Browsing by Author "Zaid, Mohammad Abu"

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    Altered metabolite levels and correlations in patients with colorectal cancer and polyps detected using seemingly unrelated regression analysis
    (Springer Nature, 2017-11) Chen, Chen; Gowda, G. A. Nagana; Zhu, Jiangjiang; Deng, Lingli; Gu, Haiwei; Chiorean, E. Gabriela; Zaid, Mohammad Abu; Harrison, Marietta; Zhang, Dabao; Zhang, Min; Raftery, Daniel; Graduate Medical Education, IU School of Medicine
    Introduction: Metabolomics technologies enable the identification of putative biomarkers for numerous diseases; however, the influence of confounding factors on metabolite levels poses a major challenge in moving forward with such metabolites for pre-clinical or clinical applications. Objectives: To address this challenge, we analyzed metabolomics data from a colorectal cancer (CRC) study, and used seemingly unrelated regression (SUR) to account for the effects of confounding factors including gender, BMI, age, alcohol use, and smoking. Methods: A SUR model based on 113 serum metabolites quantified using targeted mass spectrometry, identified 20 metabolites that differentiated CRC patients (n = 36), patients with polyp (n = 39), and healthy subjects (n = 83). Models built using different groups of biologically related metabolites achieved improved differentiation and were significant for 26 out of 29 groups. Furthermore, the networks of correlated metabolites constructed for all groups of metabolites using the ParCorA algorithm, before or after application of the SUR model, showed significant alterations for CRC and polyp patients relative to healthy controls. Results: The results showed that demographic covariates, such as gender, BMI, BMI2, and smoking status, exhibit significant confounding effects on metabolite levels, which can be modeled effectively. Conclusion: These results not only provide new insights into addressing the major issue of confounding effects in metabolomics analysis, but also shed light on issues related to establishing reliable biomarkers and the biological connections between them in a complex disease.
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    Biomarker Panel for Chronic Graft-Versus-Host Disease
    (American Society of Clinical Oncology, 2016-08-01) Yu, Jeffrey; Storer, Barry E.; Kushekhar, Kushi; Zaid, Mohammad Abu; Zhang, Qing; Gafken, Philip R.; Ogata, Yuko; Martin, Paul J.; Flowers, Mary E.; Hansen, John A.; Arora, Mukta; Cutler, Corey; Jagasia, Madan; Pidala, Joseph; Hamilton, Betty K.; Chen, George L.; Pusic, Iskra; Lee, Stephanie J.; Paczesny, Sophie; Medicine, School of Medicine
    PURPOSE: To identify diagnostic and prognostic markers of chronic graft-versus-host disease (cGVHD), the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). PATIENTS AND METHODS: Using a quantitative proteomics approach, we compared pooled plasma samples obtained at matched time points after HCT (median, 103 days) from 35 patients with cGVHD and 18 without cGVHD (data are available via ProteomeXchange with identifier PXD002762). Of 105 proteins showing at least a 1.25-fold difference in expression, 22 were selected on the basis of involvement in relevant pathways and enzyme-linked immunosorbent assay availability. Chemokine (C-X-C motif) ligand 9 (CXCL9) and suppression of tumorigenicity 2 (ST2) also were measured on the basis of previously determined associations with GVHD. Concentrations of the four lead biomarkers were measured at or after diagnosis in plasma from two independent verification cohorts (n = 391) to determine their association with cGVHD. Their prognostic ability when measured at approximately day +100 after HCT was evaluated in plasma of a second verification cohort (n = 172). RESULTS: Of 24 proteins measured in the first verification cohort, nine proteins were associated with cGVHD, and only four (ST2, CXCL9, matrix metalloproteinase 3, and osteopontin) were necessary to compose a four-biomarker panel with an area under the receiver operating characteristic curve (AUC) of 0.89 and significant correlation with cGVHD diagnosis, cGVHD severity, and nonrelapse mortality. In a second verification cohort, this panel distinguished patients with cGVHD (AUC, 0.75), and finally, the panel measured at day +100 could predict cGVHD occurring within the next 3 months with an AUC of 0.67 and 0.79 without and with known clinical risk factors, respectively. CONCLUSION: We conclude that the biomarker panel measured at diagnosis or day +100 after HCT may allow patient stratification according to risk of cGVHD.
