Finafloxacin is an effective treatment for inhalational tularemia and plague in mouse models of infection

Infection with aerosolised Francisella tularensis or Yersinia pestis can lead to lethal disease in humans, if treatment is not initiated promptly. Finafloxacin is a novel fluoroquinolone which has demonstrated broad-spectrum activity against a range of bacterial species in vitro, in vivo and in humans, activity which is superior in acidic, infection-relevant conditions. Human equivalent doses of finafloxacin or ciprofloxacin were delivered at 24 hours (representing prophylaxis), or at 72 or 38 hours (representing treatment) post-challenge with F. tularensis or Y. pestis (respectively), in Balb/c mouse models. In addition, a short course (3 days) of therapy was compared to a longer course (7 days). Both therapies provided a high level of protection against both infections, when administered at 24 hours post-challenge, irrespective of the length of the dosing regimen, however, differences were observed when therapy was delayed. A benefit was demonstrated with finafloxacin, when compared to ciprofloxacin in both models, when therapy was delivered later in the infection. These studies suggest that finafloxacin is an effective alternative therapeutic for the prophylaxis and treatment of inhalational infections with F. tularensis or Y. pestis.

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Defective viral genomes from chikungunya virus are broad-spectrum antivirals and prevent virus dissemination in mosquitoes

PLoS Pathogens ◽

10.1371/journal.ppat.1009110 ◽

2021 ◽

Vol 17 (2) ◽

pp. e1009110

Author(s):

Laura I. Levi ◽

Veronica V. Rezelj ◽

Annabelle Henrion-Lacritick ◽

Diana Erazo ◽

J Boussier ◽

...

Keyword(s):

Aedes Aegypti ◽

Broad Spectrum ◽

Chikungunya Virus ◽

Rna Virus ◽

Viral Genomes ◽

Mosquito Cells ◽

Spectrum Activity ◽

Broad Spectrum Activity

Defective viral genomes (DVGs) are truncated and/or rearranged viral genomes produced during virus replication. Described in many RNA virus families, some of them have interfering activity on their parental virus and/or strong immunostimulatory potential, and are being considered in antiviral approaches. Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes spp. that infected millions of humans in the last 15 years. Here, we describe the DVGs arising during CHIKV infection in vitro in mammalian and mosquito cells, and in vivo in experimentally infected Aedes aegypti mosquitoes. We combined experimental and computational approaches to select DVG candidates most likely to have inhibitory activity and showed that, indeed, they strongly interfere with CHIKV replication both in mammalian and mosquito cells. We further demonstrated that some DVGs present broad-spectrum activity, inhibiting several CHIKV strains and other alphaviruses. Finally, we showed that pre-treating Aedes aegypti with DVGs prevented viral dissemination in vivo.

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A molecularly engineered antiviral banana lectin inhibits fusion and is efficacious against influenza virus infection in vivo

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1915152117 ◽

2020 ◽

Vol 117 (4) ◽

pp. 2122-2132 ◽

Cited By ~ 7

Author(s):

Evelyn M. Covés-Datson ◽

Steven R. King ◽

Maureen Legendre ◽

Auroni Gupta ◽

Susana M. Chan ◽

...

Keyword(s):

Influenza Virus ◽

Broad Spectrum ◽

Parent Compound ◽

Influenza Virus Infection ◽

Amino Acid Mutation ◽

Spectrum Activity ◽

Therapeutic Administration ◽

Broad Spectrum Activity

There is a strong need for a new broad-spectrum antiinfluenza therapeutic, as vaccination and existing treatments are only moderately effective. We previously engineered a lectin, H84T banana lectin (H84T), to retain broad-spectrum activity against multiple influenza strains, including pandemic and avian, while largely eliminating the potentially harmful mitogenicity of the parent compound. The amino acid mutation at position 84 from histidine to threonine minimizes the mitogenicity of the wild-type lectin while maintaining antiinfluenza activity in vitro. We now report that in a lethal mouse model H84T is indeed nonmitogenic, and both early and delayed therapeutic administration of H84T intraperitoneally are highly protective, as is H84T administered subcutaneously. Mechanistically, attachment, which we anticipated to be inhibited by H84T, was only somewhat decreased by the lectin. Instead, H84T is internalized into the late endosomal/lysosomal compartment and inhibits virus–endosome fusion. These studies reveal that H84T is efficacious against influenza virus in vivo, and that the loss of mitogenicity seen previously in tissue culture is also seen in vivo, underscoring the potential utility of H84T as a broad-spectrum antiinfluenza agent.

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Use of ribotyping in epidemiological surveillance of nosocomial outbreaks.

