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A novel multidimensional electromagnetic wave-absorbing material was developed by combining carboxylated carbon nanotubes (CNT) with graphene oxide (GO) through multidimensional design, and cobalt/nickel-based metal organic frameworks (Co/Ni-MOF) were subsequently loaded onto the GO surface via its rich functional groups to form the composite absorbing material CNT-rGO-Co/Ni-MOF. Incorporating 25 wt % of CNT-rGO-Co/Ni-MOF into the paraffin matrix led to a remarkable RL min value of -43 dB at 16.4 GHz, with an effective absorbing bandwidth (EAB) exceeding 4 GHz, all within a thickness of just 1.5 mm, showcasing its "lightweight, broadband, and high efficiency" characteristics. The exceptional electromagnetic wave absorption performance was attributed to multi-interface polarization loss, resistance loss, and magnetic medium loss. Furthermore, when incorporating 10 wt % of CNT-rGO-Co/Ni-MOF, the heat release capacity and peak heat release rate of EP/CNT-rGO-Co/Ni-MOF 10 decreased by 59.2 and 52.6%, respectively.

Antibody-drug conjugates (ADCs), from prototypes in the 1980s to first- and second-generation products in the 2000s, and now in their multiformats, have progressed tremendously to meet oncological challenges. Currently, 13 ADCs have been approved for medical practice, with over 200 candidates in clinical trials. Moreover, ADCs have evolved into different formats, including bispecific ADCs, probody-drug conjugates, pH-responsive ADCs, target-degrading ADCs, and immunostimulating ADCs. Technologies from biopharmaceutical industries have a crucial role in the clinical transition of these novel biotherapeutics. In this review, we highlight several features contributing to the prosperity of bioindustrial ADC development. Various proprietary technologies from biopharmaceutical companies are discussed. Such advances in biopharmaceutical industries are the backbone for the success of ADCs in development and clinical application., (Published by Elsevier Ltd.)

Rational: Patients with gastric cancer show a relatively low incidence of developing secondary myelodysplastic syndrome (MDS)., Patient Concerns: A 60-year-old man was admitted because of pain and discomfort in the upper abdomen and intermittent abdominal pain., Diagnoses: Ulcerative moderately poorly differentiated adenocarcinoma (pT2N2M0G3, stage IIB) and MDS., Interventions: The patient underwent chemotherapy with oxaliplatin (OXP, intravenously guttae on day 1) plus capecitabine (CAP, bis in die orally on day 1-14). The patient developed degree III myelosuppression after OXP plus CAP chemotherapy and MDS was subsequently confirmed by diagnosis of the bone marrow biopsy. Temporary but significant hematological improvements were observed after the patient received corresponding treatment, which helped achieve remission and improve pancytopenia., Outcomes: The patient presented partial remission after corresponding treatment and no other complications have been recorded., Lessons: Acute MDS is an unusual adverse effect induced by OXP plus CAP chemotherapy. It is urgent to suggest implementing a supplementary assessment or examination for patients receiving these therapies in future cases., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Corona Virus Disease 2019(COVID-19)is a global pandemic novel coronavirus infection disease caused by Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). Although rapid, large-scale testing plays an important role in patient management and slowing the spread of the disease. However, there has been no good and widely used drug treatment for infection and transmission of SARS-CoV-2., Key Findings: Therefore, this review updates the body of knowledge on viral structure, infection routes, detection methods, and clinical treatment, with the aim of responding to the large-section caused by SARS-CoV-2. This paper focuses on the structure of SARS-CoV-2 viral protease, RNA polymerase, serine protease and main proteinase-like protease as well as targeted antiviral drugs., Conclusion: In vitro or clinical trials have been carried out to provide deeper thinking for the pathogenesis, clinical diagnosis, vaccine development and treatment of SARS-CoV-2., Competing Interests: 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., (© 2024 The Author(s).)

Host-virus interactions can significantly impact the viral life cycle and pathogenesis; however, our understanding of the specific host factors involved in highly pathogenic avian influenza A virus H7N9 (HPAI H7N9) infection is currently restricted. Herein, we designed and synthesized 65 small interfering RNAs targeting host genes potentially associated with various aspects of RNA virus life cycles. Afterward, HPAI H7N9 viruses were isolated and RNA interference was used to screen for host factors likely to be involved in the life cycle of HPAI H7N9. Moreover, the research entailed assessing the associations between host proteins and HPAI H7N9 proteins. Twelve key host proteins were identified: Annexin A (ANXA)2, ANXA5, adaptor related protein complex 2 subunit sigma 1 (AP2S1), adaptor related protein complex 3 subunit sigma 1 (AP3S1), ATP synthase F1 subunit alpha (ATP5A1), COPI coat complex subunit alpha (COP)A, COPG1, heat shock protein family A (Hsp70) member 1A (HSPA)1A, HSPA8, heat shock protein 90 alpha family class A member 1 (HSP90AA1), RAB11B, and RAB18. Co-immunoprecipitation revealed intricate interactions between viral proteins (hemagglutinin, matrix 1 protein, neuraminidase, nucleoprotein, polymerase basic 1, and polymerase basic 2) and these host proteins, presumably playing a crucial role in modulating the life cycle of HPAI H7N9. Notably, ANXA5, AP2S1, AP3S1, ATP5A1, HSP90A1, and RAB18, were identified as novel interactors with HPAI H7N9 proteins rather than other influenza A viruses (IAVs). These findings underscore the significance of host-viral protein interactions in shaping the dynamics of HPAI H7N9 infection, while highlighting subtle variations compared with other IAVs. Deeper understanding of these interactions holds promise to advance disease treatment and prevention strategies., Competing Interests: 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., (© 2024 The Authors.)

Introduction: Gestational diabetes mellitus (GDM) and gestational hypertension (GH) are the most common pregnancy complications, predisposing to adverse pregnancy outcomes and being a major cause of maternal morbidity and mortality, often associated with significantly higher health risks for the mother and her offspring. The aim of this study was to systematically evaluate the effects of aerobic exercise performed during pregnancy on GDM, GH, and pregnancy outcomes., Evidence Acquisition: The databases PubMed, EMbase, Web of Science, China Knowledge Network, Wan fang, and Wipu were searched for clinical randomized controlled trials of exercise interventions on GDM, GH, and pregnancy outcomes, and data were analyzed and systematically evaluated using RevMan 5.3 according to the inclusion and exclusion criteria., Evidence Synthesis: Meta-analysis showed that, in terms of pregnancy complications, aerobic exercise intervention reduced the incidence of maternal GDM better than the control group, with a statistically significant difference (OR=0.39, 95% CI: 0.30, 0.50, P<0.00001); aerobic exercise intervention reduced the incidence of maternal GH better than the control group, with a statistically significant difference (OR=0.38, 95% CI: 0.27, 0.54, P<0.00001)., Conclusions: The results in pregnancy suggest that aerobic exercise is advantageous for pregnant women, as it reduces the incidence of GDM and GH and improves the incidence of adverse pregnancy outcomes to a certain extent.

