterilized bark of Kandelia candel collected at the Cotai Ecological Zone in Macao, China. Colonies were yellowish white, circular, smooth and convex. The 16S rRNA gene sequence of strain 4Q3S-7 T exhibited highest similarities to Marmoricola ginsengisoli Gsoil 097 T (97.6 %), Marmoricola solisilvae KIS18-7 T (97.6 %) and Marmoricola pocheonensis Gsoil 818 T (97.3 %). Phylogenetic analysis showed that strain 4Q3S-7 T clustered with species of the genus Marmoricola and was clearly affiliated to the genus Marmoricola. Genomic analyses, including average nucleotide identity and DNA-DNA hybridization, clearly separated strain 4Q3S-7 T from M. ginsengisoli Gsoil 097 T , M. solisilvae KIS18-7 T and M. pocheonensis Gsoil 818 T with values below the thresholds for species delineation. Strain 4Q3S-7 T had ll-2,6-diaminopimelic acid as the diagnostic diamino acid in the cell wall. The major fatty acids (>10 % of total fatty acids) were C18 : 0 10-methyl (TBSA), C18 : 1ω9c, iso-C16 : 0 and iso-C16 : 0 2-OH. The predominant menaquinone was MK-8(H4). The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylinositol and an unidentified phospholipid. The DNA G+C content of strain 4Q3S-7 T was 72.0 mol% (draft genome sequence). Based on its phylogenetic, phenotypic and chemotaxonomic features, strain 4Q3S-7 T is considered to represent a novel species of the genus Marmoricola, for which the name Marmoricola mangrovicus sp. nov. is proposed. The type strain is 4Q3S-7 T (=KCTC 39790 T =CGMCC 4.7424 T ).

The catalytic subunit p110δ of phosphoinositide 3-kinase (PI3K) encoded by PIK3CD has been implicated in some human solid tumors. However, its roles in colorectal cancer (CRC) remain largely unknown. Here we found that PIK3CD was overexpressed in colon cancer tissues and CRC cell lines and was an independent predictor for overall survival (OS) of patients with colon cancer. The ectopic overexpression of PIK3CD significantly promoted CRC cell growth, migration and invasion in vitro and tumor growth in vivo. In contrast, inhibition of PIK3CD by specific small-interfering RNA or idelalisib dramatically suppressed CRC cell growth, migration and invasion in vitro and tumor growth in vivo. Moreover, PIK3CD overexpression increased AKT activity, nuclear translocation of β-catenin and T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activity and decreased glycogen synthase kinase 3β (GSK-3β) activity, whereas PIK3CD inhibition exhibited the opposite effects. Furthermore, PIK3CD-mediated cell growth, migration and invasion were reversed by blockade of AKT signaling or depletion of β-catenin. In addition, PIK3CD expression in colon cancer tissues positively correlated with β-catenin abnormal expression, which was an independent predictor for OS of colon cancer patients. Taken together, our findings demonstrate that PIK3CD is an independent prognostic factor in CRC and that PIK3CD induces CRC cell growth, migration and invasion by activating AKT/GSK-3β/β-catenin signaling, suggesting that PIK3CD might be a novel prognostic biomarker and a potential therapeutic target for CRC., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: The inability to intraoperatively distinguish primary tumor, as well as lymphatic spread, increases the probability of positive surgical margins, tumor recurrence, and surgical toxicity. The goal of this study was to develop a tumor-specific optical probe for real-time fluorescence-guided surgery., Experimental Design: A humanized antibody fragment against PSCA (A11 minibody, A11 Mb) was conjugated with a near-infrared fluorophore, IRDye800CW. The integrity and binding of the probe to PSCA were confirmed by gel electrophoresis, size-exclusion chromatography, and flow cytometry, respectively. The ability of the probe to detect tumor-infiltrated lymph nodes and metastatic lesions was evaluated in 2 xenograft models, as well as in transgenic mice expressing human PSCA (hPSCA). An invasive intramuscular model was utilized to evaluate the efficacy of the A11 Mb-IRDye800CW-guided surgery., Results: A11 Mb was successfully conjugated with IRDye800CW and retained specific binding to PSCA. In vivo imaging showed maximal signal-to-background ratios at 48 hours. The A11 Mb-IRDye800CW specifically detected PSCA-positive primary tumors, tumor-infiltrated lymph nodes, and distant metastases with high contrast. Fluorescence guidance facilitated more complete tumor resection, reduced tumor recurrence, and improved overall survival, compared with conventional white light surgery. The probe successfully identified primary orthotopic tumors and metastatic lesions in hPSCA transgenic mice., Conclusions: Real-time fluorescence image-guided surgery with A11 Mb-IRDye800CW enabled detection of lymph node metastases and positive surgical margins, facilitated more complete tumor removal, and improved survival, compared with white light surgery. These results may be translatable into clinical practice to improve surgical and patient outcomes., (©2018 American Association for Cancer Research.)

