Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

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Abstract

BACKGROUND. Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TP53 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cell-cycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells.

METHODS. In this clinical trial, patients with myelodysplastic syndrome (n = 25) received reduced decitabine dosages (0.1–0.2 mg/kg/day compared with the FDA-approved 20–45 mg/m²/day dosage, a 75%–90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1–3 days per week, instead of pulse cycled for 3 to 5 days over a 4- to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase–dependent DNMT1 depletion.

RESULTS. The median subject age was 73 years (range, 46–85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186–1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key apoptosis genes were frequent (present in 55% of responders and in 36% of nonresponders). Noncytotoxic DNMT1 depletion was confirmed by serial BM γ-H2AX (DNA repair/damage marker) and DNMT1 analyses. MYC master oncoprotein levels were markedly decreased.

CONCLUSION. Decitabine regimens can be redesigned to minimize cytotoxicity and increase exposure time for DNMT1 depletion, to safely and effectively circumvent mutational apoptotic defects.

TRIAL REGISTRATION. Clinicaltrials.gov NCT01165996.

FUNDING. NIH (R01CA138858, CA043703); Department of Defense (PR081404); Clinical and Translational Science Award (CTSA) (UL1RR024989); and the Leukemia and Lymphoma Society (Translational Research Program).

Authors

Yogen Saunthararajah, Mikkael Sekeres, Anjali Advani, Reda Mahfouz, Lisa Durkin, Tomas Radivoyevitch, Ricki Englehaupt, Joy Juersivich, Kathleen Cooper, Holleh Husseinzadeh, Bartlomiej Przychodzen, Matthew Rump, Sean Hobson, Marc Earl, Ronald Sobecks, Robert Dean, Frederic Reu, Ramon Tiu, Betty Hamilton, Edward Copelan, Alan Lichtin, Eric Hsi, Matt Kalaycio, Jaroslaw Maciejewski

Metabolically normal obese people are protected from adverse effects following weight gain

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Abstract

BACKGROUND. Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, both of which are key risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. Here, we tested the hypothesis that people defined by IHTG content and insulin sensitivity as “metabolically normal obese” (MNO), but not those defined as “metabolically abnormal obese” (MAO), are protected from the adverse metabolic effects of weight gain.

METHODS. Body composition, multiorgan insulin sensitivity, VLDL apolipoprotein B100 (apoB100) kinetics, and global transcriptional profile in adipose tissue were evaluated before and after moderate (~6%) weight gain in MNO (n = 12) and MAO (n = 8) subjects with a mean BMI of 36 ± 4 kg/m² who were matched for BMI and fat mass.

RESULTS. Although the increase in body weight and fat mass was the same in both groups, hepatic, skeletal muscle, and adipose tissue insulin sensitivity deteriorated, and VLDL apoB100 concentrations and secretion rates increased in MAO, but not MNO, subjects. Moreover, biological pathways and genes associated with adipose tissue lipogenesis increased in MNO, but not MAO, subjects.

CONCLUSIONS. These data demonstrate that MNO people are resistant, whereas MAO people are predisposed, to the adverse metabolic effects of moderate weight gain and that increased adipose tissue capacity for lipogenesis might help protect MNO people from weight gain–induced metabolic dysfunction.

TRIAL REGISTRATION. ClinicalTrials.gov NCT01184170.

FUNDING. This work was supported by NIH grants UL1 RR024992 (Clinical Translational Science Award), DK 56341 (Nutrition and Obesity Research Center), DK 37948 and DK 20579 (Diabetes Center Grant), and UL1 TR000450 (KL2 Award); a Central Society for Clinical and Translational Research Early Career Development Award; and by grants from the Longer Life Foundation and the Kilo Foundation.

Authors

Elisa Fabbrini, Jun Yoshino, Mihoko Yoshino, Faidon Magkos, Courtney Tiemann Luecking, Dmitri Samovski, Gemma Fraterrigo, Adewole L. Okunade, Bruce W. Patterson, Samuel Klein

Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes

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Abstract

BACKGROUND. Previous efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and <2 years).