The coronavirus disease 2019 (COVID-19) pandemic caused extensive loss of life worldwide. Further, the COVID-19 and influenza mix-infection had caused great distress to the diagnosis of the disease. To control illness progression and limit viral spread within the population, a real-time reverse-transcription PCR (RT-PCR) assay for early diagnosis of COVID-19 was developed, but detection was time-consuming (4-6 h). To improve the diagnosis of COVID-19 and influenza, we herein developed a recombinase polymerase amplification (RPA) method for simple and rapid amplification of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 and Influenza A (H1N1, H3N2) and B (influenza B). Genes encoding the matrix protein (M) for H1N1, and the hemagglutinin (HA) for H3N2, and the polymerase A (PA) for Influenza B, and the nucleocapsid protein (N), the RNA-dependent-RNA polymerase (RdRP) in the open reading frame 1ab (ORF1ab) region, and the envelope protein (E) for SARS-CoV-2 were selected, and specific primers were designed. We validated our method using SARS-CoV-2, H1N1, H3N2 and influenza B plasmid standards and RNA samples extracted from COVID-19 and Influenza A/B (RT-PCR-verified) positive patients. The method could detect SARS-CoV-2 plasmid standard DNA quantitatively between 10 2 and 10 5 copies/ml with a log linearity of 0.99 in 22 min. And this method also be very effective in simultaneous detection of H1N1, H3N2 and influenza B. Clinical validation of 100 cases revealed a sensitivity of 100% for differentiating COVID-19 patients from healthy controls when the specificity was set at 90%. These results demonstrate that this nucleic acid testing method is advantageous compared with traditional PCR and other isothermal nucleic acid amplification methods in terms of time and portability. This method could potentially be used for detection of SARS-CoV-2, H1N1, H3N2 and influenza B, and adapted for point-of-care (POC) detection of a broad range of infectious pathogens in resource-limited settings., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: Cancer stem-like cells in triple-negative breast cancer (TNBC-SLCs) are the tumorigenic core for malignancy. Aberrant expression of the RON receptor tyrosine kinase has implications in TNBC tumorigenesis and malignancy., Objective: In this study, we identified the RON receptor as a pathogenic factor contributing to TNBC cell stemness and validated anti-RON antibody-drug conjugate Zt/g4-MMAE for eradication of RONexpressing TNBC-SLCs., Methods: Immunofluorescence and Western blotting were used for analyzing cellular marker expression. TNBC-SLCs were isolated by magnetic-immunofluorescence cell-sorting techniques. Spheroids were generated using the ultralow adhesion culture methods. Levels of TNBC-SLC chemosensitivity were determined by MTS assays. TNBC-SLC mediated tumor growth was determined in athymic nude mice. The effectiveness of Zt/g4-induced RON internalization was measured by immunofluorescence analysis. Efficacies of Zt/g4-MMAE in killing TNBC-SLCs in vitro and in eradicating TNBC-SLCmediated tumors were determined in mouse models. All data were statistically analyzed using the GraphPad Prism 7 software., Results: Increased RON expression existed in TNBC-SLCs with CD44+/CD24- phenotypes and ALDH activities and facilitated epithelial to mesenchymal transition. RON-positive TNBC-SLCs enhanced spheroid-formatting capability compared to RON-negative TNBC-SLCs, which were sensitive to small molecule kinase inhibitor BMS-777607. Increased RON expression also promoted TNBC-SLC chemoresistance and facilitated tumor growth at an accelerated rate. In vitro, Zt/g4-MMAE caused massive TNBC-SLC death with an average IC50 value of ~1.56 μg per/ml and impaired TNBC cell spheroid formation. In mice, Zt/g4-MMAE effectively inhibited and/or eradicated TNBC-SLC mediated tumors in a single agent regimen., Conclusion: Sustained RON expression contributes to TNBC-SLC tumorigenesis. Zt/g4-MMAE is found to be effective in vivo in killing TNBC-SLC-mediated xenograft tumors. Our findings highlight the feasibility of Zt/g4-MMAE for the eradication of TNBC-SLCs in the future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Aberrant expression of the MET receptor tyrosine kinase is an oncogenic determinant and a drug target for cancer therapy. Currently, antibody-based biotherapeutics targeting MET are under clinical trials., Objective: Here, we report the preclinical and therapeutic evaluation of a novel anti-MET antibody- drug conjugate PCMC1D3-duocarmycin SA (PCMC1D3-DCM) for targeted cancer therapy., Methods: The monoclonal antibody PCMC1D3 (IgG1a/κ), generated by a hybridoma technique and specific to one of the MET extracellular domains, was selected based on its high specificity to human MET with a binding affinity of 1.60 nM. PCMC1D3 was conjugated to DCM via a cleavable valine-citrulline dipeptide linker to form an antibody-drug conjugate with a drug-to-antibody ratio of 3.6:1. PCMC1D3-DCM in vitro rapidly induced MET internalization with an internalization efficacy ranging from 6.5 to 17.2h dependent on individual cell lines., Results: Studies using different types of cancer cell lines showed that PCMC1D3-DCM disrupted the cell cycle, reduced cell viability, and caused massive cell death within 96h after treatment initiation. The calculated IC 50 values for cell viability reduction were 1.5 to 15.3 nM. Results from mouse xenograft tumor models demonstrated that PCMC1D3-DCM in a single dose injection at 10 mg/kg body weight effectively delayed xenograft tumor growth up to two weeks without signs of tumor regrowth. The calculated tumoristatic concentration, a minimal dose required to balance tumor growth and inhibition, was around 2 mg/kg body weight. Taken together, PCMC1D3-DCM was effective in targeting the inhibition of tumor growth in xenograft models., Conclusion: This work provides the basis for the development of humanized PCMC1D3-DCM for MET-targeted cancer therapy in the future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide with high mortality. The incidence of HCC is increasing in China. Abnormal activation of glucose-6-phosphate dehydrogenase (G6PD) exists in all malignant tumors, including HCC, and is closely related to the development of HCC. In addition, the differential expression of non-coding RNAs is closely related to the development of HCC. This systematic review focuses on the relationship between G6PD, HCC, and non-coding RNA, which form the basis for the circRNA/miRNA/G6PD axis in HCC. The circular RNA (circRNA)/microRNA (miRNA)/G6PD axis is involved in development of HCC. We proposed that non-coding RNA molecules of the circRNA/miRNA/G6PD axis may be novel biomarkers for the pathological diagnosis, prognosis, and targeted therapy of HCC., (Copyright © 2021. Published by Elsevier B.V.)

The global incidence of ulcerative colitis (UC) continues to increase while it's clinical cure rate remains low. Intestinal mucosal ulcers have segmental distribution and variable severity. Intestinal bacteria are closely related to intestinal immunity and metabolism; however, the relationship between intestinal microbiome profile and the occurrence of UC, as well as the contribution of glucose metabolism, are not well understood. This was investigated in the present study using mucosal biopsies from patients with UC and healthy control subjects. We performed high throughput 16S rRNA gene sequencing to estimate microbiota composition and abundance as well as their association with clinical indices such as lesion severity. The results showed that the diversity and abundance of intestinal microbiota were significantly lower in patients with UC than in healthy subjects; however, these were unrelated to ulcer severity. Serum glucagon-like peptide 2 (GLP-2) level was associated with reduced microbiota diversity and abundance in UC. These results indicate that colonization by specific microbiota is not the main determinant of pathologic status in UC. Additionally, therapeutic strategies that increase GLP-2 levels in intestinal mucosa may be effective in the treatment of UC.

Background: The highly pathogenic Influenza H7N9 virus is believed to cause multiple organ infections. However, there have been few systematic animal experiments demonstrating the virus distribution after H7N9 virus infection. The present study was carried out to investigate the viral distribution and pathological changes in the main organs of mice after experimental infection with highly pathogenic H7N9 virus., Methods: Infection of mice with A/Guangdong/GZ8H002/2017(H7N9) virus was achieved via nasal inoculation. Mice were killed at 2, 3, and 7 days post infection. The other mice were used to observe their illness status and weight changes. Reverse transcription polymerase chain reaction and viral isolation were used to analyse the characteristics of viral invasion. The pathological changes of the main organs were observed using haematoxylin and eosin staining and immunohistochemistry., Results: The weight of H7N9 virus-infected mice increased slightly in the first two days. However, the weight of the mice decreased sharply in the following days, by up to 20%. All the mice had died by the 8th day post infection and showed multiple organ injury. The emergence of viremia in mice was synchronous with lung infection. On the third day post infection, except in the brain, the virus could be isolated from all organs (lung, heart, kidney, liver, and spleen). On the seventh day post infection, the virus could be detected in all six organs. Brain infection was detected in all mice, and the viral titre in the heart, kidney, and spleen infection was high., Conclusion: Acute diffuse lung injury was the initial pathogenesis in highly pathogenic H7N9 virus infection. In addition to lung infection and viremia, the highly pathogenic H7N9 virus could cause multiple organ infection and injury., (© 2021. The Author(s).)

