Browsing by Author "Imran, Khan Mohammad"
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- Ablative and Immunostimulatory Effects of Histotripsy Ablation in a Murine Osteosarcoma ModelHay, Alayna N.; Imran, Khan Mohammad; Hendricks-Wenger, Alissa; Gannon, Jessica M.; Sereno, Jacqueline; Simon, Alex; Lopez, Victor A.; Coutermarsh-Ott, Sheryl; Vlaisavljevich, Eli; Allen, Irving C.; Tuohy, Joanne L. (MDPI, 2023-10-09)Background: Osteosarcoma (OS) is the most frequently occurring malignant bone tumor in humans, primarily affecting children and adolescents. Significant advancements in treatment options for OS have not occurred in the last several decades, and the prognosis remains grim with only a 70% rate of 5-year survival. The objective of this study was to investigate the focused ultrasound technique of histotripsy as a novel, noninvasive treatment option for OS. Methods: We utilized a heterotopic OS murine model to establish the feasibility of ablating OS tumors with histotripsy in a preclinical setting. We investigated the local immune response within the tumor microenvironment (TME) via immune cell phenotyping and gene expression analysis. Findings: We established the feasibility of ablating heterotopic OS tumors with ablation characterized microscopically by loss of cellular architecture in targeted regions of tumors. We observed greater populations of macrophages and dendritic cells within treated tumors and the upregulation of immune activating genes 72 h after histotripsy ablation. Interpretation: This study was the first to investigate histotripsy ablation for OS in a preclinical murine model, with results suggesting local immunomodulation within the TME. Our results support the continued investigation of histotripsy as a novel noninvasive treatment option for OS patients to improve clinical outcomes and patient prognosis.
- Bioremediation of Hexavalent Chromium by Chromium Resistant Bacteria Reduces PhytotoxicityHossan, Shanewaz; Hossain, Saddam; Islam, Mohammad Rafiqul; Kabir, Mir Himayet; Ali, Sobur; Islam, Md Shafiqul; Imran, Khan Mohammad; Moniruzzaman, M.; Mou, Taslin Jahan; Parvez, Anowar Khasru; Mahmud, Zahid Hayat (MDPI, 2020-08-19)Chromium (Cr) (VI) has long been known as an environmental hazard that can be reduced from aqueous solutions through bioremediation by living cells. In this study, we investigated the efficiency of reduction and biosorption of Cr(VI) by chromate resistant bacteria isolated from tannery effluent. From 28 screened Cr(VI) resistant isolates, selected bacterial strain SH-1 was identified as Klebsiella sp. via 16S rRNA sequencing. In Luria–Bertani broth, the relative reduction level of Cr(VI) was 95%, but in tannery effluent, it was 63.08% after 72 h of incubation. The cell-free extract of SH-1 showed a 72.2% reduction of Cr(VI), which indicated a higher activity of Cr(VI) reducing enzyme than the control. Live and dead biomass of SH-1 adsorbed 51.25 mg and 29.03 mg Cr(VI) per gram of dry weight, respectively. Two adsorption isotherm models—Langmuir and Freundlich—were used for the illustration of Cr(VI) biosorption using SH-1 live biomass. Scanning electron microscopy (SEM) analysis showed an increased cell size of the treated biomass when compared to the controlled biomass, which supports the adsorption of reduced Cr on the biomass cell surface. Fourier-transform infrared analysis indicated that Cr(VI) had an effect on bacterial biomass, including quantitative and structural modifications. Moreover, the chickpea seed germination study showed beneficial environmental effects that suggest possible application of the isolate for the bioremediation of toxic Cr(VI).
- Exploration of Novel Pathways Underlying Irreversible Electroporation Induced Anti-Tumor Immunity in Pancreatic CancerImran, Khan Mohammad; Nagai-Singer, Margaret A.; Brock, Rebecca M.; Alinezhadbalalami, Nastaran; Davalos, Rafael V.; Allen, Irving C. (Frontiers, 2022-03-18)Advancements in medical sciences and technologies have significantly improved the survival of many cancers; however, pancreatic cancer remains a deadly diagnosis. This malignancy is often diagnosed late in the disease when metastases have already occurred. Additionally, the location of the pancreas near vital organs limits surgical candidacy, the tumor's immunosuppressive environment limits immunotherapy success, and it is highly resistant to radiation and chemotherapy. Hence, clinicians and patients alike need a treatment paradigm that reduces primary tumor burden, activates systemic anti-tumor immunity, and reverses the local immunosuppressive microenvironment to eventually clear distant metastases. Irreversible electroporation (IRE), a novel non-thermal tumor ablation technique, applies high-voltage ultra-short pulses to permeabilize targeted cell membranes and induce cell death. Progression with IRE technology and an array of research studies have shown that beyond tumor debulking, IRE can induce anti-tumor immune responses possibly through tumor neo-antigen release. However, the success of IRE treatment (i.e. full ablation and tumor recurrence) is variable. We believe that IRE treatment induces IFN gamma expression, which then modulates immune checkpoint molecules and thus leads to tumor recurrence. This indicates a co-therapeutic use of IRE and immune checkpoint inhibitors as a promising treatment for pancreatic cancer patients. Here, we review the well-defined and speculated pathways involved in the immunostimulatory effects of IRE treatment for pancreatic cancer, as well as the regulatory pathways that may negate these anti-tumor responses. By defining these underlying mechanisms, future studies may identify improvements to systemic immune system engagement following local tumor ablation with IRE and beyond.