Endophytic actinobacteria are one of the important pharmaceutical resources and well known for producing different types of bioactive substances. Nevertheless, detection of the novelty, diversity, and bioactivity on endophytic actinobacteria isolated from mangrove plants are scarce. In this study, five different mangrove plants, Avicennia marina, Aegiceras corniculatum, Kandelia obovota, Bruguiera gymnorrhiza , and Thespesia populnea , were collected from Beilun Estuary National Nature Reserve in Guangxi Zhuang Autonomous Region, China. A total of 101 endophytic actinobacteria strains were recovered by culture-based approaches. They distributed in 7 orders, 15 families, and 28 genera including Streptomyces, Curtobacterium, Mycobacterium, Micrococcus, Brevibacterium, Kocuria, Nocardioides, Kineococcus, Kytococcus, Marmoricola, Microbacterium, Micromonospora, Actinoplanes, Agrococcus, Amnibacterium, Brachybacterium, Citricoccus, Dermacoccus, Glutamicibacter, Gordonia, Isoptericola, Janibacter, Leucobacter, Nocardia, Nocardiopsis, Pseudokineococcus, Sanguibacter , and Verrucosispora . Among them, seven strains were potentially new species of genera Nocardioides, Streptomyces, Amnibacterium, Marmoricola , and Mycobacterium . Above all, strain 8BXZ-J1 has already been characterized as a new species of the genus Marmoricola . A total of 63 out of 101 strains were chosen to screen antibacterial activities by paper-disk diffusion method and inhibitors of ribosome and DNA biosynthesis by means of a double fluorescent protein reporter. A total of 31 strains exhibited positive results in at least one antibacterial assay. Notably, strain 8BXZ-J1 and three other potential novel species, 7BMP-1, 5BQP-J3, and 1BXZ-J1, all showed antibacterial bioactivity. In addition, 21 strains showed inhibitory activities against at least one "ESKAPE" resistant pathogens. We also found that Streptomyces strains 2BBP-J2 and 1BBP-1 produce bioactive compound with inhibitory activity on protein biosynthesis as result of translation stalling. Meanwhile, Streptomyces strain 3BQP-1 produces bioactive compound inducing SOS-response due to DNA damage. In conclusion, this study proved mangrove plants harbored a high diversity of cultivable endophytic actinobacteria, which can be a promising source for discovery of novel species and bioactive compounds.

A novel endophytic actinobacterium, designated strain 8BXZ-J1 T , was isolated from surface-sterilized branches of Thespesia populnea collected from Beilun Estuary Mangrove Forest National Nature Reserve in Guangxi, China, and examined by a polyphasic approach to determine its taxonomic position. Cells of the isolate were Gram-stain-positive, aerobic, non-spore-forming, non-motile and short rod-shaped. Phylogenetic analysis based on 16S rRNA gene sequences suggested that strain 8BXZ-J1 T belonged to the genus Marmoricola, sharing highest similarity with Marmoricola solisilvae DSM 27140 T (96.9 %). The isolate grew at 10-35 °C (optimum, 28-30 °C), at pH 6.0-8.0 (optimum, pH 7.0) and in the presence of 0-10 % (w/v) NaCl (optimum, 0-5.0 %). The organism contained ll-2,6-diaminopimelic acid as the diagnostic diamino acid of the peptidoglycan, MK-8(H4) as the major menaquinone, and a polar lipid profile including diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylinositol and two unknown lipids. The major fatty acids of strain 8BXZ-J1 T were C18 : 0 10-methyl, iso-C16 : 0 and C16 : 0. The G+C content of the genomic DNA was 68.7 mol%. These data demonstrate that strain 8BXZ-J1 T is representative of a novel species of the genus Marmoricola, for which the name Marmoricola endophyticus sp. nov. is proposed. The type strain is 8BXZ-J1 T (=KCTC 39789 T =CGMCC 1.16067 T ).