Objective: To investigate the mechanism of honokiol (HNK) on bladder cancer cells and its synergistic anticancer effect with hydroxycamptothecin (HCPT)., Methods: Control, HNK, HCPT, and HNK plus HCPT groups were established. The morphological characteristics of T24 cells were examined microscopically. The maximal experimental concentration of HNK and HCPT were determined according to IC10 detected by MTT. T24 cell viability and the percentage of apoptotic cells were assessed on the basis of MTT and flow cytometric analysis. The expression of caspase-3, caspase-9, phosphorylated nuclear factor-kappa B (NF-κB)-p65, Akt, and extracellular signal-regulated kinase (ERK) proteins were analyzed by Western blot., Results: Apoptosis in T24 cells was observed microscopically in both the HNK and HCPT groups and even more obvious in the HNK plus HCPT groups. The percentage of T24 cell viability decreased down to 19.41% , and the percentage of apoptotic cells rose to 54.08% when treated with HNK plus HCPT in an HNK dose-dependent manner. The induction of caspase-3 and caspase-9 proteins and the inhibition of phosphorylation of NF-κB-p65, Akt, and ERK proteins in T24 cells were demonstrated in the HNK groups, and more significantly in the HNK plus HCPT groups, but not in the HCPT group., Conclusion: The anticancer effect of HNK may be due to the activation of the caspase pathway and inhibition of phosphorylation of NF-κB, Akt, and ERK. HNK in combination with HCPT produces a synergistic cell-killing effect on bladder cancer cells.

Duocarmycins are a class of DNA minor-groove-binding alkylating molecules. For the past decade, various duocarmycin analogues have been used as payloads in the development of antibody-drug conjugates (ADCs). Currently, more than 15 duocarmycin-based ADCs have been studied preclinically, and some of them such as SYD985 have been granted Fast-Track Designation status. Nevertheless, progress in duocarmycin-based ADCs also faces challenges, with setbacks including the termination of BMS-936561/MDX-1203. In this review, we discuss issues associated with the efficacy, pharmacokinetic profile, and toxicological activity of these biotherapeutics. Furthermore, we summarize the latest advances in duocarmycin-based ADCs that have different target specificities and linker chemistries. Evidence from preclinical and clinical studies has indicated that duocarmycin-based ADCs are promising biotherapeutics for oncological application in the future., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The receptor protein tyrosine kinase RON belongs to the c-MET proto-oncogene family. Research has shown that RON has a role in cancer pathogenesis, which places RON on the frontline of the development of novel cancer therapeutic strategies. Hepatobiliary and pancreatic (HBP) cancers have a poor prognosis, being reported as having higher rates of cancer-related death. Therefore, to combat these malignant diseases, the mechanism underlying the aberrant expression and signaling of RON in HBP cancer pathogenesis, and the development of RON as a drug target for therapeutic intervention should be investigated. Abnormal RON expression and signaling have been identified in HBP cancers, and also act as tumorigenic determinants for HBP cancer malignant behaviors. In addition, RON is emerging as an important mediator of the clinical prognosis of HBP cancers. Thus, not only is RON significant in HBP cancers, but also RON-targeted therapeutics could be developed to treat these cancers, for example, therapeutic monoclonal antibodies and small-molecule inhibitors. Among them, antibody-drug conjugates have become increasingly popular in current research and their potential as novel anti-cancer biotherapeutics will be determined in future clinical trials., Competing Interests: Conflict-of-interest statement: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aberrant expression and/or activation of the MET receptor tyrosine kinase is characterized by genomic recombination, gene amplification, activating mutation, alternative exon-splicing, increased transcription, and their different combinations. These dysregulations serve as oncogenic determinants contributing to cancerous initiation, progression, malignancy, and stemness. Moreover, integration of the MET pathway into the cellular signaling network as an addiction mechanism for survival has made this receptor an attractive pharmaceutical target for oncological intervention. For the last 20 years, MET-targeting small-molecule kinase inhibitors (SMKIs), conventional therapeutic monoclonal antibodies (TMABs), and antibody-based biotherapeutics such as bispecific antibodies, antibody-drug conjugates (ADC), and dual-targeting ADCs have been under intensive investigation. Outcomes from preclinical studies and clinical trials are mixed with certain successes but also various setbacks. Due to the complex nature of MET dysregulation with multiple facets and underlying mechanisms, mechanism-based validation of MET-targeting therapeutics is crucial for the selection and validation of lead candidates for clinical trials. In this review, we discuss the importance of various types of mechanism-based pharmaceutical models in evaluation of different types of MET-targeting therapeutics. The advantages and disadvantages of these mechanism-based strategies for SMKIs, conventional TMABs, and antibody-based biotherapeutics are analyzed. The demand for establishing new strategies suitable for validating novel biotherapeutics is also discussed. The information summarized should provide a pharmaceutical guideline for selection and validation of MET-targeting therapeutics for clinical application in the future., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

Objective: To explore the clinical effect and adverse reactions of Strychnos nux-vomica in bortezomib-induced peripheral neuropathy (BIPN) of patients with multiple myeloma (MM)., Methods: A total of 19 MM patients with BIPN were enrolled and Nux Vomica Capsule (NVC, 0.4 g, thrice daily) were orally administrated for 30 days. Comparative analysis on parameters between pre- and post-therapy, including peripheral neuropathy (PN) grade, neurotoxicity score, Chinese medicine (CM) syndrome score, total neuropathy score (TNS), coagulation function, and serum nerve growth factor (NGF) levels were conducted. The adverse events were monitored., Results: In BIPN of MM patients who received NVC, PN grade was lowered, neurotoxicity score was obviously decreased (P⩽0.01), and both CM syndrome score and TNS were remarkably decreased (P<0.01). After the therapy, activated partial thromboplastin time was prolonged (P<0.01) and fibrinogen was declined (P<0.05), showing improvement in the hypercoagulable state of patients. No significant difference of NGF recovery degrees was detected between pre- and post-therapy (P>0.05). No evident adverse reactions were observed during the course of treatment., Conclusion: Strychnos nux-vomica L. has significantly effect with a good safety in treatment of BIPN in MM patients.

Pharmaceutical innovation in the development of novel antibody-based biotherapeutics with increased therapeutic indexes makes MET-targeted cancer therapy a clinical reality., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Advanced epithelial cancers such as gastric, lung, and pancreatic tumors are featured by invasive proliferation, distant metastasis, acquired chemoresistance, and tumorigenic stemness. For the last decade, molecular-targeted therapies using therapeutic antibodies, small molecule kinase inhibitors and immune-checkpoint blockades have been applied for these diseases with significant clinical benefits. Nevertheless, there is still a large gap to achieve curative outcomes. MET (mesenchymal-epithelial transition protein), a receptor tyrosine kinase, is a tumorigenic determinant that regulates epithelial cancer initiation, progression, and malignancy. Increased MET expression also has prognostic value for cancer progression and patient survival. These features provide the rationale to target MET for cancer treatment. In this review, we discuss the importance of MET in epithelial tumorigenesis and the development of antibody-based biotherapeutics, including bispecific antibodies and antibody-drug conjugates, for clinical application. The findings from both preclinical and clinical studies highlight the potential of MET-targeted biotherapeutics for cancer therapy in the future., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

The H7N9 virus mutated in 2017, resulting in new cases of highly pathogenic avian influenza (HPAI) H7N9 virus infection. H7N9 was found in a viraemic patient in Guangdong province, China. The present study aimed to clarify the pathogenic characteristics of HPAI H7N9. Virus was isolated from the plasma and sputum of the patient with HPAI H7N9. Liquid phase chip technology was used to detect the plasma cytokines from the infected patient and healthy controls. Mice were infected with strains A/Guangdong/GZ8H002/2017(H7N9) and A/Zhejiang/DTID-ZJU01/2013(H7N9) to observe the virus's pathogenic characteristics. Serum and brain tissue were collected at 2, 4, and 6 days after infection. The viruses in serum and brain tissue were detected and isolated. The two strains were infected into A549 cells, exosomes were extracted, and virus genes in the exosomes were assessed. Live virus was isolated from the patient's plasma. An acute cytokine storm was detected during the whole course of the disease. In animal experiments, A/Guangdong/GZ8H002/2017(H7N9) was more pathogenic than A/Zhejiang /DTID-ZJU01/2013(H7N9) and resulted in the death of mice. Live virus was isolated from infected mouse serum. Virus infection was also detected in the brain of mice. Under viral stress, A549 cells secreted exosomes containing the entire viral genome. The viraemic patient was confirmed to have an HPAI H7N9 infection. A/Guangdong/GZ8H002/2017(H7N9) showed significantly enhanced toxicity. Patient deaths might result from cytokine storms and brain infections. Extrapulmonary tissue infection might occur via the exosome pathway. The determined pathogenic characteristics of HPAI H7N9 will contribute to its future treatment.

