Search

Companion animals such as cats and dogs harbor diverse microbial communities that can potentially impact human health due to close and frequent contact. To better characterize their total infectomes and assess zoonotic risks, we characterized the overall infectomes of companion animals (cats and dogs) and evaluated their potential zoonotic risks. Meta-transcriptomic analyses were performed on 239 samples from cats and dogs collected across China, identifying 24 viral species, 270 bacterial genera, and two fungal genera. Differences in the overall microbiome and infectome composition were compared across different animal species (cats or dogs), sampling sites (rectal or oropharyngeal), and health status (healthy or diseased). Diversity analyses revealed that viral abundance was generally higher in diseased animals compared to healthy ones, while differences in microbial composition were mainly driven by sampling site, followed by animal species and health status. Disease association analyses validated the pathogenicity of known pathogens and suggested potential pathogenic roles of previously undescribed bacteria and newly discovered viruses. Cross-species transmission analyses identified seven pathogens shared between cats and dogs, such as alphacoronavirus 1, which was detected in both oropharyngeal and rectal swabs albeit with differential pathogenicity. Further analyses showed that some viruses, like alphacoronavirus 1, harbored multiple lineages exhibiting distinct pathogenicity, tissue, or host preferences. Ultimately, a systematic evolutionary screening identified 27 potential zoonotic pathogens in this sample set, with far more bacterial than viral species, implying potential health threats to humans. Overall, our meta-transcriptomic analysis reveals a landscape of actively transcribing microorganisms in major companion animals, highlighting key pathogens, those with the potential for cross-species transmission, and possible zoonotic threats., Importance: This study provides a comprehensive characterization of the entire community of infectious microbes (viruses, bacteria, and fungi) in companion animals like cats and dogs, termed the "infectome." By analyzing hundreds of samples from across China, the researchers identified numerous known and novel pathogens, including 27 potential zoonotic agents that could pose health risks to both animals and humans. Notably, some of these zoonotic pathogens were detected even in apparently healthy pets, highlighting the importance of surveillance. The study also revealed key microbial factors associated with respiratory and gastrointestinal diseases in pets, as well as potential cross-species transmission events between cats and dogs. Overall, this work sheds light on the complex microbial landscapes of companion animals and their potential impacts on animal and human health, underscoring the need for monitoring and management of these infectious agents., Competing Interests: The authors declare no conflict of interest.

Dysregulation of RNA splicing processes is intricately linked to tumorigenesis in various cancers, especially breast cancer. Cdc2-like kinase 2 (CLK2), an oncogenic RNA-splicing kinase pivotal in breast cancer, plays a significant role, particularly in the context of triple-negative breast cancer (TNBC), a subtype marked by substantial medical challenges due to its low survival rates. In this study, we employed a structure-based virtual screening (SBVS) method to identify potential CLK2 inhibitors with novel chemical structures for treating TNBC. Compound 670551 emerged as a novel CLK2 inhibitor with a 50% inhibitory concentration (IC 50 ) value of 619.7 nM. Importantly, Compound 670551 exhibited high selectivity for CLK2 over other protein kinases. Functionally, this compound significantly reduced the survival and proliferation of TNBC cells. Results from a cell-based assay demonstrated that this inhibitor led to a decrease in RNA splicing proteins, such as SRSF4 and SRSF6, resulting in cell apoptosis. In summary, we identified a novel CLK2 inhibitor as a promising potential treatment for TNBC therapy., (© 2024 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Mosquito transmitted viruses are responsible for an increasing burden of human disease. Despite this, little is known about the diversity and ecology of viruses within individual mosquito hosts. Here, using a meta-transcriptomic approach, we determined the viromes of 2,438 individual mosquitoes (81 species), spanning ~4,000 km along latitudes and longitudes in China. From these data we identified 393 viral species associated with mosquitoes, including 7 (putative) species of arthropod-borne viruses (that is, arboviruses). We identified potential mosquito species and geographic hotspots of viral diversity and arbovirus occurrence, and demonstrated that the composition of individual mosquito viromes was strongly associated with host phylogeny. Our data revealed a large number of viruses shared among mosquito species or genera, enhancing our understanding of the host specificity of insect-associated viruses. We also detected multiple virus species that were widespread throughout the country, perhaps reflecting long-distance mosquito dispersal. Together, these results greatly expand the known mosquito virome, linked viral diversity at the scale of individual insects to that at a country-wide scale, and offered unique insights into the biogeography and diversity of viruses in insect vectors., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: The purpose of this study is to explore the regulatory function of COL1A1 against the apoptosis of embryonic stem cells (ESCs) and the potential function in congenital talipes equinovarus (CTEV)., Methods: Muscle tissues were collected from 20 children with CTEV and 20 children without CTEV, followed by detecting the expression of COL1A1 using the RT-PCR method. COL1A1 was knocked down in H1 and H9 human ESCs using the RNA interference technology, followed by determining the level of COL1A1, PITX1, TBX4, HOXD10, Fas, FasL, and Bax using the Western blotting assay., Results: COL1A1 was found markedly upregulated in muscle tissues of CTEV children. In H1 and H9 human ESCs, compared to the empty vector, COL1A1, PITX1, TBX4, HOXD10, Fas, FasL, and Bax were found notably downregulated after transfected with the siRNA targeting COL1A1., Conclusion: COL1A1 induced the apoptosis of ESCs by mediating the PITX1/TBX4 signaling and might be a potential target for treating CTEV., (© 2023 The Authors. Birth Defects Research published by Wiley Periodicals LLC.)

Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC 50 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment.

Aiming at the problems of backward calibration method of smoke alarm, low production efficiency and difficult real-time monitoring, a digital twin system modeling and monitoring method of smoke alarm calibration is proposed. First, through the analysis of smoke alarm calibration requirements, the overall framework design of the digital twin calibration system for smoke alarm is proposed, and then the twin model of smoke box is constructed by running the digital twin five-dimensional model. The physical smoke box, geometric model, physical model, rule model and behavior model are introduced in detail; Then the communication system architecture, data acquisition and data mapping are used to construct the twin data model; Finally, the feasibility was verified by the calibration system of an enterprise. Through the system, the qualified rate of smoke alarm calibration was increased from 98 to 99.6%, and the repair rate of defective products was reduced by 1.6%., (© 2023. The Author(s).)

