Search

The authors have withdrawn their manuscript owing to massive revision and data validation. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Medulloblastoma is the most common malignant brain tumor in children. It has WNT-driven, SHH-driven/TP53 mutant, SHH-driven/TP53 wildtype, and non-WNT/non-SHH subgroups. MAGMAS (Mitochondrial Associated Granulocyte Macrophage colony-stimulating factor Signaling molecules) encodes a mitochondrial import inner membrane translocase subunit and is responsible for the translocation of matrix proteins across the inner membrane. We previously reported that a small molecule MAGMAS inhibitor, BT9, decreases cell proliferation, migration, and oxidative phosphorylation in adult glioblastoma cell lines. The aim of our study was to investigate whether the chemotherapeutic effect of BT9 can be extended to pediatric medulloblastoma.MethodsDAOY (SHH driven/tp53 mutant) and D425 (non-SHH group 3) were treated with BT9. For in vitro analysis, cell proliferation, death, migration, invasion, and metabolic activity were assessed using MTT assay, TUNEL staining, scratch wound assay, Matrigel invasion chambers, and seahorse assay, respectively. A D425 orthotopic xenograft mouse model was used to evaluate BT9 efficacy in vivo.ResultsBT9 treatment resulted in a significant decrease in cell proliferation (DAOY, 24 hours IC50: 3.6 μM, 48 hours IC50: 2.3 μM, 72 hours IC50: 2.1 μM; D425 24 hours IC50: 3.4 μM, 48 hours IC50: 2.2 μM, 72 hours IC50: 2.1 μM) and a significant increase in cell death (DAOY, 24 hours p = 0.0004, 48 hours p

In continuation of our previous efforts for the development of potent small molecules against brain cancer, herein we synthesized seventeen new compounds and tested their anti-gliomapotential against established glioblastoma cell lines, namely, D54MG, U251, and LN-229 as well as patient derived cell lines (DB70 and DB93). Among them, the carboxamide derivatives, BT-851 and BT-892 were found to be the most active leads in comparison to our established hit compound BT#9.The SAR studies of our hit BT#9 compound resulted in the development of two new lead compounds by hit to lead strategy. The detailed biological studies are currently underway. The active compounds could possibly act as template for the future development of newer anti-glioma agents.

Abstract: BACKGROUND: Brain tumors are the second most common type of pediatric cancer and are the leading cause of all cancer-related deaths in children. Medulloblastoma (MB) is the most common type of malignant pediatric brain tumor and has a five-year overall survival ranging from 40-75%, depending on the patient’s age and other prognostic features. There are current anti-cancer therapies against medulloblastoma, but the treatment of recurrent disease remains a challenge. Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) overexpression has been reported in multiple types of metabolically active tissue and cancer cells, including prostate cancer, pituitary adenoma, and glioma. Limited data suggest that specific subgroups of medulloblastoma may also overexpress Magmas. This study aims to examine whether Magmas inhibition by compound “BT#9” could be beneficial for the treatment of medulloblastoma. METHODS: We studied the ability of a Magmas inhibitor (BT#9) as a therapeutic agent in stable medulloblastoma cell lines (DAOY and D283) and patient-derived primary cultures with MTT assays, migration assays, and invasion assays. RESULTS: Similar to the adult GBM studies, Magmas inhibition by BT9 had significant cytotoxic effects, causing both decreased cell proliferation and blocked cell migration in medulloblastoma cell lines DAOY and D283. IC50s determined for each during different time points demonstrated an average range of less than 3μM compared to the average range seen in adult glioblastoma cell cultures (< 10 μM). These findings suggest that the inhibition of Magmas warrants further investigation as a potential therapeutic target to optimize clinical outcomes in medulloblastoma. Our future studies will include the determination of IC50s for primary cell cultures and in vitro testing with patient-derived xenograft models.