Background: Programmed death ligand 1 (PD-L1) immunotherapy remains poorly efficacious in colorectal cancer (CRC). The recepteur d'origine nantais (RON) receptor tyrosine kinase plays an important role in regulating tumor immunity., Aim: To identify the patterns of RON and PD-L1 expression and explore their clinical significance in CRC., Methods: Gene expression data from the Gene Expression Omnibus database (GEO; n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZUSM; n = 381) were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor microenvironment of CRC. HT29 cell line was treated with BMS-777607 to explore the relationship between RON activity and PD-L1 expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and Western blot., Results: In the GEO patient cohort, cut-off values for RON and PD-L1 expression were determined to be 7.70 and 4.3, respectively. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 was associated with a poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121 (32%), 43 (11%), 91 (24%), and 51 (13.4%), respectively. High expression of RON was significantly correlated with high expression of PD-L1 in the tumor cell compartment ( P < 0.001). High expression of RON and that of PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with a poor prognosis. In vitro , BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in CRC cells., Conclusion: RON, PD-L1, and their crosstalk are significant in predicting the prognostic value of CRC. Moreover, phosphorylation of RON upregulates PD-L1 expression, which provides a novel approach to immunotherapy in CRC., Competing Interests: Conflict-of-interest statement: The authors confirm that there are no known conflicts of interest associated with this publication. The manuscript has been read and approved by all authors and there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of authors., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Advanced colorectal adenocarcinoma (CRAC), featured by distinctive histopathological appearance, distant organ metastasis, acquired chemoresistance, and tumorigenic stemness is a group of heterogeneous cancers with unique genetic signatures and malignant phenotypes. Treatment of CRAC is a daunting task for oncologists. Currently, various strategies including molecular targeting using therapeutic monoclonal antibodies, small molecule kinase inhibitors and immunoregulatory checkpoint therapy have been applied to combat this deadly disease. However, these therapeutic modalities and approaches achieve only limited success. Thus, there is a pharmaceutical need to discover new targets and develop novel therapeutics for CRAC therapy. MET and RON receptor tyrosine kinases have been implicated in CRAC pathogenesis. Clinical studies have revealed that aberrant MET and/or RON expression and signaling are critical in regulating CRAC progression and malignant phenotypes. Increased MET and/or RON expression also has prognostic value for CRAC progression and patient survival. These features provide the rationale to target MET and RON for clinical CRAC intervention. At present, the use of small molecule kinase inhibitors targeting MET for CRAC treatment has achieved significant progress with several approvals for clinical application. Nevertheless, antibody-based biotherapeutics, although under clinical trials for more than 8 years, have made very little progress. In this review, we discuss the importance of MET and/or RON in CRAC tumorigenesis and development of anti-MET, anti-RON, and MET and RON-dual targeting antibody-drug conjugates for clinical application. The findings from both preclinical studies and clinical trials highlight the potential of this novel type of biotherapeutics for CRAC therapy in the future.

The inflammatory response has been implicated in various cardiac and systemic diseases. Epigallocatechin-3-gallate (EGCG), the major polyphenol extracted from green tea, has various biological and pharmacological properties, such as anti-inflammation, anti-oxidative and anti-tumorigenesis. To some extent, the mechanism of EGCG in the inflammatory response that characterizes myocardial dysfunction is not fully understood. The present study aimed to investigate the inhibiting effect of EGCG on lipopolysaccharide (LPS)-induced inflammation in vitro . Treatment with LPS affected rat H9c2 cardiomyocytes and induced an inflammatory response. However, the LPS-induced effects were attenuated after treatment with EGCG. The present results demonstrated that EGCG treatment repressed several inflammatory mediators, such as vascular endothelial growth factor, chemokine ligand 5, chemokine ligand 2, intercellular adhesion molecule-1, matrix metalloproteinase-2, tumor necrosis factor-α and nitric oxide (induced by LPS), and the repressing effect of EGCG on inflammatory response was dose-dependent in the range of 6.25-100 µM. EGCG inhibited these marked inflammatory key signaling molecules by reducing the expression of phospho-nuclear factor-κB p65, -Akt, -ERK and -MAPK p38 while the total protein level of these signal proteins were not affected. In conclusion, the present findings suggested that EGCG possesses cardiomyocyte-protective action in reducing the LPS-induced inflammatory response due to the inhibition of the phosphorylation of Akt and ERK signaling molecules., (Copyright: © Li et al.)

To investigate the main transcriptional and biological changes of human host during low and highly pathogenic avian H7N9 influenza virus infection and to analyze the possible causes of escalated virulence and the systematic progression of H7N9 virus infection, we utilized whole transcriptome sequencing (RNA-chip and RNA-seq) and other biomolecular methods to analyze and verify remarkable changes of host cells during these two subtypes of H7N9 influenza viruses infection. Whole transcriptome analysis showed the global profiles of differentially expressed genes (DEGs) and identified 458 DEGs associated with major changes in biological processes of the host cells after infection with 2017 HPAI H7N9 virus versus 2013 LPAI H7N9 virus, mainly including drastically increased defense responses to viruses (e.g. negative regulation of viral gene replication), IFNs related pathways, immune response/native immune response, and inflammatory response. Genes of programmed cell death 1 (PD-1) pathways were found changed remarkably and several highly correlated non-coding RNAs were identified. The results suggested that HPAI H7N9 virus induces stronger immune response and suppressing response than LPAI H7N9. Meanwhile, PD-1/PD-Ls signaling pathways work together in regulating host responses including antiviral defense, lethal inflammation caused by the virus and immune response, thus contribute to the high pathogenicity of 2017H7N9 virus that can be regulated by non-coding RNAs. The present study represents a comprehensive understanding and good reference of regulation of pathogenicity of H7N9 virus even other fatal viruses and correlated host immune responses., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest with contents of this article., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Triple-negative breast cancer (TNBC) is highly malignant and has poor prognosis and a high mortality rate. The lack of effective therapy has spurred our investigation of new targets for treating this malignant cancer. Here, we identified RON (macrophage-stimulating 1 receptor) and MET (MET proto-oncogene, receptor tyrosine kinase) as a prognostic biomarker and therapeutic targets for potential TNBC treatment., Materials and Methods: We analyzed RON and MET expression in 187 primary TNBC clinical samples with immunohistochemistry. We validated the targeted therapeutic effects of RON and MET in TNBC using three tyrosine kinase inhibitors (TKIs): BMS-777607, INCB28060, and tivantinib. The preclinical therapeutic efficacy of the TKIs was mainly estimated using a TNBC xenograft model., Results: Patients with TNBC had widespread, abnormal expression of RON and MET. There was RON overexpression, MET overexpression, and RON and MET co-overexpression in 63 (33.7%), 63 (33.7%), and 43 cases (23.0%), respectively, which had poor prognosis and short survival. In vivo, the TKI targeting RON ant MET inhibited the activation of the downstream signaling molecules, inhibited TNBC cell migration and proliferation, and increased TNBC cell apoptosis; in the xenograft model, they significantly inhibited tumor growth and shrank tumor volumes. The TKI targeting RON and Met, such as BMS-777607 and tivantinib, yielded stronger anti-tumor effects than INCB28060., Conclusion: RON and MET co-overexpression can be significant pathological characteristics in TNBC for poor prognosis. TKIs targeting RON and MET have stronger drug development potential for treating TNBC.