The K 2 S 2 O 8 -mediated generation of p -iminoquinone contributed to the regioselective substitution of isoquinolin-5,8-dione. This hydroxyl group-guided substitution was also applied to selected heterocycles and addressed the regioselectivity issue of quinones. This study has provided an expeditious pathway from isoquinolin-5-ol (5) to ellipticine (1) and isoellipticine (2), which benefits the comprehensive comparison of their activity. Compounds 1 and 2 displayed marked MYLK4 inhibitory activity with IC 50 values of 7.1 and 6.1 nM, respectively. In the cellular activity of AML cells (MV-4-11 and MOLM-13), compound 1 showed better AML activity than compound 2., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The estimated prevalence of anti-HCV was 3.1% in Taiwan. Studies have shown iatrogenic behavior was the major transmission route. It is highest in specific populations including patients with end stage renal disease (ESRD), human immunodeficiency virus infection, who inject drug (PWID), and under opioid substitution treatment. Approximately 405,160 patients were seropositive for HCV RNA and in need of treatment. Taiwan government claims to reach WHO's 2030 goal of HCV elimination by 2025 and works hard to resolve several barriers of HCV elimination including political commitment, sustainable financing, minimize reimbursement restrictions, instituted monitoring, and perform micro-elimination of specific populations. The last stage of HCV elimination is to accelerate the universal HCV screening program of populations aged 45-79 years and resolve the unawareness issue of HCV infection. Hopefully, we can achieve the targets of HCV elimination set by WHO and reach the goal earlier in 2025., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

TC31 is a new type of high-temperature titanium alloy, but few researchers have studied the combination of forming and heat treatment of a component using this material. The component with high ribs and thin webs was studied by numerical simulation and trail production. Based on the establishment of the finite element model, the forming process was analyzed by simulation software, and the maximum forming load of the component was 1920 kN. Ultimately, there were no folding defects of the component during the forming process. The material flow law was revealed by selecting the typical section of the component, and then the forming process was verified and the fully filled component was obtained. After that, the component was subjected to post-processing, and three heat treatment methods were designed to conduct heat treatment experiments on it (heat treatment: solution treatment and aging treatment). By analyzing the influence of three heat treatment methods on mechanical properties, the optimal heat treatment method was obtained, namely a solution treatment at 960 °C for 2.5 h and aging treatment at 610 °C for 7 h. The ultimate tensile strength, yield strength, elongation, and section shrinkage of the component through forging forming and heat treatment are higher than those of original material; meanwhile, it also indicates that the designed heat treatment has a better effect on the high-temperature mechanical properties of this titanium alloy at 650 °C than that at 450 °C. The research on the combination of the forming and heat treatment of this component provides a reference for the engineering application of high-temperature titanium alloys.

Bruton tyrosine kinase (BTK) is linked to multiple signalling pathways that regulate cellular survival, activation, and proliferation. A covalent BTK inhibitor has shown favourable outcomes for treating B cell malignant leukaemia. However, covalent inhibitors require a high reactive warhead that may contribute to unexpected toxicity, poor selectivity, or reduced effectiveness in solid tumours. Herein, we report the identification of a novel noncovalent BTK inhibitor. The binding interactions (i.e. interactions from known BTK inhibitors) for the BTK binding site were identified and incorporated into a structure-based virtual screening (SBVS). Top-rank compounds were selected and testing revealed a BTK inhibitor with >50% inhibition at 10 µM concentration. Examining analogues revealed further BTK inhibitors. When tested across solid tumour cell lines, one inhibitor showed favourable inhibitory activity, suggesting its potential for targeting BTK malignant tumours. This inhibitor could serve as a basis for developing an effective BTK inhibitor targeting solid cancers.

Acute ischemic stroke of the posterior circulation as a result of vertebrobasilar artery occlusions is often associated with severe morbidity and mortality rates. Vertebrobasilar artery occlusion retrieval via mechanical thrombectomy (MT) is a novel treatment modality for occlusive strokes. Nevertheless, factors associated with positive outcomes have not yet been adequately investigated. Thus, the present study focused on factors associated with good prognosis following this type of treatment. The present study retrospectively analyzed a series of 17 patients with acute vertebral artery occlusions (VAOs) and basilar artery occlusions (BAOs) treated with MT. In all patients, information such as sex and age, time from admission to the onset of femoral artery access, the number of thrombi removed, the time of femoral artery access to recanalization, pre- and post-operative National Institutes of Health Stroke Scale (NIHSS) scores, pre- and post-operative thrombolysis in cerebral infarction, as well as modified Rankin scale scores were documented and analyzed. The analysis comprised of 11 patients with BAOs and 6 patients with VAOs. A recanalization rate of 70.6% was achieved with an overall good functional outcome of 58.8% at 90 days. Observationally, there was a notable improvement in outcomes when comparing the NIHSS prior to surgery with NIHSS at 1 week after the surgery. A lower NIHSS score prior to MT may be a good prognostic factor. An average time of ~5.5 h from patient admittance to recanalization with a 70.6% recanalization rate with an overall good functional outcome of 58.8% at 90 days suggested that, patients for whom the surgeries were performed within 5 h of admittance may still have hope for recanalization compared to an initial 1.5-h average time for recanalization., Competing Interests: All authors declare that they have no competing interests., (Copyright: © Yu et al.)

Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self-renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well-established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor-associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy-resistant or -refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC-directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC-directed therapeutics, with a special focus on those with application approval or under clinical evaluation., Competing Interests: The authors declared no conflict of interests., (© 2022 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Alzheimer's disease (AD) is a neurodegenerative disease known to affect brain functional connectivity (FC). Linear FC measures have been applied to study the differences in AD by splitting neurophysiological signals such as electroencephalography (EEG) recordings into discrete frequency bands and analysing them in isolation. We address this limitation by quantifying cross-frequency FC in addition to the traditional within-band approach. Cross-bispectrum, a higher-order spectral analysis, is used to measure the nonlinear FC and is compared with the cross-spectrum, which only measures the linear FC within bands. Each frequency coupling is then used to construct an FC network, which is in turn vectorised and used to train a classifier. We show that fusing features from networks improves classification accuracy. Although both within-frequency and cross-frequency networks can be used to predict AD with high accuracy, our results show that bispectrum-based FC outperforms cross-spectrum suggesting an important role of cross-frequency FC. Clinical relevance-This establishes diagnostic relevance of cross-frequency coupling in Alzheimer's disease.

