Browsing by Author "Zyromski, Nicholas"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Global Survey on Pancreatic Surgery During the COVID-19 Pandemic
    (Lippincott Williams & Wilkins, 2020-06-24) Oba, Atsushi; Stoop, Thomas F.; Löhr, Matthias; Hackert, Thilo; Zyromski, Nicholas; Nealon, William H.; Unno, Michiaki; Schulick, Richard D.; Al-Musawi, Mohammed H.; Wu, Wenming; Zhao, Yupei; Satoi, Sohei; Wolfgang, Christopher L.; Hilal, Mohammad Abu; Besselink, Marc G.; Del Chiaro, Marco; Surgery, School of Medicine
    This global survey among members of seven international pancreatic associations and study groups elucidates the role of pancreatic surgery during the COVID-19 pandemic, regarding patient selection for the surgical and oncological treatment of pancreatic diseases to support clinical decision-making and creating a starting point for further discussion.
  • Thumbnail Image
    Item
    Interventions for Pancreatitis-New Approaches, Knowledge Gaps, and Research Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop
    (Wolters Kluwer, 2024) Evans Phillips, Anna; Hughes, Steven J.; Andersen, Dana K.; Bell, Adam; Brand, Randall; Coté, Gregory A.; Cowdin, Adriana; Diazgranados, Nancy; Dudeja, Vikas; Duggan, Sinead N.; Fogel, Evan; Forsmark, Chris E.; Freeman, A. Jay; Gittes, George; Hart, Phil A.; Jeon, Christie; Nealon, William; Neoptolemos, John; Palermo, Tonya M.; Pandol, Stephen; Roberts, Kristen M.; Rosenthal, Martin; Singh, Vikesh K.; Yadav, Dhiraj; Whitcomb, David C.; Zyromski, Nicholas; Medicine, School of Medicine
    There exists no cure for acute, recurrent acute or chronic pancreatitis and treatments to date have been focused on managing symptoms. A recent workshop held by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) focused on interventions that might disrupt or perhaps even reverse the natural course of this heterogenous disease, aiming to identify knowledge gaps and research opportunities that might inform future funding initiatives for NIDDK. The breadth and variety of identified active or planned clinical trials traverses the spectrum of the disease and was conceptually grouped for the workshop into behavioral, nutritional, pharmacologic and biologic, and mechanical interventions. Cognitive and other behavioral therapies are proven interventions for pain and addiction, but barriers exist to their use. Whilst a disease specific instrument quantifying pain is now validated, an equivalent is lacking for nutrition - and both face challenges in ease and frequency of administration. Multiple pharmacologic agents hold promise. Ongoing development of Patient Reported Outcome (PRO) measurements can satisfy Investigative New Drug (IND) regulatory assessments. Despite multiple randomized clinical trials demonstrating benefit, great uncertainty remains regarding patient selection, timing of intervention, and type of mechanical intervention (endoscopic versus surgery). Challenges and opportunities to establish beneficial interventions for patients were identified.
  • Thumbnail Image
    Item
    Novel Preoperative Patient-centered Surgical Wellness Program Impacts Length of Stay Following Pancreatectomy
    (International Institute of Anticancer Research, 2021-04) Soufi, Mazhar; Deperalta, Danielle K.; Simpson, Rachel; Flick, Katelyn; Yip-Schneider, Michele T.; Schmidt, Christian M., II; Kilbane, Molly; Colgate, Cameron; Kelley, Kristen E.; Wooden, William; Ceppa, Eugene P.; House, Michael; Zyromski, Nicholas; Nakeeb, Atilla; Schmidt, C. Max; Surgery, School of Medicine
    Background/Aim: We created a novel, preoperative wellness program (WP) that promotes recovery. This study assessed its impact on patient outcomes after pancreatectomy. Patients and Methods: Pancreatoduodenectomies (PD) and distal pancreatectomies (DP) performed from 2015 to 2018 were reviewed using our institutional NSQIP database. Patients in the WP had their medical conditions optimized and were provided with the following: chlorhexidine, topical mupirocin, incentive spirometer, and immune-nutrition supplements. Results: Out of a total of 669 pancreatectomy patients (411 PD, 258 DP), 308 were enrolled in the WP (188 PD, 120 DP). In the PD subgroup, on multivariable analysis (MVA), the WP patients had shorter lengths of hospital stay (LOS) (12 vs. 10 days, p<0.001). On MVA, WP patients had less post-op transfusion (20 vs. 10%, p=0.027). For the combined groups on MVA, LOS continued to be significant (OR=0.89, 95%CI=0.82-0.97, p<0.007). Conclusion: A preoperative patient centered WP may reduce the length of stay.
  • Thumbnail Image
    Item
    Regulation of HIF1 under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual-Targeting in Patient-Derived 3D Pancreatic Cancer Models
    (Office of the Vice Chancellor for Research, 2016-04-08) Logsdon, Derek P.; Grimard, Michelle; Shahda, Safi; Zyromski, Nicholas; Schipani, Ernestina; Carta, Fabrizio; Supuran, Claudiu T.; Korc, Murray; Ivan, Mircea; Kelley, Mark R.; Fishel, Melissa L.