This study investigated the anticancer effects of geraniin on ovarian cancer cells and the signaling pathways involved. Ovarian cancer cells were treated with different concentrations of geraniin for 48 h and examined for viability, apoptosis, mitochondrial membrane depolarization, and gene expression. Xenograft tumor studies were performed to determine the anticancer activity of geraniin in vivo. Geraniin significantly decreased cancer cell viability in a concentration-dependent fashion. Geraniin significantly triggered apoptosis, which was accompanied by loss of mitochondrial membrane potential and increased cytochrome c release and caspsase-3 activity. Mechanistically, geraniin significantly downregulated Mcl-1 and impaired NF-κB p65 binding to the mcl-1 promoter. Overexpression of Mcl-1 significantly reversed geraniin-induced apoptosis in OVCAR3 cells. In addition, geraniin retarded ovarian cancer growth and reduced expression of phospho-p65 and Mcl-1. Collectively, geraniin elicits growth suppression in ovarian cancer through inhibition of NF-κB and Mcl-1 and may provide therapeutic benefits for this malignancy., (© 2017 Wiley Periodicals, Inc.)

A halotolerant actinobacterium, designated J12GA03T, was isolated from a rhizosphere soil sample of Suaeda salsa collected from a dried saline lake in Hebei Province, China. Cells were Gram-staining-positive, non-motile and non-spore-forming cocci. Strain J12GA03T grew optimally at 28‒37 °C, 0‒3 % NaCl (w/v) and pH 6.5‒7.5. It contained meso-diaminopimelic acid as the diagnostic diamino acid and arabinose, galactose and ribose as the diagnostic whole-cell sugars. MK-8 and MK-7 were detected as predominant menaquinones. Major fatty acids were C17 : 1ω8c, C16 : 0 and C17 : 0. Polar lipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol, phosphatidylglycerol, phosphoglycolipids, glycolipids, unidentified phospholipids and additional lipids. The muramyl residue was acetyl. Mycolic acids (34-38 carbon atoms) were present. The G+C content of the genomic DNA was 55.8 mol%. It shared the highest 16S rRNA gene sequence similarities with Amycolicicoccus subflavus DQS3-9A1T (98.18 %) and Hoyosella altamirensis OFN S31T (97.75 %). Phylogenetic trees showed that strain J12GA03T firmly formed a distinct monophyletic branch in the clade with A.subflavus DQS3-9A1T and H.altamirensis DSM 45258T. The levels of DNA-DNA relatedness with A.subflavus DSM 45089T and H.altamirensis DSM 45258T were 39.7±3.9 % and 35.7±3.0 %, respectively. Combining the evidence from the polyphasic taxonomic study, strain J12GA03T represents a novel species of the genus Hoyosella, for which the name Hoyosella rhizosphaerae sp. nov. is proposed. The type strain is J12GA03T (=DSM 101985T=CGMCC 1.15478T).

Purpose: The inability to visualize cancer during prostatectomy contributes to positive margins, cancer recurrence, and surgical side effects. A molecularly targeted fluorescent probe offers the potential for real-time intraoperative imaging. The goal of this study was to develop a probe for image-guided prostate cancer surgery., Experimental Design: An antibody fragment (cys-diabody, cDb) against prostate stem cell antigen (PSCA) was conjugated to a far-red fluorophore, Cy5. The integrity and binding of the probe to PSCA was confirmed by gel electrophoresis, size exclusion, and flow cytometry, respectively. Subcutaneous models of PSCA-expressing xenografts were used to assess the biodistribution and in vivo kinetics, whereas an invasive intramuscular model was utilized to explore the performance of Cy5-cDb-mediated fluorescence guidance in representative surgical scenarios. Finally, a prospective, randomized study comparing surgical resection with and without fluorescent guidance was performed to determine whether this probe could reduce the incidence of positive margins., Results: Cy5-cDb demonstrated excellent purity, stability, and specific binding to PSCA. In vivo imaging showed maximal signal-to-background ratios at 6 hours. In mice carrying PSCA(+) and negative (-) dual xenografts, the mean fluorescence ratio of PSCA(+/-) tumors was 4.4:1. In surgical resection experiments, residual tumors <1 mm that were missed on white light surgery were identified and resected using fluorescence guidance, which reduced the incidence of positive surgical margins (0/8) compared with white light surgery alone (7/7)., Conclusions: Fluorescently labeled cDb enables real-time in vivo imaging of prostate cancer xenografts in mice, and facilitates more complete tumor removal than conventional white light surgery alone., (©2015 American Association for Cancer Research.)

