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  1. Article ; Online: Rational Design of a Self‐Assembling High Performance Organic Nanofluorophore for Intraoperative NIR‐II Image‐Guided Tumor Resection of Oral Cancer

    Xianwei Sun / Praveen Kumar Chintakunta / Andrew A. Badachhape / Rohan Bhavane / Huan‐Jui Lee / David S. Yang / Zbigniew Starosolski / Ketan B. Ghaghada / Peter G. Vekilov / Ananth V. Annapragada / Eric A. Tanifum

    Advanced Science, Vol 10, Iss 10, Pp n/a-n/a (2023)

    2023  

    Abstract: Abstract The first line of treatment for most solid tumors is surgical resection of the primary tumor with adequate negative margins. Incomplete tumor resections with positive margins account for over 75% of local recurrences and the development of ... ...

    Abstract Abstract The first line of treatment for most solid tumors is surgical resection of the primary tumor with adequate negative margins. Incomplete tumor resections with positive margins account for over 75% of local recurrences and the development of distant metastases. In cases of oral cavity squamous cell carcinoma (OSCC), the rate of successful tumor removal with adequate margins is just 50–75%. Advanced real‐time imaging methods that improve the detection of tumor margins can help improve success rates,overall safety, and reduce the cost. Fluorescence imaging in the second near‐infrared (NIR‐II) window has the potential to revolutionize the field due to its high spatial resolution, low background signal, and deep tissue penetration properties, but NIR‐II dyes with adequate in vivo performance and safety profiles are scarce. A novel NIR‐II fluorophore, XW‐03‐66, with a fluorescence quantum yield (QY) of 6.0% in aqueous media is reported. XW‐03‐66 self‐assembles into nanoparticles (≈80 nm) and has a systemic circulation half‐life (t1/2) of 11.3 h. In mouse models of human papillomavirus (HPV)+ and HPV‐ OSCC, XW‐03‐66 outperformed indocyanine green (ICG), a clinically available NIR dye, and enabled intraoperative NIR‐II image‐guided resection of the tumor and adjacent draining lymph node with negative margins. In vitro and in vivo toxicity assessments revealed minimal safety concerns for in vivo applications.
    Keywords intraoperative imaging ; mesoscopic solute‐rich clusters ; NIR‐II margin delineation ; NIR‐II probe ; organic nanofluorophore ; self‐assembling ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2023-04-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Advanced photon counting CT imaging pipeline for cardiac phenotyping of apolipoprotein E mouse models

    Alex J. Allphin / Ali Mahzarnia / Darin P. Clark / Yi Qi / Zay Y. Han / Prajwal Bhandari / Ketan B. Ghaghada / Alexandra Badea / Cristian T. Badea

    PLoS ONE, Vol 18, Iss

    2023  Volume 10

    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Photon Counting CT and Radiomic Analysis Enables Differentiation of Tumors Based on Lymphocyte Burden

    Alex J. Allphin / Yvonne M. Mowery / Kyle J. Lafata / Darin P. Clark / Alex M. Bassil / Rico Castillo / Diana Odhiambo / Matthew D. Holbrook / Ketan B. Ghaghada / Cristian T. Badea

    Tomography, Vol 8, Iss 61, Pp 740-

    2022  Volume 753

    Abstract: The purpose of this study was to investigate if radiomic analysis based on spectral micro-CT with nanoparticle contrast-enhancement can differentiate tumors based on lymphocyte burden. High mutational load transplant soft tissue sarcomas were initiated ... ...

    Abstract The purpose of this study was to investigate if radiomic analysis based on spectral micro-CT with nanoparticle contrast-enhancement can differentiate tumors based on lymphocyte burden. High mutational load transplant soft tissue sarcomas were initiated in Rag2 +/− and Rag2 −/− mice to model varying lymphocyte burden. Mice received radiation therapy (20 Gy) to the tumor-bearing hind limb and were injected with a liposomal iodinated contrast agent. Five days later, animals underwent conventional micro-CT imaging using an energy integrating detector (EID) and spectral micro-CT imaging using a photon-counting detector (PCD). Tumor volumes and iodine uptakes were measured. The radiomic features (RF) were grouped into feature-spaces corresponding to EID, PCD, and spectral decomposition images. The RFs were ranked to reduce redundancy and increase relevance based on TL burden. A stratified repeated cross validation strategy was used to assess separation using a logistic regression classifier. Tumor iodine concentration was the only significantly different conventional tumor metric between Rag2 +/− (TLs present) and Rag2 −/− (TL-deficient) tumors. The RFs further enabled differentiation between Rag2 +/− and Rag2 −/− tumors. The PCD-derived RFs provided the highest accuracy (0.68) followed by decomposition-derived RFs (0.60) and the EID-derived RFs (0.58). Such non-invasive approaches could aid in tumor stratification for cancer therapy studies.
    Keywords micro-CT ; spectral CT ; photon counting detector ; preclinical ; nanoparticles ; radiomics ; Computer applications to medicine. Medical informatics ; R858-859.7
    Subject code 333
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Indocyanine green fluorescence in second near-infrared (NIR-II) window.

