All Publications

  • Environmental Risk Factors for Pediatric Epistaxis vary by Climate Zone. The Laryngoscope Wei, E. X., Green, A., Chang, M. T., Hwang, P. H., Sidell, D. R., Qian, Z. J. 2023


    Prior studies have provided variable results regarding environmental risk factors for epistaxis. These studies were conducted in varying climate zones, which may explain discrepancies in results. The objective of this study is to investigate correlations between season, temperature, and humidity on frequency of pediatric epistaxis across climate zones.Children seen in the outpatient setting for epistaxis were identified from the 2007-2010 IBM MarketScan database. Climate zones were assigned according to International Energy Conservation Code (IECC) classification, where temperature zones in the United States and territories were assigned on an ordinal scale from 1 (tropical) to 8 (subarctic), and humidity zones were categorized as moist, dry, or marine. The control population was a sample of all well-child visits matched by age and county.We identified 184,846 unique children seen for epistaxis and 1,897,012 matched controls. Moderate temperature zones were associated with lower odds of epistaxis compared with the hottest and coldest zones. Humidity was associated inversely with epistaxis rates in moderate temperature zones but was not a significant predictor of epistaxis in climates with extreme heat. Additionally, summer was associated with lower odds of epistaxis compared to winter. Interestingly, however, there were significantly higher rates of cautery procedures during summer months, driven largely by increased procedures performed in clinic, as opposed to the operating room or emergency room.Environmental risk factors for epistaxis vary by climate zone. The model presented reconciles prior reports and may allow for more personalized clinical management based on regional climate.Level 3 Laryngoscope, 2023.

    View details for DOI 10.1002/lary.30961

    View details for PubMedID 37589269

  • Development of a Patient-Derived 3D Immuno-Oncology Platform to Potentiate Immunotherapy Responses in Ascites-Derived Circulating Tumor Cells. Cancers Gerton, T. J., Green, A., Campisi, M., Chen, M., Gjeci, I., Mahadevan, N., Lee, C. A., Mishra, R., Vo, H. V., Haratani, K., Li, Z. H., Hasselblatt, K. T., Testino, B., Connor, T., Lian, C. G., Elias, K. M., Lizotte, P., Ivanova, E. V., Barbie, D. A., Dinulescu, D. M. 2023; 15 (16)


    High-grade serous ovarian cancer (HGSOC) is responsible for the majority of gynecology cancer-related deaths. Patients in remission often relapse with more aggressive forms of disease within 2 years post-treatment. Alternative immuno-oncology (IO) strategies, such as immune checkpoint blockade (ICB) targeting the PD-(L)1 signaling axis, have proven inefficient so far. Our aim is to utilize epigenetic modulators to maximize the benefit of personalized IO combinations in ex vivo 3D patient-derived platforms and in vivo syngeneic models. Using patient-derived tumor ascites, we optimized an ex vivo 3D screening platform (PDOTS), which employs autologous immune cells and circulating ascites-derived tumor cells, to rapidly test personalized IO combinations. Most importantly, patient responses to platinum chemotherapy and poly-ADP ribose polymerase inhibitors in 3D platforms recapitulate clinical responses. Furthermore, similar to clinical trial results, responses to ICB in PDOTS tend to be low and positively correlated with the frequency of CD3+ immune cells and EPCAM+/PD-L1+ tumor cells. Thus, the greatest response observed with anti-PD-1/anti-PD-L1 immunotherapy alone is seen in patient-derived HGSOC ascites, which present with high levels of systemic CD3+ and PD-L1+ expression in immune and tumor cells, respectively. In addition, priming with epigenetic adjuvants greatly potentiates ICB in ex vivo 3D testing platforms and in vivo tumor models. We further find that epigenetic priming induces increased tumor secretion of several key cytokines known to augment T and NK cell activation and cytotoxicity, including IL-6, IP-10 (CXCL10), KC (CXCL1), and RANTES (CCL5). Moreover, epigenetic priming alone and in combination with ICB immunotherapy in patient-derived PDOTS induces rapid upregulation of CD69, a reliable early activation of immune markers in both CD4+ and CD8+ T cells. Consequently, this functional precision medicine approach could rapidly identify personalized therapeutic combinations able to potentiate ICB, which is a great advantage, especially given the current clinical difficulty of testing a high number of potential combinations in patients.

