74 results on '"Ponnala S"'
Search Results
2. Applying Epistemic Network Analysis to Explore The Distribution of Work Across Dementia Care Networks
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Linden, A.R., primary, Ponnala, S., additional, and Werner, N.E., additional
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- 2022
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Catalog
3. Role of shigella infection in endometriosis: A novel hypothesis
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Kodati, V.L., Govindan, S., Movva, S., Ponnala, S., and Hasan, Q.
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- 2008
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4. Conceptualizing caregiver workload: an exploratory study guided by NASA TLX
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Rutkowski, R.A., primary, Ponnala, S., additional, Gonzalez-Vargas, J., additional, Gilmore-Bykovskyi, A., additional, Block, L., additional, Kind, A.J., additional, and Werner, N.E., additional
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- 2019
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5. Effect of the radiometal on the pharmacokinetics of a PSMA-targeting ligand for radioligand therapy
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Kelly, J., primary, Amor-Coarasa, A., additional, Ponnala, S., additional, Nikolopoulou, A., additional, Williams, C., additional, and Babich, J., additional
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- 2019
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6. A comparison of chelate labeling with Ac-225: application to PSMA-targeting radiopharmaceuticals
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Kelly, J., primary, Amor-Coarasa, A., additional, Ponnala, S., additional, Thiele, N., additional, Nikolopoulou, A., additional, Williams, C., additional, Wilson, J., additional, Vallabhajosula, S., additional, and Babich, J., additional more...
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- 2019
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7. Production, purification and use of 66Ga for “in vivo” screening of therapeutic compounds
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Amor-Coarasa, A., primary, Kelly, J., additional, Ponnala, S., additional, Nikolopoulou, A., additional, Williams, C., additional, and Babich, J., additional
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- 2019
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8. Defining the origins of multiple emission/excitation in rhenium-bisthiazole complexes
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Azzarelli, N., Ponnala, S., Aguirre, A., Dampf, S.J., Davis, M.P., Ruggiero, M.T., Lopez Diaz, V., Babich, J.W., Coogan, M., Korter, T., Doyle, R.P., Zubieta, J., Azzarelli, N., Ponnala, S., Aguirre, A., Dampf, S.J., Davis, M.P., Ruggiero, M.T., Lopez Diaz, V., Babich, J.W., Coogan, M., Korter, T., Doyle, R.P., and Zubieta, J. more...
- Abstract
The underlying mechanism of the unusual emissive behavior of [Re(CO) 3 -1,1-bis-4-thiazole-(1,4)-diaminobutane)] bromide (4-BT) has been investigated. Synthesis and spectroscopic characterization of structurally similar isomers ([Re(CO) 3 -1,1-bis-2-thiazole-(1,4)-diaminobutane)] bromide (2-BT)) and the location of triplet states, solid state and low temperature spectroscopic measurements, and DFT calculations show that the photophysical properties are not due to photoisomerization as previously hypothesized. The results show that the unusual emissive behavior is not observed in structural isomers, is specific to the previously reported complex, 4-BT, and may arise from vibrational energy relaxation and vibrational cooling. Translation of the unusual emissive behavior to the solid state offers an interesting platform allowing this complex to be potentially utilized as a probe, sensor or photonic device. more...
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- 2019
9. PP#144 - Effect of the radiometal on the pharmacokinetics of a PSMA-targeting ligand for radioligand therapy
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Kelly, J., Amor-Coarasa, A., Ponnala, S., Nikolopoulou, A., Williams, C., and Babich, J.
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- 2019
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10. PP#82 - Production, purification and use of 66Ga for “in vivo” screening of therapeutic compounds
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Amor-Coarasa, A., Kelly, J., Ponnala, S., Nikolopoulou, A., Williams, C., and Babich, J.
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- 2019
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11. OP#27 - A comparison of chelate labeling with Ac-225: application to PSMA-targeting radiopharmaceuticals
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Kelly, J., Amor-Coarasa, A., Ponnala, S., Thiele, N., Nikolopoulou, A., Williams, C., Wilson, J., Vallabhajosula, S., and Babich, J.
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- 2019
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12. Oxidative Heteroannulation Route to Benzoxazoles and Benzimidazoles
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Sahu, D., primary and Ponnala, S., additional
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- 2007
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13. Oxidative Heteroannulation Route to Benzoxazoles and Benzimidazoles.
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Ponnala, S. and Sahu, D.P.
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- 2007
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14. In vitro and ex vivo evaluation of preclinical models for FAP-targeted theranostics: differences and relevance for radiotracer evaluation.
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van der Heide CD, Campeiro JD, Ruigrok EAM, van den Brink L, Ponnala S, Hillier SM, and Dalm SU
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Background: Fibroblast activation protein (FAP) is an attractive target for cancer theranostics. Although FAP-targeted nuclear imaging demonstrated promising clinical results, only sub-optimal results are reported for targeted radionuclide therapy (TRT). Preclinical research is crucial in selecting promising FAP-targeted radiopharmaceuticals and for obtaining an increased understanding of factors essential for FAP-TRT improvement. FAP is mainly expressed by cancer-associated fibroblasts in the tumor stroma and less on cancer cells themselves. Therefore, other (complex) factors impact FAP-TRT efficacy compared to currently clinically applied TRT strategies. For accurate evaluation of these aspects, selection of a representative preclinical model is important. Currently mainly human cancer cell lines transduced to (over)express FAP are applied, lacking clinical representation. It is unclear how these and more physiological FAP-expressing models compare to each other, and whether/how the model influences the study outcome. We aimed to address this by comparing FAP tracer behavior in FAP-transduced HT1080-huFAP and HEK293-huFAP cells, and endogenous FAP-expressing U-87 MG cancer cells and PS-1 pancreatic stellate cells. [
111 In]In-FAPI-46 and a fluorescent FAP-targeted tracer (RTX-1370S) were used to compare tracer binding/uptake and localization in vitro and ex vivo. Additionally, FAP expression was determined with RT-qPCR and anti-FAP IHC., Results: Although FAP expression was highest in HEK293-huFAP cells and cell line derived xenografts, this did not result in the highest tracer uptake. [111 In]In-FAPI-46 uptake was highest in HT1080-huFAP, closely followed by HEK293-huFAP, and a 6-10-fold lower uptake for U-87 MG and PS-1 cells. However, ex vivo U-87 MG xenografts only showed a 2-fold lower binding compared to HT1080-huFAP and HEK293-huFAP xenografts, mainly because the cell line attracts murine fibroblasts as demonstrated in our RT-qPCR and IHC studies., Conclusions: The interaction between FAP and FAP-targeted tracers differs between models, indicating the need for appropriate model selection and that comparing results across studies using different models is difficult., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted according to the guidelines of the Declaration of Helsinki. Consent for participation was not applicable. Consent for publication: Not applicable. Competing interests: Shashikanth Ponnala and Shawn M Hillier are employees and shareholders of Ratio Therapeutics, Inc., (© 2024. The Author(s).) more...- Published
- 2024
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15. A proactive learning approach toward building adaptive capacity during COVID-19: A radiology case study.
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Hegde S, Larsen E, Torbett O, Ponnala S, Pohl E, Sze R, and Schaeubinger MM
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- Child, Humans, Pandemics, Learning, Radiography, COVID-19, Radiology
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The COVID-19 pandemic has challenged organizations to adapt under uncertainty and time pressure, with no pre-existing protocols or guidelines available. For organizations to learn to adapt effectively, there is a need to understand the perspectives of the frontline workforce involved in everyday operations. This study implemented a survey-tool to elicit narratives of successful adaptation based on the lived experiences frontline radiology staff at a large multispecialty pediatric hospital. Fifty-eight members of the radiology frontline staff responded to the tool between July and October of 2020. Qualitative analysis of the free-text data revealed five categories of themes that underpinned adaptive capacity of the radiology department during the pandemic: information flow, attitudes and initiative, new and adjusted workflows, availability and utilization of resources, and collaboration and teamwork. Enablers of adaptive capacity included timely and clear communication about procedures and policies from the leadership to frontline staff, and revised workflows with flexible work arrangements, such as remote patient screening. Responses to multiple choice questions in the tool helped identify the main categories of challenges faced by staff, factors that enabled successful adaptation, and resources used. The study demonstrates the use of a survey-tool to proactively identify frontline adaptations. The paper also reports a system-wide intervention resulting directly from a discovery enabled by the findings based on the use of RETIPS in the radiology department. In general, the tool could be used in concert with existing learning mechanisms, such as safety event reporting systems, to inform leadership-level decisions to support adaptive capacity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.) more...
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- 2023
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16. Partnering for Integrated Care: A Learning Collaborative for Primary Care and Oral Health Teams.
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Cardenas K, Weilnau T, Aguilar C, Ali A, Eidelman A, Ponnala S, Russel T, Schwanderla J, Sievers K, Wu H, Silk H, Hunt LS, Barrow J, Riedy CA, and Phillips RS
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- Humans, Oral Health, Primary Health Care, Gingivitis, Hypertension diagnosis, Hypertension therapy, Delivery of Health Care, Integrated
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Purpose: The Teaming and Integrating for Smiles and Health (TISH) Learning Collaborative was developed to help health care organizations accelerate progress in integrating delivery of oral and primary care. By providing expert support and a structure for testing change, the project aimed to improve the early detection of hypertension in the dental setting and of gingivitis in the primary care setting, and to increase the rate of bidirectional referrals between oral and primary care partners. We report its outcomes., Methods: A total of 17 primary and oral health care teams were recruited to participate in biweekly virtual calls over 3 months. Participants tested changes to their models of care through Plan-Do-Study-Act cycles between calls. Sites tracked the percentages of patients screened and referred, completed the TeamSTEPPS (Team Strategies and Tools to Enhance Performance and Patient Safety) and Interprofessional Assessment questionnaires, and provided qualitative feedback and updates in storyboard presentations., Results: On average, with implementation of the TISH Learning Collaborative, sites displayed a nonrandom improvement in the percentages of patients screened for hypertension, referred for hypertension, referred to primary care, and referred for gingivitis. Gingivitis screening and referral to oral health care were not markedly improved. Qualitative responses indicated that teams made progress in screening and referral workflows, improved communication between medical and dental partners, and furthered understanding of the connection between primary care and oral care among staff and patients., Conclusions: The TISH project is evidence that a virtual Learning Collaborative is an accessible and productive avenue to improve interprofessional education, further primary care and oral partnerships, and achieve practical progress in integrated care., Competing Interests: Conflicts of interest: Dr Phillips is an advisor for Bicycle Health, a for-profit company providing telemedicine services to patients with opioid use disorder. He is also an advisor for Grow Therapy, a for-profit company that assists social workers and psychiatric nurse practitioners with insurance credentialing, record keeping, billing, and marketing. The other authors report no conflicts., (© 2023 Annals of Family Medicine, Inc.) more...