Treatment of triple-negative breast cancer (TNBC) is a challenge to oncologists. Currently, the lack of effective therapy has fostered a major effort to discover new targets and therapeutics to combat this disease. The recepteur d'origine nantais (RON) receptor has been implicated in the pathogenesis of TNBC. Clinical studies have revealed that aberrant RON expression is crucial in regulating TNBC malignant phenotypes. Increased RON expression also has prognostic value for breast cancer progress. These features provide the rationale to target RON for TNBC treatment. In this review, we discuss the importance of RON in TNBC tumorigenesis and the development of anti-RON antibody-drug conjugates (ADCs) for clinical application. The findings from preclinical studies lay the foundation for clinical trials of this novel biotherapeutic for TNBC therapy., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Dichlorprop [( RS )-2-(2,4-dichlorophenoxy)propanoic acid; DCPP], an important phenoxyalkanoic acid herbicide (PAAH), is extensively used in the form of racemic mixtures ( Rac -DCPP), and the environmental fates of both DCPP enantiomers [( R )-DCPP and ( S )-DCPP] mediated by microorganisms are of great concern. In this study, a bacterial strain Sphingopyxis sp. DBS4 was isolated from contaminated soil and was capable of utilizing both ( R )-DCPP and ( S )-DCPP as the sole carbon source for growth. Strain DBS4 preferentially catabolized ( S )-DCPP as compared to ( R )-DCPP. The optimal conditions for Rac -DCPP degradation by strain DBS4 were 30 °C and pH 7.0. In addition to Rac -DCPP, other PAAHs such as ( RS )-2-(4-chloro-2-methylphenoxy)propanoic acid, 2,4-dichlorophenoxyacetic acid, 4-chloro-2-methylphenoxyacetic acid, and 2,4-dichlorophenoxyacetic acid butyl ester could also be catabolized by strain DBS4. Bioremediation of Rac -DCPP-contaminated soil by inoculation of strain DBS4 exhibited an effective removal of both ( R )-DCPP and ( S )-DCPP from the soil. Due to its broad substrate spectrum, strain DBS4 showed great potential in the bioremediation of PAAH-contaminated sites.

The recepteur d'origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody-drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro , efficacy in tumor models, and toxicological activities in primates., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor prognosis and high mortality. Molecular aberrations associated with PDAC pathogenesis and progression have been extensively investigated. Nevertheless, these findings have not been translated into clinical practice. Lack of therapeutics for PDAC treatment is another challenge. Recent application of molecularly targeted and immunoregulatory therapies appears to be disappointing. Thus, discovery of new targets and therapeutics is urgently needed to combat this malignant disease. The RON receptor tyrosine kinase is a tumorigenic determinant in PDAC malignancy, which provides the rationale to target RON for PDAC treatment. In this review, we summarize the latest evidence of RON in PDAC pathogenesis and the development of anti-RON antibody-drug conjugates for potential PDAC therapy. The finding that anti-RON antibody-drug conjugates show efficacy in preclinical animal models highlights the potential of this novel class of anti-cancer biotherapeutics in future clinical trials., Competing Interests: Declaration of Competing Interest All authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Swep is an excellent carbamate herbicide that kills weeds by interfering with metabolic processes and inhibiting cell division at the growth point. Due to the large amount of use, swep residues in soil and water not only cause environmental pollution but also accumulate through the food chain, ultimately pose a threat to human health. This herbicide is degraded in soil mainly by microbial activity, but no studies on the biotransformation of swep have been reported., Results: In this study, a consortium consisting of two bacterial strains, Comamonas sp. SWP-3 and Alicycliphilus sp. PH-34, was enriched from a contaminated soil sample and shown to be capable of mineralizing swep. Swep was first transformed by Comamonas sp. SWP-3 to the intermediate 3,4-dichloroaniline (3,4-DCA), after which 3,4-DCA was mineralized by Alicycliphilus sp. PH-34. An amidase gene, designated as ppa, responsible for the transformation of swep into 3,4-DCA was cloned from strain SWP-3. The expressed Ppa protein efficiently hydrolyzed swep and a number of other structural analogues, such as propanil, chlorpropham and propham. Ppa shared less than 50% identity with previously reported arylamidases and displayed maximal activity at 30 °C and pH 8.6. Gly449 and Val266 were confirmed by sequential error prone PCR to be the key catalytic sites for Ppa in the conversion of swep., Conclusions: These results provide additional microbial resources for the potential remediation of swep-contaminated sites and add new insights into the catalytic mechanism of amidase in the hydrolysis of swep.

RON (recepteur d'origine nantais) and MET (hepatocyte growth factor receptor) are tyrosine kinase receptors. Various cancers have aberrant RON and MET expression and activation, which contribute to cancer cell proliferation, invasiveness, and metastasis. Here, we explored RON and MET expression in pancreatic cancer and their relationship with overall survival (OS) time, and evaluated their significance as therapeutic targets of tyrosine kinase inhibitors in pancreatic cancer. We enrolled 227 patients with pancreatic cancer in the study. RON and MET expression was analyzed by immunohistochemical staining. Four human pancreatic cancer cell lines expressing variable levels of RON or MET and four MET superfamily inhibitors (BMS777607, PHA665752, INCB28060, Tivantinib) were used. The effect of the four tyrosine kinase inhibitors on cell viability, migration, and apoptosis were determined using cell viability, scratch wound healing, and Caspase-Glo 3/7 assays. Cellular signaling was analyzed by immunoprecipitation and western blotting. The therapeutic efficacy of the tyrosine kinase inhibitors was determined with mouse xenograft pancreatic cancer models in vivo . There was wide aberrant RON and MET expression in the cancer tissues. In 227 pancreatic cancer samples, 33% had RON overexpression, 41% had MET overexpression, and 15.4% had RON and MET co-overexpression. RON and MET expression were highly correlated. RON and MET expression levels were significantly related to OS. Patients with RON and MET co-overexpression had poorer OS. BMS777607 and PHA665752 inhibited pancreatic cancer cell viability and migration, and promoted apoptosis by inhibiting RON and MET phosphorylation and further inhibiting the downstream signaling pathways in vitro . They also inhibited tumor growth and further inhibited phosphorylated (phosphor)-RON and phospho-MET expression in the mouse xenograft models in vivo effectively. INCB28060, which inhibits the MET signaling pathway alone, was not effective. RON and MET can be important indicators of prognosis in pancreatic cancer. Tyrosine kinase inhibitors targeting RON and MET in pancreatic cancer are a novel and potential approach for pancreatic cancer therapy., (Copyright © 2019 Hu, Xu, Hong, Wu, Qian, Weng, Liu, Tang, Wang and Yao.)

Middle East respiratory syndrome (MERS) is a viral respiratory disease caused by a de novo coronavirus-MERS-CoV-that is associated with high mortality. However, the mechanism by which MERS-CoV infects humans remains unclear. To date, there is no effective vaccine or antibody for human immunity and treatment, other than the safety and tolerability of the fully human polyclonal Immunoglobulin G (IgG) antibody (SAB-301) as a putative therapeutic agent specific for MERS. Although rapid diagnostic and public health measures are currently being implemented, new cases of MERS-CoV infection are still being reported. Therefore, various effective measures should be taken to prevent the serious impact of similar epidemics in the future. Further investigation of the epidemiology and pathogenesis of the virus, as well as the development of effective therapeutic and prophylactic anti-MERS-CoV infections, is necessary. For this purpose, detailed information on MERS-CoV proteins is needed. In this review, we describe the major structural and nonstructural proteins of MERS-CoV and summarize different potential strategies for limiting the outbreak of MERS-CoV. The combination of computational biology and virology can accelerate the advanced design and development of effective peptide therapeutics against MERS-CoV. In summary, this review provides important information about the progress of the elimination of MERS, from prevention to treatment., (© 2019 THE AUTHORS.)