    Zbigniew Starosolski / Rohan Bhavane / Ketan B Ghaghada / Sanjeev A Vasudevan / Alexander Kaay / Ananth Annapragada

    PLoS ONE, Vol 12, Iss 11, p e

    2017  Volume 0187563

    Abstract: Indocyanine green (ICG), a FDA approved near infrared (NIR) fluorescent agent, is used in the clinic for a variety of applications including lymphangiography, intra-operative lymph node identification, tumor imaging, superficial vascular imaging, and ... ...

    Abstract Indocyanine green (ICG), a FDA approved near infrared (NIR) fluorescent agent, is used in the clinic for a variety of applications including lymphangiography, intra-operative lymph node identification, tumor imaging, superficial vascular imaging, and marking ischemic tissues. These applications operate in the so-called "NIR-I" window (700-900 nm). Recently, imaging in the "NIR-II" window (1000-1700 nm) has attracted attention since, at longer wavelengths, photon absorption, and scattering effects by tissue components are reduced, making it possible to image deeper into the underlying tissue. Agents for NIR-II imaging are, however, still in pre-clinical development. In this study, we investigated ICG as a NIR-II dye. The absorbance and NIR-II fluorescence emission of ICG were measured in different media (PBS, plasma and ethanol) for a range of ICG concentrations. In vitro and in vivo testing were performed using a custom-built spectral NIR assembly to facilitate simultaneous imaging in NIR-I and NIR-II window. In vitro studies using ICG were performed using capillary tubes (as a simulation of blood vessels) embedded in Intralipid solution and tissue phantoms to evaluate depth of tissue penetration in NIR-I and NIR-II window. In vivo imaging using ICG was performed in nude mice to evaluate vascular visualization in the hind limb in the NIR-I and II windows. Contrast-to-noise ratios (CNR) were calculated for comparison of image quality in NIR-I and NIR-II window. ICG exhibited significant fluorescence emission in the NIR-II window and this emission (similar to the absorption profile) is substantially affected by the environment of the ICG molecules. In vivo imaging further confirmed the utility of ICG as a fluorescent dye in the NIR-II domain, with the CNR values being ~2 times those in the NIR-I window. The availability of an FDA approved imaging agent could accelerate the clinical translation of NIR-II imaging technology.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2017-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Computed Tomography Imaging of Solid Tumors Using a Liposomal-Iodine Contrast Agent in Companion Dogs with Naturally Occurring Cancer.

    Ketan B Ghaghada / Amy F Sato / Zbigniew A Starosolski / John Berg / David M Vail

    PLoS ONE, Vol 11, Iss 3, p e

    2016  Volume 0152718

    Abstract: Companion dogs with naturally occurring cancer serve as an important large animal model in translational research because they share strong similarities with human cancers. In this study, we investigated a long circulating liposomal-iodine contrast agent ...