A pretargeted oncologic positron emission tomography (PET) imaging that leverages the power of supramolecular nanoparticles with in vivo bioorthogonal chemistry was demonstrated for the clinically relevant problem of tumor imaging. The advantages of this approach are that (i) the pharmacokinetics (PKs) of tumor-targeting and imaging agents can be independently altered via chemical alteration to achieve the desired in vivo performance and (ii) the interplay between the two PKs and other controllable variables confers a second layer of control toward improved PET imaging. In brief, we utilized supramolecular chemistry to synthesize tumor-targeting nanoparticles containing transcyclooctene (TCO, a bioorthogonal reactive motif), called TCO⊂SNPs. After the intravenous injection and subsequent concentration of the TCO⊂SNPs in the tumors of living mice, a small molecule containing both the complementary bioorthogonal motif (tetrazine, Tz) and a positron-emitting radioisotope ((64)Cu) was injected to react selectively and irreversibly to TCO. High-contrast PET imaging of the tumor mass was accomplished after the rapid clearance of the unreacted (64)Cu-Tz probe. Our nanoparticle approach encompasses a wider gamut of tumor types due to the use of EPR effects, which is a universal phenomenon for most solid tumors.

Malignant ascites is a common complication in the late stages of epithelial ovarian cancer (EOC) that greatly diminishes the quality of life of patients. Malignant ascites is a known consequence of vascular dysfunction, but current approved treatments are not effective in preventing fluid accumulation. In this study, we investigated an alternative strategy of targeting macrophage functions to reverse the vascular pathology of malignant ascites using fluid from human patients and an immunocompetent murine model (ID8) of EOC that mirrors human disease by developing progressive vascular disorganization and leakiness culminating in massive ascites. We demonstrate that the macrophage content in ascites fluid from human patients and the ID8 model directly correlates with vascular permeability. To further substantiate macrophages' role in the pathogenesis of malignant ascites, we blocked macrophage function in ID8 mice using a colony-stimulating factor 1 receptor kinase inhibitor (GW2580). Administration of GW2580 in the late stages of disease resulted in reduced infiltration of protumorigenic (M2) macrophages and dramatically decreased ascites volume. Moreover, the disorganized peritoneal vasculature became normalized and sera from GW2580-treated ascites protected against endothelial permeability. Therefore, our findings suggest that macrophage-targeted treatment may be a promising strategy toward a safe and effective means to control malignant ascites of EOC., (©2015 American Association for Cancer Research.)

A Gram-stain-positive, aerobic, straight or slightly bent rod-shaped, non-motile, non-spore-forming bacterium, designated strain CC5-806T, was isolated from a soil sample collected from a wild karst cave in the Wulong region, Chongqing, PR China and examined using a polyphasic approach to clarify its taxonomic position. This bacterium did not produce substrate mycelium or aerial hyphae, and no diffusible pigments were observed on the media tested. Strain CC5-806T grew optimally without NaCl at 20 °C and at pH 7.0. Phylogenetic analysis, based on 16S rRNA gene sequences, indicated that strain CC5-806T belonged to the family Microbacteriaceae and showed the highest levels of 16S rRNA gene sequence similarities with Frigoribacterium endophyticum EGI 6500707T (97.56 %), Frigoribacterium faeni 801T (97.53 %) and Glaciihabitans tibetensis MP203T (97.42 %). Phylogenetic trees revealed that strain CC5-806T did not show a clear affiliation to any genus within the family Microbacteriaceae. The DNA G+C content of strain CC5-806T was 62.6 mol%. The cell-wall peptidoglycan contained l-lysine as a diagnostic diamino acid. The predominant menaquinones were MK-11, MK-10 and MK-9. Phosphatidylglycerol, diphosphatidylglycerol, an unidentified glycolipid, four unidentified phospholipids and other polar lipids were detected in the polar lipid extracts. The major fatty acids were anteiso-C15 : 0, iso-C16 : 0 and iso-C14 : 0. On the basis of the phylogenetic analysis, and phenotypic and chemotaxonomic characteristics, strain CC5-806T was distinguishable from phylogenetically related genera in the family Microbacteriaceae. It represents a novel species of a novel genus, for which the name Lysinibacter cavernae gen. nov., sp. nov. is proposed. The type strain is CC5-806T ( = DSM 27960T = CGMCC 1.14983T).