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    Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML
    (Impact Journals, 2017-12-25) Sayar, Hamid; Liu, Yan; Gao, Rui; Zaid, Mohammad Abu; Cripe, Larry D.; Weisenbach, Jill; Sargent, Katie J.; Nassiri, Mehdi; Li, Lang; Konig, Heiko; Suvannasankha, Attaya; Pan, Feng; Shanmugam, Rajasubramaniam; Goswami, Chirayu; Kapur, Reuben; Xu, Mingjiang; Boswell, H. Scott; Medicine, School of Medicine
    Co-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML's, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3, occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3/Wnt antagonist de-repression (80%) and ID1 downregulation (85%), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.
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    Diagnostic Evidence GAuge of Single cells (DEGAS): a flexible deep transfer learning framework for prioritizing cells in relation to disease
    (BMC, 2022-02-01) Johnson, Travis S.; Yu, Christina Y.; Huang, Zhi; Xu, Siwen; Wang, Tongxin; Dong, Chuanpeng; Shao, Wei; Zaid, Mohammad Abu; Huang, Xiaoqing; Wang, Yijie; Bartlett, Christopher; Zhang, Yan; Walker, Brian A.; Liu, Yunlong; Huang, Kun; Zhang, Jie; Medicine, School of Medicine
    We propose DEGAS (Diagnostic Evidence GAuge of Single cells), a novel deep transfer learning framework, to transfer disease information from patients to cells. We call such transferrable information "impressions," which allow individual cells to be associated with disease attributes like diagnosis, prognosis, and response to therapy. Using simulated data and ten diverse single-cell and patient bulk tissue transcriptomic datasets from glioblastoma multiforme (GBM), Alzheimer's disease (AD), and multiple myeloma (MM), we demonstrate the feasibility, flexibility, and broad applications of the DEGAS framework. DEGAS analysis on myeloma single-cell transcriptomics identified PHF19high myeloma cells associated with progression.
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    Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease
    (Massachusetts Medical Society, 2021-01-07) Farag, Sherif S.; Zaid, Mohammad Abu; Schwartz, Jennifer E.; Thakrar, Teresa C.; Blakley, Ann J.; Abonour, Rafat; Robertson, Michael J.; Broxmeyer, Hal E.; Zhang, Shuhong; Medicine, School of Medicine
    Background: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. Methods: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. Results: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. Conclusions: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation.
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    High-dose sitagliptin for systemic inhibition of dipeptidylpeptidase-4 to enhance engraftment of single cord umbilical cord blood transplantation
    (Impact Journals, 2017-11-27) Farag, Sherif S.; Nelson, Robert; Cairo, Mitchell S.; O’Leary, Heather A.; Zhang, Shuhong; Huntley, Carol; Delgado, David; Schwartz, Jennifer; Zaid, Mohammad Abu; Abonour, Rafat; Robertson, Michael; Broxmeyer, Hal; Medicine, School of Medicine
    Delayed engraftment remains a limitation of umbilical cord blood (UCB) transplantation. We previously showed that inhibition of dipeptidylpeptidase (DPP)-4 using sitagliptin 600 mg daily was safe with encouraging results on engraftment, but inhibition was not sustained. We evaluated the efficacy and feasibility of higher doses of sitagliptin to enhance engraftment of UCB in patients with hematological cancers. Fifteen patients, median age 41 (range, 18-59) years, received single UCB grafts matched at 4 (n=11) or 5 (n=4) of 6 HLA loci with median nucleated cell dose of 3.5 (range, 2.57-4.57) x107/kg. Sitagliptin 600 mg every 12 hours was administered days -1 to +2. All patients engrafted by day 30, with 12 (80%) engrafting by day 21. The median time to neutrophil engraftment was 19 (range, 12-30) days. Plasma DPP-4 activity was better inhibited with a mean residual trough DPP-4 activity of 70%±19%. Compared to patients previously treated with 600 mg/day, sitagliptin 600 mg every 12 hours appeared to improve engraftment, supporting the hypothesis that more sustained DPP-4 inhibition is required. In-vivo inhibition of DPP-4 using high-dose sitagliptin compares favorably with other approaches to enhance UCB engraftment with greater simplicity, and may show synergy in combination with other strategies.
