7 results on '"Wesley M. Smith"'
Search Results
2. A Phase <scp>II</scp> Study of Durvalumab in Combination with Tremelimumab in Patients with Rare Cancers
- Author
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Elizabeth H. Cull, Julie C. Martin, Wesley M. Smith, William Jeffery Edenfield, Ki Y. Chung, Mark Allen O'Rourke, William Larry Gluck, and Heather Bowers
- Subjects
Cancer Research ,medicine.medical_specialty ,Durvalumab ,Population ,Phases of clinical research ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,030212 general & internal medicine ,education ,Pneumonitis ,education.field_of_study ,business.industry ,Clinical Trial Results ,Standard treatment ,Antibodies, Monoclonal ,Unevaluable ,medicine.disease ,Clinical trial ,Oncology ,030220 oncology & carcinogenesis ,business ,Tremelimumab ,medicine.drug - Abstract
Lessons Learned Disease control with signals of response were demonstrated, which should lead to future validating clinical trials using checkpoint inhibitors in this underserved rare malignancy population. Although the study of single types of rare cancers is practically challenging, clinical trial designs that aggregate such patients into cohorts treated similarly are feasible, even in the community setting. Background Patients with rare cancers are an underserved population with limited access to clinical trials aside from phase I trials in the refractory setting. Treatment of these patients is often based on collections of anecdotes and small denominator review articles. Despite broad evidence of efficacy of combined immune checkpoint blockade across multiple tumor types, patients with rare tumors have not been afforded the opportunity for these therapies. Methods A phase II, investigator-initiated, single institution trial using durvalumab (1,500 mg every [Q]4 weeks × 13) and tremelimumab (75 mg Q4 weeks × 7, then Q12 weeks × 2) is reported. The population included 50 patients with advanced rare solid tumors (incidence Results A complete response was demonstrated in one patient with anal cancer. Striking partial responses were seen in four patients. Prolonged disease stability was noted in 18 patients. Thirteen patients experienced disease progression. Patients were considered unevaluable if unable to initiate therapy (n = 6) or unable to complete two cycles of therapy (n = 8). In all cases, patients were unevaluable because of clinical deterioration. The toxicity profile paralleled prior published studies. Toxicities were manageable and without new signals. There were two events of grade 4 immune-mediated hepatitis and one death from pneumonitis. Conclusion This single-cohort basket trial demonstrated clinical activity from combined checkpoint blockade in 23 of the 36 evaluable patients. Patients with rare cancers, not eligible for immunotherapy via conventional clinical trial mechanisms, should be considered for this therapy through compassionate use, further clinical trials, and national registry programs.
- Published
- 2021
3. Efficacy of Therapeutic Plasma Exchange Alone or in Combination with Ruxolitinib for the Treatment of Penn Class 3 and 4 Cytokine Release Syndrome Complicating COVID-19
- Author
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Robert A. Brevetta, Sergio Arce, Antine E. Stenbit, Julie C. Martin, Wesley M. Smith, W Larry Gluck, W Jeffery Edenfield, Sean P. Callahan, and Anna V. Blenda
- Subjects
Oncology ,medicine.medical_specialty ,Ruxolitinib ,Coronavirus disease 2019 (COVID-19) ,business.industry ,medicine.disease ,Clinical trial ,Cytokine release syndrome ,Respiratory failure ,Internal medicine ,Medicine ,Therapeutic plasma exchange ,business ,medicine.drug - Published
- 2021
4. Clinical Applicability of a Proposed Algorithm for Referral to Hematologic Genetic Screening of Patients Diagnosed with Acute Myeloid Leukemia (AML), Aplastic Anemia (AA) and Myelodysplastic Syndrome (MDS) in a Community Based Hospital
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Madison Bessonny, Elizabeth H. Cull, Wesley M. Smith, Aniket Saha, Allison Bellomo, and Alyssa I. Clay-Gilmour
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Community based ,Transplantation ,Pediatrics ,medicine.medical_specialty ,Referral ,business.industry ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,medicine ,Molecular Medicine ,Immunology and Allergy ,Aplastic anemia ,business - Published
