@article{corder_gadi_vachieri_jayes_cullen_khan_taylor_2021, title={Using rheology to quantify the effects of localized collagenase treatments on uterine fibroid digestion}, volume={134}, ISSN={["1878-7568"]}, DOI={10.1016/j.actbio.2021.08.003}, abstractNote={Uterine fibroids are stiff, benign tumors containing excessive, disordered collagens that occur in 70-80% of women before age 50 and cause bleeding and pain. Collagenase Clostridium histolyticum (CCH) is a bacterial enzyme capable of digesting the collagens present in fibroids. By combining CCH with injectable drug delivery systems to enhance effectiveness, a new class of treatments could be developed to reduce the stiffness of fibroids, preventing the need for surgical removal and preserving fertility. In this work, we achieved localization of CCH via physical entrapment by co-injecting a thermoresponsive pNIPAM-based polymeric delivery system called LiquoGel (LQG), which undergoes a sol-gel transition upon heating. Toxicity study results for LQG injected subcutaneously into mice demonstrate that LQG does not induce lesions or other adverse effects. We then used rheology to quantify the effects of localized CCH injections on the modulus and viscoelasticity of uterine fibroids, which exhibit gel-like behavior, through ex vivo and in vivo digestion studies. Ex vivo CCH injections reduce the tissue modulus by over two orders of magnitude and co-injection of LQG enhances this effect. Rheological results from an in vivo digestion study in mice show a significant reduction in tissue modulus and increase in tissue viscoelasticity 7 days after a single injection of LQG+CCH. Parallel histological staining validates that the observed rheological changes correspond to an increase in collagen lysis after treatment by LQG+CCH. These results show promise for development of injectable and localized enzymatic therapies for uterine fibroids and other dense tumors. STATEMENT OF SIGNIFICANCE: Uterine fibroids are stiff, benign tumors containing high collagen levels that cause bleeding and pain in women. Fertility-preserving and minimally-invasive treatments to soften fibroids are needed as an alternative to surgical removal via hysterectomy. We demonstrate through ex vivo and in vivo studies that co-injecting a thermoresponsive polymer delivery system (LQG) alongside a bacterial collagenase (CCH) enzyme significantly increases treatment effectiveness at softening fibroids through CCH localization. We use rheology to measure the modulus and viscoelasticity of fibroids and histology to show that fibroid softening corresponds to a decrease in collagen after treatment with LQG+CCH. These results highlight the utility of rheology at quantifying tissue properties and present a promising injectable therapy for fibroids and other dense tumors.}, journal={ACTA BIOMATERIALIA}, author={Corder, Ria D. and Gadi, Sashi V and Vachieri, Robert B. and Jayes, Friederike L. and Cullen, John M. and Khan, Saad A. and Taylor, Darlene K.}, year={2021}, month={Oct}, pages={443–452} }
 @article{canuti_williams_sagan_munnink_gadi_verhoeven_kellam_cotten_lang_junge_et al._2019, title={Virus discovery reveals frequent infection by diverse novel members of the Flaviviridae in wild lemurs}, volume={164}, ISSN={["1432-8798"]}, DOI={10.1007/s00705-018-4099-9}, abstractNote={Lemurs are highly endangered mammals inhabiting the forests of Madagascar. In this study, we performed virus discovery on serum samples collected from 84 wild lemurs and identified viral sequence fragments from 4 novel viruses within the family Flaviviridae, including members of the genera Hepacivirus and Pegivirus. The sifaka hepacivirus (SifHV, two genotypes) and pegivirus (SifPgV, two genotypes) were discovered in the diademed sifaka (Propithecus diadema), while other pegiviral fragments were detected in samples from the indri (Indri indri, IndPgV) and the weasel sportive lemur (Lepilemur mustelinus, LepPgV). Although data are preliminary, each viral species appeared host species-specific and frequent infection was detected (18 of 84 individuals were positive for at least one virus). The complete coding sequence and partial 5' and 3' untranslated regions (UTRs) were obtained for SifHV and its genomic organization was consistent with that of other hepaciviruses, with one unique polyprotein and highly structured UTRs. Phylogenetic analyses showed the SifHV belonged to a clade that includes several viral species identified in rodents from Asia and North America, while SifPgV and IndPgV were more closely related to pegiviral species A and C, that include viruses found in humans as well as New- and Old-World monkeys. Our results support the current proposed model of virus-host co-divergence with frequent occurrence of cross-species transmission for these genera and highlight how the discovery of more members of the Flaviviridae can help clarify the ecology and evolutionary history of these viruses. Furthermore, this knowledge is important for conservation and captive management of lemurs.}, number={2}, journal={ARCHIVES OF VIROLOGY}, author={Canuti, Marta and Williams, Cathy V. and Sagan, Selena M. and Munnink, Bas B. Oude and Gadi, Sashi and Verhoeven, Joost T. P. and Kellam, Paul and Cotten, Matthew and Lang, Andrew S. and Junge, Randall E. and et al.}, year={2019}, month={Feb}, pages={509–522} }