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- 2023
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17. Intraoperative workload during robotic radical prostatectomy: Comparison between multi-port da Vinci Xi and single port da Vinci SP robots.
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Norasi H, Tetteh E, Law KE, Ponnala S, Hallbeck MS, and Tollefson M
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- Humans, Male, Prospective Studies, Prostatectomy methods, Workload, Robotic Surgical Procedures methods, Robotics
- Abstract
The goal of this study was to quantify and compare prospective self-reported intraoperative workload and teamwork during robot-assisted radical prostatectomy (RARP) for multi-port da Vinci Xi (MP) and single-port da Vinci SP (SP) robots. The self-reported workload (surgeon and surgical team) and teamwork (surgeon) measures were collected and compared between MP and SP RARPs, as well as the learning curve. Results from 25 MP and SP RARPs showed that overall, the NASA-TLX workload subscales were lower, and the teamwork modified NOTECHS subscales were higher for the MP RARPs compared to the SP RARPs. The underlying reason for the significant differences between these two RARP surgical procedures could be other factors (e.g., robot design factors) in addition to the surgeon and surgical team's experience. The results also suggested learning effects through the 25 SP RARPs; however, twenty-five procedures may not be enough to achieve proficiency with the SP system., (Copyright © 2022 Elsevier Ltd. All rights reserved.) more...
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- 2022
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18. A human factors and ergonomics approach to conceptualizing care work among caregivers of people with dementia.
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Werner NE, Rutkowski RA, Holden RJ, Ponnala S, and Gilmore-Bykovskyi A
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- Ergonomics, Humans, Qualitative Research, Caregivers, Dementia
- Abstract
Society relies upon informal (family, friend) caregivers to provide much of the care to the estimated 43.8 million individuals living with Alzheimer's disease and related dementias globally. Caregivers rarely receive sufficient training, resources, or support to meet the demands associated with dementia care, which is often associated with increased risk of suboptimal outcomes. Human factors and ergonomics (HFE) can address the call for new approaches to better understand caregiving and support caregiver performance through systematic attention to and design of systems that support the work of caregivers- their care work. Thus, our objective was to perform a work system analysis of care work. We conducted a qualitative study using a Critical Incident Technique interviewing approach and Grounded Dimensional Analysis analytic procedures. Our findings introduce a new conceptual framework for understanding the care work system of dementia caregivers and suggest that care work is influenced by interactions among distinct caregiver goals, the task demands of the care needs of the person with dementia, daily life needs of the caregiver and family, and contextual factors that shape caregivers' perceptions surrounding care. The initial work system model produced by this study provides a foundation from which future work can further elucidate the care work system, determine how the care work system intersects and coordinates with other work systems such as the patient work system, and design systems that address caregivers' individual caregiving context., (Copyright © 2022 Elsevier Ltd. All rights reserved.) more...
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- 2022
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19. A Trifunctional Theranostic Ligand Targeting Fibroblast Activation Protein-α (FAPα).
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Kelly JM, Jeitner TM, Ponnala S, Williams C Jr, Nikolopoulou A, DiMagno SG, and Babich JW
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- Animals, Cell Line, Tumor, Female, Humans, Ligands, Mice, Positron Emission Tomography Computed Tomography, Tissue Distribution, Xenograft Model Antitumor Assays, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Cancer-Associated Fibroblasts metabolism, Endopeptidases metabolism, Membrane Proteins metabolism, Precision Medicine methods, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics
- Abstract
Purpose: Fibroblast activation protein-α (FAPα) is uniquely expressed in activated fibroblasts, including cancer-associated fibroblasts that populate tumor stroma and contribute to proliferation and immunosuppression. Radiolabeled FAPα inhibitors enable imaging of multiple human cancers, but time-dependent clearance from tumors currently limits their utility as FAPα-targeted radiotherapeutics. We sought to increase the area under the curve (AUC) by constructing a trifunctional ligand that binds FAPα with high affinity and also binds albumin and theranostic radiometals., Procedures: RPS-309 comprised a FAPα-targeting moiety, an albumin-binding group, and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Inhibition of recombinant human FAPα (rhFAPα) was determined by colorimetric assay. Affinity for human serum albumin (HSA) was determined by high-performance affinity chromatography. The tissue distribution of [
68 Ga]Ga-RPS-309 in SW872 tumor xenograft-bearing mice was imaged by microPET/CT and quantified by biodistribution studies performed from 30 min to 3 h post injection (p.i.). The biodistribution of [177 Lu]Lu-RPS-309 was determined at 4, 24, and 96 h p.i., Results: RPS-309 inhibits rhFAPα with IC50 = 7.3 ± 1.4 nM. [68 Ga]Ga-RPS-309 is taken up specifically by FAPα-expressing cells and binds HSA with Kd = 4.6 ± 0.1 μM. Uptake of the radiolabeled ligand in tumors was evident from 30 min p.i. (> 5 %ID/g) and was significantly reduced by co-injection of RPS-309. Specific skeletal uptake was also observed. Activity in tumors was constant through 4 h p.i., but cleared significantly by 24 h. The AUC in this period was 127 (%ID/g) × h., Conclusions: RPS-309 is a high-affinity FAPα inhibitor with prolonged plasma residence. Introduction of the albumin-binding group did not compromise FAPα binding. Although initial tumor uptake was high and FAPα-specific, RPS-309 also progressively cleared from tumors. Nevertheless, RPS-309 incorporates multiple sites in which structural diversity can be introduced, and therefore serves as a platform for future structure-activity relationship studies., (© 2021. World Molecular Imaging Society.) more...- Published
- 2021
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20. Physiologic Monitor Alarm Burden and Nurses' Subjective Workload in a Children's Hospital.
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Rasooly IR, Kern-Goldberger AS, Xiao R, Ponnala S, Ruppel H, Luo B, Craig S, Khan A, McLoone M, Ferro D, Muthu N, Won J, and Bonafide CP
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- Child, Cross-Sectional Studies, Hospitals, Pediatric, Humans, Workload, Clinical Alarms, Nurses
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Background and Objectives: Physiologic monitor alarms occur at high rates in children's hospitals; ≤1% are actionable. The burden of alarms has implications for patient safety and is challenging to measure directly. Nurse workload, measured by using a version of the National Aeronautics and Space Administration Task Load Index (NASA-TLX) validated among nurses, is a useful indicator of work burden that has been associated with patient outcomes. A recent study revealed that 5-point increases in the NASA-TLX score were associated with a 22% increased risk in missed nursing care. Our objective was to measure the relationship between alarm count and nurse workload by using the NASA-TLX., Methods: We conducted a repeated cross-sectional study of pediatric nurses in a tertiary care children's hospital to measure the association between NASA-TLX workload evaluations (using the nurse-validated scale) and alarm count in the 2 hours preceding NASA-TLX administration. Using a multivariable mixed-effects regression accounting for nurse-level clustering, we modeled the adjusted association of alarm count with workload., Results: The NASA-TLX score was assessed in 26 nurses during 394 nursing shifts over a 2-month period. In adjusted regression models, experiencing >40 alarms in the preceding 2 hours was associated with a 5.5 point increase (95% confidence interval 5.2 to 5.7; P < .001) in subjective workload., Conclusion: Alarm count in the preceding 2 hours is associated with a significant increase in subjective nurse workload that exceeds the threshold associated with increased risk of missed nursing care and potential patient harm., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.) more...
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- 2021
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21. Attending Surgeons Demonstrate Greater Correlations of Skill Assessment and Anticipation of Adverse Events Than Residents During Laparoscopic Cholecystectomy.
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Lau N, Hartman-Kenzler J, Fichtel E, Park J, Ponnala S, Parker SH, Fitzgibbons S, and Safford SD
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- Adult, Aged, Cholecystectomy, Laparoscopic adverse effects, Educational Measurement, Female, Humans, Male, Middle Aged, Self-Assessment, Young Adult, Cholecystectomy, Laparoscopic education, Clinical Competence, Internship and Residency, Surgeons
- Abstract
Background: Surgical training includes the development of technical and nontechnical skills. While technical skills are more easily quantified, nontechnical skills such as situation awareness (SA) are more difficult to measure and quantify. This study investigated the relationships between different SA elements and expertise., Methods: Twenty attending and resident surgeons rated their anticipation of an impending adverse event while watching 20 videos of laparoscopic cholecystectomies with and without adverse events. After watching each video, they assessed surgeon skills and self-assessed their anticipation ratings. All participants answered a general confidence questionnaire before and after the study., Results: Videos with adverse events led to significantly higher anticipation of adverse events (P < 0.001), lower surgeon skill rating (P < 0.001), and higher self-assessment in their anticipation ratings (P < 0.001) across both participant groups. General confidence was significantly lower for residents than that for attending surgeons (P < 0.001). Compared with the residents, attendings exhibited stronger and more stable correlations between measurements of SA. When viewing videos with adverse events, attendings showed significantly higher correlation between anticipation of an impending adverse event and skill assessment of the surgeon (P = 0.005)., Conclusions: This study investigated how different elements of SA and their relationships were influenced by experience. The results indicated that attendings had stronger and more stable correlations between SA elements than residents, demonstrating how measurement correlations could be meaningful and sensitive indicators of expertise and autonomy readiness., (Copyright © 2021 Elsevier Inc. All rights reserved.) more...