Clinical Microbiology Reviews ◽

10.1128/cmr.7.3.311 ◽

1994 ◽

Vol 7 (3) ◽

pp. 311-327 ◽

Cited By ~ 75

Author(s):

E H Bingen ◽

E Denamur ◽

J Elion

Keyword(s):

Bacterial Species ◽

Epidemiological Surveillance ◽

Clinical Microbiology Laboratory ◽

Pseudomonas Cepacia ◽

Strain Differentiation ◽

Species Specific ◽

Simple Technology ◽

High Level

Over the past few years, genotypic methods based on the study of bacterial DNA polymorphism have shown high discriminatory power for strain differentiation and superiority over most phenotypic methods commonly available in the clinical microbiology laboratory. Some of the methods used, however, required either a high level of technology and sophisticated equipment (e.g., pulsed-field gel electrophoresis) or species-specific reagents of restricted availability (randomly cloned DNA probes or gene-specific probes). Because ribotyping uses a universal probe (rRNA) and is a rather simple technology, particularly since the advent of nonradioactive labelling systems, it has been widely used for strain differentiation of most bacterial species involved in nosocomial outbreaks. In vitro and in vivo stability of the markers studied has been demonstrated. Although there may be limitation to this approach, ribotyping was found to be highly discriminative, particularly for typing members of the family Enterobacteriaceae, Pseudomonas cepacia, and Xanthomonas maltophilia. In many cases, it has improved the understanding of the mechanism of nosocomial acquisition of organisms by allowing a distinction between endogenous and exogenous infections. Among exogenous infections, it has distinguished between individual and epidemic strains, thus differentiating cross-infection from independent acquisition.

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In Vitro Activities of Caspofungin Compared with Those of Fluconazole and Itraconazole against 3,959 Clinical Isolates of Candida spp., Including 157 Fluconazole-Resistant Isolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.3.1068-1071.2003 ◽

2003 ◽

Vol 47 (3) ◽

pp. 1068-1071 ◽

Cited By ~ 103

Author(s):

M. A. Pfaller ◽

D. J. Diekema ◽

S. A. Messer ◽

R. J. Hollis ◽

R. N. Jones

Keyword(s):

Antifungal Drugs ◽

Broth Microdilution ◽

Candida Spp ◽

Medical Centers ◽

Spectrum Activity ◽

Fluconazole Resistant ◽

High Level ◽

Level Resistance ◽

Broad Spectrum Activity

ABSTRACT Caspofungin is an echinocandin antifungal agent with broad-spectrum activity against Candida and Aspergillus spp. The in vitro activities of caspofungin against 3,959 isolates of Candida spp. obtained from over 95 different medical centers worldwide were compared with those of fluconazole and itraconazole. The MICs of the antifungal drugs were determined by broth microdilution tests performed according to the NCCLS method using RPMI 1640 as the test medium. Caspofungin was very active against Candida spp. (MIC at which 90% of the isolates were inhibited [MIC90], 1 μg/ml; 96% of MICs were ≤2 μg/ml). Candida albicans, C. dubliniensis, C. tropicalis, and C. glabrata were the most susceptible species of Candida (MIC90, 0.25 to 0.5 μg/ml), and C. guilliermondii was the least susceptible (MIC90, >8 μg/ml). Caspofungin was very active against Candida spp., exhibiting high-level resistance to fluconazole and itraconazole (99% of MICs were ≤1 μg/ml). These results provide further evidence for the spectrum and potency of caspofungin activity against a large and geographically diverse collection of clinically important isolates of Candida spp.

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Production of Novel Bioactive Compounds by the Bacteria Associated with Some Marine Sponges of Gulf of Mannar and Palk Bay, Southeast Coast of India

International Journal of Emerging Research in Management and Technology ◽

10.23956/ijermt.v6i8.136 ◽

2018 ◽

Vol 6 (8) ◽

pp. 183

Author(s):

V. Ramadas ◽

G. Chandralega

Keyword(s):

Bioactive Compounds ◽

Bacterial Species ◽

Marine Sponges ◽

Marine Organisms ◽

Gulf Of Mannar ◽

Bacterial Symbionts ◽

Palk Bay ◽

Excellent Source

Sponges, exclusively are aquatic and mostly marine, are found from the deepest oceans to the edge of the sea. There are approximately 15,000 species of sponges in the world, of which, 150 occur in freshwater, but only about 17 are of commercial value. A total of 486 species of sponges have been identified in India. In the Gulf of Mannar and Palk Bay a maximum of 319 species of sponges have been recorded. It has been proved that marine organisms are excellent source of bioactive secondary metabolites and number of compounds of originated from marine organisms had been reported to possess in-vitro and in-vivo immuno stimulatory activity. Extracts from 20 sponge species were tested for bacterial symbionts and bioactive compounds were isolated from such associated bacterial species in the present study.

