EGFR/EGFRvIII-targeted immunotoxin therapy for the treatment of glioblastomas via convection-enhanced delivery

Glioblastoma is the most aggressive malignant brain tumor among all primary brain and central nervous system tumors. The median survival time for glioblastoma patients given the current standard of care treatment (surgery, radiation, and chemotherapy) is less than 15 months. Thus, there is an urgent need to develop more efficient therapeutics to improve the poor survival rates of patients with glioblastoma. To address this need, we have developed a novel tumor-targeted immunotoxin (IT), D2C7-(scdsFv)-PE38KDEL (D2C7-IT), by fusing the single chain variable fragment (scFv) from the D2C7 monoclonal antibody (mAb) with the Pseudomonas Exotoxin (PE38KDEL). D2C7-IT reacts with both the wild-type epidermal growth factor receptor (EGFRwt) and EGFR variant III (EGFRvIII), two onco-proteins frequently amplified or overexpressed in glioblastomas. Surface plasmon resonance and flow cytometry analyses demonstrated a significant binding capacity of D2C7-IT to both EGFRwt and EGFRvIII proteins. In vitro cytotoxicity data showed that D2C7-IT can effectively inhibit protein synthesis and kill a variety of EGFRwt-, EGFRvIII-, and both EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells and human tumor cell lines. Furthermore, D2C7-IT exhibited a robust anti-tumor efficacy in orthotopic mouse glioma models when administered via intracerebral convection-enhanced delivery (CED). A preclinical toxicity study was therefore conducted to determine the maximum tolerated dose (MTD) and no-observed-adverse-effect-level (NOAEL) of D2C7-IT via intracerebral CED for 72 hours in rats. Based on this successful rat toxicity study, an Investigational New Drug (IND) application (#116855) was approved by the Food and Drug Administration (FDA), and is now in effect for a Phase I/II D2C7-IT clinical trial (D2C7 for Adult Patients with Recurrent Malignant Glioma, https://clinicaltrials.gov/ct2/show/NCT02303678). While it is still too early to draw conclusions from the trial, results thus far are promising

Toxin-Based Targeted Therapy for Malignant Brain Tumors

Despite advances in conventional treatment modalities for malignant brain tumors—surgery, radiotherapy, and chemotherapy—the prognosis for patients with high-grade astrocytic tumor remains dismal. The highly heterogeneous and diffuse nature of astrocytic tumors calls for the development of novel therapies. Advances in genomic and proteomic research indicate that treatment of brain tumor patients can be increasingly personalized according to the characteristics of the targeted tumor and its environment. Consequently, during the last two decades, a novel class of investigative drug candidates for the treatment of central nervous system neoplasia has emerged: recombinant fusion protein conjugates armed with cytotoxic agents targeting tumor-specific antigens. The clinical applicability of the tumor-antigen-directed cytotoxic proteins as a safe and viable therapy for brain tumors is being investigated. Thus far, results from ongoing clinical trials are encouraging, as disease stabilization and patient survival prolongation have been observed in at least 109 cases. This paper summarizes the major findings pertaining to treatment with the different antiglioma cytotoxins at the preclinical and clinical stages

ISOLATION AND CHARACTERIZATION OF SULPHUR OXIDIZING BACTERIA

Sulphur oxidizing bacteria were isolated from different samples viz., paddy rhizosphere, pulse rhizosphere, sewage, biogas slurry, tannery effluent and mine soil. Out of the 28 isolates obtained, 14 were screened based on their efficacy to reduce the pH of the growth medium from 8.0 to 64 5.0. The selected isolates were characterized and related to the genus Thiobacillus

COMPARISON OF ETEST AND AGAR DILUTION FOR DETERMINING MINIMUM INHIBITORY CONCENTRATION OF VANCOMYCIN TO HEALTHCARE-ASSOCIATED METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS

ABSTRACTObjectives: To compare agar dilution method and Etest in the determination of minimum inhibitory concentration (MIC) of vancomycin to healthcareassociatedmethicillin-resistantStaphylococcusaureus(HA-MRSA).Methods: A total of 98 non-duplicate strains of HA-MRSA isolated from different clinical specimens were tested for their antibiotic susceptibilitypattern by Kirby-Bauer disk diffusion method and vancomycin MIC by agar dilution method and Etest (BioMerieux, France).Results: Out of 98 strains of HA-MRSA, 94 (95.9%) were vancomycin susceptible (MIC ≤2 µg/ml and 4 (4.1%) were vancomycin intermediate (MIC4 µg/ml) by agar dilution method. By Etest, 53 (54.1%) were vancomycin susceptible, 4 (4.1%) were vancomycin intermediate, and the remaining 41isolates had vancomycin MIC between 2 µg/ml and 4 µg/ml.Conclusion: Etest allows the detection of HA-MRSA strains with intermediate MIC values in addition to traditional dilutions. These properties willhelp in detection of MIC creep and also decision-making in using vancomycin for the treatment of serious infections caused by HA-MRSA.Keyword: Vancomycin, Minimum inhibitory concentration, Etest, Agar dilution

Prognostic Role of Epithelial Mesenchymal Transition Transcription Factors in Carcinoma- A Systematic Review and Meta-Analysis

Background: We conducted the present meta-analysis to delineate the prognostic significance of epithelial to mesenchymal transition- transcription factors in carcinoma patients. Method: For the determination of the pooled hazard ratio (HR) values based on the fixed- effects model, in this retrospective study, we employed comprehensive meta-analysis software. Results: This retrospective analysis identified the expression patterns of 6645 patients in 36 studies. Expression of TWIST1 correlated with the least prognosis rate (HR= 2.129, 95% CI= 1.373 - 3.302) as compared to SNAIL1 (HR= 1.804, 95% CI= 1.151 - 2.827), SLUG (HR= 1.724, 95% CI= 0.992 - 2.997) and ZEB1 (HR= 1.590, 95% CI= 1.358 - 1.861). Conclusion: These findings suggested the implication of TWIST1 as an effective biomarker for an early tumor diagnosis and therapy for metastasis

Comparative genomics of the pathogenic ciliate Ichthyophthirius multifiliis, its free-living relatives and a host species provide insights into adoption of a parasitic lifestyle and prospects for disease control

Background: Ichthyophthirius multifiliis, commonly known as Ich, is a highly pathogenic ciliate responsible for ‘white spot’, a disease causing significant economic losses to the global aquaculture industry. Options for disease control are extremely limited, and Ich’s obligate parasitic lifestyle makes experimental studies challenging. Unlike most well-studied protozoan parasites, Ich belongs to a phylum composed primarily of free-living members. Indeed, it is closely related to the model organism Tetrahymena thermophila. Genomic studies represent a promising strategy to reduce the impact of this disease and to understand the evolutionary transition to parasitism. Results: We report the sequencing, assembly and annotation of the Ich macronuclear genome. Compared with its free-living relative T. thermophila, the Ich genome is reduced approximately two-fold in length and gene density and three-fold in gene content. We analyzed in detail several gene classes with diverse functions in behavior, cellular function and host immunogenicity, including protein kinases, membrane transporters, proteases, surface antigens and cytoskeletal components and regulators. We also mapped by orthology Ich’s metabolic pathways in comparison with other ciliates and a potential host organism, the zebrafish Danio rerio. Conclusions: Knowledge of the complete protein-coding and metabolic potential of Ich opens avenues for rational testing of therapeutic drugs that target functions essential to this parasite but not to its fish hosts. Also, a catalog of surface protein-encoding genes will facilitate development of more effective vaccines. The potential to use T. thermophila as a surrogate model offers promise toward controlling ‘white spot’ disease and understanding the adaptation to a parasitic lifestyle