Abstract: Glioblastoma (WHO Grade IV glioma) is the most aggressive brain cancer. The current standard of care treatment includes surgery, radiation, and chemotherapy. Tumor recurrence is almost inevitable as less than 50% of patients survive more than two years. The low survival rate poses a dire need to develop an effective therapy for GBM patients. GBM cells are resistant to treatment, as they activate their DNA damage response mechanisms to overcome the effects of radiation and temozolomide (TMZ) treatments. Recurrent tumors can arise from slow cycling and self-renewing stem/tumor-initiating cells resistant to radiation and TMZ. No second-line therapy was proven to prolong survival after TMZ failure. Magmas (Mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a subunit of the TIM23 complex regulating precursor protein trafficking into the mitochondrial matrix. Magmas is encoded by pam16, known to be upregulated in human pituitary adenomas, prostate cancer and GBM. Previous studies have demonstrated that Magmas negatively regulates the stimulatory activity of Pam18, which in turn stimulates the ATPase activity of mitochondrial heat shock protein 70 (mtHsp70). No small molecules targeting Magmas are in clinical use. We developed a novel small molecule inhibitor (BT9) that has been specifically designed to inhibit Magmas binding to Pam18. BT9 induces apoptosis through cleavage of caspase-3, reduced mitochondrial respiration and glycolysis. Our recent findings also demonstrate that BT9 treatment reduced protein trafficking of Lon protease into the mitochondrial matrix. Pretreatment of glioma cells with BT9 sensitizes cells to radiation treatment and enhances the TMZ activity. BT9 can cross the blood-brain-barrier and improve survival in intracranial glioma PDX models. BT9 has potential therapeutic value by directly dysregulating mitochondrial function in GBM, enhancing radiation and chemotherapy response, and improving survival in a relevant animal model.

Abstract Glioblastoma (GBM), a WHO grade IV brain cancer, exhibits strong treatment resistance and a high rate of reoccurrence, which gives it a dismal prognosis, a 5% survival rate in the first 5 years. LonP1, a mitochondrial master regulator, can drive metabolic transformation, cytokine production, EMT, and treatment resistance in various cancer types, but its role in GBM remains unexplored. Our research group has previously shown that LonP1 is overexpressed in human malignant gliomas, particularly glioblastoma, and that this is associated with disease prognosis. Here, we present findings that demonstrate that LonP1 seems to drive enhanced tumor progression, invasiveness, angiogenesis in different high grade glioblastomas based on TCGA-subtype. Furthermore, in collaboration with Professor Bhaskar Das, we have validated a lead compound, BT317, with on-target inhibition of LonP1 protease activity. BT317 has enhanced activity against glioma stem cell lines (GSC) and has demonstrated low toxicity and efficacy in an intracranial xenograft model. This preliminary data highlights the potential of using combinatorial, pharmacological LonP1 and proteasome inhibition as a novel strategy for targeting specific subtypes of GBM.

Background: Environmental soil contamination is a serious problem for humans worldwide, as it causes many diseases. Methods: The present study focuses on utilizing biosurfactants produced by Pseudomonas stutzeri (P. stutzeri) NA3 and Bacillus cereus (B. cereus) EN6, as an electrolyte for removing chromium (Cr) from contaminated soil using the electrokinetic (EK) process. Results: As a result, biosurfactants produced by P. stutzeri NA3 and B. cereus EN6, being lipopeptides, increase heavy metal mobility in the EK process. The Cr removal efficiency of a novel electrolyte (biosurfactants) in the EK process was compared with that of NA3 and EN6 biosurfactants. The EK results revealed a maximum Cr removal of 75 and 70% by NA3 and EN6, respectively, at the end of 7 days. Discussion: The biosurfactant aids in the breaking down of the heavy metals that are present deeper into the soil matrix. From the metagenomics analysis, it was identified that biosurfactant changes the microbial community with an enhanced ability to remove heavy metals. The phytotoxicity assay confirms that NA3 biosurfactant solution showed 95% seed germination and can lower hazardous pollutants in the soil. Conclusion: The application of biosurfactants as a potent electrolyte for the remediation of hazardous pollutants is an integrated process. Overall, the results of this study suggest that biosurfactants can serve as an economic and efficient electrolyte in the EK process to remove Cr from polluted soil. [ABSTRACT FROM AUTHOR]