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- 2021
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22. [Retracted] Metabolic remodeling precedes mitochondrial outer membrane permeabilization in human glioma xenograft cells.
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Ponnala S, Chetty C, Veeravalli KK, Dinh DH, Klopfenstein JD, and Rao JS
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Following the publication of the above paper, we were contacted by the University of Illinois at Chicago, to request the retraction of the above article. Following a formal institutional investigation, the investigation panel concluded that the images in question had falsifying elements. Regarding the above study, the specific allegations that were investigated were that of falsifying elements of Fig. 6A, row 2, columns 2 and 3. Following a review of this paper conducted independently by the Editor of International Journal of Oncology , the Editor concurred with the conclusions of the investigation panel, and therefore the above paper has been retracted from the publication. We also tried to contact the authors, but did not receive a reply. The Editor apologizes to the readership for the inconvenience caused.[the original article was published in International Journal of Oncology 40: 509‑518, 2012; DOI: 10.3892/ijo.2011.1255]. more...
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- 2021
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23. Human factors/ergonomics work system analysis of patient work: state of the science and future directions.
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Werner NE, Ponnala S, Doutcheva N, and Holden RJ
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- Adult, Caregivers, Chronic Disease, Humans, Ergonomics, Patient Safety
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Purpose: To demonstrate the use and value of the Human Factors/Ergonomics-based Systems Engineering Initiative for Patient Safety (SEIPS) family of work system models for studying and improving patient work., Data Sources: We conducted a review of the published empirical literature applying the SEIPS family of work system models for patient work., Study Selection: Included studies had to apply one of the SEIPS family of work system models to study patient work; be published in a peer-reviewed journal in English and include analysis of data. We identified 16 articles that met our inclusion criteria., Data Extraction: For each study, we extracted settings and situations in which models were applied; research design; study methods; model(s) used; type and number of study participants; study objective(s); whether the study included an intervention; specific aspects of the model used; knowledge generated about patient work and benefits of using the models., Results of Data Synthesis: Our analysis revealed that a majority of studies were conducted in the United States, used qualitative or mixed methods and employed a variety of data collection techniques to study adult patient populations with chronic illness and their informal caregivers and healthcare providers performing patient work in the home and clinical setting. The studies resulted in a variety of useful products, demonstrating several benefits of using the models., Conclusion: Our review has demonstrated the value of using the SEIPS family of work systems models to study and improve patient and family contributions to health-related work., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...
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- 2021
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24. A process-based approach to exploring the information behavior of informal caregivers of people living with dementia.
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Rutkowski RA, Ponnala S, Younan L, Weiler DT, Bykovskyi AG, and Werner NE
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- Access to Information, Caregivers, Communication, Humans, Dementia, Medical Informatics
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Introduction and Purpose: Informal caregivers of persons living with dementia have significant unmet information needs that, if met, would better equip them to provide effective care. Despite the existence of health information technologies, websites, resources, and organizations dedicated to dementia caregiving, caregivers continue to report unmet information needs. Caregivers' continued unmet information needs suggest a misalignment between information products, and caregivers' information behavior-how caregivers generate, acquire, manage, use, communicate, and seek information. Researchers have developed conceptual models for understanding caregivers' information behavior, but these models are limited in that they are task-oriented, and they assume that caregivers' information needs will be met if they engage in information behavior. To address these limitations, the present study sought to explore caregivers' information behavior as a sociotechnical-systems-based process., Methods: We conduced semi-structured interviews with 30 self-identified caregivers to explore their daily experience of caregiving activities, including their information behavior. We applied a process-based conceptual framework that takes into account inputs, processes, outputs, and feedback mechanisms within a sociotechnical system to guide analysis. The process of interest was caregivers' information behavior as modeled by the information-seeking and communication model (ISCM). We conducted a deductive content analysis guided by the components of the ISCM. We then used team-based affinity diagramming to collapse and categorize the ISCM components into inputs, processes, outputs, and feedback., Results: We developed a conceptual model to depict caregivers' information behavior as a sociotechnical-systems-based process of inputs, processes, and outputs that feedback into the system. The conceptual model consisted of three inputs (i.e., information users, information providers, and information products), three information seeking and communication processes (i.e., information access, information interaction, and information assessment and processing), two outputs (i.e., utility and credibility), and feedback., Discussion and Conclusion: Building on and addressing the gaps in previous information behavior models, our conceptual framework advances the previous task-level understandings of caregivers' information behavior into a comprehensive feedback-driven, process-level perspective consisting of context-based inputs, information seeking and communication processes, outputs, and feedback. A sociotechnical-systems-based understanding of caregivers' information behavior allows for misalignments between information providers and products, and caregivers' information behavior not only to be illuminated, but systematically addressed., (Copyright © 2020. Published by Elsevier B.V.) more...
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- 2021
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25. Preclinical Evaluation of a High-Affinity Sarcophagine-Containing PSMA Ligand for 64 Cu/ 67 Cu-Based Theranostics in Prostate Cancer.
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Kelly JM, Ponnala S, Amor-Coarasa A, Zia NA, Nikolopoulou A, Williams C Jr, Schlyer DJ, DiMagno SG, Donnelly PS, and Babich JW
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- Animals, Cell Line, Male, Mice, Inbred BALB C, Molecular Structure, Positron Emission Tomography Computed Tomography, Precision Medicine methods, Prostatic Neoplasms metabolism, Copper chemistry, Copper Radioisotopes chemistry, Prostate-Specific Antigen metabolism, Prostatic Neoplasms diagnostic imaging
- Abstract
The application of small molecules targeting prostate-specific membrane antigen (PSMA) has emerged as a highly promising clinical strategy for visualization and treatment of prostate cancer. Ligands that integrate the ability to both quantify the distribution of radioactivity and treat disease through the use of a matched pair of radionuclides have particular value in clinical and regulatory settings. In this study, we describe the development and preclinical evaluation of RPS-085, a ligand that binds PSMA and serum albumin and exploits the
64/67 Cu radionuclide pair for prostate cancer theranostics. RPS-085 was synthesized by conjugation of a PSMA-targeting moiety, an Nε -(2-(4-iodophenyl)acetyl)lysine albumin binding group, and a bifunctionalized MeCOSar chelator. The IC50 of the metal-free RPS-085 was determined in a competitive binding assay. The affinity for human serum albumin of the radiolabeled compound was determined by high-performance affinity chromatography. Radiolabeling was performed in NH4 OAc buffer at 25 °C. The stability of the radiolabeled compounds was assessed in vitro and in vivo. The biodistribution of [64/67 Cu]Cu-RPS-085 was determined following intravenous administration to male BALB/c mice bearing LNCaP tumor xenografts. The radiochemical yields of [64/67 Cu]Cu-RPS-085 were nearly quantitative after 20 min. The metal-free complex is a potent inhibitor of PSMA (IC50 = 29 ± 2 nM), and the radiolabeled compound has moderate affinity for human serum albumin ( Kd = 9.9 ± 1.7 μM). Accumulation of the tracer in mice was primarily evident in tumor and kidneys. Activity in all other tissues, including blood, was negligible, and the radiolabeled compounds demonstrated high stability in vitro and in vivo. Tumor activity reached a maximum at 4 h post injection (p.i.) and cleared gradually over a period of 96 h. By contrast, activity in the kidney cleared rapidly from 4 to 24 h p.i. As a consequence, by 24 h p.i., the tumor-to-kidney ratio exceeds 2, and the predicted dose to tumors is significantly greater than the dose to kidneys. [64 Cu]Cu-RPS-085 combines rapid tissue distribution and clearance with prolonged retention in LNCaP tumor xenografts. The pharmacokinetics should enable radioligand therapy using [67 Cu]Cu-RPS-085. By virtue of its rapid kidney clearance, the therapeutic index of [67 Cu]Cu-RPS-085 likely compares favorably to its parent structure, [177 Lu]Lu-RPS-063, a highly avid PSMA-targeting compound. On this basis, [64/67 Cu]Cu-RPS-085 show great promise as PSMA-targeting theranostic ligands for prostate cancer imaging and therapy. more...- Published
- 2020
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26. Conceptualizing caregiving activities for persons with dementia (PwD) through a patient work lens.
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Ponnala S, Block L, Lingg AJ, Kind AJ, and Werner NE
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- Aged, Aged, 80 and over, Cost of Illness, Female, Humans, Male, Middle Aged, Qualitative Research, Social Support, Work psychology, Caregivers psychology, Dementia, Ergonomics
- Abstract
Informal caregivers are an integral part of care delivery for persons with dementia (PwD). Informal caregivers take part in a wide range of care activities both individually and collaboratively with other caregivers. Caregiving often involves high demands in the face of limited resources, which can lead to stress, burden, and burnout. To support caregivers, we need to conceptualize caregiving activities they perform, and the networks and roles through which they perform work. We performed a directed content analysis on interview data from twenty caregivers and applied a human factors approach to characterize informal caregiving work. Our results revealed 1) nuances in caregiving roles, 2) differences in caregiving networks, and 3) 13 categories of caregiving activities characterized by time commitments; physical, cognitive and socio-behavioral demands; and varying network dependencies. These findings can be applied in future studies to evaluate the needs of caregiving networks and how to better support them., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.) more...
- Published
- 2020
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27. A general 11 C-labeling approach enabled by fluoride-mediated desilylation of organosilanes.