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Aberrantly high activation of a FoxM1–STMN1 axis contributes to progression and tumorigenesis in FoxM1-driven cancers

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00396-0 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Jun Liu ◽

Jipeng Li ◽

Ke Wang ◽

Haiming Liu ◽

Jianyong Sun ◽

...

Keyword(s):

Cell Proliferation ◽

Poor Prognosis ◽

Soft Agar ◽

Transcriptional Level ◽

Regulation Mechanism ◽

Strong Positive Correlation ◽

Cell Viability Assay ◽

High Level

AbstractFork-head box protein M1 (FoxM1) is a transcriptional factor which plays critical roles in cancer development and progression. However, the general regulatory mechanism of FoxM1 is still limited. STMN1 is a microtubule-binding protein which can inhibit the assembly of microtubule dimer or promote depolymerization of microtubules. It was reported as a major responsive factor of paclitaxel resistance for clinical chemotherapy of tumor patients. But the function of abnormally high level of STMN1 and its regulation mechanism in cancer cells remain unclear. In this study, we used public database and tissue microarrays to analyze the expression pattern of FoxM1 and STMN1 and found a strong positive correlation between FoxM1 and STMN1 in multiple types of cancer. Lentivirus-mediated FoxM1/STMN1-knockdown cell lines were established to study the function of FoxM1/STMN1 by performing cell viability assay, plate clone formation assay, soft agar assay in vitro and xenograft mouse model in vivo. Our results showed that FoxM1 promotes cell proliferation by upregulating STMN1. Further ChIP assay showed that FoxM1 upregulates STMN1 in a transcriptional level. Prognostic analysis showed that a high level of FoxM1 and STMN1 is related to poor prognosis in solid tumors. Moreover, a high co-expression of FoxM1 and STMN1 has a more significant correlation with poor prognosis. Our findings suggest that a general FoxM1-STMN1 axis contributes to cell proliferation and tumorigenesis in hepatocellular carcinoma, gastric cancer and colorectal cancer. The combination of FoxM1 and STMN1 can be a more precise biomarker for prognostic prediction.

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627 The DLL3-targeted half-life extended bispecific T cell engager (HLE BiTE®) immune-oncology therapy AMG 757 has potent antitumor activity in neuroendocrine cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0627 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A663-A663

Author(s):

Keegan Cooke ◽

Juan Estrada ◽

Jinghui Zhan ◽

Jonathan Werner ◽

Fei Lee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Growth ◽

Mouse Models ◽

T Cell Activation ◽

Phase 1 ◽

Phase 1 Study ◽

Human T Cells

BackgroundNeuroendocrine tumors (NET), including small cell lung cancer (SCLC), have poor prognosis and limited therapeutic options. AMG 757 is an HLE BiTE® immune therapy designed to redirect T cell cytotoxicity to NET cells by binding to Delta-like ligand 3 (DLL3) expressed on the tumor cell surface and CD3 on T cells.MethodsWe evaluated activity of AMG 757 in NET cells in vitro and in mouse models of neuroendocrine cancer in vivo. In vitro, co-cultures of NET cells and human T cells were treated with AMG 757 in a concentration range and T cell activation, cytokine production, and tumor cell killing were assessed. In vivo, AMG 757 antitumor efficacy was evaluated in xenograft NET and in orthotopic models designed to mimic primary and metastatic SCLC lesions. NSG mice bearing established NET were administered human T cells and then treated once weekly with AMG 757 or control HLE BiTE molecule; tumor growth inhibition was assessed. Pharmacodynamic effects of AMG 757 in tumors were also evaluated in SCLC models following a single administration of human T cells and AMG 757 or control HLE BiTE molecule.ResultsAMG 757 induced T cell activation, cytokine production, and potent T cell redirected killing of DLL3-expressing SCLC, neuroendocrine prostate cancer, and other DLL3-expressing NET cell lines in vitro. AMG 757-mediated redirected lysis was specific for DLL3-expressing cells. In patient-derived xenograft and orthotopic models of SCLC, single-dose AMG 757 effectively engaged human T cells administered systemically, leading to a significant increase in the number of human CD4+ and CD8+ T cells in primary and metastatic tumor lesions. Weekly administration of AMG 757 induced significant tumor growth inhibition of SCLC (figure 1) and other NET, including complete regression of established tumors and clearance of metastatic lesions. These findings warranted evaluation of AMG 757 (NCT03319940); the phase 1 study includes dose exploration (monotherapy and in combination with pembrolizumab) and dose expansion (monotherapy) in patients with SCLC (figure 2). A study of AMG 757 in patients with neuroendocrine prostate cancer is under development based on emerging data from the ongoing phase 1 study.Abstract 627 Figure 1AMG 757 Significantly reduced tumor growth in orthotopic SCLC mouse modelsAbstract 627 Figure 2AMG 757 Phase 1 study designConclusionsAMG 757 engages and activates T cells to kill DLL3-expressing SCLC and other NET cells in vitro and induces significant antitumor activity against established xenograft tumors in mouse models. These preclinical data support evaluation of AMG 757 in clinical studies of patients with NET.Ethics ApprovalAll in vivo work was conducted under IACUC-approved protocol #2009-00046.