Background: Antibody-drug conjugates (ADCs) targeting the RON receptor, a tumorigenic factor contributing to cancer malignancy, has been considered as a novel strategy for cancer therapy. Here we describe a humanized antibody recognizing the RON plexin-semaphorin-integrin (PSI) domain with increased drug delivery capability for potential clinical application., Method: Monoclonal antibody PCM5B14 specific to the human and monkey RON PSI domain was generated and characterized by various immunological methods. Humanized antibody H5B14 was created by grafting PCM5B14 complementarity-determining regions into human IgG1/κ acceptor frameworks and conjugated with monomethyl auristatin E and duocarmycin to form two H5B14-based ADCs. Stability of H5B14-based ADCs in human plasma was measured using hydrophobic interaction chromatography. Various biochemical and biological assays were used to determine ADC- regulated RON internalization, cell viability, spheroid formation, and death of cancer stem-like cells. Efficacies of H5B14-based ADCs in vivo were validated using tumor xenograft models. Maximal tolerated doses of H5B14-based ADCs were established in mice., Results: H5B14 was highly specific to the human RON PSI domain and superior over other anti-RON ADCs in induction of RON internalization in various cancer cell lines tested. H5B14-based ADCS had a drug to antibody ratio of ~ 3.70:1 and were stable in human plasma with a minimal dissociation within a 10-day period. Functionally, H5B14-mediated drug delivery decreased cell viability at early stages with an average IC 50 at ~ 20 nM in multiple cancer cell lines examined. H5B14-based ADCs also inhibited spheroid formation and caused death of cancer stem-like cells with RON + /CD44 + /ESA + phenotypes. In vivo, H5B14-based ADCs in a single injection inhibited tumor xenograft growth mediated by multiple cancer cell lines. Tumoristatic concentrations calculated from xenograft tumor models were in the range of 0.63 to 2.0 mg/kg bodyweight. Significantly, H5B14-based ADCs were capable of eradicating tumors at variable levels across multiple xenograft models regardless their malignant statuses. Toxicologically, H5B14-based ADCs were well tolerated in mice up to 60 mg/kg., Conclusion: H5B14-based ADCs targeting the RON PSI domain are superior in inducing RON internalization, leading to robust drug delivery and overall inhibition and eradication of tumors in multiple xenograft models. These findings warrant H5B14-based ADCs for clinical trials in the future.

A novel Gram-stain-negative, strictly aerobic, non-spore-forming, motile with one polar flagellum and short rod-shaped bacterium, designated strain ZLT-5 T , was isolated from procymidone-contaminated soil sampled in Nanjing, Jiangsu, PR China. Growth occurred at 26-37 °C (optimum, 37 °C), at pH 6.0-9.0 (pH 7.0) and in the presence of 0-1.5 % NaCl (0.5 %). Phylogenetic analysis based on the 16S rRNA gene sequences showed that strain ZLT-5 T belonged to the genus Sphingomonas , with the highest sequence similarity to Sphingomonas kyeonggiensis THG-DT81 T (96.6 %), followed by Sphingomonas dokdonensis DSM 21029 T (96.5 %) and Sphingomonas silvisoli RP18 T (96.3 %). The G+C content of strain ZLT-5 T was 68.0 mol% (draft genome sequence). The average nucleotide identity value of the draft genomes between strain ZLT-5 T and S. kyeonggiensis THG-DT81 T was 75.4 %. Strain ZLT-5 T contained ubiquinone-10 as the predominant isoprenoid quinone and sym -homospermidine as the major polyamine. The major polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, phosphoaminolipid and sphingoglycolipid. The main cellular fatty acids (>10 % of the total fatty acids) of strain ZLT-5 T were C 17 : 1 ω6 c , summed feature 3 (C 16 : 1 ω7 c and/or C 15 : 0 ISO 2-OH) and summed feature 8 (C 18 : 1 ω7 c and/or C 18 : 1 ω6 c ). Based on phylogenetic analysis and physiological and biochemical characterization, strain ZLT-5 T is described as a novel species of the genus Sphingomonas , for which the name Sphingomonas flavalba sp. nov. is proposed. The type strain is ZLT-5 T (=CCTCC AB 2018188 T =KCTC 62840 T ).

Background: Aberrant expression of the RON receptor tyrosine kinase is a pathogenic feature and a validated drug target in various types of cancers. Currently, therapeutic antibodies targeting RON for cancer therapy are under intensive evaluation. Here we report the development and validation of a novel humanized anti-RON antibody-drug conjugate for cancer therapy., Methods: Antibody humanization was achieved by grafting sequences of complementarity-determining regions from mouse monoclonal antibody Zt/g4 into human IgG1/κ acceptor frameworks. The selected humanized Zt/g4 subclone H1L3 was conjugated with monomethyl auristatin E using a dipeptide linker to form H-Zt/g4-MMAE. Pharmacokinetic analysis of H-Zt/g4-MMAE was determined using hydrophobic interaction chromatography and a MMAE ADC ELISA kit. Biochemical and biological assays were used for measuring RON expression, internalization, cell viability and death. Therapeutic efficacies of H-Zt/g4-MMAE were validated in vivo using three pancreatic cancer xenograft models. Toxicological activities of H-Zt/g4-MMAE were determined in mouse and cynomolgus monkey., Results: H-Zt/g4-MMAE had a drug to antibody ratio of 3.77:1 and was highly stable in human plasma with a dissociation rate less than 5% within a 20 day period. H-Zt/g4-MMAE displayed a favorable pharmacokinetic profile in both mouse and cynomolgus monkey. In vitro, H-Zt/g4-MMAE induced RON internalization, which results in killing of pancreatic cancer cells with IC 50 values at 10-20 nM. In vivo, H-Zt/g4-MMAE inhibited pancreatic cancer xenograft growth with tumoristatic concentrations at 1~3 mg/kg bodyweight. Significantly, H-Zt/g4-MMAE eradicated tumors across multiple xenograft models regardless their chemoresistant and metastatic statuses. Moreover, H-Zt/g4-MMAE inhibited and eradicated xenografts mediated by pancreatic cancer stem-like cells and by primary cells from patient-derived tumors. Toxicologically, H-Zt/g4-MMAE is well tolerated in mice up to 60 mg/kg. In cynomolgus monkey, H-Zt/g4-MMAE up to 30 mg/kg had a manageable and reversible toxicity profile., Conclusions: H-Zt/g4-MMAE is superior in eradication of pancreatic cancer xenografts with favorable pharmacokinetic profiles and manageable toxicological activities. These findings warrant the transition of H-Zt/g4-MMAE into clinical trials in the future.

A novel Gram-stain negative, facultatively anaerobic, non-spore-forming, motile and rod-shaped bacterium (NS-104 T ) was isolated from a propanil-contaminated soil in Nanjing, China. Growth occurred at pH 5.0-9.0 (optimum 6.0), 16-37 °C (optimum 30 °C) and in the presence of 0-2.0% (w/v) NaCl (optimum, without NaCl). Strain NS-104 T showed high 16S rRNA gene sequence identity to Rhizobium azooxidifex DSM 100211 T (96.7%). The phylogenetic analysis of the 16S rRNA gene as well as the housekeeping genes recA, atpD and glnA demonstrated that strain NS-104 T belongs to the genus Rhizobium. Strain NS-104 T did not form nodules on six different legumes, and the nodD, nodC and nifH genes were neither amplified by PCR nor found in the draft genome of strain NS-104 T . The sole respiratory quinone was ubiquinone Q-10. The polar lipid profile included the major amounts phosphatidylmonomethylethanolamine, phosphatidylglycerol and moderate amounts of phosphatidylethanolamine, phosphatidylcholine, diphosphatidylglycerol and unidentified aminolipids. The major cellular fatty acids were C 18:1 ω7c (39.6%), C 19:0 cyclo ω8c (29.8%) and C 16:0 (11.5%). The G + C content of strain NS-104 T was 61.9 mol%. Strain NS-104 T therefore represents a new species, for which the name Rhizobium album sp. nov. is proposed, with the type strain NS-104 T (= KCTC 62327 T  = CCTCC AB 2017250 T ).