- Author
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Qu W, Hu B, Babich JW, Waterhouse N, Dooley M, Ponnala S, and Urgiles J
- Subjects
- Acetoacetates chemistry, Methylation, Raclopride pharmacology, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals chemistry, Carbon Radioisotopes chemistry, Fluorides chemistry, Organosilicon Compounds chemistry
- Abstract
Carbon-11 (
11 C) is one of the most ideal positron emitters for labeling bioactive molecules for molecular imaging studies. The lack of convenient and fast incorporation methods to introduce11 C into organic molecules often hampers the use of this radioisotope. Here, a fluoride-mediated desilylation (FMDS)11 C-labeling approach is reported. This method relies on thermodynamically favored Si-F bond formation to generate a carbanion, therefore enabling the highly efficient and speedy incorporation of [11 C]CO2 and [11 C]CH3 I into molecules with diversified structures. It provides facile and rapid access to11 C-labeled compounds with carbon-11 attached at various hybridized carbons as well as oxygen, sulfur and nitrogen atoms with broad functional group tolerance. The exemplified syntheses of several biologically and clinically important radiotracers illustrates the potentials of this methodology. more...- Published
- 2020
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28. Improving the Intraoperative Educational Experience: Understanding the Role of Confidence in the Resident-Attending Relationship.
- Author
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Park J, Ponnala S, Fichtel E, Tehranchi K, Fitzgibbons S, Parker SH, Lau N, and Safford SD
- Subjects
- Attitude, Self Report, General Surgery education, Internship and Residency, Interprofessional Relations, Medical Staff, Hospital psychology, Self Concept, Surgeons psychology
- Abstract
Objective: With recent changes to graduate medical education, the balance between resident autonomy and need for supervision impacts the educational and training experience of residents. The objective of this study was to understand the relationship between the confidence of attendings and residents and their different perspectives of perceived educational experience and autonomy in the operating room (OR). We hypothesized that the attending's confidence in the resident would be an important factor in improving the educational experience and resident's autonomy in the OR., Design: Self-reported confidence-rating and operative experience surveys were administered to teams of post-graduate year (PGY 1) through PGY 5 surgical residents and attendings in two temporal sets (Early: Sept-Dec 2015, n = 20; Late: Jan-Apr 2016, n = 22). A second "end-of-year" survey was distributed to residents (n = 9, 37.5% response) and attendings (n = 10, 35% response) asking questions regarding their educational experience and operative experience during the past year., Setting: Large rural teaching hospital., Participants: Nineteen general surgery residents (PGY 1 - 5) and 14 general surgery attendings., Results: Resident perception of confidence differs from junior to senior residents, and that there was discordance between resident's confidence and skill as perceived by attendings, particularly in senior residents. Results also showed that attending's confidence in residents was positively correlated with attending's perceived educational experience in the OR. Residents and attendings both indicated attending's confidence in residents as an important factor in increasing resident autonomy in the OR, thus the attending's confidence in residents could have a positive impact on resident autonomy and educational experience in the OR., Conclusions: We have demonstrated a relationship between self-confidence for residents and improved confidence from attendings in residents' capabilities. Based on these findings, we would propose identifying methods to expand resident's awareness of surgical situations and develop attending's confidence in residents., (Copyright © 2019 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2019
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29. Improved synthesis of the bifunctional chelator p-SCN-Bn-HOPO.
- Author
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Bhupathiraju NVSDK, Younes A, Cao M, Ali J, Cicek HT, Tully KM, Ponnala S, Babich JW, Deri MA, Lewis JS, Francesconi LC, and Drain CM
- Subjects
- Chelating Agents chemistry, Molecular Structure, Positron-Emission Tomography, Chelating Agents chemical synthesis, Pyridones chemistry, Spermine chemistry
- Abstract
The bifunctional ligand p-SCN-Bn-HOPO, which has four 1,2-hydroxypyridinone groups on a spermine backbone with an isothiocyanate linker, has been shown to be an efficient and stable chelator for Zr(iv) and, more importantly, the radioisotope 89Zr for use in radiolabeling antibodies for positron emission tomography (PET) imaging. Previous studies of 89Zr-HOPO-trastuzumab in mice showed low background, good tumor to organ contrast, and very low bone uptake which show p-SCN-Bn-HOPO to be an important next-generation bifunctional chelator for radioimmunoPET imaging with 89Zr. However, the reported synthesis of p-SCN-Bn-HOPO involves nine steps and multiple HPLC purifications with an overall yield of about 1.4%. Herein we report an improved and efficient synthesis of p-SCN-Bn-HOPO in four steps with 14.3% overall yield which will improve its availability for further biological studies and wider application in PET imaging. The new synthetic route also allows variation in linker length and chemistries which may be helpful in modifying in vivo clearance behaviors of future agents. more...
- Published
- 2019
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30. Eye tracking in surgical education: gaze-based dynamic area of interest can discriminate adverse events and expertise.
- Author
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Fichtel E, Lau N, Park J, Henrickson Parker S, Ponnala S, Fitzgibbons S, and Safford SD
- Subjects
- Clinical Competence, Educational Measurement methods, Humans, Video Recording, Education, Medical, Graduate methods, Eye Movements, Internship and Residency, Surgical Procedures, Operative education
- Abstract
Background: Eye-gaze metrics derived from areas of interest (AOIs) have been suggested to be effective for surgical skill assessment. However, prior research is mostly based on static images and simulated tasks that may not translate to complex and dynamic surgical scenes. Therefore, eye-gaze metrics must advance to account for changes in the location of important information during a surgical procedure., Methods: We developed a dynamic AOI generation technique based on eye gaze collected from an expert viewing surgery videos. This AOI updated as the gaze of the expert moved with changes in the surgical scene. This technique was evaluated through an experiment recruiting a total of 20 attendings and residents to view 10 videos associated with and another 10 without adverse events., Results: Dwell time percentage (i.e., gaze duration) inside the AOI differentiated video type (U = 13508.5, p < 0.001) between videos with the presence (Mdn = 16.75) versus absence (Mdn = 19.95) of adverse events. This metric also differentiated participant group (U = 14029.5, p < 0.001) between attendings (Mdn = 15.45) and residents (Mdn = 19.80). This indicates that our dynamic AOIs reflecting the expert eye gaze was able to differentiate expertise, and the presence of unexpected adverse events., Conclusion: This dynamic AOI generation technique produced dynamic AOIs for deriving eye-gaze metrics that were sensitive to expertise level and event characteristics. more...
- Published
- 2019
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31. A Single Dose of 225 Ac-RPS-074 Induces a Complete Tumor Response in an LNCaP Xenograft Model.
- Author
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Kelly JM, Amor-Coarasa A, Ponnala S, Nikolopoulou A, Williams C Jr, Thiele NA, Schlyer D, Wilson JJ, DiMagno SG, and Babich JW
- Subjects
- Animals, Cell Line, Tumor, Dose-Response Relationship, Radiation, Half-Life, Humans, Male, Mice, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Radiochemistry, Radiometry, Tissue Distribution, Treatment Outcome, Cell Transformation, Neoplastic, Prostatic Neoplasms radiotherapy
- Abstract
Promising biochemical responses to
225 Ac-prostate-specific membrane antigen (PSMA) 617, even in patients who are refractory to β-particle radiation, illustrate the potential of targeted α-therapy for the treatment of metastatic castration-resistant prostate cancer. However, side effects such as xerostomia are severe and irreversible. To fully harness the potential of targeted α-therapy, it is necessary to increase the therapeutic index of the targeted radioligands. One emerging strategy is to increase clearance half-life through enhanced binding to serum albumin. We have evaluated the albumin-binding PSMA-targeting ligand RPS-074 in a LNCaP xenograft model to determine its potential value to the treatment of prostate cancer. Methods:225 Ac-RPS-074 was evaluated in male BALB/c mice bearing LNCaP xenograft tumors. A biodistribution study was performed over 21 d to determine the dosimetry in tumors and normal tissue. The dose response was measured in groups of 7 mice using 37, 74, and 148 kBq of225 Ac-RPS-074 and compared with positive and negative control groups. Mice were sacrificed when tumor volume exceeded 1,500 mm3 Results:225 Ac-RPS-074 was labeled in greater than 98% radiochemical yield and showed high (>10% injected dose/g) and sustained accumulation in LNCaP tumors from 24 h to beyond 14 d. Signal in blood and highly vascularized tissues was evident over the first 24 h after injection and cleared by 7 d. The tumor-to-kidney ratio was 4.3 ± 0.7 at 24 h and 62.2 ± 9.5 at 14 d. A single injection of 148 kBq induced a complete response in 6 of 7 tumors, with no apparent toxic effects. Treatment with 74 kBq induced a partial response in 7 of 7 tumors, but from 42 d, 6 of 7 experienced significant regrowth. The 37-kBq group experienced a survival benefit relative to the negative control but not compared with the positive control group. Conclusion: A single dose of 148 kBq of225 Ac-RPS-074 induced a complete response in 86% of tumors, with tumor-to-normal-tissue ratios that predict an improved therapeutic index. The use of the macropa chelator enabled quantitative radiolabeling and may facilitate the clinical translation of this promising targeted α-therapeutic., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.) more...- Published
- 2019
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32. Albumin-Binding PSMA Ligands: Implications for Expanding the Therapeutic Window.