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MiR-211 determines brain metastasis specificity through SOX11/NGN2 axis in triple-negative breast cancer

Oncogene ◽

10.1038/s41388-021-01654-3 ◽

2021 ◽

Author(s):

Jhih-Kai Pan ◽

Cheng-Han Lin ◽

Yao-Lung Kuo ◽

Luo-Ping Ger ◽

Hui-Chuan Cheng ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Survival Outcomes ◽

Poor Survival ◽

Breast Cancer Brain Metastasis ◽

High Level

AbstractBrian metastasis, which is diagnosed in 30% of triple-negative breast cancer (TNBC) patients with metastasis, causes poor survival outcomes. Growing evidence has characterized miRNAs involving in breast cancer brain metastasis; however, currently, there is a lack of prognostic plasma-based indicator for brain metastasis. In this study, high level of miR-211 can act as brain metastatic prognostic marker in vivo. High miR-211 drives early and specific brain colonization through enhancing trans-blood–brain barrier (BBB) migration, BBB adherence, and stemness properties of tumor cells and causes poor survival in vivo. SOX11 and NGN2 are the downstream targets of miR-211 and negatively regulate miR-211-mediated TNBC brain metastasis in vitro and in vivo. Most importantly, high miR-211 is correlated with poor survival and brain metastasis in TNBC patients. Our findings suggest that miR-211 may be used as an indicator for TNBC brain metastasis.

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Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains

Science Advances ◽

10.1126/sciadv.aau8857 ◽

2019 ◽

Vol 5 (5) ◽

pp. eaau8857 ◽

Cited By ~ 30

Author(s):

M. Di Rienzo ◽

M. Antonioli ◽

C. Fusco ◽

Y. Liu ◽

M. Mari ◽

...

Keyword(s):

Mouse Models ◽

Muscle Atrophy ◽

Ubiquitin Ligase ◽

Muscle Dystrophy ◽

Polyubiquitin Chains ◽

Autophagy Induction ◽

Atrophic Muscle ◽

Autophagic Activity

Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32’s ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.

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Experimental Models for Studying HPV-Positive and HPV-Negative Penile Cancer: New Tools for An Old Disease

Cancers ◽

10.3390/cancers13030460 ◽

2021 ◽

Vol 13 (3) ◽

pp. 460

Author(s):

Beatriz Medeiros-Fonseca ◽

Antonio Cubilla ◽

Haissa Brito ◽

Tânia Martins ◽

Rui Medeiros ◽

...

Keyword(s):

Mouse Models ◽

Cell Lines ◽

Penile Cancer ◽

Hpv Infection ◽

Experimental Models ◽

In Vivo Models ◽

Recent Developments ◽

Key Aspects

Penile cancer is an uncommon malignancy that occurs most frequently in developing countries. Two pathways for penile carcinogenesis are currently recognized: one driven by human papillomavirus (HPV) infection and another HPV-independent route, associated with chronic inflammation. Progress on the clinical management of this disease has been slow, partly due to the lack of preclinical models for translational research. However, exciting recent developments are changing this landscape, with new in vitro and in vivo models becoming available. These include mouse models for HPV+ and HPV− penile cancer and multiple cell lines representing HPV− lesions. The present review addresses these new advances, summarizing available models, comparing their characteristics and potential uses and discussing areas that require further improvement. Recent breakthroughs achieved using these models are also discussed, particularly those developments pertaining to HPV-driven cancer. Two key aspects that still require improvement are the establishment of cell lines that can represent HPV+ penile carcinomas and the development of mouse models to study metastatic disease. Overall, the growing array of in vitro and in vivo models for penile cancer provides new and useful tools for researchers in the field and is expected to accelerate pre-clinical research on this disease.

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