Arctigenin, a bioactive component of Arctium lappa (Nubang), has anti-inflammatory activity. Here, we investigated the effects of arctigenin on lipopolysaccharide (LPS)-induced acute lung injury. Mice were divided into four groups: control, LPS, LPS + DMSO, and LPS + Arctigenin. Mice in the LPS + Arctigenin group were injected intraperitoneally with 50 mg/kg of arctigenin 1 h before an intratracheal administration of LPS (5 mg/kg). Lung tissues and bronchoalveolar lavage fluids (BALFs) were collected. Histological changes of the lung were analyzed by hematoxylin and eosin staining. Arctigenin decreased LPS-induced acute lung inflammation, infiltration of inflammatory cells into BALF, and production of pro-inflammatory cytokines. Moreover, arctigenin pretreatment reduced the malondialdehyde level and increased superoxide dismutase and catalase activities and glutathione peroxidase/glutathione disulfide ratio in the lung. Mechanically, arctigenin significantly reduced the production of nitric oxygen and inducible nitric oxygen synthase (iNOS) expression, enhanced the expression of heme oxygenase-1, and decreased the phosphorylation of mitogen-activated protein kinases (MAPKs). Arctigenin has anti-inflammatory and antioxidative effects on LPS-induced acute lung injury, which are associated with modulation of MAPK, HO-1, and iNOS signaling.

A novel endophytic actinobacterium, designated strain SP28S-3(T), was isolated from a surface-sterilized stem of Tamarix taklamakanensis collected from the southern edge of Taklamakan desert, Xinjiang, China. Strain SP28S-3(T) was found to show chemotaxonomic and morphological properties consistent with its classification in the genus Prauserella. The polar lipids were found to consist of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphoglycolipid, phosphatidylcholine, phosphatidylinositol, a glycolipid, an aminolipid and unidentified phospholipids. The major fatty acids (>10 %) were identified as iso-C16:0 and C16:0. The genomic DNA G+C content was determined to be 69.7 mol%. Phylogenetic analysis of strain SP28S-3(T) clearly showed that the strain had the highest similarity of 16S rRNA gene sequence with Prauserella coralliicola SCSIO 11529(T) (99.9 %), followed by Prauserella marina DSM 45268(T) (97.0 %) and is affiliated with the genus Prauserella. The low level (47.8 ± 5.5 %) of DNA-DNA relatedness between strain SP28S-3(T) and P. coralliicola SCSIO 11529(T) combined with other polyphasic taxonomic evidence clearly support the conclusion that strain SP28S-3(T) represents a novel Prauserella species, for which the name Prauserella endophytica sp. nov. is proposed. The type strain is SP28S-3(T) (=DSM 46655(T) = CGMCC 4.7182 (T)).

An alkaliphilic and moderately halophilic actinobacterium, designated strain GP10-3(T), was isolated from Populus euphratica collected from the southern edge of Taklimakan desert, Xinjiang, China. Cells of this strain were Gram-stain-positive, non-motile and non-spore-forming short rods. Strain GP10-3(T) grew optimally at 37 °C on LB agar media in the presence of 5-10% (w/v) NaCl at pH 9.0. The menaquinones were MK-7, MK-8 and MK-9. The major fatty acids (>10%) were anteiso-C17 : 0, anteiso-C15 : 0 and iso-C16 : 0. The peptidoglycan type was variation A4α, L-Lys-L-Glu. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylglycolipid, phosphatidylcholine, phosphatidylinositol, glycolipid and an unidentified phospholipid. The DNA G+C content was 67.4 mol%. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain GP10-3(T) belonged to the genus Nesterenkonia , sharing 94.6-96.9% sequence similarity with the type strains of species within this genus with validly published names. Based on the evidence of the polyphasic taxonomic study, strain GP10-3(T) represents a novel species of the genus Nesterenkonia , for which the name Nesterenkonia populi sp. nov. is proposed. The type strain is GP10-3(T) ( = DSM 27959(T) = KCTC 29119(T))., (© 2015 IUMS.)