- Author
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Kelly JM, Amor-Coarasa A, Ponnala S, Nikolopoulou A, Williams C Jr, DiMagno SG, and Babich JW
- Subjects
- Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, Humans, Male, Mice, Mice, Inbred BALB C, Positron Emission Tomography Computed Tomography, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Radiochemistry, Tissue Distribution, Treatment Outcome, Albumins metabolism, Antigens, Surface metabolism, Glutamate Carboxypeptidase II metabolism, Prostatic Neoplasms radiotherapy
- Abstract
Despite significant gains in the treatment of metastatic castration-resistant prostate cancer by radioligands targeting prostate-specific membrane antigen (PSMA), 30% of patients never respond to therapy. One possible explanation is insufficient dose delivery to the tumor because of suboptimal pharmacokinetics. We have recently described RPS-063, a trifunctional ligand targeting PSMA with high uptake in LNCaP xenograft tumors but also in kidneys. We aimed to use structural modifications to increase the tumor-to-kidney ratio through increased albumin binding and tumor uptake and reduction of kidney activity. Methods: Four structurally related trifunctional PSMA-targeting small molecules were prepared by either varying the albumin-binding group or inserting a polyethylene glycol 8 linker into a common structure. The compounds were ranked by PSMA affinity and albumin affinity and were radiolabeled with
68 Ga and177 Lu. Tissue kinetics were determined in male BALB/C nu/nu mice bearing LNCaP xenograft tumors. Results: Each of the compounds binds PSMA with a half-maximal inhibitory concentration of no more than 10 nM. The albumin-binding group had a minimal effect on PSMA affinity but changed albumin affinity by an order of magnitude. However, the addition of a polyethylene glycol 8 spacer weakened affinity for albumin in each case. Increased affinity for albumin corresponded with delayed blood clearance and modified uptake kinetics in the tumor and kidney. Uptake of177 Lu-RPS-072 (34.9 ± 2.4 %ID/g) and177 Lu-RPS-077 (27.4 ± 0.6 %ID/g) increased up to 24 h after injection, and washout by 96 h was not significant. As a result, the area under the curve (AUC) in the tumor was in the following order:177 Lu-RPS-072 >177 Lu-RPS-077 >177 Lu-RPS-063 >177 Lu-RPS-071. Increased linker length corresponded to more rapid clearance from kidneys. Consequently, the ratio of tumor AUC and kidney AUC was 4.7 ± 0.3 for177 Lu-RPS-072. Conclusion: The tumor AUC and tumor-to-kidney ratio of177 Lu-RPS-072 are significantly enhanced compared with any small molecule investigated in a LNCaP xenograft model to date. In comparison to other PSMA-targeting radioligands that have been evaluated in a PC3-PIP model, activity in kidneys is reduced and activity in tumors compares favorably when the different PSMA expression levels in LNCaP and PC3-PIP cells are considered. RPS-072 therefore exhibits an increased therapeutic index, shows the potential to increase the dose delivered to tumors, and is a highly promising candidate for targeted radioligand therapy., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.) more...- Published
- 2019
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33. [ 18 F]Fluoroethyltriazolyl Monocyclam Derivatives as Imaging Probes for the Chemokine Receptor CXCR4.
- Author
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Amor-Coarasa A, Kelly JM, Singh PK, Ponnala S, Nikolopoulou A, Williams C Jr, Vedvyas Y, Jin MM, Warren JD, and Babich JW
- Subjects
- Animals, Cell Line, Tumor, Coordination Complexes chemistry, Fluorine Radioisotopes chemistry, Gene Expression Regulation drug effects, Humans, Ligands, Mice, Peptides, Cyclic chemistry, Positron-Emission Tomography, Radiopharmaceuticals chemistry, Receptors, CXCR4 chemistry, Xenograft Model Antitumor Assays, Coordination Complexes administration & dosage, Molecular Imaging, Peptides, Cyclic administration & dosage, Radiopharmaceuticals administration & dosage, Receptors, CXCR4 genetics
- Abstract
Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [
68 Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of68 Ga. We screened a library of >200 fluorine-containing structural derivatives of AMD-3465 to identify promising candidates for in vivo imaging of CXCR4 expression by positron emission tomography (PET). Compounds containing fluoroethyltriazoles consistently achieved higher docking scores. Six of these higher scoring compounds were radiolabeled by click chemistry and evaluated in PC3-CXCR4 cells and BALB/c mice bearing bilateral PC3-WT and PC3-CXCR4 xenograft tumors. The apparent CXCR4 affinity of the ligands was relatively low, but tumor uptake was CXCR4-specific. The tumor uptake of [18 F]RPS-534 (7.2 ± 0.3 %ID/g) and [18 F]RPS-547 (3.1 ± 0.5 %ID/g) at 1 h p.i. was highest, leading to high tumor-to-blood, tumor-to-muscle, and tumor-to-lung ratios. Total cell-associated activity better predicted in vivo tumor uptake than did the docking score or apparent CXCR4 affinity. By this metric, and on the basis of their high yielding radiosynthesis, high tumor uptake, and good contrast to background, [18 F]RPS-547, and especially [18 F]RPS-534, are promising18 F-labeled candidates for imaging CXCR4 expression. more...- Published
- 2019
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34. 66 Ga: A Novelty or a Valuable Preclinical Screening Tool for the Design of Targeted Radiopharmaceuticals?
- Author
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Amor-Coarasa A, Kelly JM, Ponnala S, Nikolopoulou A, Williams C Jr, and Babich JW
- Subjects
- Animals, Drug Design, Humans, Ligands, Metals chemistry, Mice, Neoplasms diagnostic imaging, Neoplasms pathology, Positron Emission Tomography Computed Tomography, Positron-Emission Tomography, Solutions, X-Ray Microtomography, Gallium Radioisotopes chemistry, Gallium Radioisotopes isolation & purification, Radiopharmaceuticals chemistry, Radiopharmaceuticals isolation & purification
- Abstract
Emerging interest in extending the plasma half-life of small molecule radioligands warrants a consideration of the appropriate radionuclide for PET imaging at longer time points (>8 h). Among candidate positron-emitting radionuclides,
66 Ga (t1/2 = 9.5 h, β+ = 57%) has suitable nuclear and chemical properties for the labeling and PET imaging of radioligands of this profile. We investigated the value of66 Ga to preclinical screening and the evaluation of albumin-binding PSMA-targeting small molecules.66 Ga was produced by irradiation of anat Zn target.66 Ga3+ ions were separated from Zn2+ ions by an optimized UTEVA anion exchange column that retained 99.99987% of Zn2+ ions and allowed 90.2 ± 2.8% recovery of66 Ga3+ . Three ligands were radiolabeled in 46.4 ± 20.5%; radiochemical yield and >90% radiochemical purity. Molar activity was 632 ± 380 MBq/µmol. Uptake in the tumor and kidneys at 1, 3, 6, and 24 h p.i. was determined by µPET/CT imaging and more completely predicted the distribution kinetics than uptake of the [68 Ga]Ga-labeled ligands did. Although there are multiple challenges to the use of66 Ga for clinical PET imaging, it can be a valuable research tool for ligand screening and preclinical imaging beyond 24 h. more...- Published
- 2018
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35. Trifunctional PSMA-targeting constructs for prostate cancer with unprecedented localization to LNCaP tumors.
- Author
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Kelly J, Amor-Coarasa A, Ponnala S, Nikolopoulou A, Williams C Jr, Schlyer D, Zhao Y, Kim D, and Babich JW
- Subjects
- Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, Humans, Male, Mice, Molecular Targeted Therapy, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Radiometry, Tissue Distribution, Antigens, Surface metabolism, Glutamate Carboxypeptidase II metabolism, Prostatic Neoplasms radiotherapy
- Abstract
Purpose: Treatment of late-stage prostate cancer by targeted radiotherapeutics such as
131 I-MIP-1095 and177 Lu-PSMA-617 has shown encouraging early results. Lu-177 is preferred to I-131 in clinical settings, but targeted radioligand therapy (RLT) with177 Lu-PSMA-617 has not reached its full potential due to insufficient dose delivery to the tumor. We recently developed a dual-targeting radioiodinated ligand, RPS-027, that targets PSMA and uses albumin binding to enable good tumor uptake and significantly reduced kidney uptake in a preclinical model. Further development of this ligand is limited by the inability to independently modify PSMA and albumin binding and the requirement of I-131 for therapeutic application. We therefore sought to devise a new class of trifunctional ligands for RLT with (1) a high-affinity PSMA-binding domain, (2) an albumin-binding group (ABG), and (3) a chelator for radiometals such as68 Ga3+ ,177 Lu3+ and225 Ac3+ ., Methods: Ligands incorporating a triazolylphenylurea-containing PSMA-targeting group, an Nε -(2-(4-iodophenyl)acetyl)lysine ABG and the bifunctional chelator p-SCN-Bn-DOTA linked by a PEG-containing polymer containing 0,3,4,6,8 or 12 repeats were prepared. PSMA affinity was determined in LNCaP cells and uptake and tissue distribution was studied in mice bearing LNCaP tumor xenografts and compared to177 Lu-PSMA-617. Imaging studies were performed up to 24 h post-injection (p.i.) using66 Ga3+ and biodistribution studies at 4 h, 24 h and 96 h p.i. with177 Lu3+ ., Results: PSMA affinity was high (IC50 = 1-10 nM) and inversely proportional to the linker length. Tumor uptake correlated with binding affinity and was significantly greater than for177 Lu-PSMA-617 over 96 h. The highest uptake was achieved with177 Lu-RPS-063 (30.0 ± 6.9 %ID/g; 4 h p.i.). Kidney uptake was generally high, with the exception of the lowest affinity ligand177 Lu-RPS-067. Each of the compounds showed slower blood clearance than177 Lu-PSMA-617, with clearance proportional to linker length., Conclusions: The high tumor uptake achieved with these trifunctional ligands predicts larger (up to 4×) doses delivered to the tumor than can be achieved with177 Lu-PSMA-617. Although PSMA-mediated kidney uptake was also observed, the exceptional area under the curve (AUC) in the tumor warrants further investigation of these novel ligands as candidates for RLT. more...- Published
- 2018
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36. [ 18 F]RPS-544: A PET tracer for imaging the chemokine receptor CXCR4.