 @article{canuti_williams_gadi_jebbink_munnink_farsani_cullen_hoek_2014, title={Persistent viremia by a novel parvovirus in a slow loris (Nycticebus coucang) with diffuse histiocytic sarcoma}, volume={5}, ISSN={["1664-302X"]}, DOI={10.3389/fmicb.2014.00655}, abstractNote={Cancer is one of the leading health concerns for human and animal health. Since the tumorigenesis process is not completely understood and it is known that some viruses can induce carcinogenesis, it is highly important to identify novel oncoviruses and extensively study underlying oncogenic mechanisms. Here, we investigated a case of diffuse histiocytic sarcoma in a 22 year old slow loris (Nycticebus coucang), using a broad spectrum virus discovery technique. A novel parvovirus was discovered and the phylogenetic analysis performed on its fully sequenced genome demonstrated that it represents the first member of a novel genus. The possible causative correlation between this virus and the malignancy was further investigated and 20 serum and 61 organ samples from 25 animals (N. coucang and N. pygmaeus) were screened for the novel virus but only samples collected from the originally infected animal were positive. The virus was present in all tested organs (intestine, liver, spleen, kidneys, and lungs) and in all banked serum samples collected up to 8 years before death. All attempts to identify a latent viral form (integrated or episomal) were unsuccessful and the increase of variation in the viral sequences during the years was consistent with absence of latency. Since it is well known that parvoviruses are dependent on cell division to successfully replicate, we hypothesized that the virus could have benefitted from the constantly dividing cancer cells and may not have been the cause of the histiocytic sarcoma. It is also possible to conjecture that the virus had a role in delaying the tumor progression and this report might bring new exciting opportunities in recognizing viruses to be used in cancer virotherapy.}, journal={FRONTIERS IN MICROBIOLOGY}, author={Canuti, Marta and Williams, Cathy V. and Gadi, Sashi R. and Jebbink, Maarten F. and Munnink, Bas B. Oude and Farsani, Seyed Mohammad Jazaeri and Cullen, John M. and Hoek, Lia}, year={2014}, month={Dec} }
 @article{burke_cullen_state_gadi_wilber_rosenthal_bulysheva_pease_mauro_fuchs_2011, title={Development of an Animal Model for Radiofrequency Ablation of Primary, Virally Induced Hepatocellular Carcinoma in the Woodchuck}, volume={22}, ISSN={["1051-0443"]}, DOI={10.1016/j.jvir.2011.08.020}, abstractNote={To develop a consistent and reproducible method in an animal model for studies of radiofrequency (RF) ablation of primary hepatocellular carcinoma (HCC).Fifteen woodchucks were inoculated with woodchuck hepatitis virus (WHV) to establish chronic infections. When serum γ-glutamyl transpeptidase levels became elevated, the animals were evaluated with ultrasound, and, in most cases, preoperative magnetic resonance (MR) imaging to confirm tumor development. Ultimately, RF ablation of tumors was performed by using a 1-cm probe with the animal submerged in a water bath for grounding. Ablation effectiveness was evaluated with contrast-enhanced MR imaging and gross and histopathologic analysis.RF ablation was performed in 15 woodchucks. Modifications were made to the initial study design to adapt methodology for the woodchuck. The last 10 of these animals were treated with a standardized protocol using a 1-cm probe that produced a consistent area of tumor necrosis (mean size of ablation, 10.2 mm × 13.1 mm) and led to no complications.A safe, reliable and consistent method was developed to study RF ablation of spontaneous primary HCC using chronically WHV-infected woodchucks, an animal model of hepatitis B virus-induced HCC.}, number={11}, journal={JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY}, author={Burke, Charles T. and Cullen, John M. and State, Andrei and Gadi, Sashi and Wilber, Kathy and Rosenthal, Michael and Bulysheva, Anna and Pease, Anthony and Mauro, Mathew A. and Fuchs, Henry}, year={2011}, month={Nov}, pages={1613–1618} }
 @article{livingston_tuong_gadi_haigler_gelman_cullen_2010, title={3D volumes constructed from pixel-based images by digitally clearing plant and animal tissue}, volume={240}, ISSN={0022-2720}, url={http://dx.doi.org/10.1111/j.1365-2818.2010.03393.x}, DOI={10.1111/j.1365-2818.2010.03393.x}, abstractNote={Summary}, number={2}, journal={Journal of Microscopy}, publisher={Wiley}, author={Livingston, D.P. and Tuong, T.D. and Gadi, S.R.V. and Haigler, C.H. and Gelman, R.S. and Cullen, J.M.}, year={2010}, month={Jun}, pages={122–129} }