    Abstract Companion dogs with naturally occurring cancer serve as an important large animal model in translational research because they share strong similarities with human cancers. In this study, we investigated a long circulating liposomal-iodine contrast agent (Liposomal-I) for computed tomography (CT) imaging of solid tumors in companion dogs with naturally occurring cancer.The institutional animal ethics committees approved the study and written informed consent was obtained from all owners. Thirteen dogs (mean age 10.1 years) with a variety of masses including primary and metastatic liver tumors, sarcomas, mammary carcinoma and lung tumors, were enrolled in the study. CT imaging was performed pre-contrast and at 15 minutes and 24 hours after intravenous administration of Liposomal-I (275 mg/kg iodine dose). Conventional contrast-enhanced CT imaging was performed in a subset of dogs, 90 minutes prior to administration of Liposomal-I. Histologic or cytologic diagnosis was obtained for each dog prior to admission into the study.Liposomal-I resulted in significant (p < 0.05) enhancement and uniform opacification of the vascular compartment. Non-renal, reticulo-endothelial systemic clearance of the contrast agent was demonstrated. Liposomal-I enabled visualization of primary and metastatic liver tumors. Sub-cm sized liver lesions grossly appeared as hypo-enhanced compared to the surrounding normal parenchyma with improved lesion conspicuity in the post-24 hour scan. Large liver tumors (> 1 cm) demonstrated a heterogeneous pattern of intra-tumoral signal with visibly higher signal enhancement at the post-24 hour time point. Extra-hepatic, extra-splenic tumors, including histiocytic sarcoma, anaplastic sarcoma, mammary carcinoma and lung tumors, were visualized with a heterogeneous enhancement pattern in the post-24 hour scan.The long circulating liposomal-iodine contrast agent enabled prolonged visualization of small and large tumors in companion dogs with naturally occurring cancer. The study warrants future work to assess the sensitivity and specificity of the Liposomal-I agent in various types of naturally occurring canine tumors.
    Keywords Medicine ; R ; Science ; Q
    Subject code 630
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Pre-clinical dose-ranging efficacy, pharmacokinetics, tissue biodistribution, and toxicity of a targeted contrast agent for MRI of amyloid deposition in Alzheimer’s disease

    Andrew A. Badachhape / Peter K. Working / Mayank Srivastava / Prajwal Bhandari / Igor V. Stupin / Laxman Devkota / Eric A. Tanifum / Ananth V. Annapragada / Ketan B. Ghaghada

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 10

    Abstract: Abstract In these preclinical studies, we describe ADx-001, an Aβ-targeted liposomal macrocyclic gadolinium (Gd) imaging agent, for MRI of amyloid plaques. The targeting moiety is a novel lipid-PEG conjugated styryl-pyrimidine. An MRI-based contrast ... ...

    Abstract Abstract In these preclinical studies, we describe ADx-001, an Aβ-targeted liposomal macrocyclic gadolinium (Gd) imaging agent, for MRI of amyloid plaques. The targeting moiety is a novel lipid-PEG conjugated styryl-pyrimidine. An MRI-based contrast agent such as ADx-001 is attractive because of the lack of radioactivity, ease of distribution, long shelf life, and the prevalence of MRI scanners. Dose-ranging efficacy studies were performed on a 1 T MRI scanner using a transgenic APP/PSEN1 mouse model of Alzheimer’s disease. ADx-001 was tested at 0.10, 0.15, and 0.20 mmol Gd/kg. Gold standard post-mortem amyloid immunostaining was used for the determination of sensitivity and specificity. ADx-001 toxicity was evaluated in rats and monkeys at doses up to 0.30 mmol Gd/kg. ADx-001 pharmacokinetics were determined in monkeys and its tissue distribution was evaluated in rats. ADx-001-enhanced MRI demonstrated significantly higher (p < 0.05) brain signal enhancement in transgenic mice relative to wild type mice at all dose levels. ADx-001 demonstrated high sensitivity at 0.20 and 0.15 mmol Gd/kg and excellent specificity at all dose levels for in vivo imaging of β amyloid plaques. ADx-001 was well tolerated in rats and monkeys and exhibited the slow clearance from circulation and tissue biodistribution typical of PEGylated nanoparticles.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

    Ling Tao / Mahmoud A. Mohammad / Giorgio Milazzo / Myrthala Moreno-Smith / Tajhal D. Patel / Barry Zorman / Andrew Badachhape / Blanca E. Hernandez / Amber B. Wolf / Zihua Zeng / Jennifer H. Foster / Sara Aloisi / Pavel Sumazin / Youli Zu / John Hicks / Ketan B. Ghaghada / Nagireddy Putluri / Giovanni Perini / Cristian Coarfa /
    Eveline Barbieri

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 17

    Abstract: Half of high-risk neuroblastoma patients have MYCN amplification. Here, the authors show that MYCN induces fatty acid uptake and synthesis to support neuroblastoma and inhibition of a fatty acid transporter impairs tumor progression in preclinical models. ...