- Author
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Amor-Coarasa A, Kelly J, Ponnala S, Vedvyas Y, Nikolopoulou A, Williams C Jr, Jin MM, David Warren J, and Babich JW
- Subjects
- Animals, Fluorine Radioisotopes chemistry, Humans, Isotope Labeling, Mice, Mice, Nude, PC-3 Cells, Radioactive Tracers, Radiochemistry, Tissue Distribution, Positron-Emission Tomography methods, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics, Receptors, CXCR4 metabolism
- Abstract
Introduction: CXCR4 specific [
18 F]-labeled positron emission tomography (PET) imaging agents are needed which would enable general distribution of the radiotracer for clinical investigation. We sought to synthesize, radiolabel and evaluate [18 F]RPS-544, a novel non-peptide CXCR4 antagonist as a CXCR4 specific probe. We compared [18 F]RPS-544 with the previously published [18 F]-3 ([18 F]RPS-510 in this paper) in a bi-lateral tumor model of differential CXCR4 expression for its ability to selectively target CXCR4 expression., Methods: Radiolabeling of [18 F]RPS-544 and [18 F]RPS-510 was performed by aromatic substitution on a 6-nitropyridyl group using no-carrier-added [18 F]fluoride under basic conditions.18 F incorporation was determined by radioHPLC. Semi-preparative HPLC was used to purify the final product prior to reformulation. Imaging and biodistribution was performed in nude mice with bilateral PC3 (CXCR4+ and WT) xenograft tumors at 1, 2 and 4 h post injection., Results: RPS-544 bound CXCR4 with an IC50 of 4.9 ± 0.3 nM. [18 F]RPS-544 showed preferential uptake in CXCR4+ tumors, with a CXCR4/WT ratio of 3.3 ± 1.3 at 1 h p.i. and 2.3 ± 0.5 at 2 h p.i. Maximum uptake in the CXCR4+ tumors was 3.4 ± 1.2%ID/g at 1 h p.i., significantly greater (p = 0.003) than the uptake in the WT tumor. Tumor/blood ratios were 2.5 ± 0.4 and 3.6 ± 0.3 at 1 and 2 h p.i. Tumor/muscle ratios were >4 at all time-points. Tumor/lung ratios were >2 at 1 h and 2 h p.i. Substantial uptake was observed in the liver (15-25%ID/g), kidneys (25-35%ID/g), the small intestine (1-7%ID/g) and the large intestine (1-12%ID/g). Blood concentrations varied over time (0.5-2%ID/g). All other organs showed uptake of <1%ID/g at all time points studied with clearance profiles similar to blood clearance., Conclusions: Here we present, to the best of our knowledge, the first high affinity [18F]-labeled tracer, suitable for in vivo PET imaging of CXCR4. [18F]RPS-544 displayed high affinity for CXCR4 and good tumor uptake with a maximum uptake at 1 h p.i.. CXCR4 dependent uptake was demonstrated using bilateral tumors with differential CXCR4 expression as well as pharmacological blockade using the known CXCR4 antagonist, AMD-3100. Tissue contrast as judged by tumor to normal tissue ratios was positive in several key tissues. The structural and pharmacological similarities between [18F]RPS-544 and the approved drug AMD-3465, combined with the ease of synthesis and high molar activity (>185 GBq/μmol) achieved during radiosynthesis could lead to accelerated translation into the clinic., (Copyright © 2018. Published by Elsevier Inc.) more...- Published
- 2018
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37. An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy.
- Author
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Thiele NA, Brown V, Kelly JM, Amor-Coarasa A, Jermilova U, MacMillan SN, Nikolopoulou A, Ponnala S, Ramogida CF, Robertson AKH, Rodríguez-Rodríguez C, Schaffer P, Williams C Jr, Babich JW, Radchenko V, and Wilson JJ more...
- Subjects
- Animals, Heterografts, Humans, Ligands, Mice, Trastuzumab chemistry, Actinium chemistry, Actinium therapeutic use, Alpha Particles, Macrocyclic Compounds chemistry
- Abstract
The 18-membered macrocycle H
2 macropa was investigated for225 Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all225 Ac (26 kBq) in 5 min at RT. [225 Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled225 Ac in just minutes at RT, and macropa-Tmab retained >99 % of its225 Ac in human serum after 7 days. In LNCaP xenograft mice,225 Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free225 Ac over 96 h. These findings establish macropa to be a highly promising ligand for225 Ac chelation that will facilitate the clinical development of225 Ac TAT for the treatment of soft-tissue metastases., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...- Published
- 2017
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38. Synthesis and pre-clinical evaluation of a new class of high-affinity 18 F-labeled PSMA ligands for detection of prostate cancer by PET imaging.
- Author
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Kelly J, Amor-Coarasa A, Nikolopoulou A, Kim D, Williams C Jr, Ponnala S, and Babich JW
- Subjects
- Animals, Antigens, Surface metabolism, Cell Line, Tumor, Fluorine Radioisotopes chemistry, Glutamate Carboxypeptidase II metabolism, Humans, Ligands, Male, Mice, Mice, Nude, Phenylurea Compounds pharmacokinetics, Protein Binding, Radiopharmaceuticals pharmacokinetics, Radiopharmaceuticals pharmacology, Tissue Distribution, Triazoles pharmacokinetics, Glutamate Carboxypeptidase II antagonists & inhibitors, Phenylurea Compounds chemical synthesis, Positron-Emission Tomography, Prostatic Neoplasms diagnostic imaging, Radiopharmaceuticals chemical synthesis, Triazoles chemical synthesis
- Abstract
Purpose: Current clinical imaging of PSMA-positive prostate cancer by positron emission tomography (PET) mainly features
68 Ga-labeled tracers, notably [68superscript> Ga]Ga-PSMA-HBED-CC. The longer half-life of fluorine-18 offers significant advantages over Ga-68, clinically and logistically. We aimed to develop high-affinity PSMA inhibitors labeled with fluorine-18 as alternative tracers for prostate cancer., Methods: Six triazolylphenyl ureas and their alkyne precursors were synthesized from the Glu-urea-Lys PSMA binding moiety. PSMA affinity was determined in a competitive binding assay using LNCaP cells. The [ 18 F]triazoles were isolated following a Cu(I)-catalyzed click reaction between the alkynes and [18 F]fluoroethylazide. The18 F-labeled compounds were evaluated in nude mice bearing LNCaP tumors and compared to [68 Ga]Ga-PSMA-HBED-CC and [18 F]DCFPyL. Biodistribution studies of the two tracers with the highest imaged-derived tumor uptake and highest PSMA affinity were undertaken at 1 h, 2 h and 4 h post-injection (p.i.), and co-administration of PMPA was used to determine whether uptake was PSMA-specific., Results: F-18-labeled triazolylphenyl ureas were prepared with a decay-corrected RCY of 20-40 %, >98 % radiochemical and chemical purity, and specific activity of up to 391 GBq/μmol. PSMA binding (IC50 ) ranged from 3-36 nM. The position of the triazole influenced tumor uptake (3 > 4 > 2), and direct conjugation of the triazole with the phenylurea moiety was preferred to insertion of a spacer group. Image-derived tumor uptake ranged from 6-14 %ID/g at 2 h p.i., the time of maximum tumor uptake; uptake of [68 Ga]Ga-PSMA-HBED-CC and [18 F]DCFPyL was 5-6 %ID/g at 1-3 h p.i., the time of maximum tumor uptake. Biodistribution studies of the two most promising compounds gave maximum tumor uptakes of 10.9 ± 1.0 % and 14.3 ± 2.5 %ID/g, respectively, as compared to 6.27 ± 1.44 %ID/g for [68 Ga]Ga-PSMA-HBED-CC., Conclusions: Six [18 F]triazolylphenyl ureas were prepared in good radiochemical yield. Compounds showed PSMA-specific uptake in LNCaP tumors as high as 14 % ID/g, more than a 2-fold increase over [68 Ga]Ga-PSMA-HBED-CC. The facile and high-yielding radiosynthesis of these18 F-labeled triazoles as well as their promising in vitro and in vivo characteristics make them worthy of clinical development for PET imaging of prostate cancer. more...- Published
- 2017
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39. A 26-Year-Old Female with Systemic Mastocytosis with Associated Myeloid Neoplasm with Eosinophilia and Abnormalities of PDGFRB, t(4;5)(q21;q33).
- Author
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Brown LE, Zhang D, Persons DL, Yacoub A, Ponnala S, and Cui W
- Abstract
Various translocations involving the PDGFRB gene are identified in myeloid neoplasms. However, the PRKG2/PDGFRB fusion gene associated with t(4;5)(q21;q33) has previously been reported in only 3 patients. We present the case of a 26-year-old woman with microcytic anemia, basophilia, thrombocytosis, and massive splenomegaly, who was found to have systemic mastocytosis and associated clonal hematological non-mast cell lineage disease (SM-AHNMD), with myeloid neoplasm with PRKG2/PDGFRB rearrangement. Initial findings included basophilia (37%, 4.1 k/μL), hypercellular marrow with eosinophilia, and increased and atypical megakaryocytes, suggestive of myeloproliferative neoplasm. Additional studies revealed large clusters of CD25 positive mast cells, fulfilling the criteria for the diagnosis of systemic mastocytosis. Consistent with prior reports of this translocation, our patient has responded well to imatinib. This case, in conjunction with others in the literature, suggests a possible connection between t(4;5)(q21;q33) PRKG2/PDGFRB and systemic mastocytosis and highlights their favorable response to imatinib. more...
- Published
- 2016
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40. p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for (89)Zr ImmunoPET.