METHODS. A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean ± SD) was 24.6 ± 10 years; mean BMI was 25.4 ± 5.2 kg/m²; mean A1c was 6.5% ± 1.1%; insulin use was 0.31 ± 0.22 units/kg/d; and length of diagnosis was 1 ± 0.5 years.

RESULTS. Combination ATG/G-CSF treatment tended to preserve β cell function in patients with established T1D. The mean difference in MMTT-stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001–0.552, P = 0.050). A1c was lower in ATG/G-CSF–treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs.

CONCLUSIONS. Patients with established T1D may benefit from combination immunotherapy approaches to preserve β cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease.

TRIAL REGISTRATION. Clinicaltrials.gov NCT01106157.

FUNDING. The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi.

Authors

Michael J. Haller, Stephen E. Gitelman, Peter A. Gottlieb, Aaron W. Michels, Stephen M. Rosenthal, Jonathan J. Shuster, Baiming Zou, Todd M. Brusko, Maigan A. Hulme, Clive H. Wasserfall, Clayton E. Mathews, Mark A. Atkinson, Desmond A. Schatz

Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity

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Abstract

BACKGROUND. Roux-en-Y gastric bypass (RYGB) surgery causes profound weight loss and improves insulin sensitivity (S_I) in obese patients. Regular exercise can also improve S_I in obese individuals; however, it is unknown whether exercise and RYGB surgery–induced weight loss would additively improve S_I and other cardiometabolic factors.

METHODS. We conducted a single-blind, prospective, randomized trial with 128 men and women who recently underwent RYGB surgery (within 1–3 months). Participants were randomized to either a 6-month semi-supervised moderate exercise protocol (EX, n = 66) or a health education control (CON; n = 62) intervention. Main outcomes measured included S_I and glucose effectiveness (S_G), which were determined from an intravenous glucose tolerance test and minimal modeling. Secondary outcomes measured were cardiorespiratory fitness (VO₂ peak) and body composition. Data were analyzed using an intention-to-treat (ITT) and per-protocol (PP) approach to assess the efficacy of the exercise intervention (>120 min of exercise/week).

RESULTS. 119 (93%) participants completed the interventions, 95% for CON and 91% for EX. There was a significant decrease in body weight and fat mass for both groups (P < 0.001 for time effect). S_I improved in both groups following the intervention (ITT: CON vs. EX; +1.64 vs. +2.24 min^–1/μU/ml, P = 0.18 for Δ, P < 0.001 for time effect). A PP analysis revealed that exercise produced an additive S_I improvement (PP: CON vs. EX; +1.57 vs. +2.69 min^–1/μU/ml, P = 0.019) above that of surgery. Exercise also improved S_G (ITT: CON vs. EX; +0.0023 vs. +0.0063 min^–1, P = 0.009) compared with the CON group. Exercise improved cardiorespiratory fitness (VO₂ peak) compared with the CON group.

CONCLUSION. Moderate exercise following RYGB surgery provides additional improvements in S_I, S_G, and cardiorespiratory fitness compared with a sedentary lifestyle during similar weight loss.

TRIAL REGISTRATION. clinicaltrials.gov identifier: NCT00692367.

FUNDING. This study was funded by the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK078192) and an NIH/National Center for Research Resources/Clinical and Translational Science Award (UL1 RR024153.

Authors

Paul M. Coen, Charles J. Tanner, Nicole L. Helbling, Gabriel S. Dubis, Kazanna C. Hames, Hui Xie, George M. Eid, Maja Stefanovic-Racic, Frederico G.S. Toledo, John M. Jakicic, Joseph A. Houmard, Bret H. Goodpaster

HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial

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Abstract

BACKGROUND. Vector prime-boost immunization strategies induce strong cellular and humoral immune responses. We examined the priming dose and administration order of heterologous vectors in HIV Vaccine Trials Network 078 (HVTN 078), a randomized, double-blind phase Ib clinical trial to evaluate the safety and immunogenicity of heterologous prime-boost regimens, with a New York vaccinia HIV clade B (NYVAC-B) vaccine and a recombinant adenovirus 5–vectored (rAd5-vectored) vaccine.