- Improved Therapeutic Delivery Targeting Clinically Relevant Orthotopic Human Pancreatic Tumors Engrafted in Immunocompromised Pigs Using Ultrasound-Induced Cavitation: A Pilot StudyImran, Khan Mohammad; Tintera, Benjamin; Morrison, Holly A.; Tupik, Juselyn D.; Nagai-Singer, Margaret A.; Ivester, Hannah; Council-Troche, McAlister; Edwards, Michael; Coutermarsh-Ott, Sheryl; Byron, Christopher; Clark-Deener, Sherrie; Uh, Kyungjun; Lee, Kiho; Boulos, Paul; Rowe, Cliff; Coviello, Christian; Allen, Irving C. (MDPI, 2023-05-24)Pancreatic tumors can be resistant to drug penetration due to high interstitial fluid pressure, dense stroma, and disarrayed vasculature. Ultrasound-induced cavitation is an emerging technology that may overcome many of these limitations. Low-intensity ultrasound, coupled with co-administered cavitation nuclei consisting of gas-stabilizing sub-micron scale SonoTran Particles, is effective at increasing therapeutic antibody delivery to xenograft flank tumors in mouse models. Here, we sought to evaluate the effectiveness of this approach in situ using a large animal model that mimics human pancreatic cancer patients. Immunocompromised pigs were surgically engrafted with human Panc-1 pancreatic ductal adenocarcinoma (PDAC) tumors in targeted regions of the pancreas. These tumors were found to recapitulate many features of human PDAC tumors. Animals were intravenously injected with the common cancer therapeutics Cetuximab, gemcitabine, and paclitaxel, followed by infusion with SonoTran Particles. Select tumors in each animal were targeted with focused ultrasound to induce cavitation. Cavitation increased the intra-tumor concentrations of Cetuximab, gemcitabine, and paclitaxel by 477%, 148%, and 193%, respectively, compared to tumors that were not targeted with ultrasound in the same animals. Together, these data show that ultrasound-mediated cavitation, when delivered in combination with gas-entrapping particles, improves therapeutic delivery in pancreatic tumors under clinically relevant conditions.
- Novel Approaches in Pancreatic Cancer Treatment: Bridging Mechanics, Cells, and ImmunityImran, Khan Mohammad (Virginia Tech, 2024-01-04)The heterogeneity of pancreatic cancer renders many available general therapies ineffective holding the five-year survival rate close to 10% for decades. Surgical resection eligibility, resistance to chemotherapy and limited efficacy of immunotherapy emphasize the dire need for diverse and innovative treatments to combat this challenging disease. This study evaluates co-therapy strategies that combine non-thermal, minimally invasive ablation technology and targeted drug delivery to enhance treatment efficacy. Our research begins by uncovering the multifaceted potential of Irreversible Electroporation (IRE), a cutting-edge non-thermal tumor ablation technique. This study demonstrates IRE-mediated ability to trigger programmed necrotic cell death, induce cell cycle arrest, and modulate immune cell populations within the tumor microenvironment. This transformation from a pro-tumor state to a proinflammatory milieu, enriched with cytotoxic T lymphocytes and neutrophils. IRE-induced proinflammation in the tumor site renders immunologically "cold" tumor into immunologically "hot" tumor and holds significant promise of improving treatment efficacy. Notably, IRE-treated mice exhibited an extended period of progression-free survival, implying clinical potential. The transient nature of these effects suggests potential mechanisms of tumor recurrence highlighting the need for further studies to maximize the efficacy of IRE. Our mechanistic studies evaluated the IFN-STAT1-PD-L1 feedback loop as a possible reason for pancreatic tumor recurrence. Our data also suggest a stronger IFN-PD-L1 feedback loop compared to mammary, osteosarcoma and glioblastoma tumors rendering pancreatic cancer immunologically "cold". This study also investigates the use of histotripsy (a non-thermal, noninvasive, nonionizing ultrasound-guided ablation modality) to treat pancreatic cancer utilizing a novel immunocompromised swine model. We successfully generated human orthotopic pancreatic tumors in the immune deficient pigs, which allowed for consequent investigation of clinical challenges presented by histotripsy. While rigorous clinical studies are indispensable for validation, the promise of histotripsy offers new hope for patients. In parallel, we used our immunocompromised swine model of orthotopic pancreatic cancer to investigate the SonoTran® system, which employs ultrasound-activated oscillating particles to enhance drug delivery within hard-to-reach tumors. Our study demonstrates that SonoTran® significantly enhances the intratumoral penetrance of therapeutic agents, including commonly used chemotherapy drugs like paclitaxel and gemcitabine. Additionally, SonoTran® improved delivery of the anti-epidermal growth factor (EGFR) monoclonal antibody, cetuximab- which is frequently used in cancer immunotherapy. Together, our findings address challenges in the delivery of a range of therapeutics while simultaneously exposing challenges like off-target damage. In conclusion, this study presents a multifaceted approach to confront the complex characteristics of pancreatic cancer. Given the variations in patient response and the complexity of the disease, it is clear that a singular solution is unlikely. Our research, which combines IRE, histotripsy, and SonoTran®, to interrogate a promising array of tools to tackle different challenges to provide tailored treatments. In the ever-evolving landscape of pancreatic cancer therapy, this research opens new avenues to investigate deeper into molecular mechanisms, co-therapy treatment options, future preclinical and clinical studies which eventually encourage the potential for improved patient outcomes.