- Author
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Deri MA, Ponnala S, Kozlowski P, Burton-Pye BP, Cicek HT, Hu C, Lewis JS, and Francesconi LC
- Subjects
- Animals, Cell Line, Tumor, Chelating Agents pharmacokinetics, Deferoxamine pharmacokinetics, Female, Humans, Immunoconjugates pharmacokinetics, Mice, Nude, Models, Molecular, Pyridones pharmacokinetics, Tissue Distribution, Trastuzumab chemistry, Zirconium pharmacokinetics, Breast diagnostic imaging, Breast Neoplasms diagnostic imaging, Chelating Agents chemistry, Deferoxamine chemistry, Immunoconjugates chemistry, Positron-Emission Tomography methods, Pyridones chemistry, Zirconium chemistry
- Abstract
Zirconium-89 has an ideal half-life for use in antibody-based PET imaging; however, when used with the chelator DFO, there is an accumulation of radioactivity in the bone, suggesting that the (89)Zr(4+) cation is being released in vivo. Therefore, a more robust chelator for (89)Zr could reduce the in vivo release and the dose to nontarget tissues. Evaluation of the ligand 3,4,3-(LI-1,2-HOPO) demonstrated efficient binding of (89)Zr(4+) and high stability; therefore, we developed a bifunctional derivative, p-SCN-Bn-HOPO, for conjugation to an antibody. A Zr-HOPO crystal structure was obtained showing that the Zr is fully coordinated by the octadentate HOPO ligand, as expected, forming a stable complex. p-SCN-Bn-HOPO was synthesized through a novel pathway. Both p-SCN-Bn-HOPO and p-SCN-Bn-DFO were conjugated to trastuzumab and radiolabeled with (89)Zr. Both complexes labeled efficiently and achieved specific activities of approximately 2 mCi/mg. PET imaging studies in nude mice with BT474 tumors (n = 4) showed good tumor uptake for both compounds, but with a marked decrease in bone uptake for the (89)Zr-HOPO-trastuzumab images. Biodistribution data confirmed the lower bone activity, measuring 17.0%ID/g in the bone at 336 h for (89)Zr-DFO-trastuzumab while (89)Zr-HOPO-trastuzumab only had 2.4%ID/g. We successfully synthesized p-SCN-Bn-HOPO, a bifunctional derivative of 3,4,3-(LI-1,2-HOPO) as a potential chelator for (89)Zr. In vivo studies demonstrate the successful use of (89)Zr-HOPO-trastuzumab to image BT474 breast cancer with low background, good tumor to organ contrast, and, importantly, very low bone uptake. The reduced bone uptake seen with (89)Zr-HOPO-trastuzumab suggests superior stability of the (89)Zr-HOPO complex. more...
- Published
- 2015
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41. Synthesis and evaluation of aporphine analogs containing C1 allyl isosteres at the h5-HT(2A) receptor.
- Author
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Ponnala S, Kapadia N, Madapa S, Alberts IL, and Harding WW
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- Adrenergic alpha-1 Receptor Antagonists chemical synthesis, Adrenergic alpha-1 Receptor Antagonists pharmacology, Aporphines chemical synthesis, Heterocyclic Compounds, 4 or More Rings chemical synthesis, Humans, Hydrophobic and Hydrophilic Interactions, Ligands, Molecular Docking Simulation, Receptor, Serotonin, 5-HT2A metabolism, Serotonin 5-HT2 Receptor Agonists chemical synthesis, Structure-Activity Relationship, Aporphines pharmacology, Heterocyclic Compounds, 4 or More Rings pharmacology, Serotonin 5-HT2 Receptor Agonists pharmacology
- Abstract
A series of C1 aporphine analogs related to compound 5 and that contain substituted allylic, alkynyl, nitrile, ester and benzyl groups was synthesized and evaluated for affinity at h5HT2A and α1A receptors in functional activity assays that measure calcium release. The presence of branched allylic substituent groups diminished affinity for the h5HT2A receptor. Likewise, the alkynyl, nitrile and ester derivatives evaluated displayed lower 5-HT2A receptor affinity as compared to 5. Hydrophobic, steric and electronic effects impact the affinity of p-substituted benzyl derivatives 8i-8k but in different ways. High hydrophobicity and size favor 5-HT2A affinity whereas, high electronegativity disfavors 5-HT2A affinity. p-Bromobenzyl analog 8k was identified as a 5-HT2A receptor selective ligand, with the highest 5-HT2A receptor affinity of any aporphine known to date. Most of the other analogs were selective for the 5-HT2A versus the α1A receptor. ChemScore binding energies from docking studies correlated qualitatively with the observed trends in affinity for 8i-8k, although the binding energies were not well differentiated quantitatively., (Copyright © 2015 Elsevier Ltd. All rights reserved.) more...
- Published
- 2015
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42. A divergent route to 9, 10-oxygenated tetrahydroprotoberberine and 8-oxoprotoberberine alkaloids: synthesis of (±)-isocorypalmine and oxypalmatine.
- Author
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Gadhiya S, Ponnala S, and Harding WW
- Abstract
A new route which is germane to the synthesis of 9,10-oxygenated tetrahydroprotoberberines and 8-oxoprotoberberines is described. The route features the use of a diester ( 14 ) generated from reaction of dimethylmalonate with an aryl halide in the presence of n -butyllithium. The amide 17 prepared in subsequent steps is a versatile precursor for the synthesis of tetrahydroprotoberberine and 8-oxoprotoberberine scaffolds using standard high-yielding reactions. In this manner, (±)-isocorypalmine and oxypalmatine have been synthesized in 23% and 22 % yields respectively. more...
- Published
- 2015
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43. Aporphinoid antagonists of 5-HT2A receptors: further evaluation of ring A substituents and the size of ring C.
- Author
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Ponnala S, Kapadia N, Navarro HA, and Harding WW
- Subjects
- Chemistry Techniques, Synthetic, Molecular Docking Simulation, Serotonin 5-HT2 Receptor Antagonists chemical synthesis, Aporphines chemistry, Serotonin 5-HT2 Receptor Antagonists chemistry, Serotonin 5-HT2 Receptor Antagonists pharmacology, Structure-Activity Relationship
- Abstract
A series of ring A-modified analogs of nantenine as well as structural variants in ring C were synthesized and evaluated for antagonist activity at 5-HT2A and α1A receptors. Halogenation improves 5-HT2A antagonist potency in molecules containing a C1 methoxyl/C2 methoxyl or C1 methoxyl/C2 hydroxyl moiety. Bromination or iodination (but not chlorination) with the latter moiety also significantly increased α1A antagonist potency. Homologation or contraction of ring C adversely affected antagonist activity at both receptors, implying that a six-membered ring C motif is beneficial for high antagonist potency at both receptors. Molecular docking studies suggest that the improved antagonist activity (by virtue of improved affinity) of C3-halogenated aporphines in this study is attributable to favorable interactions with the C3 halogen and F339 and/or F340., (© 2014 John Wiley & Sons A/S.) more...
- Published
- 2014
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44. Alternative chelator for ⁸⁹Zr radiopharmaceuticals: radiolabeling and evaluation of 3,4,3-(LI-1,2-HOPO).
- Author
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Deri MA, Ponnala S, Zeglis BM, Pohl G, Dannenberg JJ, Lewis JS, and Francesconi LC
- Subjects
- Animals, Chelating Agents pharmacokinetics, Coordination Complexes pharmacokinetics, Drug Stability, Female, Isotope Labeling, Mice, Mice, Nude, Positron-Emission Tomography, Pyridones pharmacokinetics, Radioisotopes, Radiopharmaceuticals pharmacokinetics, Spermine chemistry, Spermine pharmacokinetics, Tissue Distribution, Chelating Agents chemistry, Coordination Complexes chemistry, Pyridones chemistry, Radiopharmaceuticals chemistry, Spermine analogs & derivatives, Zirconium
- Abstract
Zirconium-89 is an effective radionuclide for antibody-based positron emission tomography (PET) imaging because its physical half-life (78.41 h) matches the biological half-life of IgG antibodies. Desferrioxamine (DFO) is currently the preferred chelator for (89)Zr(4+); however, accumulation of (89)Zr in the bones of mice suggests that (89)Zr(4+) is released from DFO in vivo. An improved chelator for (89)Zr(4+) could eliminate the release of osteophilic (89)Zr(4+) and lead to a safer PET tracer with reduced background radiation dose. Herein, we present an octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO) as a potentially superior alternative to DFO. The HOPO ligand formed a 1:1 Zr-HOPO complex that was evaluated experimentally and theoretically. The stability of (89)Zr-HOPO matched or surpassed that of (89)Zr-DFO in every experiment. In healthy mice, (89)Zr-HOPO cleared the body rapidly with no signs of demetalation. Ultimately, HOPO has the potential to replace DFO as the chelator of choice for (89)Zr-based PET imaging agents. more...
- Published
- 2014
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45. Evaluation of structural effects on 5-HT(2A) receptor antagonism by aporphines: identification of a new aporphine with 5-HT(2A) antagonist activity.
- Author
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Ponnala S, Gonzales J, Kapadia N, Navarro HA, and Harding WW
- Subjects
- Aporphines chemical synthesis, Aporphines chemistry, Dose-Response Relationship, Drug, Humans, Molecular Structure, Serotonin 5-HT2 Receptor Antagonists chemical synthesis, Serotonin 5-HT2 Receptor Antagonists chemistry, Structure-Activity Relationship, Aporphines pharmacology, Receptor, Serotonin, 5-HT2A metabolism, Serotonin 5-HT2 Receptor Antagonists pharmacology
- Abstract
A set of aporphine analogs related to nantenine was evaluated for antagonist activity at 5-HT2A and α1A adrenergic receptors. With regards to 5-HT2A receptor antagonism, a C2 allyl group is detrimental to activity. The chiral center of nantenine is not important for 5-HT2A antagonist activity, however the N6 nitrogen atom is a critical feature for 5-HT2A antagonism. Compound 12b was the most potent 5-HT2A aporphine antagonist identified in this study and has similar potency to previously identified aporphine antagonists 2 and 3. The ring A and N6 modifications examined were detrimental to α1A antagonism. A slight eutomeric preference for the R enantiomer of nantenine was observed in relation to α1A antagonism., (Copyright © 2014 Elsevier Ltd. All rights reserved.) more...