METHODS. NYVAC-B included HIV-1 clade B Gag-Pol-Nef and gp120, while rAd5 included HIV-1 clade B Gag-Pol and clades A, B, and C gp140. Eighty Ad5-seronegative subjects were randomized to receive 2 × NYVAC-B followed by 1 × 10¹⁰ PFU rAd5 (NYVAC/Ad5_hi); 1 × 10⁸ PFU rAd5 followed by 2 × NYVAC-B (Ad5_lo/NYVAC); 1 × 10⁹ PFU rAd5 followed by 2 × NYVAC-B (Ad5_med/NYVAC); 1 × 10¹⁰ PFU rAd5 followed by 2 × NYVAC-B (Ad5_hi/NYVAC); or placebo. Immune responses were assessed 2 weeks after the final vaccination. Intracellular cytokine staining measured T cells producing IFN-γ and/or IL-2; cross-clade and epitope-specific binding antibodies were determined; and neutralizing antibodies (nAbs) were assessed with 6 tier 1 viruses.

RESULTS. CD4⁺ T cell response rates ranged from 42.9% to 93.3%. NYVAC/Ad5_hi response rates (P ≤ 0.01) and magnitudes (P ≤ 0.03) were significantly lower than those of other groups. CD8⁺ T cell response rates ranged from 65.5% to 85.7%. NYVAC/Ad5_hi magnitudes were significantly lower than those of other groups (P ≤ 0.04). IgG response rates to the group M consensus gp140 were 89.7% for NYVAC/Ad5_hi and 21.4%, 84.6%, and 100% for Ad5_lo/NYVAC, Ad5_med/NYVAC, and Ad5_hi/NYVAC, respectively, and were similar for other vaccine proteins. Overall nAb responses were low, but aggregate responses appeared stronger for Ad5_med/NYVAC and Ad5_hi/NYVAC than for NYVAC/Ad5_hi.

CONCLUSIONS. rAd5 prime followed by NYVAC boost is superior to the reverse regimen for both vaccine-induced cellular and humoral immune responses. Higher Ad5 priming doses significantly increased binding and nAbs. These data provide a basis for optimizing the design of future clinical trials testing vector-based heterologous prime-boost strategies.

TRIAL REGISTRATION. ClinicalTrials.gov NCT00961883.

FUNDING. National Institute of Allergy and Infectious Diseases (NIAID), NIH UM1AI068618, AI068635, AI068614, and AI069443.

Authors

Pierre-Alexandre Bart, Yunda Huang, Shelly T. Karuna, Samuel Chappuis, Julien Gaillard, Nidhi Kochar, Xiaoying Shen, Mary A. Allen, Song Ding, John Hural, Hua-Xin Liao, Barton F. Haynes, Barney S. Graham, Peter B. Gilbert, M. Juliana McElrath, David C. Montefiori, Georgia D. Tomaras, Giuseppe Pantaleo, Nicole Frahm

Disposable platform provides visual and color-based point-of-care anemia self-testing

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Abstract

BACKGROUND. Anemia, or low blood hemoglobin (Hgb) levels, afflicts 2 billion people worldwide. Currently, Hgb levels are typically measured from blood samples using hematology analyzers, which are housed in hospitals, clinics, or commercial laboratories and require skilled technicians to operate. A reliable, inexpensive point-of-care (POC) Hgb test would enable cost-effective anemia screening and chronically anemic patients to self-monitor their disease. We present a rapid, stand-alone, and disposable POC anemia test that, via a single drop of blood, outputs color-based visual results that correlate with Hgb levels.

METHODS. We tested blood from 238 pediatric and adult patients with anemia of varying degrees and etiologies and compared hematology analyzer Hgb levels with POC Hgb levels, which were estimated via visual interpretation using a color scale and an optional smartphone app for automated analysis.