Background: Vitamin K is involved in the formation of coronary artery calcification which is an independent predictor of coronary heart disease. This study aims to explore the association between coronary artery calcification score and serum concentrations of vitamin K1, menaquinone-4 (MK-4) and menaquinone-7 (MK-7) in middle-aged and elderly Chinese population., Methods: A total of 116 patients who underwent CT coronary angiography were consecutively enrolled. Serum concentrations of vitamin K1, MK-4 and MK-7 were determined by high performance liquid chromatography tandem mass spectrometry. The relationships between coronary artery calcification score and serum vitamin K concentrations were analyzed., Results: Significantly lower serum vitamin K1 concentration was found in the patients with CACS > 400, comparing with the other CACS categories, respectively. Log (CACS + 1) was significantly higher in MK-4 < 0.05 ng/ml group compared with MK-4 ≥ 0.05 ng/ml group [2.03(0.21, 2.58) vs 1.31(0.00, 2.19), P < 0.05]. In subjects with established coronary calcification (defined as CACS > 10), vitamin K1 was found to be an independent factor contributing to higher CACS (r = -0.288, P = 0.013)., Conclusions: In this retrospective analysis, serum vitamin K1 and MK-4 concentrations were significantly lower in middle-aged and elderly cohorts with increasing calcification scores. The significant effect of vitamin K1 on CACS was only found in individuals who already had calcification. Whether the detection of circulating vitamin K in patients with preexisting coronary calcification could guide vitamin K supplementation needs further exploration., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with poor overall survival characterized by various genetic changes. The continuous activation of oncogenic pathways leads to the development of drug resistance and limits current therapeutic efficacy. Therefore, a multi-targeting inhibitor may overcome drug resistance observed in AML treatment. Recently, groups of flavonoids, such as flavones and flavonols, have been shown to inhibit a variety of kinase activities, which provides potential opportunities for further anticancer applications., Purpose: In this study, we evaluated the anticancer effects of flavonoid compounds collected from our in-house library and investigated their potential anticancer mechanisms by targeting multiple kinases for inhibition in AML cells., Methods: The cytotoxic effect of the compounds was detected by cell viability assays. The kinase inhibitory activity of the selected compound was detected by kinase-based and cell-based assays. The binding conformation and interactions were investigated by molecular docking analysis. Flow cytometry was used to evaluate the cell cycle distribution and cell apoptosis. The protein and gene expression were estimated by western blotting and qPCR, respectively., Results: In this study, an O-methylated flavonol (compound 11) was found to possess remarkable cytotoxic activity against AML cells compared to treatment in other cancer cell lines. The compound was demonstrated to act against multiple kinases, which play critical roles in survival signaling in AML, including FLT3, MNK2, RSK, DYRK2 and JAK2 with IC 50 values of 1 - 2 μM. Compared to our previous flavonoid compounds, which only showed inhibitions against MNKs or FLT3, compound 11 exhibited multiple kinase inhibitory abilities. Moreover, compound 11 showed effectiveness in inhibiting internal tandem duplications of FLT3 (FLT3-ITDs), which accounts for 25% of AML cases. The interactions between compound 11 and targeted kinases were investigated by molecular docking analysis. Mechanically, compound 11 caused dose-dependent accumulation of leukemic cells at the G 0 /G 1 phase and followed by the cells undergoing apoptosis., Conclusion: O-methylated flavonol, compound 11, can target multiple kinases, which may provide potential opportunities for the development of novel therapeutics for drug-resistant AMLs. This work provides a good starting point for further compound optimization., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

The dysregulation of DYRK1A is implicated in many diseases such as cancer, diabetes, and neurodegenerative diseases. Alzheimer's disease is one of the most common neurodegenerative disease and has elevated interest in DYRK1A research. Overexpression of DYRK1A has been linked to the formation of tau aggregates. Currently, an effective therapeutic treatment that targets DYRK1A is lacking. A specific small-molecule inhibitor would further our understanding of the physiological role of DYRK1A in neurodegenerative diseases and could be presented as a possible therapeutic option. In this study, we identified pharmacological interactions within the DYRK1A active site and performed a structure-based virtual screening approach to identify a selective small-molecule inhibitor. Several compounds were selected in silico for enzymatic and cellular assays, yielding a novel inhibitor. A structure-activity relationship analysis was performed to identify areas of interactions for the compounds selected in this study. When tested in vitro, reduction of DYRK1A dependent phosphorylation of tau was observed for active compounds. The active compounds also improved tau turbidity, suggesting that these compounds could alleviate aberrant tau aggregation. Testing the active compound against a panel of kinases across the kinome revealed greater selectivity towards DYRK1A. Our study demonstrates a serviceable protocol that identified a novel and selective DYRK1A inhibitor with potential for further study in tau-related pathologies., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Chronic inflammation is an underlying cause in a number of diseases. Cyclin-dependent kinase 8 (CDK8) has been implicated as an inflammatory mediator, indicating its potential as an anti-inflammatory target. Herein, we performed structure-based virtual screening (SBVS) to identify novel CDK8 inhibitors. The pharmacological interactions for CDK8 were identified and incorporated into a SBVS protocol. Selected compounds were tested in enzymatic assays, and one compound was confirmed to be a CDK8 inhibitor with a 50% inhibitory concentration (IC 50 ) value of 1684.4 nM. Comparing structural analogs identified a compound, F059-1017, with greater potency (IC 50 558.1 nM). When tested in cell lines, the compounds displayed low cytotoxicity. Cellular assays revealed that the identified CDK8 inhibitors can reduce phosphorylation and expression of signaling mediators associated with inflammation. In addition, results of kinase profiling showed that compound F059-1017 is selective towards CDK8. These findings suggest that the new inhibitors have great potential as lead compounds for developing novel anti-inflammatory therapeutics., (Copyright © 2021. Published by Elsevier Masson SAS.)

The STE20 kinase family is a complex signalling cascade that regulates cytoskeletal organisation and modulates the stress response. This signalling cascade includes various kinase mediators, such as TAOK1 and MAP4K5. The dysregulation of the STE20 kinase pathway is linked with cancer malignancy. A small-molecule inhibitor targeting the STE20 kinase pathway has therapeutic potential. In this study, a structure-based virtual screening (SBVS) approach was used to identify potential dual TAOK1 and MAP4K5 inhibitors. Enzymatic assays confirmed three potential dual inhibitors (>50% inhibition) from our virtual screening, and analysis of the TAOK1 and MAP4K5 binding sites indicated common interactions for dual inhibition. Compound 1 revealed potent inhibition of colorectal and lung cancer cell lines. Furthermore, compound 1 arrested cancer cells in the G0/G1 phase, which suggests the induction of apoptosis. Altogether, we show that the STE20 signalling mediators TAOK1 and MAP4K5 are promising targets for drug research.

A series of ring-opened dihydroxybenzamides have been designed and synthesized as heat shock protein 90 inhibitors. One of derivatives, compound 6b ((N-ethyl-2,4-dihydroxy-5-isopropyl-N-(pyridin-3-yl)benzamide)) demonstrated remarkable antiproliferative activity against in human KRAS mutant A549 and EGFR T790 M mutant H1975 lung cancer cell lines with GI 50 values of 0.07 and 0.05 μM, respectively. It is also active against in other cancer cell lines, such as colorectal HCT116 (GI 50  = 0.09 μM), liver Hep3B (GI 50  = 0.20 μM) and breast MDA-MB-231 (GI 50  = 0.09 μM), and shows no evidence of toxicity in normal cell line. Compound 6b has an IC 50 of 110.18 nM in HSP90α inhibitory activity, slightly better than reference compound 1 (17-AAG, IC 50  = 141.62 nM) and achieves the degradation of multiple HSP90 client proteins in a dose- and time-dependent manner and downstream signaling of Akt in a concentration- and time-dependent manner in the human A549 lung cancer cell line. In the Boyden chamber assay, compound 6b can efficiently inhibit the migration of A549 cells when compared to the reference compound 1. It also induce significant activity through the apoptotic pathway. Treatment with 6b showed no vision toxicity (IC 50  > 10 μM) on 661w photoreceptor cells as compared to AUY922 (3a) with a 0.04 μM values of IC 50 and has no effect in hERG test. In a bidirectional Caco-2 permeability assay, compound 6b was classified as a highly permeable compound which is not a substrate of efflux transporters. In a pharmacokinetic study in rats, 6b showed an F = 17.8% of oral bioavailability. The effect of metabolic stability of compound 6b in human hepatocytes showed a T 1/2 of 67.59 min. Compound 6b (50 mg/kg, po, daily) exhibits antitumor activity with a 72% TGD (tumor growth delay) in human A549 lung xenograft. The combination of 6b and afatinib, orally administered, showed tumor growth suppression with 67.5% of TGI in lung H1975 xenograft model. Thus compound 6b is a lead compound for further development of potential agents to treat lung cancer., 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 © 2021. Published by Elsevier Masson SAS.)