- Published
- 2014
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46. Involvement of nitric oxide synthase in matrix metalloproteinase-9- and/or urokinase plasminogen activator receptor-mediated glioma cell migration.
- Author
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Zhuang T, Chelluboina B, Ponnala S, Velpula KK, Rehman AA, Chetty C, Zakharian E, Rao JS, and Veeravalli KK
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Enzyme Inhibitors pharmacology, Gene Expression, Glioma genetics, Glioma pathology, Heterografts, Humans, Integrins metabolism, Matrix Metalloproteinase 9 genetics, Mice, Models, Biological, NG-Nitroarginine Methyl Ester pharmacology, Nitric Oxide Synthase antagonists & inhibitors, Nitric Oxide Synthase genetics, Nitric Oxide Synthase Type II antagonists & inhibitors, Nitric Oxide Synthase Type II genetics, Nitric Oxide Synthase Type II metabolism, Protein Binding, RNA Interference, Receptors, Urokinase Plasminogen Activator genetics, Cell Movement genetics, Glioma metabolism, Matrix Metalloproteinase 9 metabolism, Nitric Oxide Synthase metabolism, Receptors, Urokinase Plasminogen Activator metabolism
- Abstract
Background: Src tyrosine kinase activates inducible nitric oxide synthase (iNOS) and, in turn, nitric oxide production as a means to transduce cell migration. Src tyrosine kinase plays a key proximal role to control α9β1 signaling. Our recent studies have clearly demonstrated the role of α9β1 integrin in matrix metalloproteinase-9 (MMP-9) and/or urokinase plasminogen activator receptor (uPAR)-mediated glioma cell migration. In the present study, we evaluated the involvement of α9β1 integrin-iNOS pathway in MMP-9- and/or uPAR-mediated glioma cell migration., Methods: MMP-9 and uPAR shRNAs and overexpressing plasmids were used to downregulate and upregulate these molecules, respectively in U251 glioma cells and 5310 glioma xenograft cells. The effect of treatments on migration and invasion potential of these glioma cells were assessed by spheroid migration, wound healing, and Matrigel invasion assays. In order to attain the other objectives we also performed immunocytochemical, immunohistochemical, RT-PCR, Western blot and fluorescence-activated cell sorting (FACS) analysis., Results: Immunohistochemical analysis revealed the prominent association of iNOS with glioblastoma multiforme (GBM). Immunofluorescence analysis showed prominent expression of iNOS in glioma cells. MMP-9 and/or uPAR knockdown by respective shRNAs reduced iNOS expression in these glioma cells. RT-PCR analysis revealed elevated iNOS mRNA expression in either MMP-9 or uPAR overexpressed glioma cells. The migration potential of MMP-9- and/or uPAR-overexpressed U251 glioma cells was significantly inhibited after treatment with L-NAME, an inhibitor of iNOS. Similarly, a significant inhibition of the invasion potential of the control or MMP-9/uPAR-overexpressed glioma cells was noticed after L-NAME treatment. A prominent reduction of iNOS expression was observed in the tumor regions of nude mice brains, which were injected with 5310 glioma cells, after MMP-9 and/or uPAR knockdown. Protein expressions of cSrc, phosphoSrc and p130Cas were reduced with simultaneous knockdown of both MMP-9 and uPAR., Conclusions: Taken together, our results from the present and earlier studies clearly demonstrate that α9β1 integrin-mediated cell migration utilizes the iNOS pathway, and inhibition of the migratory potential of glioma cells by simultaneous knockdown of MMP-9 and uPAR could be attributed to the reduced α9β1 integrin and iNOS levels. more...
- Published
- 2013
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47. A New Route to Azafluoranthene Natural Products via Direct Arylation.
- Author
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Ponnala S and Harding WW
- Abstract
Microwave-assisted direct arylation was successfully employed in the synthesis of azafluoranthene alkaloids for the first time. Direct arylation reactions on a diverse set of phenyltetrahydroisoquinolines produces the indeno[1,2,3- ij ]isoquinoline nucleus en route to a high yielding azafluoranthene synthesis. The method was used as a key step in the efficient preparation of the natural products rufescine and triclisine. As demonstrated herein, this synthetic approach should be generally applicable to the preparation of natural and un-natural azafluoranthene alkaloids as well as "azafluoranthene-like" isoquinoline alkaloids. more...
- Published
- 2013
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- View/download PDF
48. Role of MDR1 C3435T and GABRG2 C588T gene polymorphisms in seizure occurrence and MDR1 effect on anti-epileptic drug (phenytoin) absorption.
- Author
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Ponnala S, Chaudhari JR, Jaleel MA, Bhiladvala D, Kaipa PR, Das UN, and Hasan Q
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Adolescent, Adult, Aged, Anticonvulsants therapeutic use, Child, Child, Preschool, Cohort Studies, Female, Genotype, Humans, India epidemiology, Infant, Male, Middle Aged, Phenytoin therapeutic use, Polymerase Chain Reaction methods, Polymorphism, Restriction Fragment Length, Seizures drug therapy, Seizures epidemiology, Seizures, Febrile drug therapy, Seizures, Febrile epidemiology, White People genetics, Young Adult, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Anticonvulsants pharmacokinetics, Phenytoin pharmacokinetics, Polymorphism, Genetic, Receptors, GABA-A genetics, Seizures genetics, Seizures, Febrile genetics
- Abstract
Aims: To assess the role of MDR1 and gamma-aminobutyric acid receptor-gamma 2 sub unit (GABRG2) gene polymorphism in seizure susceptibility in generalized seizure (GS) and febrile seizure (FS) patients and to evaluate MDR1 C3435T gene polymorphism's role in absorption of the anti-epileptic drug, phenytoin (PHT) in a cohort of patients., Methods: One hundred twenty-seven cases of seizure (86 GS and 41 FS) patients were analyzed for MDR1 C3435T and GABRG2 C588T gene polymorphisms using restriction fragment length polymorphism-polymerase chain reaction. Serum PHT levels were analyzed., Results: The T allele of MDR1 C3435T and GABRG2 C588T gene polymorphism was higher in GS in the Indian population compared with controls. From the data in GS, CT and TT genotype carriers of the MDR1 gene and TT genotype carriers of the GABRG2 gene had more recurrent seizures compared with others. MDR1 T allele carriers in the seizure reoccurrence (SR) group of GS and FS were high compared with the well-controlled seizure group (with no seizures after treatment). TT genotype carriers in SR group were high in FS (with regard to MDR1 gene polymorphism) and GS (with regard to GABRG2 gene polymorphism) compared with a well-controlled seizure group. MDR1 C3435T gene polymorphism affects serum PHT levels (p<0.015). Association of dose PHT ratio and genotype groups of MDR1 C3435T gene polymorphism showed a significant association (p<0.05). MDR1*CC genotype was more common in cases with low serum PHT levels.In addition, it is evident that CT and TT genotype carriers have a high percentage of SR with elevated serum PHT levels., Conclusions: Our results show that the MDR1 3435T and GABRG2 588T alleles play a role in seizure occurrence. Moreover, the MDR1 3435T allele also affects PHT absorption. We suggest MDR1 C3435T and GABRG2 C588T genotyping would be of value in order to lower the risk of concentration-dependent drug toxicity and for better patient management. more...
- Published
- 2012
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49. Commentary.
- Author
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Ponnala S
- Published
- 2012
50. Metabolic remodeling precedes mitochondrial outer membrane permeabilization in human glioma xenograft cells.
- Author
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Ponnala S, Chetty C, Veeravalli KK, Dinh DH, Klopfenstein JD, and Rao JS
- Subjects
- Antineoplastic Agents pharmacology, Apoptosis, Apoptosis Regulatory Proteins metabolism, Cathepsin B genetics, Cathepsin B metabolism, Cell Line, Tumor drug effects, Cell Survival drug effects, Electron Transport Chain Complex Proteins metabolism, Gene Knockdown Techniques, Glycolysis, Humans, Matrix Metalloproteinase 9 genetics, Matrix Metalloproteinase 9 metabolism, Oxidative Phosphorylation, Permeability, Protein Processing, Post-Translational, RNA Interference, RNA, Small Interfering pharmacology, Receptors, Urokinase Plasminogen Activator genetics, Receptors, Urokinase Plasminogen Activator metabolism, Glioma metabolism, Mitochondrial Membranes metabolism
- Abstract
Glioma cancer cells adapt to changing microenvironment and shift from mitochondrial oxidative phosphorylation to aerobic glycolysis for their metabolic needs irrespective of oxygen availability. In the present study, we show that silencing MMP-9 in combination with uPAR/cathepsin B switch the glycolytic metabolism of glioma cells to oxidative phosphorylation (OXPHOS) and generate reactive oxygen species (ROS) to predispose glioma cells to mitochondrial outer membrane permeabilization. shRNA for MMP-9 and uPAR (pMU) as well as shRNA for MMP-9 and cathepsin B (pMC) activated complexes of mitochondria involved in OXPHOS and inhibited glycolytic hexokinase expression. The decreased interaction of hexokinase 2 with mitochondria in the treated cells indicated the inhibition of glycolysis activation. Overexpression of Akt reversed the pMU- and pMC-mediated OXPHOS to glycolysis switch. The OXPHOS un-coupler oligomycin A altered the expression levels of the Bcl-2 family of proteins; treatment with pMU or pMC reversed this effect and induced mitochondrial outer membrane permeabilization. In addition, our results show changes in mitochondrial pore transition to release cytochrome c due to changes in the VDAC-Bcl-XL and BAX-BAK interaction with pMU and pMC treatments. Taken together, our results suggest that pMU and pMC treatments switch glioma cells from the glycolytic to the OXPHOS pathway through an inhibitory effect on Akt, ROS induction and an increase of cytosolic cytochrome c accumulation. These results demonstrate the potential of pMU and pMC as therapeutic candidates for the treatment of glioma. more...
- Published
- 2012
- Full Text
- View/download PDF
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