RESULTS. POC Hgb levels correlated with hematology analyzer Hgb levels (r = 0.864 and r = 0.856 for visual interpretation and smartphone app, respectively), and both POC test methods yielded comparable sensitivity and specificity for detecting any anemia (n = 178) (<11 g/dl) (sensitivity: 90.2% and 91.1%, specificity: 83.7% and 79.2%, respectively) and severe anemia (n = 10) (<7 g/dl) (sensitivity: 90.0% and 100%, specificity: 94.6% and 93.9%, respectively).

CONCLUSIONS. These results demonstrate the feasibility of this POC color-based diagnostic test for self-screening/self-monitoring of anemia.

TRIAL REGISTRATION. Not applicable.

FUNDING. This work was funded by the FDA-funded Atlantic Pediatric Device Consortium, the Georgia Research Alliance, Children’s Healthcare of Atlanta, the Georgia Center of Innovation for Manufacturing, and the InVenture Prize and Ideas to Serve competitions at the Georgia Institute of Technology.

Authors

Erika A. Tyburski, Scott E. Gillespie, William A. Stoy, Robert G. Mannino, Alexander J. Weiss, Alexa F. Siu, Rayford H. Bulloch, Karthik Thota, Anyela Cardenas, Wilena Session, Hanna J. Khoury, Siobhán O’Connor, Silvia T. Bunting, Jeanne Boudreaux, Craig R. Forest, Manila Gaddh, Traci Leong, L. Andrew Lyon, Wilbur A. Lam

Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease

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Abstract

BACKGROUND. Autoimmune inner ear disease (AIED) is a rare disease that results in progressive sensorineural hearing loss. Patients with AIED initially respond to corticosteroids; however, many patients become unresponsive to this treatment over time, and there is no effective alternative therapy for these individuals.

METHODS. We performed a phase I/II open-label, single-arm clinical trial of the IL-1 receptor antagonist anakinra in corticosteroid-resistant AIED patients. Given that the etiology of corticosteroid resistance is likely heterogeneous, we used a Simon 2-stage design to distinguish between an unacceptable (≤10%) and an acceptable (≥30%) response rate to anakinra therapy. Subjects received 100 mg anakinra by subcutaneous injection for 84 days, followed by a 180-day observational period.

RESULTS. Based on patient responses, the Simon 2-stage rule permitted premature termination of the trial after 10 subjects completed the 84-day drug period, as the target efficacy for the entire trial had been achieved. Of these 10 patients, 7 demonstrated audiometric improvement, as assessed by pure tone average (PTA) and word recognition score (WRS). In these 7 responders, reduced IL-1β plasma levels correlated with clinical response. Upon discontinuation of treatment, 3 subjects relapsed, which correlated with increased IL-1β plasma levels.

CONCLUSION. We demonstrated that IL-1β inhibition in corticosteroid-resistant AIED patients was effective in a small cohort of patients and that IL-1β plasma levels associated with both clinical hearing response and disease relapse. These results suggest that a larger phase II randomized clinical trial of IL-1β inhibition is warranted.

TRIAL REGISTRATION. ClinicalTrials.gov NCT01267994.

FUNDING. NIH, Merrill & Phoebe Goodman Otology Research Center, and Long Island Hearing & Speech Society.

Authors

Andrea Vambutas, Martin Lesser, Virginia Mullooly, Shresh Pathak, Gerald Zahtz, Lisa Rosen, Elliot Goldofsky

Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients

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Abstract

BACKGROUND. Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMT^hi). Coadministration of O⁶-benzylguanine (O⁶BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O⁶BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome.

METHODS. We enrolled 7 newly diagnosed glioblastoma patients with MGMT^hi tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O⁶BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated.

RESULTS. Gene therapy permitted a significant increase in the mean number of tolerated O⁶BG/TMZ cycles (4.4 cycles per patient, P < 0.05) compared with historical controls without gene therapy (n = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5–57⁺) months and OS of 20 (range 13–57⁺) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O⁶BG.

CONCLUSION. These data support further development of chemoprotective gene therapy in combination with O⁶BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT.

TRIAL REGISTRATION. Clinicaltrials.gov NCT00669669.

FUNDING. R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970.