Acute leukemia is a highly heterogeneous disease; therefore, combination therapy is commonly used for patient treatment. Drug-drug interaction is a major concern of combined therapy; hence, dual/multi-target inhibitors have become a dominant approach for cancer drug development. HDACs and HSP90 are involved in the activation of various oncogenic signaling pathways, including PI3K/AKT/mTOR, JAK/STAT, and RAF/MEK/ERK, which are also highly enriched in acute leukemia gene expression profiles. Therefore, we suggest that dual HDAC and HSP90 inhibitors could represent a novel therapeutic approach for acute leukemia. MPT0G449 is a dual effect inhibitor, and it showed cytotoxic effectiveness in acute leukemia cells. Molecular docking analysis indicated that MPT0G449 possessed dual HDAC and HSP90 inhibitory abilities. Furthermore, MPT0G449 induced G 2 arrest and caspase-mediated cell apoptosis in acute leukemia cells. The oncogenic signaling molecules AKT, mTOR, STAT3, STAT5, MEK, and ERK were significantly downregulated after MPT0G449 treatment in HL-60 and MOLT-4 cells. In vivo xenograft models confirmed the antitumor activity and showed the upregulation of acetyl-histone H3 and HSP70, biomarkers of pan-HDAC and HSP90 inhibition, with MPT0G449 treatment. These findings suggest that the dual inhibition of HDAC and HSP90 can suppress the expression of oncogenic pathways in acute leukemia, and MPT0G449 represents a novel therapeutic for anticancer treatment.

Introduction: Cerebrospinal Fluid (CSF) is produced mainly by the choroid plexus but with a substantial influence by the ependymal lining of the ventricles in the brain. Hydrocephalus occurs as a result of discrepancy in the production as well as circulation of CSF as a result of congenital and acquired conditions. Nevertheless, studies on the differences between CSF dynamics according to age and gender are still insufficient. Thus, this study evaluated the volume of intracranial CSF in healthy people and hydrocephalus patients taking into account the differences between CSF dynamics according to age and gender using Sampling Perfection with Application optimised Contrast using different flip-angle Evolution (SPACE) sequence., Methods: 120 healthy volunteers and 60 patients with hydrocephalus were included in this study. SPACE sequence was used to evaluate intracranial CSF with a 3.0T magnetic resonance machine. The total volume of intracranial CSF and the amount of CSF in the ventricle were obtained using a software, and the volume ratio of CSF in the subarachnoid space, the ventricle and the subarachnoid space were calculated., Results: The mean volume of intracranial CSF, ventricular CSF, and subarachnoid CSF of male volunteers were (206.9±47.7) cm3, (33.0±10.7) cm3, (173.9±37.9) cm3 respectively. The average volume of intracranial CSF, ventricular CSF, and subarachnoid CSF of female volunteers were (199.7±44.9) cm3, (30.8±9.4) cm3, and (168.9±37.0) cm3, respectively. Thus, no significant statistically (P>0.05) difference between males and females was found. (3) The mean values of intracranial CSF, ventricle CSF and subarachnoid CSF, ventricle and subarachnoid CSF volume ratio in patients with hydrocephalus were significantly greater than health volunteers. Thus, the difference between the two groups was statistically significant (P<0.05)., Conclusion: SPACE sequence can quantitatively determine the content of CSF. The change of CSF volume has nothing to do with gender but with age. It is feasible to use SPACE sequence to evaluate the spatial distribution and volume of intracranial CSF., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The immune system works in conjunction with inflammation. Excessive inflammation underlies various human diseases, such as asthma, diabetes and heart disease. Previous studies found that 5-lipoxygenase (5-LOX) plays a crucial role in metabolizing arachidonic acid into inflammatory mediators and is a potential therapeutic target. In this study, we performed an in silico approach to establish a site-moiety map (SiMMap) to screen for new 5-LOX inhibitors. The map is composed of several anchors that contain key residues, moiety preferences, and their interaction types (i.e., electrostatic (E), hydrogen-bonding (H), and van der Waals (V) interactions) within the catalytic site. In total, we identified one EH, one H, and five V anchors, within the 5-LOX catalytic site. Based on the SiMMap, three 5-LOX inhibitors (YS1, YS2, and YS3) were identified. An enzyme-based assay validated inhibitory activity of YS1, YS2, and YS3 against 5-LOX with an IC 50 value of 2.7, 4.2, and 5.3 μM, respectively. All three inhibitors significantly decrease LPS-induced TNF-α and IL-6 production, which suggests its potential use an anti-inflammatory agent. In addition, the identified 5-LOX inhibitors contain a novel scaffold. The discovery of these inhibitors presents an opportunity for designing specific anti-inflammatory drugs.

[This retracts the article DOI: 10.18632/oncotarget.6427.]., (Copyright: © 2020 Chao et al.)

This study reports the synthesis of a series of 2-aroylisoindoline hydroxamic acids employing N-benzyl, long alkyl chain and acrylamide units as diverse linkers. In-vitro studies led to the identification of N-benzyl linker-bearing compound (10) and long chain linker-containing compound (17) as dual selective HDAC6/HSP90 inhibitors. Compound 17 displays potent inhibition of HDAC6 isoform (IC 50  = 4.3 nM) and HSP90a inhibition (IC 50  = 46.8 nM) along with substantial cell growth inhibitory effects with GI 50  = 0.76 μM (lung A549) and GI 50  = 0.52 μM (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI 50  = 0.37 μM) and lung H1975 cell lines (GI 50  = 0.13 μM) mediated through selective HDAC6 inhibition (IC 50  = 33.3 nM) and HSP90 inhibition (IC 50  = 66 nM). In addition, compound 17 also modulated the expression of signatory biomarkers associated with HDAC6 and HSP90 inhibition. In the in vivo efficacy evaluation in human H1975 xenografts, 17 induced slightly remarkable suppression of tumor growth both in monotherapy as well as the combination therapy with afatinib (20 mg/kg). Moreover, compound 17 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner suggesting that dual inhibition of HDAC6 and HSP90 can modulate immunosuppressive ability of tumor area., 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 © 2020. Published by Elsevier Masson SAS.)