    Abstract Half of high-risk neuroblastoma patients have MYCN amplification. Here, the authors show that MYCN induces fatty acid uptake and synthesis to support neuroblastoma and inhibition of a fatty acid transporter impairs tumor progression in preclinical models.
    Keywords Science ; Q
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Nanoparticle Contrast-enhanced T1-Mapping Enables Estimation of Placental Fractional Blood Volume in a Pregnant Mouse Model

    Andrew A. Badachhape / Laxman Devkota / Igor V. Stupin / Poonam Sarkar / Mayank Srivastava / Eric A. Tanifum / Karin A. Fox / Chandrasekhar Yallampalli / Ananth V. Annapragada / Ketan B. Ghaghada

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 9

    Abstract: Abstract Non-invasive methods for estimating placental fractional blood volume (FBV) are of great interest for characterization of vascular perfusion in placentae during pregnancy to identify placental insufficiency that may be indicative of local ... ...

    Abstract Abstract Non-invasive methods for estimating placental fractional blood volume (FBV) are of great interest for characterization of vascular perfusion in placentae during pregnancy to identify placental insufficiency that may be indicative of local ischemia or fetal growth restriction (FGR). Nanoparticle contrast-enhanced magnetic resonance imaging (CE-MRI) may enable direct placental FBV estimation and may provide a reliable, 3D alternative to assess maternal-side placental perfusion. In this pre-clinical study, we investigated if placental FBV at 14, 16, and 18 days of gestation could be estimated through contrast-enhanced MRI using a long circulating blood-pool liposomal gadolinium contrast agent that does not penetrate the placental barrier. Placental FBV estimates of 0.47 ± 0.06 (E14.5), 0.50 ± 0.04 (E16.5), and 0.52 ± 0.04 (E18.5) were found through fitting pre-contrast and post-contrast T1 values in placental tissue using a variable flip angle method. MRI-derived placental FBV was validated against nanoparticle contrast-enhanced computed tomography (CE-CT) derived placental FBV, where signal is directly proportional to the concentration of iodine contrast agent. The results demonstrate successful estimation of the placental FBV, with values statistically indistinguishable from the CT derived values.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: MDM4 inhibition

    Sarah E. Woodfield / Yan Shi / Roma H. Patel / Zhenghu Chen / Aayushi P. Shah / Richard S. Whitlock / Aryana M. Ibarra / Samuel R. Larson / Stephen F. Sarabia / Andrew Badachhape / Zbigniew Starosolski / Ketan B. Ghaghada / Pavel Sumazin / D. Allen Annis / Dolores López-Terrada / Sanjeev A. Vasudevan

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    a novel therapeutic strategy to reactivate p53 in hepatoblastoma

    2021  Volume 17

    Abstract: Abstract Hepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient ... ...

    Abstract Abstract Hepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient quality of life. Most HB cases are TP53 wild-type; therefore, we hypothesized that targeting the p53 regulator Murine double minute 4 (MDM4) to reactivate p53 signaling may show efficacy. MDM4 expression was elevated in HB patient samples, and increased expression was strongly correlated with decreased expression of p53 target genes. Treatment with NSC207895 (XI-006), which inhibits MDM4 expression, or ATSP-7041, a stapled peptide dual inhibitor of MDM2 and MDM4, showed significant cytotoxic and antiproliferative effects in HB cells. Similar phenotypes were seen with short hairpin RNA (shRNA)-mediated inhibition of MDM4. Both NSC207895 and ATSP-7041 caused significant upregulation of p53 targets in HB cells. Knocking-down TP53 with shRNA or overexpressing MDM4 led to resistance to NSC207895-mediated cytotoxicity, suggesting that this phenotype is dependent on the MDM4-p53 axis. MDM4 inhibition also showed efficacy in a murine model of HB with significantly decreased tumor weight and increased apoptosis observed in the treatment group. This study demonstrates that inhibition of MDM4 is efficacious in HB by upregulating p53 tumor suppressor signaling.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Author Correction

    Sarah E. Woodfield / Yan Shi / Roma H. Patel / Zhenghu Chen / Aayushi P. Shah / Rohit K. Srivastava / Richard S. Whitlock / Aryana M. Ibarra / Samuel R. Larson / Stephen F. Sarabia / Andrew Badachhape / Zbigniew Starosolski / Ketan B. Ghaghada / Pavel Sumazin / D. Allen Annis / Dolores López-Terrada / Sanjeev A. Vasudevan

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma

    2021  Volume 1

    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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