Authors

Jennifer E. Adair, Sandra K. Johnston, Maciej M. Mrugala, Brian C. Beard, Laura A. Guyman, Anne L. Baldock, Carly A. Bridge, Andrea Hawkins-Daarud, Jennifer L. Gori, Donald E. Born, Luis F. Gonzalez-Cuyar, Daniel L. Silbergeld, Russell C. Rockne, Barry E. Storer, Jason K. Rockhill, Kristin R. Swanson, Hans-Peter Kiem

Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization

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Abstract

BACKGROUND. Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy.

METHODS. Following superovulation with recombinant follicle-stimulating hormone and administration of gonadotropin-releasing hormone antagonist to prevent premature ovulation, 53 women were administered a single subcutaneous injection of kisspeptin-54 (1.6 nmol/kg, n = 2; 3.2 nmol/kg, n = 3; 6.4 nmol/kg, n = 24; 12.8 nmol/kg, n = 24) to induce a luteinizing hormone surge and egg maturation. Eggs were retrieved transvaginally 36 hours after kisspeptin injection, assessed for maturation (primary outcome), and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos.

RESULTS. Egg maturation was observed in response to each tested dose of kisspeptin-54, and the mean number of mature eggs per patient generally increased in a dose-dependent manner. Fertilization of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of kisspeptin-54–treated patients. Biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53), respectively.

CONCLUSION. This study demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing in vitro fertilization therapy. Subsequent fertilization of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy.

TRIAL REGISTRATION. ClinicalTrials.gov NCT01667406

FUNDING. Medical Research Council, Wellcome Trust, and National Institute for Health Research.

Authors

Channa N. Jayasena, Ali Abbara, Alexander N. Comninos, Gurjinder M.K. Nijher, Georgios Christopoulos, Shakunthala Narayanaswamy, Chioma Izzi-Engbeaya, Mathini Sridharan, Alexina J. Mason, Jane Warwick, Deborah Ashby, Mohammad A. Ghatei, Stephen R. Bloom, Anna Carby, Geoffrey H. Trew, Waljit S. Dhillo

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

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Abstract

BACKGROUND. Hepatitis C virus (HCV) infects approximately 170 million people worldwide and may lead to cirrhosis and hepatocellular carcinoma in chronically infected individuals. Treatment is rapidly evolving from IFN-α–based therapies to IFN-α–free regimens that consist of directly acting antiviral agents (DAAs), which demonstrate improved efficacy and tolerability in clinical trials. Virologic relapse after DAA therapy is a common cause of treatment failure; however, it is not clear why relapse occurs or whether certain individuals are more prone to recurrent viremia.

METHODS. We conducted a clinical trial using the DAA sofosbuvir plus ribavirin (SOF/RBV) and performed detailed mRNA expression analysis in liver and peripheral blood from patients who achieved either a sustained virologic response (SVR) or relapsed.

RESULTS. On-treatment viral clearance was accompanied by rapid downregulation of IFN-stimulated genes (ISGs) in liver and blood, regardless of treatment outcome. Analysis of paired pretreatment and end of treatment (EOT) liver biopsies from SVR patients showed that viral clearance was accompanied by decreased expression of type II and III IFNs, but unexpectedly increased expression of the type I IFN IFNA2. mRNA expression of ISGs was higher in EOT liver biopsies of patients who achieved SVR than in patients who later relapsed.

CONCLUSION. These results suggest that restoration of type I intrahepatic IFN signaling by EOT may facilitate HCV eradication and prevention of relapse upon withdrawal of SOF/RBV.

TRIAL REGISTRATION. ClinicalTrials.gov NCT01441180.

FUNDING. Intramural Programs of the National Institute of Allergy and Infectious Diseases, National Institutes of Health Clinical Center, and National Cancer Institute; German Research Foundation.

Authors

Eric G. Meissner, David Wu, Anu Osinusi, Dimitra Bon, Kimmo Virtaneva, Dan Sturdevant, Steve Porcella, Honghui Wang, Eva Herrmann, John McHutchison, Anthony F. Suffredini, Michael Polis, Stephen Hewitt, Ludmila Prokunina-Olsson, Henry Masur, Anthony S. Fauci, Shyamasundaran Kottilil