Novel dual inhibitors of histone deacetylase (HDAC) and heat-shock protein 90 (HSP90) are synthesized and evaluated. These compounds are endowed with potent HDAC and HSP90 inhibitory activities with IC 50 values in nanomolar range with Compound 20 (HDAC IC 50  = 194 nM; HSP90α IC 50  = 153 nM) and compound 26 (HDAC IC 50  = 360 nM; HSP90α IC 50  = 77 nM) displaying most potent HDAC and HSP90α inhibitory activities. Both of these compounds induce HSP70 expression and down regulate HSP90 client proteins which play important roles in the regulation of survival and invasiveness in cancer cells. In addition, compounds 20 and 26 induce acetylation of α-tubulin and histone H3. Significantly, compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner. These findings suggest that dual inhibition of HDAC and HSP90 that can modulate immunosuppressive ability of tumor area may provide a better therapeutic strategy for cancer treatment in the future., (Copyright © 2019. Published by Elsevier Masson SAS.)

Tenascin-C (TNC), a very large multimeric glycoprotein, is overexpressed in human glioblastomas, leading to a highly motile and invasive phenotype of glioma cells. However, the regulation of TNC expression in glioma has remained unclear until now. Our data suggest that interleukin-33 (IL-33) may promote the accumulation of TNC protein by autocrine or paracrine modes of action in glioma. In the present study, the expression levels of TNC, IL-33, and ST2 were measured in glioma tissue specimens, and the impact of altered IL-33 expression on TNC was investigated in vitro and in vivo. In contrast with control treatment, IL-33 treatment increased TNC expression, and knockdown of IL-33 attenuated TNC expression in glioma cells. Furthermore, IL-33 induced the activation of nuclear factor κB (NF-κB) and increased the expression of TNC in U251 cells. In addition, blockage of the IL-33-ST2-NFκB pathway resulted in downregulation of TNC production. IL-33 promoted glioma cell invasion by stimulating the secretion of TNC. Similarly, knockdown of TNC inhibited the invasiveness of glioma cells. These findings provide a novel perspective on the role of the IL-33/NF-κB/TNC signalling pathway in supporting cancer progression. Thus, targeting the IL-33/NF-κB/TNC signalling pathway may be a useful therapeutic approach in glioma.

The study is focused on the design and synthesis of amide tethered quinoline-resorcinol hybrid constructs as a new class of HSP90 inhibitor. In-vitro studies of the synthetic compounds led to the identification of compound 11, which possesses potent cell growth inhibitory effects against HCT116, Hep3B and PC-3 cell lines, exerted through HSP90 inhibition. Compound 11 triggers degradation of HSP90 client proteins along with concomitant induction of HSP70, demonstrates apoptosis inducing ability and causes G2M phase cell cycle arrest in PC-3 cells. Molecular modeling was used to dock compound 11 into the HSP90 active site and key interactions with the amino acid residues of the HSP90 chaperone protein were determined., (Copyright © 2019. Published by Elsevier Inc.)

Objective: To establish a recombinase-aided isothermal amplification (RAA) assay for detection of Cryptosporidium ., Methods: Based on Cryptosporidium -specific 18S rRNA selected as the target gene to be detected, and the primer sequences and fluorescent probes designed using the software Amplfix, and a fluorescent RAA assay was established and optimized. The fluorescent RAA assay was performed to detect 18S RNA target sequence-contained recombinant plasmids at various copies, genomic DNA of Cryptosporidium oocysts at various concentrations, and genomic DNA extracted from various numbers of Cryptosporidium oocysts to assess the sensitivity of the assay, and to detect genomic DNA extracted from Cryptosporidium oocysts, Giardia lamblia cysts, Schistosoma japonicum eggs, Ascaris lumbricoides eggs, Clonorchis sinensis eggs, Salmonella and Shigella to determine the specificity of the assay., Results: A fluorescent RAA assay was successfully established, which was effective to amplify the specific 18S RNA gene fragments of Cryptosporidium within 20 min at 39 ℃. The lowest limits of the fluorescent RAA assay were 10 2 copies/μL for detection of 18S RNA target sequence-contained recombinant plasmids at various copies, 1 pg/μL for detection of genomic DNA of Cryptosporidium oocysts at various concentrations, and one Cryptosporidium oocyst/μL for detection of genomic DNA extracted from various numbers of Cryptosporidium oocysts, and the fluorescent RAA assay was all negative for detection of genomic DNA from G. lamblia cysts, S. japonicum eggs, A. lumbricoides eggs, C. sinensis eggs, Salmonella and Shigella., Conclusions: A novel fluorescent RAA assay is successfully established, which is simple, rapid, sensitive and specific to detect genomic DNA of Cryptosporidium oocysts.

The purpose of this study was to assess the utility of a fascicular turnover flap for facial nerve repair and to investigate its possible application in the field of facial nerve repair using a rat model of facial paralysis. Twenty-four Wistar rats were used in this study. A left vibrissal muscle palsy model was established via excision of the buccal and marginal branches through a periauricular incision. In Group 1, the nerve gap was not reconstructed. In Group 2, the nerve gap of the marginal mandibular branch was reconstructed using an autograft, and in Group 3, the gap was reconstructed using a fascicular turnover flap. At 12 weeks after the operation, the nerve regeneration was assessed based on clinical, histopathological and electrophysiological evaluations. The functional recovery of the vibrissal muscle was observed with a fascicular turnover flap. The functional recovery of whisker movement was almost same between Groups 2 and 3 (p = .57). The histopathological examinations almost same result between Groups 2 and 3 (p = .17). The compound muscle action potential after reconstruction was also almost same between Groups 2 and 3 (p = .99). We found that the fascicular turnover flap could be applied to facial nerve gap reconstruction. However, further evaluations will be necessary to clarify its indication and mechanism in human.

Background: Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028., Methods: The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo., Results: The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone., Conclusions: The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status.

Background: There are some limitations of standard chemotherapy for acute leukemia. Vincristine and doxorubicin are commonly used for acute leukemia, but they may induce serious side effects such as cardiomyopathy and neurotoxicity. Furthermore, chemotherapy resistance occurs more and more frequently. Therefore, effective treatment strategies are needed. Histone deacetylase 6 inhibition is considered as a potential therapeutic strategy for acute leukemia, since it is observed that HDAC6 is overexpressed in acute leukemia and regulates tumor survival. Combination therapy for cancer is used to minimize adverse drug effects, reduce drug dosage, enhance efficacy, and prevent drug resistance. In order to improve efficacy of chemotherapy agents of acute leukemia, this study will investigate the effects of combination MPT0G211, a novel histone deacetylase 6 inhibitor, with doxorubicin or vincristine on human acute leukemia cells., Results: MPT0G211 combined with doxorubicin induces DNA damage response on human acute myeloid leukemia cells. MPT0G211 can additionally increase Ku70 acetylation and release BAX to mitochondria. Ectopic expression of HDAC6 successively reversed the apoptosis triggered by the combined treatment. Moreover, co-treatment of MPT0G211 and vincristine may alter microtubule dynamics, triggering acute lymphoblastic leukemia cells arrest in mitotic phase followed by induction of the apoptotic pathway. Finally, MPT0G211 plus doxorubicin or vincristine can significantly improve the tumor growth delay in a tumor xenograft model., Conclusions: Collectively, our data highlighted that MPT0G211 in combination with chemotherapy drugs has significant anticancer activity, suggesting a novel strategy for the treatment of acute leukemia.