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    Intron retention-induced neoantigen load correlates with unfavorable prognosis in multiple myeloma
    (Springer Nature, 2021-10) Dong, Chuanpeng; Cesarano, Annamaria; Bombaci, Giuseppe; Reiter, Jill L.; Yu, Christina Y.; Wang, Yue; Jiang, Zhaoyang; Zaid, Mohammad Abu; Huang, Kun; Lu, Xiongbin; Walker, Brian A.; Perna, Fabiana; Liu, Yunlong; BioHealth Informatics, School of Informatics and Computing
    Neoantigen peptides arising from genetic alterations may serve as targets for personalized cancer vaccines and as positive predictors of response to immune checkpoint therapy. Mutations in genes regulating RNA splicing are common in hematological malignancies leading to dysregulated splicing and intron retention (IR). In this study, we investigated IR as a potential source of tumor neoantigens in multiple myeloma (MM) patients and the relationship of IR-induced neoantigens (IR-neoAg) with clinical outcomes. MM-specific IR events were identified in RNA-sequencing data from the Multiple Myeloma Research Foundation CoMMpass study after removing IR events that also occurred in normal plasma cells. We quantified the IR-neoAg load by assessing IR-induced novel peptides that were predicted to bind to major histocompatibility complex (MHC) molecules. We found that high IR-neoAg load was associated with poor overall survival in both newly diagnosed and relapsed MM patients. Further analyses revealed that poor outcome in MM patients with high IR-neoAg load was associated with high expression levels of T-cell co-inhibitory molecules and elevated interferon signaling activity. We also found that MM cells exhibiting high IR levels had lower MHC-II protein abundance and treatment of MM cells with a spliceosome inhibitor resulted in increased MHC-I protein abundance. Our findings suggest that IR-neoAg may represent a novel biomarker of MM patient clinical outcome and further that targeting RNA splicing may serve as a potential therapeutic strategy to prevent MM immune escape and promote response to checkpoint blockade.
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    Phase II trial of brentuximab vedotin in relapsed/refractory germ cell tumors
    (Springer, 2021) Ashkar, Ryan; Feldman, Darren R.; Adra, Nabil; Zaid, Mohammad Abu; Funt, Samuel A.; Althouse, Sandra K.; Perkins, Susan M.; Snow, Christin I.; Lazzara, Kayla M.; Sego, Lina M.; Quinn, David I.; Hanna, Nasser H.; Einhorn, Lawrence H.; Albany, Costantine; Biostatistics, School of Public Health
    Background: CD-30 is highly expressed in some patients with non-seminomatous germ-cell tumors. Brentuximab vedotin is an antibody–drug conjugate directed to CD-30. We report a phase 2 trial of brentuximab vedotin in patients with chemo-refractory GCT. Patients and methods: This is a single arm, two cohort phase 2 trial investigating brentuximab vedotin 1.8 mg/kg IV every 3 weeks until disease progression or intolerable toxicities in patients with relapsed GCT who have no curative options. Patients with mGCT who progressed after first line cisplatin-based chemotherapy and after at least 1 salvage regimen (high-dose or standard-dose chemotherapy) were eligible. CD30 expression was assessed and two cohorts defined: CD30 positive and CD30 negative/unknown. Results: 18 patients were enrolled. Median age 34.7 (range, 23–56). All patients had non-seminoma. Median AFP 4.9 (range, 1–219,345) and hCG 282 (range, 0.6–172,064). Five patients had late relapse (> 2 years). Median number of previous chemotherapy regimens was 3 (range, 2–7). Ten patients received prior high-dose chemotherapy. Seven patients had positive CD30 staining. There were two grade 3 treatment-related adverse events. No partial or complete responses were observed. 6 patients achieved radiographic stable disease (range, 9–14.9 weeks), 5 had elevated AFP or hCG at trial entry and all 5 had transient > 50% decline in baseline AFP/hCG: 4 had CD30 −ve and 2 had CD30 + ve staining; 10 patients had progression of disease as their best response; 2 were not evaluable for response. Conclusion: Brentuximab vedotin does not appear to have clinically meaningful single-agent activity in patients with refractory GCT.