    View details for DOI 10.3390/cancers15164128

    View details for PubMedID 37627156

    View details for PubMedCentralID PMC10452550

  • Inaugurating High-Throughput Profiling of Extracellular Vesicles for Earlier Ovarian Cancer Detection. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Jo, A., Green, A., Medina, J. E., Iyer, S., Ohman, A. W., McCarthy, E. T., Reinhardt, F., Gerton, T., Demehin, D., Mishra, R., Kolin, D. L., Zheng, H., Cheon, J., Crum, C. P., Weinberg, R. A., Rueda, B. R., Castro, C. M., Dinulescu, D. M., Lee, H. 2023: e2301930


    Detecting early cancer through liquid biopsy is challenging due to the lack of specific biomarkers for early lesions and potentially low levels of these markers. The current study systematically develops an extracellular-vesicle (EV)-based test for early detection, specifically focusing on high-grade serous ovarian carcinoma (HGSOC). The marker selection is based on emerging insights into HGSOC pathogenesis, notably that it arises from precursor lesions within the fallopian tube. This work thus establishes murine fallopian tube (mFT) cells with oncogenic mutations and performs proteomic analyses on mFT-derived EVs. The identified markers are then evaluated with an orthotopic HGSOC animal model. In serially-drawn blood of tumor-bearing mice, mFT-EV markers increase with tumor initiation, supporting their potential use in early cancer detection. A pilot clinical study (n = 51) further narrows EV markers to five candidates, EpCAM, CD24, VCAN, HE4, and TNC. The combined expression of these markers distinguishes HGSOC from non-cancer with 89% sensitivity and 93% specificity. The same markers are also effective in classifying three groups (non-cancer, early-stage HGSOC, and late-stage HGSOC). The developed approach, for the first time inaugurated in fallopian tube-derived EVs, could be a minimally invasive tool to monitor women at high risk of ovarian cancer for timely intervention.

    View details for DOI 10.1002/advs.202301930

    View details for PubMedID 37485618

  • Sustained delivery of PARP inhibitor Talazoparib for the treatment of BRCA-deficient ovarian cancer FRONTIERS IN ONCOLOGY Yang, S., Green, A., Brown, N., Robinson, A., Senat, M., Testino, B., Dinulescu, D. M., Sridhar, S. 2023; 13: 1175617


    Ovarian cancer has long been known to be the deadliest cancer associated with the female reproductive system. More than 15% of ovarian cancer patients have a defective BRCA-mediated homologous recombination repair pathway that can be therapeutically targeted with PARP inhibitors (PARPi), such as Talazoparib (TLZ). The expansion of TLZ clinical approval beyond breast cancer has been hindered due to the highly potent systemic side effects resembling chemotherapeutics. Here we report the development of a novel TLZ-loaded PLGA implant (InCeT-TLZ) that sustainedly releases TLZ directly into the peritoneal (i.p.) cavity to treat patient-mimicking BRCA-mutated metastatic ovarian cancer (mOC).InCeT-TLZ was fabricated by dissolving TLZ and PLGA in chloroform, followed by extrusion and evaporation. Drug loading and release were confirmed by HPLC. The in vivo therapeutic efficacy of InCeT-TLZ was carried out in a murine Brca2-/-p53R172H/-Pten-/- genetically engineered peritoneally mOC model. Mice with tumors were divided into four groups: PBS i.p. injection, empty implant i.p. implantation, TLZ i.p. injection, and InCeT-TLZ i.p. implantation. Body weight was recorded three times weekly as an indicator of treatment tolerance and efficacy. Mice were sacrificed when the body weight increased by 50% of the initial weight.Biodegradable InCeT-TLZ administered intraperitoneally releases 66 μg of TLZ over 25 days. In vivo experimentation shows doubled survival in the InCeT-TLZ treated group compared to control, and no significant signs of toxicity were visible histologically in the surrounding peritoneal organs, indicating that the sustained and local delivery of TLZ greatly maximized therapeutic efficacy and minimized severe clinical side effects. The treated animals eventually developed resistance to PARPi therapy and were sacrificed. To explore treatments to overcome resistance, in vitro studies with TLZ sensitive and resistant ascites-derived murine cell lines were carried out and demonstrated that ATR inhibitor and PI3K inhibitor could be used in combination with the InCeT-TLZ to overcome acquired PARPi resistance.Compared to intraperitoneal PARPi injection, the InCeT-TLZ better inhibits tumor growth, delays the ascites formation, and prolongs the overall survival of treated mice, which could be a promising therapy option that benefits thousands of women diagnosed with ovarian cancer.