    Abstract Half of all patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) die within a year despite extensive surgery and/or a highly aggressive chemotherapy regimen. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including reactive stroma and hypoxia. Hypoxia signaling creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. Carbonic anhydrase IX (CA9) functions as part of the cellular hypoxia response to regulate intracellular pH, promoting cell survival. Apurinic/Apyrimidinic Endonuclease-1-Reduction/oxidation Effector Factor 1 (APE1/Ref-1) is a multi-functional protein with two major activities: an endonuclease function in DNA base excision repair and a redox signaling function that reduces oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. We explored the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling control of hypoxia inducible factor 1 alpha (HIF1), a critical factor in hypoxiainduced CA9 transcription. We hypothesized that obstructing the HIF-CA9 axis at two points via APE1/Ref-1 inhibition and CA9 inhibition will result in enhanced PDAC cell killing under hypoxic conditions. Methods: We performed qRT-PCR and Western Blots to confirm changes in CA9 expression in PDAC cells following APE1/Ref-1 inhibition and hypoxia exposure. Proliferation assays were used to assess cell killing following inhibition of APE1/Ref-1 and CA9 under hypoxia. Ex vivo 3-Dimensional co-culture models including both tumor and CAFs were used to examine whether we could enhance the efficacy of APE1/Ref-1 and/or CA9 inhibition with a dual-targeting approach to kill tumor spheroids. Results: HIF1-mediated induction of CA9 is significantly diminished in PDAC cells following APE1/Ref-1 redox inhibition. Additionally, dual-targeting of APE1/Ref-1 and CA9 reduces PDAC tumor cell growth under hypoxic conditions and in 3D tumor co-cultures.
  • Thumbnail Image
    Item
    Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models
    (AACR, 2016-11-01) Logsdon, Derek P.; Grimard, Michelle; Luo, Meihua; Shahda, Safi; Jiang, Yanlin; Tong, Yan; Yu, Zhangsheng; Zyromski, Nicholas; Schipani, Ernestina; Carta, Fabrizio; Supuran, Claudiu T.; Korc, Murray; Ivan, Mircea; Kelley, Mark R.; Fishel, Melissa L.; Department of Pediatrics, School of Medicine
    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multifunctional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia-inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as a part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with the hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α–mediated induction of CA9. Furthermore, an ex vivo three-dimensional tumor coculture model demonstrates dramatic enhancement of APE1/Ref-1–induced cell killing upon dual targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development; therefore, these studies have the potential to direct novel PDAC therapeutic treatment.
  • Thumbnail Image
    Item
    Targeting Ref-1/APE1 Pathway Inhibition in Pancreatic Cancer Using APX3330 for Clinical Trials
    (Office of the Vice Chancellor for Research, 2016-04-08) Fishel, Melissa L.; Logsdon, Derek P.; Supuran, Claudiu T.; Zyromski, Nicholas; Ivan, Mircea; Kelley, Mark R.; Shah, Fenil
    Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer-related mortality in the US. Most patients present with advanced disease and ~95% die within five years, most surviving under six months. Targeted therapies offer modest improvement in survival, albeit at an increase in side effects and unwanted toxicities. Ref-1 regulates transcription factors involved in pancreatic cancer cell survival signaling due to its redox-coactivator activity, such as HIF-1α, NFκB, NRF2 and STAT3. High expression levels of Ref-1 indicate decreased survival in PDAC and other cancers. APX3330, a specific Ref-1 inhibitor, has been shown in multiple in vitro and in vivo pancreatic cancer models to be effective in reducing tumor growth and metastases. The safety and dose administration of APX3330 have been previously established, including toxicology, phase I, and phase II clinical evaluation in non-cancer patients in Japan (Eisai). We have partnered with ApeX Therapeutics to develop APX3330 for cancer treatment (phase I trial anticipated early 2016). We studied interactions of Ref-1, APX3330, convergent pathways; i.e. HIF-1α and STAT3, and downstream targets like CAIX. We performed in vivo studies demonstrating single and combination effects of APX3330 with Gemcitabine (Gem) showing significantly decreased tumor volume in the combination treatments. We also tested single and combination studies of APX3330 in an ex vivo 3-D tumor-stroma model system using patient derived tumor cells along with patient derived cancer-associated fibroblasts. We used the CAIX inhibitor SLC-0111 and JAK2 inhibitor, Ruxolitinib; both in clinical trials. In our system, APX3330 decreases the tumor area and intensity in a dose-dependent manner. The combination of APX3330 with Gem demonstrated an additive enhancement effect in the tumor, and APX3330 with SLC-0111/Ruxolitinib enhanced tumor killing. These data demonstrate APX3330 single agent efficacy in our 3D patient model and enhanced tumor killing when pathways regulated by Ref-1, HIF-1 and STAT3 are blocked.