Propanil, one of the most extensively used post-emergent contact herbicides, has also been reported to have adverse effect on environmental safety. A bacterial strain of Ochrobactrum sp. PP-2, which was capable of transforming propanil, was isolated from a propanil-contaminated soil collected from a chemical factory. An arylamidase gene mah responsible for transforming propanil to 3,4-dichloroaniline (3,4-DCA) was cloned from strain PP-2 by shotgun method and subsequently confirmed by function expression. The arylamidase Mah shares low amino acid sequence identity (27-50%) with other biochemically characterized amidases and shows less than 30% identities to other reported propanil hydrolytic enzymes. Mah was most active at pH 8 and 35 °C. Mah had a remarkable activity toward propanil (K m = 6.3 ± 1.2 µM), showing the highest affinity efficiency for propanil as compared with other reported propanil hydrolytic enzymes. Our study also provides a new arylamidase for the hydrolysis of propanil., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC) is a highly diverse group of malignant neoplasia with poor outcome. Currently, the lack of effective therapy has fostered a major effort to discover new targets to treat this malignant cancer. Here we identified the RON receptor tyrosine kinase as a therapeutic target for potential TNBC treatment. We analyzed RON expression in 168 primary TNBC samples via tissue microarray using anti-RON IHC staining and demonstrated that RON was widely expressed in 76.8% TNBC samples with overexpression in 76 cases (45.2%). These results provide the molecular basis to target RON for TNBC therapy. To this end, anti-RON monoclonal antibody Zt/g4-drug monomethyl auristatin E conjugate (Zt/g4-MMAE) was developed with a drug to antibody ratio of 3.29 and tested in a panel of TNBC cell lines with different phenotypes. In vitro , Zt/g4-MMAE rapidly induced RON internalization, resulted in cell-cycle arrest followed by massive cell death. The calculated IC 50 values ranged from 0.06 to 3.46 μg/mL dependent on individual TNBC cell lines tested. Zt/g4-MMAE also effectively killed TNBC stem-like cells with RON + /CD44 + /CD24 - phenotypes and RON-negative TNBC cells through the bystander effect. In vivo , Zt/g4-MMAE at 10 mg/kg in a Q12 × 2 regimen completely eradicated TNBC xenografts without the regrowth of xenograft tumors. In conclusion, increased RON expression is a pathogenic feature in primary TNBC samples. Zt/g4-MMAE is highly effective in eradicating TNBC xenografts in preclinical models. These findings lay the foundation for using anti-RON Zt/g4-MMAE in clinical trials as a novel strategy for TNBC treatment., (©2018 American Association for Cancer Research.)

Phenylurea herbicides (PHs) are frequently detected as major water contaminants in areas where there is extensive use. In this study, Diaphorobacter sp. strain LR2014-1, which initially hydrolyzes linuron to 3,4-dichloroanaline, and Achromobacter sp. strain ANB-1, which further mineralizes the produced aniline derivatives, were isolated from a linuron-mineralizing consortium despite being present at low abundance in the community. The synergistic catabolism of linuron by the consortium containing these two strains resulted in more efficient catabolism of linuron and growth of both strains. Strain LR2014-1 harbors two evolutionary divergent hydrolases from the amidohydrolase superfamily Phh and the amidase superfamily TccA2, which functioned complementarily in the hydrolysis of various types of PHs, including linuron ( N-methoxy- N-methyl-substituted), diuron, chlorotoluron, fluomethuron ( N, N-dimethyl-substituted), and siduron. These findings show that a bacterial consortium can contain catabolically synergistic species for PH mineralization, and one strain could harbor functionally complementary hydrolases for a broadened substrate range.

Ebolavirus (EBOV) life cycle involves interactions with numerous host factors, but it remains poorly understood, as does pathogenesis. Herein, we synthesized 65 siRNAs targeting host genes mostly connected with aspects of the negative-sense RNA virus life cycle (including viral entry, uncoating, fusion, replication, assembly, and budding). We produced EBOV transcription- and replication-competent virus-like particles (trVLPs) to mimic the EBOV life cycle. After screening host factors associated with the trVLP life cycle, we assessed interactions of host proteins with trVLP glycoprotein (GP), VP40, and RNA by co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP). The results demonstrate that RNAi silencing with 11 siRNAs (ANXA5, ARFGAP1, FLT4, GRP78, HSPA1A, HSP90AB1, HSPA8, MAPK11, MEK2, NTRK1, and YWHAZ) decreased the replication efficiency of trVLPs. Co-IP revealed nine candidate host proteins (FLT4, GRP78, HSPA1A, HSP90AB1, HSPA8, MAPK11, MEK2, NTRK1, and YWHAZ) potentially interacting with trVLP GP, and four (ANXA5, GRP78, HSPA1A, and HSP90AB1) potentially interacting with trVLP VP40. Ch-IP identified nine candidate host proteins (ANXA5, ARFGAP1, FLT4, GRP78, HSPA1A, HSP90AB1, MAPK11, MEK2, and NTRK1) interacting with trVLP RNA. This study was based on trVLP and could not replace live ebolavirus entirely; in particular, the interaction between trVLP RNA and host proteins cannot be assumed to be identical in live virus. However, the results provide valuable information for further studies and deepen our understanding of essential host factors involved in the EBOV life cycle.

Hepatitis C virus (HCV) is one of the most important virus as the cause of liver disease in China. The aim of the present study was to explore whether sofosbuvir and ribavirin-based treatment can cure patients with chronic hepatitis C in eastern China. We examined a cohort of HCV-monoinfected patients and 9 patients agreed to participate in our treatment and research. The patients were diagnosed with chronic hepatitis C with or without cirrhosis. Nine patients including 4 female and 5 male met the requirements for selection and were willing to participate in this experiment. Sofosbuvir and ribavirin-based treatment with or without interferon was given to the patients. Viral loads, cytokines, and chemokines were recorded during treatment and after treatment. After 2 weeks of sofosbuvir and ribavirin-based treatment, the viral load of patients decreased to limits of detection. Eight patients were cured. Patients had rapid virological response (RVR) with undetectable viral load at week 4 and sustained virological response (SVR). The interferon-inducible protein-10 (IP-10) decreased after the treatment. However, the patient with cirrhosis failed, as the virus reappeared during SVR4. At the same time, the IP-10 dramatically increased as the relapse of the HCV virus. In summary, the IP-10 has the potential to be the biomarker for the prognostic of HCV.

Aberrant expression of the RON receptor tyrosine kinase, a cell surface protein, is a pathogenic feature in pancreatic cancer, which renders it a drug target for targeted therapy. Nevertheless, development of therapeutics targeting RON for pancreatic cancer therapy is hampered due to the lack of full addiction by pancreatic cancer cells to RON signaling for growth and survival. Here we describe a novel strategy using anti-RON antibody-directed drug delivery in the form of an antibody-drug conjugate for inhibition and/or eradication of pancreatic cancers. Monoclonal antibody Zt/g4 specific to the RON Sema domain was selected as the drug carrier based on its ability to induce robust RON internalization. Conjugation of Zt/g4 with monomethyl auristatin E, designated as Zt/g4-MMAE, was achieved through a protease-sensitive dipeptide linker to reach a drug to antibody ratio of 3.29:1. Zt/g4-MMAE was stable in human plasma with a dissociation rate less than 4% within a 10 day period. In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulting in cell cycle arrest followed by massive cell death. The maximal effect was seen in pancreatic cancer cells with more than 10 000 receptor molecules per cell. Zt/g4-MMAE also synergized in vitro with chemotherapeutics including gemcitabine, 5-fluorouracil, and oxaliplatin to further reduce PDAC cell viability. In vivo, Zt/g4-MMAE exerts a long-lasting activity, which not only inhibited but also eradicated pancreatic xenograft tumors. These finding indicate that Zt/g4-directed drug delivery is highly effective for eradicating pancreatic tumors. Thus, Zt/g4-MMAE is a novel biotherapeutic with potential for therapy of RON-expressing pancreatic malignancies.