A rod- or coccus-shaped, non-spore-forming actinobacterium, designated strain SC8A-24(T), was isolated from a soil sample collected from the rhizosphere of Alhagi sparsifolia on the southern edge of the Taklimakan desert, Xinjiang, China, and examined by a polyphasic approach to clarify its taxonomic position. This actinobacterium was Gram-staining-positive and aerobic. Substrate and aerial mycelia were not observed, and no diffusible pigments were observed on the media tested. Strain SC8A-24(T) grew optimally without NaCl at 28-30 °C and pH 7.0-8.0. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain SC8A-24(T) belonged to the genus Nocardioides and shared the highest 16S rRNA gene sequence similarity with Nocardioides salarius CL-Z59(T) (96.51%), N. pyridinolyticus OS4(T) (96.43%) and N. ginsengagri BX5-10(T) (96.37%). The DNA G+C content of strain SC8A-24(T) was 71 mol%. The cell-wall peptidoglycan contained ll-2,6-diaminopimelic acid, and MK-8(H4) was the predominant menaquinone. The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol, an unidentified glycolipid and an unidentified phospholipid. The major fatty acids were C17 : 1ω8c, 10-methyl C17 : 0 and C18 : 1ω9c. On the basis of phylogenetic analysis and phenotypic and chemotaxonomic characteristics, strain SC8A-24(T) represents a novel species of the genus Nocardioides , for which the name Nocardioides deserti sp. nov. is proposed. The type strain is SC8A-24(T) ( =DSM 26045(T)  = CGMCC 4.7183(T))., (© 2015 IUMS.)

Purpose: Prostate stem cell antigen (PSCA) is highly expressed in local prostate cancers and prostate cancer bone metastases and its expression correlates with androgen receptor activation and a poor prognosis. In this study, we investigate the potential clinical applications of immunoPET with the anti-PSCA A11 minibody, an antibody fragment optimized for use as an imaging agent. We compare A11 minibody immunoPET to (18)F-Fluoride PET bone scans for detecting prostate cancer bone tumors and evaluate the ability of the A11 minibody to image tumor response to androgen deprivation., Experimental Design: Osteoblastic, PSCA-expressing, LAPC-9 intratibial xenografts were imaged with serial (124)I-anti-PSCA A11 minibody immunoPET and (18)F-Fluoride bone scans. Mice bearing LAPC-9 subcutaneous xenografts were treated with either vehicle or MDV-3100 and imaged with A11 minibody immunoPET/CT scans pre- and posttreatment. Ex vivo flow cytometry measured the change in PSCA expression in response to androgen deprivation., Results: A11 minibody demonstrated improved sensitivity and specificity over (18)F-Fluoride bone scans for detecting LAPC-9 intratibial xenografts at all time points. LAPC-9 subcutaneous xenografts showed downregulation of PSCA when treated with MDV-3100 which A11 minibody immunoPET was able to detect in vivo., Conclusions: A11 minibody immunoPET has the potential to improve the sensitivity and specificity of clinical prostate cancer metastasis detection over bone scans, which are the current clinical standard-of-care. A11 minibody immunoPET additionally has the potential to image the activity of the androgen signaling axis in vivo which may help evaluate the clinical response to androgen deprivation and the development of castration resistance., (©2014 American Association for Cancer Research.)

A new species of structurally preserved fern rhizome, Ashicaulis plumites (Osmundaceae, Filicales), is described from the Middle Jurassic Tiaojishan Formation in western Liaoning Province, NE China. The new species is characterized by a peculiar sclerenchyma mass in the petiolar vascular bundle concavity. This sclerenchyma mass varies from a linear-shape to a mushroom-like shape with a remarkable outward protuberance, which distinguishes the present new species from other Ashicaulis species. Such a protuberance is very rare among osmundaceous ferns, and should represent a unique type for sclerenchymatous tissue in the osmundaceous vascular bundle concavity. Recognition of the peculiar structure of this new fossil species enriches anatomical diversity of permineralized osmundaceous ferns, indicating that the family Osmundaceae might have experienced a remarkable diversification during the Middle Jurassic in NE China. The new species show anatomical similarities to Osmunda pluma Miller from the Palaeocene of North America. The occurrence of A. plumites in the Middle Jurassic of China provides a new clue for understanding the evolution of some members of the living subgenus Osmunda.