- 2021
5. Critical structural and functional roles for the N-terminal insertion sequence in surfactant protein B analogs.
- Author
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Frans J Walther, Alan J Waring, Jose M Hernandez-Juviel, Larry M Gordon, Zhengdong Wang, Chun-Ling Jung, Piotr Ruchala, Andrew P Clark, Wesley M Smith, Shantanu Sharma, and Robert H Notter
- Subjects
Medicine ,Science - Abstract
Surfactant protein B (SP-B; 79 residues) belongs to the saposin protein superfamily, and plays functional roles in lung surfactant. The disulfide cross-linked, N- and C-terminal domains of SP-B have been theoretically predicted to fold as charged, amphipathic helices, suggesting their participation in surfactant activities. Earlier structural studies with Mini-B, a disulfide-linked construct based on the N- and C-terminal regions of SP-B (i.e., approximately residues 8-25 and 63-78), confirmed that these neighboring domains are helical; moreover, Mini-B retains critical in vitro and in vivo surfactant functions of the native protein. Here, we perform similar analyses on a Super Mini-B construct that has native SP-B residues (1-7) attached to the N-terminus of Mini-B, to test whether the N-terminal sequence is also involved in surfactant activity.FTIR spectra of Mini-B and Super Mini-B in either lipids or lipid-mimics indicated that these peptides share similar conformations, with primary alpha-helix and secondary beta-sheet and loop-turns. Gel electrophoresis demonstrated that Super Mini-B was dimeric in SDS detergent-polyacrylamide, while Mini-B was monomeric. Surface plasmon resonance (SPR), predictive aggregation algorithms, and molecular dynamics (MD) and docking simulations further suggested a preliminary model for dimeric Super Mini-B, in which monomers self-associate to form a dimer peptide with a "saposin-like" fold. Similar to native SP-B, both Mini-B and Super Mini-B exhibit in vitro activity with spread films showing near-zero minimum surface tension during cycling using captive bubble surfactometry. In vivo, Super Mini-B demonstrates oxygenation and dynamic compliance that are greater than Mini-B and compare favorably to full-length SP-B.Super Mini-B shows enhanced surfactant activity, probably due to the self-assembly of monomer peptide into dimer Super Mini-B that mimics the functions and putative structure of native SP-B.
- Published
- 2010
- Full Text
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6. Efficacy of therapeutic plasma exchange in the treatment of penn class 3 and 4 cytokine release syndrome complicating COVID-19
- Author
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Julie C. Martin, Robert A. Brevetta, Sean P. Callahan, Wesley M. Smith, W Larry Gluck, W Jeffery Edenfield, Antine E. Stenbit, Anna V. Blenda, and Sergio Arce
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,Oxygenation index ,Critical Illness ,medicine.medical_treatment ,Pilot Projects ,Respiratory failure ,Severity of Illness Index ,Therapeutic plasma exchange ,Cytokine release syndrome ,Therapeutic benefit ,Severity of illness ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Original Research ,Plasma Exchange ,SARS-CoV-2 ,business.industry ,Oxygen Inhalation Therapy ,COVID-19 ,Oxygenation ,Middle Aged ,medicine.disease ,Respiration, Artificial ,Cytokine ,Anesthesia ,Room air distribution ,Female ,Respiratory Insufficiency ,business - Abstract
Objectives Cytokine release syndrome (CRS) is a potentially severe complication of COVID-19 most commonly resulting in respiratory failure. This ten-patient study was designed to determine the efficacy of therapeutic plasma exchange (TPE) in improving oxygenation and in reducing the cytokine load in a critically ill subset of patients. Methods Five single volume plasma exchanges over eight days within a 14-day study period. In mechanically ventilated patients, oxygenation was measured via the PaO2/FiO2 (P/F) ratio and the oxygenation index (OI) daily for 14 days. Supplemental oxygen requirements were tracked daily for non-ventilated patients. Results Non-ventilated patients were liberated from supplemental oxygen after TPE. The response was rapid with an 87% average reduction in oxygenation requirements following and average time to return to room air of 5.25 days. All mechanically ventilated patients demonstrated improvement in oxygenation with a 78% average improvement in the P/F ratio and a 43% improvement in OI. C-reactive protein (CRP) and serum levels of IL-6, IL-8, IL-10, TNFα, IFNγ and GM-CSF, were measured daily with immediate post TPE levels drawn on days 1, 2, 4, 6 and 8. All patients demonstrated significant reductions in CRP, IL-6, IL-10 and TNFα. Conclusions In the majority of patients with Penn class 3 and 4 CRS complicating COVID-19, TPE demonstrated a prompt improvement in oxygenation and reduction in cytokine load without compromising patient safety. As this pilot study was envisioned to be hypothesis generating, expanded trials using TPE alone and in conjunction with novel pharmacologic agents are warranted. Registration ClinicalTrials.gov NCT04374149., Highlights • Plasmapheresis can effectively reduce injurious cytokines that complicate COVID-19. • Plasmapheresis can produce clinically meaningful improvement in oxygenation. • Plasmapheresis can be safely used as a treatment for COVID-19 cytokine storm.