The JAK2/STAT signaling pathway mediates cytokine receptor signals that are involved in cell growth, survival and homeostasis. JAK2 is a member of the Janus kinase (JAK) family and aberrant JAK2/STAT is involved with various diseases, making the pathway a therapeutic target. The similarity between the ATP binding site of protein kinases has made development of specific inhibitors difficult. Current JAK2 inhibitors are not selective and produce unwanted side effects. It is thought that increasing selectivity of kinase inhibitors may reduce the side effects seen with current treatment options. Thus, there is a great need for a selective JAK inhibitor. In this study, we identified a JAK2 specific inhibitor. We first identified key pharmacological interactions in the JAK2 binding site by analyzing known JAK2 inhibitors. Then, we performed structure-based virtual screening and filtered compounds based on their pharmacological interactions and identified compound NSC13626 as a potential JAK2 inhibitor. Results of enzymatic assays revealed that against a panel of kinases, compound NSC13626 is a JAK2 inhibitor and has high selectivity toward the JAK2 and JAK3 isozymes. Our cellular assays revealed that compound NSC13626 inhibits colorectal cancer cell (CRC) growth by downregulating phosphorylation of STAT3 and arresting the cell cycle in the S phase. Thus, we believe that compound NSC13626 has potential to be further optimized as a selective JAK2 drug.

This paper investigates the problem of state estimation for discrete time-delayed genetic regulatory networks with stochastic process noises and bounded exogenous disturbances under the Round-Robin (RR) protocols. The network measurement outputs obtained by two groups of sensors are transmitted to two remote sub-estimators via two independent communication channels, respectively. To lighten the communication loads of the networks and reduce the occurrence rate of data collisions, two RR protocols are utilized to orchestrate the transmission orders of sensor nodes in two groups, respectively. The error dynamics of the state estimation is governed by a switched system with periodic switching parameters. By constructing a transmission-order-dependent Lyapunov-like functional and utilizing the up-to-date discrete Wirtinger-based inequality together with the reciprocally convex approach, sufficient conditions are established to guarantee the exponentially ultimate boundedness of the estimation error dynamics in mean square with a prescribed upper bound on the decay rate. An asymptotic upper bound of the outputs of the estimation errors in mean square is derived and the estimator parameters are then obtained by minimizing such an upper bound subject to linear matrix inequality constraints. The repressilator model is utilized to illustrate the effectiveness of the designed estimator.

As an important member of the interleukin (IL)-1 family, IL‑33 plays a significant role in tumor progression. To explore this, we previously analyzed the association between IL‑33 expression and the prognosis of patients with glioma. However, the function of the IL‑33/ST2 axis in glioma remained unclear. In the present study, immunofluorescent staining results revealed that the expression levels of IL‑33 and ST2 receptor in glioma tissues were higher than those in normal brain tissues. Invasion and migration assays demonstrated that IL‑33 significantly increased glioma cell invasion and migration in vitro. Furthermore, knockdown of ST2 by siRNA attenuated the IL‑33-induced increase in invasion and migration. In addition, ELISA results revealed that IL‑33 upregulated the expression of matrix metalloproteinase (MMP)2 and MMP9. Western blot analysis results indicated that IL‑33 stimulation increased the phosphorylation of nuclear factor-κB (NF-κB) in a time- and dose-dependent manner. Moreover, silencing of the NF-κB pathway by BAY 11‑7082 resulted in the inhibition of IL‑33-induced invasion and migration, as well as the downregulation of MMP2 and MMP9 production. These findings indicate that IL‑33 may be involved in the process of glioma cell invasion and migration by upregulating MMP2 and MMP9 via the ST2-NF-κB signaling pathway. Thus, IL‑33 may be a novel therapeutic target for glioma.

Objective: The purpose of this study was to compare the outcomes of the buccal mucosa and lingual mucosa used in children who received multiple failed hypospadias surgeries., Method: We conducted a retrospective study of 62 children who received buccal or lingual mucosa graft urethroplasty in our hospital between 2012 and 2015. The ages ranged from 3.5-11 y. All cases included multiple failed hypospadias procedures, and the subjects received previous operations 2-3 times. All patients underwent one-stage operations. Thirty-three cases were treated with lingual mucosa grafts. The patient ages ranged from 3.5 to 11 y (median 7.5 y), and they had previous operations 2-3 times (mean 2.8±0.7). Grafts ranged from lengths of 2-6 cm (mean 5.1±0.46 cm) and widths of 0.5-1.5 cm (mean 1.2± 0.16 cm). Our follow-up was 5 to 12 m (mean 8.3±1.2 m). Twenty-nine cases were treated with buccal mucosa grafts. The patient ages ranged from 4 to 9.2 y (median 7.0 y), and they had previous operations 2-3 times (mean 2.5±0.2). Grafts ranged from lengths of 2-5.3 cm (mean 4.9± 0.28 cm) and widths of 0.5-1.5 cm (mean 1.0±0.11 cm). Our follow-up was 5 to 12 m (mean 7.9±0.5 m). The results were tested with SPSS 18.0. The rates of complications were compared by a chi-square test, and pre-operative conditions were compared by t test., Results: For the outcomes of the two groups, there was no significant difference between the groups in terms of age, preoperative surgery time, and the length and width of the grafts (p>0.05). For the lingual mucosa graft group, fistula: 2/33 (6.0%), stricture: 1/33(3.0%), ventral curvature: 2/33(6.0%), complications: 5/33(15.0%), success rate: 28/33(84.8%), Hose score: 14.34±0.95, peak flow: 6.5 ml/s-12.0 ml/s, and mean peak flow: 9.3±0.4 ml/s. For the buccal mucosa graft group, fistula: 2/29(6.8%), stricture: 2/29(6.8%), ventral curvature: 1/29 (3.4%), complication rate: 5/29(17.0%), success rate: 24/29 (83.0%), Hose score: 14.28±1.03, peak flow: 6.5 ml/s-12.0 ml/s, and mean peak flow: 9.2±0.2 ml/s. There were no differences between the two groups for overall success, complication rates, peak flow, and the Hose scores(P>0.05)., Conclusion: The lingual mucosal graft and the buccal mucosa graft both achieved good outcomes, and the lingual mucosa graft made up for the shortcomings of the buccal mucosa graft, which provided a reliable way to treat the multiple failed hypospadias surgeries in pre-pubertal boys.