A novel Gram-staining-negative, non-motile and rod-shaped bacterial strain ZQBW T , which was isolated from a diuron-polluted soil collected near Nanjing, PR China, was investigated for its taxonomic position by a polyphasic approach. ZQBW T grew well at pH 6.0-12.0 (optimum, pH 7.0), 26-35 °C (optimum, 30 °C) and up to 0.5 % NaCl (optimally the absence of NaCl) in R2A broth. The major fatty acids of ZQBW T were C18 : 1ω7c (82.7 %) and C18 : 0 (5.3 %). The polar lipid profile included the major compounds phophatidylcholine, phosphatidylglycerol and phosphatidylmethylethanolamine. The only respiratory quinone was ubiquinone Q-10. The G+C content of genomic DNA was 67.0 mol%. Comparisons with 16S rRNA gene sequences revealed that ZQBW T has the highest sequence similarities with members of the genus Tabrizicola (≤95.97 %), followed by Rhodobacter(≤95.96 %) and Falsirhodobacter(95.95 %) which all belong to the family Rhodobacteraceaein the phylum Proteobacteria. Photosynthesis genes pufLM were not found and photosynthesis pigments were not formed in ZQBW T . On the basis of the results from chemotaxonomic, phenotypic and phylogenetic analysis, ZQBW T represents a novel species of a novel genus, for which the name Xinfangfangia soli gen. nov., sp. nov. is proposed. The type strain is ZQBW T (=KCTC 62102 T =CCTCC AB 2017177 T ).

Objective: To evaluate the efficacy of corneal confocal microscopy (CCM) as a non-invasive test to assess diabetic peripheral neuropathy in Chinese patients diagnosed with type 2 diabetes., Research Design and Methods: Diabetic distal symmetric polyneuropathy (DSPN) and its severity degrees were assessed based on the modified Toronto diagnostic criteria in 128 patients with type 2 diabetes (No DSPN [n = 49], mild DSPN [n = 43], moderate-to-severe DSPN [n = 36]) and 24 age-matched controls. CCM was also examined in all enrolled subjects. Corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD) and corneal nerve fiber density (CNFD) were analyzed by Fiji imaging analysis software. The efficacy of CCM as a non-invasive test to assess diabetic peripheral neuropathy was determined., Results: CNFL was 17.99 ± 0.66, 15.82 ± 0.64, 14.98 ± 0.63, and 12.49 ± 0.93 in healthy controls, T2DM patients with no, mild, and moderate-to-severe DPN, respectively. CNFL in type 2 diabetes patients with no, mild, and moderate-to-severe DSPN demonstrated a significant reduction than in healthy controls (P = .012, .003 and <.001, respectively). CNFL in patients with moderate-to-severe DSPN was significantly shorter than in patients with no or mild DSPN (P < .001 and .004, respectively). CNBD was 41.48 ± 3.35, 33.02 ± 2.50, 30.91 ± 2.33, and 18.00 ± 2.33 in healthy controls, T2DM patients with no, mild, and moderate-to-severe DPN, respectively. CNBD in healthy control was significantly higher than in type 2 diabetes patients with no, mild, and moderate-to-severe DSPN (P = .036, 0.016 and < .001, respectively). CNBD in patients with moderate-to-severe DSPN was significantly lower than in patients with no or mild DSPN (P < .001 for both). CNFD was 35.32 ± 1.18, 35.68 ± 1.10, 34.54 ± 1.12, and 32.28 ± 1.76 in healthy controls, T2DM patients with no, mild, and moderate-to-severe DPN, respectively. CNFD did not differ among the four groups. In an analysis that divided CNFL, CNFD and CNBD into quartiles, there were no significant differences in electromyography findings and vibration perception threshold among the 4 groups; however, significant differences were seen in the positive distribution of temperature perception measurements following CNFL and CNBD stratification (P = .001 and < .001, respectively)., Conclusion: CCM might be a non-invasive method for detecting DSPN and its severity degree in Chinese patients diagnosed with type 2 diabetes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The histone acetyltransferases (HATs) adenovirus E1A-associated protein (p300) and CREB binding protein (CBP) serve as coactivators during a diverse assortment of cellular processes. In the present study, p300 and CBP were highly expressed in 5 gastric cancer (GC) cell lines (SGC‑7901, MKN45, MGC-803, BGC-823 and KATO III) compared with human normal gastric epithelial cell line (GES-1). C646, a selective inhibitor of p300 and CBP, inhibited cell viability and cell cycle and promoted cell apoptosis in all 5 GC cell lines. In addition, C646 suppressed the migration and invasion capability of the GC cell lines, except for the middle-differentiated SGC-7901 cell line. Furthermore, we detected the differential expression of corresponding oncogenic signalling molecules, such as c-Met, Akt, Bcl-2, Bax, cyclin D1, MMP7 and MMP9, in GC cells following C646 treatment. In conclusion, our results suggest that C646 inhibits the acetylation of histone H3 via inactivation of p300 and CBP, resulting in antineoplastic effects toward GC cells. Thus, the selective HAT inhibitor C646 could be a promising antitumour reagent for GC treatment.

Ebola haemorrhagic fever causes deadly disease in humans and non-human primates resulting from infection with the Ebola virus (EBOV) genus of the family Filoviridae . However, the mechanisms of EBOV lifecycle in host cells, including viral entry, membrane fusion, RNP formation, GP-tetherin interaction, and VP40-inner leaflet association remain poorly understood. This review describes the biological functions of EBOV proteins and their roles in the lifecycle, summarizes the factors related to EBOV proteins or RNA expression throughout the different phases, and reviews advances with regards to the molecular events and mechanisms of the EBOV lifecycle. Furthermore, the review outlines the aspects remain unclear that urgently need to be solved in future research., Competing Interests: CONFLICTS OF INTEREST No conflicts of interests.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm featured by activated mutations of KIT and PDGFRA. Although overall survival rates have greatly improved by the development of receptor tyrosine kinase inhibitors, most patients ultimately acquire resistance due to secondary mutations of KIT or PDGFRA. Inhibition of the histone acetyltransferases (HATs) CREB‑binding protein (CBP) and p300 results in antineoplastic effects in various cancers. To determine whether CBP/p300 can serve as an antineoplastic target for GISTs, specific short interfering RNA sequences and the selective HAT inhibitor C646 were administered to GIST882 cells. Cell viability, apoptosis and the cell cycle were analysed using the Cell Counting Kit-8, a caspase-3/7 activity assay or Annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining and PI staining. Gene and protein expression levels were measured by quantitative real-time polymerase chain reaction and western blotting, respectively. Transcriptional blockage of CBP, rather than p300, resulted in suppression of cell proliferation. Interestingly, both CBP and p300 depletion enhanced caspase-3/7 activity. A lack of CBP and p300 caused ETS translocation variant 1 (ETV1) downregulation and KIT inhibition in GIST cells. Nevertheless, the absence of CBP, not p300, leads to extracellular signal-regulated kinase 1/2 inactivation and c-Jun NH2-terminal kinase activation, suggesting a more crucial role for CBP than p300 in cell proliferation and survival. Furthermore, proliferation of GIST cells was reduced by administration of C646, a selective HAT inhibitor for CBP/p300. Apoptosis induction and cell cycle arrest were detected after exposure to C646, indicating that its antitumor activities were supported by its antiproliferative and proapoptotic effects. Additionally, C646 treatment attenuated ETV1 protein expression and inactivated KIT-dependent pathways. Taken together, the present study suggests that CBP/p300 may serve as novel antineoplastic targets and that use of the selective HAT inhibitor C646 is a promising antitumor strategy for GISTs.