    View details for DOI 10.3389/fonc.2023.1175617

    View details for Web of Science ID 000992495000001

    View details for PubMedID 37228496

    View details for PubMedCentralID PMC10203577

  • Manganese dioxide nanosheets induce mitochondrial toxicity in fish gill epithelial cells NANOTOXICOLOGY Browning, C. L., Green, A., Gray, E. P., Hurt, R., Kane, A. B. 2021; 15 (3): 400-417


    The development and production of engineered 2D nanomaterials are expanding exponentially, increasing the risk of their release into the aquatic environment. A recent study showed 2D MnO2 nanosheets, under development for energy and biomedical applications, dissolve upon interaction with biological reducing agents, resulting in depletion of intracellular glutathione levels within fish gill cells. However, little is known concerning their toxicity and interactions with subcellular organelles. To address this gap, we examined cellular uptake, cytotoxicity and mitochondrial effects of 2D MnO2 nanosheets using an in vitro fish gill cell line to represent a target tissue of rainbow trout, a freshwater indicator species. The data demonstrate cellular uptake of MnO2 nanosheets into lysosomes and potential mechanisms of dissolution within the lysosomal compartment. MnO2 nanosheets induced severe mitochondrial dysfunction at sub-cytotoxic doses. Quantitative, single cell fluorescent imaging revealed mitochondrial fission and impaired mitochondrial membrane potential following MnO2 nanosheet exposure. Seahorse analyses for cellular respiration revealed that MnO2 nanosheets inhibited basal respiration, maximal respiration and the spare respiratory capacity of gill cells, indicating mitochondrial dysfunction and reduced cellular respiratory activity. MnO2 nanosheet exposure also inhibited ATP production, further supporting the suppression of mitochondrial function and cellular respiration. Together, these observations indicate that 2D MnO2 nanosheets impair the ability of gill cells to respond to energy demands or prolonged stress. Finally, our data demonstrate significant differences in the toxicity of the 2D MnO2 nanosheets and their microparticle counterparts. This exemplifies the importance of considering the unique physical characteristics of 2D nanomaterials when conducting safety assessments.

    View details for DOI 10.1080/17435390.2021.1874562

    View details for Web of Science ID 000612410000001

    View details for PubMedID 33502918

    View details for PubMedCentralID PMC8026737

  • Chemical and Colloidal Dynamics of MnO2 Nanosheets in Biological Media Relevant for Nanosafety Assessment SMALL Gray, E. P., Browning, C. L., Vaslet, C. A., Gion, K. D., Green, A., Liu, M., Kane, A. B., Hurt, R. H. 2020; 16 (21): e2000303


    Many layered crystal phases can be exfoliated or assembled into ultrathin 2D nanosheets with novel properties not achievable by particulate or fibrous nanoforms. Among these 2D materials are manganese dioxide (MnO2 ) nanosheets, which have applications in batteries, catalysts, and biomedical probes. A novel feature of MnO2 is its sensitivity to chemical reduction leading to dissolution and Mn2+ release. Biodissolution is critical for nanosafety assessment of 2D materials, but the timing and location of MnO2 biodissolution in environmental or occupational exposure scenarios are poorly understood. This work investigates the chemical and colloidal dynamics of MnO2 nanosheets in biological media for environmental and human health risk assessment. MnO2 nanosheets are insoluble in most aqueous phases, but react with strong and weak reducing agents in biological fluid environments. In vitro, reductive dissolution can be slow enough in cell culture media for MnO2 internalization by cells in the form of intact nanosheets, which localize in vacuoles, react to deplete intracellular glutathione, and induce cytotoxicity that is likely mediated by intracellular Mn2+ release. The results are used to classify MnO2 nanosheets within a new hazard screening framework for 2D materials, and the implications of MnO2 transformations for nanotoxicity testing and nanosafety assessment are discussed.

    View details for DOI 10.1002/smll.202000303

    View details for Web of Science ID 000520536700001

    View details for PubMedID 32191401

    View details for PubMedCentralID PMC7461694

  • Synthesis and characterization of iron nanoparticles on partially reduced graphene oxide as a cost-effective catalyst for polymer electrolyte membrane fuel cells MRS COMMUNICATIONS Green, A., Isseroff, R., Lin, S., Wang, L., Rafailovich, M. 2017; 7 (2): 166-172