Despite great advances in the treatment of acute leukemia, a renaissance of current chemotherapy needs to be improved. The present study elucidates the underlying mechanism of a new synthetic quinoline derivative, MPT0B392 (B392) against acute leukemia and its potential anticancer effect in drug resistant cells. B392 caused mitotic arrest and ultimately led to apoptosis. It was further demonstrated to be a novel microtubule-depolymerizing agent. The effects of oral administration of B392 showed relative potent anti-leukemia activity in an in vivo xenograft model. Further investigation revealed that B392 triggered induction of the mitotic arrest, followed by mitochondrial membrane potential loss and caspases cleavage by activation of c-Jun N-terminal kinase (JNK). In addition, B392 enhanced the cytotoxicity of sirolimus in sirolimus-resistant acute leukemic cells through inhibition of Akt/mTOR pathway and Mcl-1 protein expression, and also was active in the p-glycoprotein (p-gp)-overexpressing National Cancer Institute/Adriamycin-Resistant cells with little susceptibility to p-gp. Taken together, B392 has potential as an oral mitotic drug and adjunct treatment for drug resistant cancer cells.

Recent studies have revealed that cardiac glycosides, such as digitalis and digoxin, have anticancer activity and may serve as lead compounds for the development of cancer treatments. The poor prognosis of hepatocellular carcinoma (HCC) patients reflects the development of resistance to current chemotherapeutic agents, highlighting the need for discovering new small-molecule therapeutics. Here, we found that lanatoside C, an anti-arrhythmic agent extracted from Digitalis lanata, inhibited the growth of HCC cells and dramatically decreased tumor volume as well as delayed tumor growth without obvious body weight loss. Moreover, lanatoside C triggered mitochondrial membrane potential (MMP) loss, activation of caspases and translocation of apoptosis-inducing factor (AIF) into the nucleus, which suggests that lanatoside C induced apoptosis through both caspase-dependent and -independent pathways. Furthermore, we discovered that lanatoside C activated protein kinase delta (PKCδ) via Thr505 phosphorylation and subsequent membrane translocation. Inhibition of PKCδ reversed lanatoside C-induced MMP loss and apoptosis, confirming that lanatoside C caused apoptosis through PKCδ activation. We also found that the AKT/mTOR pathway was negatively regulated by lanatoside C through PKCδ activation. In conclusion, we provide the first demonstration that the anticancer effects of lanatoside C are mainly attributable to PKCδ activation.

Objective: To synthesize 5-fluorouracil-nicotinamide (5-FU-NCT) cocrystal and to investigate its physicochemical and biological properties. Methods: The cocrystal of 5-Fu-NCT was prepared through the cooling technology. PXRD, NMR, FTIR and DSC were used to characterize the structure of 5-FU-NCT cocrystal. Solubility was measured by HPLC method. Drug resistant human liver cancer BEL-7402/5-FU cells were treated with 5-FU-NCT cocrystal, the inhibition effect was tested by MTT and HE staining, and cancer cell migration was determined by scratch test. Results: According to PXRD, NMR, FTIR and DSC results, the cocrystal of 5-Fu-NCT had been synthesized successfully. The characteristic diffraction peaks (2θ/°) of the cocrystal were 16.4, 20.4, 22.3, 27.9 and 30.1. The solubility of 5-FU-NCT was 13.5 g/L as measured by HPLC. The antitumor activity tests showed that 5-FU-NCT cocrystal enhanced anticancer effect of 5-FU, and the IC50 of 5-FU and 5-FU-NCT was 129.6 μg/mL and 42.6 μg/mL, respectively. Conclusion: 5-Fu-NCT cocrystal have been synthesized successfully through the cooling technology and it shows an enhanced anticancer effect in comparison to 5-FU on BEL-7402/5-FU cells.

Objective: To prepare a nano-carrier based on combining bacterial outer membrane vesicles (OMV) with three block polymer pluronic F127 (PEO 100 -PPO 65 -PEO 100 ) (OMV-F127) and to investigate its immunological activity. Methods: Attenuated salmonella (sal) was cultivated. OMV were separated by centrifugal ultrafiltration or ultrasonication, and OMV-F127 was prepared by mechanical extrudation method. The protein contents and compositions were tested with BCA and SDS-PAGE; the morphology of OMV, F127 and OMV-F127 were observed with FM and TEM; the particle sizes and their zeta potential were determined with DLS. Mouse macrophage RAW246.7 cells were treated with OMV-F127 (50 μg/mL, 100 μg/mL) in vitro, and the concentrations of IL-12, TNF-α and IFN-γ in culture supernatant were measured with ELISA kits. Results: The contents of protein in separated OMV by centrifugal ultrafiltration and ultrasonication were 2.8 mg/mL and 2.7 mg/mL, respectively. SDS-PAGE showed the marker protein OmpF/C in OMV. Under the FM and TEM, ball-like structure of F127 and OMV-F127 was observed. Size analysis revealed that the diameters of OMV, F127 and OMV-F127 were 72±2 nm, 90±3 nm and 92±2 nm, respectively. ELISA tests revealed that OMV-F127 significantly stimulated the secretion of IL-12, TNF-α and IFN-γ in RAW246.7 cells. Conclusion: A nano-carrier based on bacterial outer membrane vesicles has been prepared, which can stimulate the secretion of cytokines and may have immunomodulatory effects.

Objective: To design and synthesize photosensitizers with different substituents and to identify its physicochemical characteritics and photodynamic effect on cancer cells. Methods: Two kinds of BODIPY photosensitizers BPOI and BPCI were synthesized through condensation reaction between aldehyde and reactive hydrogen of pyrrole, followed with electrophilic substitution reaction. Physicochemical properties were characterized by 1 H NMR, FT-IR and UV-visible absorption spectra and fluorescence emission spectra. The ability to produce reactive oxygen species was detected by BPDF and DCFH-DA. Photodynamic therapy effect on rat glioma C6 cells in vitro was determined by MTT method. Results: Two kinds of BODIPY photosensitizers BPOI and BPCI were successfully synthesized with different substituents, which were confirmed by 1 H NMR, FT-IR. Both materials had low toxicity and could be readily taken up by tumor cells. The ability of synthesized photosensitizers to produce reactive oxygen species was strongly influenced by solvent polarity when the substituent was electron-donating group, while no effect was found when the substituent was electron-withdrawing group. Conclusion: Photosensitizer BPOI with electron-donating substituent produces reactive oxygen species with a slow rate in a highly polar environment, while greatly enhanced this effect in a low polarity environment, which is expected to be used for environmental-selective photodynamic therapy in tumor cells.