- Published
- 2020
7. Critical structural and functional roles for the N-terminal insertion sequence in surfactant protein B analogs
- Author
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Zhengdong Wang, Chun-Ling Jung, Robert H. Notter, Alan J. Waring, Frans J. Walther, Andrew P. Clark, Piotr Ruchala, Larry M. Gordon, Wesley M. Smith, José M. Hernández-Juviel, and Shantanu Sharma
- Subjects
Male ,Models, Molecular ,Stereochemistry ,Protein Conformation ,Dimer ,Molecular Sequence Data ,lcsh:Medicine ,Peptide ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Protein structure ,Pulmonary surfactant ,Respiratory Medicine/Respiratory Failure ,Spectroscopy, Fourier Transform Infrared ,Animals ,Pulmonary surfactant-associated protein B ,Amino Acid Sequence ,lcsh:Science ,Peptide sequence ,030304 developmental biology ,Gel electrophoresis ,chemistry.chemical_classification ,0303 health sciences ,Multidisciplinary ,Pulmonary Surfactant-Associated Protein B ,Chemistry ,lcsh:R ,Protein superfamily ,Surface Plasmon Resonance ,Respiratory Medicine/Respiratory Pediatrics ,Rats ,Molecular Weight ,Biochemistry ,Electrophoresis, Polyacrylamide Gel ,lcsh:Q ,Pediatrics and Child Health/Neonatology ,030217 neurology & neurosurgery ,Research Article - Abstract
Background Surfactant protein B (SP-B; 79 residues) belongs to the saposin protein superfamily, and plays functional roles in lung surfactant. The disulfide cross-linked, N- and C-terminal domains of SP-B have been theoretically predicted to fold as charged, amphipathic helices, suggesting their participation in surfactant activities. Earlier structural studies with Mini-B, a disulfide-linked construct based on the N- and C-terminal regions of SP-B (i.e., approximately residues 8-25 and 63-78), confirmed that these neighboring domains are helical; moreover, Mini-B retains critical in vitro and in vivo surfactant functions of the native protein. Here, we perform similar analyses on a Super Mini-B construct that has native SP-B residues (1-7) attached to the N-terminus of Mini-B, to test whether the N-terminal sequence is also involved in surfactant activity. Methodology/results FTIR spectra of Mini-B and Super Mini-B in either lipids or lipid-mimics indicated that these peptides share similar conformations, with primary alpha-helix and secondary beta-sheet and loop-turns. Gel electrophoresis demonstrated that Super Mini-B was dimeric in SDS detergent-polyacrylamide, while Mini-B was monomeric. Surface plasmon resonance (SPR), predictive aggregation algorithms, and molecular dynamics (MD) and docking simulations further suggested a preliminary model for dimeric Super Mini-B, in which monomers self-associate to form a dimer peptide with a "saposin-like" fold. Similar to native SP-B, both Mini-B and Super Mini-B exhibit in vitro activity with spread films showing near-zero minimum surface tension during cycling using captive bubble surfactometry. In vivo, Super Mini-B demonstrates oxygenation and dynamic compliance that are greater than Mini-B and compare favorably to full-length SP-B. Conclusion Super Mini-B shows enhanced surfactant activity, probably due to the self-assembly of monomer peptide into dimer Super Mini-B that mimics the functions and putative structure of native SP-B.
- Published
- 2010
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