This study investigates the efficacy of newly synthesized inhibitor with a dual function of corrosion inhibition and biocide for control of microbial influenced corrosion (MIC) in carbon steel API 5LX in the cooling tower water (CTW) environment. Four types of N-substituted tetrabromophthalic inhibitor (N-TBI) were synthesized, and the structural characterization was performed via proton nuclear magnetic resonance spectroscopy, thermogravimetric analysis and high-resolution mass spectrometry. These studies revealed the distinctive optical, thermal, and dielectric properties of the synthesized inhibitors. The corrosion inhibition efficiency has been evaluated by the weight loss (WL) analysis and electrochemical measurements (ECM) and biofilm assay. Biofilm assays and WL showed that inhibitor II exhibited the highest inhibition efficiency 74% and 79% respectively than others. Further ECM showed that the higher charge transfer resistance and the lower corrosion current, suggesting a protective film formed on the metal surface which was due to the adsorption of the N-TBI. Fourier transform infrared spectroscopy confirmed the adsorption of the N-TBI as C–O stretching and C–H bending with the Fe complex. X-ray diffractometer revealed that the presence of inhibitors in the corrosion product (Fe3O4, Fe2O3, FeH2O2, FeS) were highly reduced than the control system. Overall, this study highlighted the potential application of N-TBI with dual function of corrosion inhibition and biocide to control the MIC for carbon steel API 5LX used in the CTW environment. [ABSTRACT FROM AUTHOR]

Carbapenem-resistant Escherichia coli pose a significant threat to global public health due to the dearth of available treatment options, resulting in infections with high mortality and morbidity. The study aimed to investigate the mechanism of carbapenem resistance in a carbapenem non-susceptible E. coli isolate recovered from an urinary tract infection patient admitted to a tertiary referral hospital, through whole-genome sequencing using Illumina NovaSeq 6000 platform. Carbapenemase production followed by antibiotic susceptibility testing were performed following Clinical Laboratory Standard Institute guidelines. Polymerase chain reaction targeting carbapenemase genes was performed followed by an investigation of horizontal transferability. The Center for Genomic Epidemiology database was used to analyze the sequenced data. ST2519 E. coli BJD_EC1808 with a genome size of 5.8 Mb harbored Col440I plasmid and a chromosomally located blaOXA-116 gene with an IS18 element upstream, along with multiple antibiotic resistance genes conferring clinical resistance toward beta-lactams, aminoglycosides, amphenicols, sulfonamides, tetracyclines, trimethoprim, rifampin, macrolide, and streptogramin antibiotics and antiseptics. E. coli ST2519 harboring blaOXA-116 associated with a mobile genetic element exhibiting carbapenem resistance is a public health threat due to its limiting effect on the therapeutic usage of carbapenem and their dissemination into carbapenem non-susceptible phenotypes will contribute to carbapenem resistance burden and, therefore, warrants urgent monitoring and clinical intervention. [ABSTRACT FROM AUTHOR]

Soil contamination, particularly by chromium from industrial effluents, remains a significant global environmental concern. Contaminant removal stands out as a pressing requirement in the current environmental landscape. The increased levels of these contaminants underscore the urgency for effective removal measures. This study focuses on the electrokinetic remediation of chromium-contaminated soil collected from Puliyantangal Lake, Ranipet, Tamil Nadu. Investigating the effects of supply voltage and bone dust amendment on chromium removal efficiency, the research sheds light on the details of this emerging in situ remediation technique. The results indicate that the optimal removal efficiency of hexavalent chromium [Cr(VI)] was achieved at 15 V with a maximum removal of 66.97%. Increased voltage enhanced Cr(VI) remediation through electromigration, while the dissociation of bone dust constituent (hydroxyapatite) positively impacted the removal process through chromium (III) hydroxide [Cr(OH)3] deposition and elevated Cr(VI) reduction. Furthermore, the study reveals a synergistic reduction in total chromium content through electromigration and chemical reduction of chromium species under direct current source application. The decreasing trend of Cr(VI) content from cathode to anode was observed for both 15 and 30 V, with enhanced reduction at higher voltages. Interestingly, the combination of bone dust amendment showed superior Cr(VI) removal efficiency at 15 V, emphasizing the significance of the relationship between voltage and amendment effectiveness. This unique interaction between hindered electromigration and enhanced Cr(VI) reduction holds promise for optimizing electrokinetic remediation strategies, providing valuable insights for future environmental remediation studies. [ABSTRACT FROM AUTHOR]