Cancers are the major cause of death worldwide. Chemotherapy using cytotoxic drugs and targeted therapy is required when surgery is difficult, ineffective, or impossible. We previously synthesized the novel synthetic 1-benzylindole derivative 21-900 and found that it inhibits histone deacetylase (HDAC) activities and tubulin assembly. Here we tested its effects on the human leukaemia cell lines HL-60 and MOLT-4 in vitro and in vivo. We found that its potent cytotoxic effects were mediated through cell cycle arrest at the G2/M phase, which increased the population of sub-G1 cells, leading to apoptosis. Further, tubulin was depolymerized by 21-900 in a manner similar to that of vincristine, leading to disruption of microtubule dynamics and increased levels of the mitotic marker MPM-2. Further, 21-900 increased the expression of cleavage form of poly (ADP-ribose) polymerase (PARP), caspase 3, 7 (cleavage form), and pro-apoptotic protein BAK and decreased the expression of pro-survival BCL-2-family proteins BCL-2, MCL-1, and BID pro-form, leading to the induction of apoptosis. The growth of tumours in nude mice formed by xenografts of HL-60 and MOLT-4 cells was significantly inhibited by 21-900 without causing the mice to lose body weight. These findings indicate that 21-900 may serve as a potent anti-leukaemia drug., Competing Interests: The authors declare no competing financial interests.

The epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitors (TKIs) have shown remarkable benefits in non-small cell lung cancer (NSCLC) patients with drug-sensitive mutations in the EGFR gene. Responsive patients are usually continuously prescribed with TKIs until disease progression. Glucocorticoids (GCs) are potent homeostasis maintaining drugs and are frequently used in cancer patients to alleviate discomforts caused by anti-cancer therapies. Several previous studies reported that concomitant use of GCs may compromise the efficacy of chemo-therapeutics in patients with solid tumors. Little is known in the concomitant use of target therapy with GCs in treating NSCLC. In this study, we hypothesized that concomitant use of GCs in EGFR-TKI therapy may be detrimental and addressed this issue using cell cultures and xenograft studies followed by a retrospective population study based on data from the Taiwan national health insurance system. In cell cultures and xenograft studies, GCs were shown to unequally compromise the anti-cancer efficacy of TKIs in both PC9 and NCI-H1975 NSCLC cells models. In the retrospective population study, patients with similar disease status that were co-medicated with GCs had a significantly higher risk of disease progression.

Introduction: Congenital anterior urethral diverticula in adult males are infrequent urological diseases, which they were mainly found in women. The etiology of female diverticula is that (Mohan et al. in J Urol 123(4):592-594, 1980) women have anatomically poorly supported urethral. Clinical presentation frequently involves urinary urgency, polyuria, postmicturition dribble, and hematuria., Case Description: A 37 year-old male was presented to us complaining of infertility about 6 years after marriage., Discussion and Evaluation: However, the complaint of infertility is extremely rare. Diagnostic imaging is useful to effectively confirm this disease in most cases. A complete review of the literature on this topic was also carried out., Conclusion: Manifestation as complaining of infertility is extremely rare among the congenital patients. The purpose of the operation is to complete the removal of the urethral diverticulum, reconstruct the urethra and maintain urinary tract unobstructed. This article and the operation could help the patient resolve the problem of infertility and dissatisfactory with the ejaculation.

Background: Over the past two decades, Snodgrass tubularized incised plate (TIP) urethroplasty has become one of the dominant surgical techniques with wide applications and excellent cosmetic results. However, TIP has many limitations. We performed a retrospective study at our department and assessed the outcome of the inlay internal preputial graft for extending the applications of TIP., Methods: Between January 2009 and December 2013, we performed a retrospective study consisting of approximately 508 primary distal and moderate cases. Patients with primary distal hypospadias who had mild or no chordee and good penile development were divided into the following 3 groups based on their procedures: (1) classic TIP hypospadias repair group (n = 198); (2) inlay buccal mucosa graft group (n = 150); and (3) inlay internal preputial graft group (n = 160). The median age was 1.6 years (range 1-4 years). Our data were analyzed statistically by the Chi square test with P  < 0.05 indicating significant differences., Results: The mean follow-up period was 18 months (range 6‒24 months). In the classic TIP group, the incidence of urinary fistula and meatal stenosis were both 3.0 % (6/198); in the inlay buccal mucosal graft group, the incidence of urinary fistula was 3.3 % (5/150), and the incidence of stenosis was 2.7 % (4/150); and in the inlay internal preputial graft group, the incidence of urinary fistula was 3.1 % (5/160), and the incidence of meatal stenosis was 4.4 % (7/160). The success rates of each group were as follows: the classic TIP group has a success rate of 93.9 % (186/198); the inlay buccal mucosa graft group had a success rate of 94.0 % (141/150); and the inlay internal preputial graft group had a success rate of 92.5 % (148/160). There were no statistically significant differences between the 3 groups with respect to complication rates., Conclusions: As the inner foreskin Snodgraft does not appear to be worse than the buccal mucosa graft, it is a good method for hypospadias repair, and this method is not inferior to TIP.

Developing new anticancer agents against ovarian cancer is an urgent medical need. MPT0G066, a novel synthetic arylsulfonamide compound, was shown to inhibit cell growth and decrease viability in human ovarian cancer cells. MPT0G066 induced arrest of the cell cycle at the multipolyploidy (MP) phase in SKOV3 and at the G2/M phase in A2780 cells, while increasing the proportion of cells in the subG1. Additionally, MPT0G066 induced c-Jun-NH2 terminal kinase (JNK) activation, influenced cell cycle regulatory and Bcl-2 family proteins, which triggered intrinsic apoptotic pathways through cleavage of caspase-3, -7, -9, and poly-(ADP-ribose) polymerase (PARP). Flow cytometry analysis of p-glycoprotein (p-gp) function showed that MPT0G066 was not a substrate of p-gp. Additionally, it was shown that MPT0G066 could decrease cell viability in multiple-drug-resistant human ovarian cancer cells. Furthermore, the combination of MPT0G066 and cisplatin presented a synergistic cytotoxic effect against ovarian cancer cell lines in vitro. MPT0G066 also significantly suppressed the growth of ovarian carcinoma and potentiated the antineoplastic effects of cisplatin in vivo. In conclusion, these findings indicate that MPT0G066 can be a potential anticancer agent against ovarian cancer that worthy of further development.

Pancreatic cancer is the leading cause of cancer death worldwide with a poor survival rate. The objective of this study was to determine the mechanism of action of a novel antimitotic and Stat3 inhibitor, LTP-1, on human pancreatic cancer in vitro and in vivo. We found that LTP-1 inhibited pancreatic cancer cell growth and viability with significant G2/M arrest and disruption of microtubule dynamics. LTP-1 also caused G2/M arrest-independent Stat3 dephosphorylation along with ERK activation, which indicated the possible dual function of LTP-1. Long-term treatment of LTP-1 also induced polyploidy, activated caspases, induced subG1 cell population, and therefore, triggered pancreatic cancer cell apoptosis. Finally, we used an in vivo xenograft model to demonstrate that LTP-1 suppressed the growth of pancreatic adenocarcinoma. In summary, our data suggest that LTP-1 may alter microtubule dynamics, which ultimately causes polyploidy and apoptosis, thereby inhibiting pancreatic cancer growth in vitro and in vivo. This study provides evidence that LTP-1 could be a potential therapeutic agent for further development of pancreatic cancer treatment.