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    Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post-allogeneic HCT.
    (American Society of Hematology, 2017-01-12) Zaid, Mohammad Abu; Wu, Juan; Wu, Cindy; Logan, Brent R.; Yu, Jeffrey; Cutler, Corey; Antin, Joseph H.; Paczesny, Sophie; Choi, Sung Won; Department of Pediatrics, IU School of Medicine
    A phase 3 clinical trial (BMT CTN 0402) comparing tacrolimus/sirolimus (Tac/Sir) vs tacrolimus/methotrexate (Tac/Mtx) as graft-versus-host disease (GVHD) prophylaxis after matched-related allogeneic hematopoietic cell transplantation (HCT) recently showed no difference between study arms in acute GVHD-free survival. Within this setting of a prospective, multicenter study with uniform GVHD prophylaxis, conditioning regimen, and donor source, we explored the correlation of 10 previously identified biomarkers with clinical outcomes after allogeneic HCT. We measured biomarkers from plasma samples collected in 211 patients using enzyme-linked immunosorbent assay (Tac/Sir = 104, Tac/Mtx = 107). High suppression of tumorigenicity-2 (ST2) and T-cell immunoglobulin mucin-3 (TIM3) at day 28 correlated with 2-year nonrelapse mortality in multivariate analysis (P = .0050, P = .0075, respectively) and in a proportional hazards model with time-dependent covariates (adjusted hazard ratio: 2.43 [1.49-3.95], P = .0038 and 4.87 [2.53-9.34], P < .0001, respectively). High ST2 and TIM3 correlated with overall survival. Chemokine (C-X-C motif) ligand 9 (CXCL9) levels above the median were associated with chronic GVHD compared with levels below the median in a time-dependent proportional hazard analysis (P = .0069). Low L-Ficolin was associated with hepatic veno-occlusive disease (P = .0053, AUC = 0.80). We confirmed the correlation of plasma-derived proteins, previously assessed in single-center cohorts, with clinical outcomes after allogeneic HCT within this prospective, multicenter study.
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    Solid and Hematologic Neoplasms After Testicular Cancer: A US Population-Based Study of 24 900 Survivors
    (Oxford University Press, 2020-03-17) Milano, Michael T.; Dinh, Paul C.; Yang, Hongmei; Zaid, Mohammad Abu; Fossa, Sophie D.; Feldman, Darren R.; Monahan, Patrick O.; Travis, Lois B.; Fung, Chunkit; Medicine, School of Medicine
    Background: No large US population-based study focusing on recent decades, to our knowledge, has comprehensively examined risks of second malignant solid and hematological neoplasms (solid-SMN and heme-SMN) after testicular cancer (TC), taking into account initial therapy and histological type. Methods: Standardized incidence ratios (SIR) vs the general population and 95% confidence intervals (CI) for solid-SMN and heme-SMN were calculated for 24 900 TC survivors (TCS) reported to the National Cancer Institute's Surveillance, Epidemiology, and End Results registries (1973-2014). All statistical tests were two-sided. Results: The median age at TC diagnosis was 33 years. Initial management comprised chemotherapy (n = 6340), radiotherapy (n = 9058), or surgery alone (n = 8995). During 372 709 person-years of follow-up (mean = 15 years), 1625 TCS developed solid-SMN and 228 (107 lymphomas, 92 leukemias, 29 plasma cell dyscrasias) developed heme-SMN. Solid-SMN risk was increased 1.06-fold (95% CI = 1.01 to 1.12), with elevated risks following radiotherapy (SIR = 1.13, 95% CI = 1.06 to 1.21) and chemotherapy (SIR = 1.36, 95% CI = 1.12 to 1.41) but not surgery alone (SIR = 0.83, 95% CI = 0.75 to 0.92). Corresponding risks for seminoma were 1.13 (95% CI = 1.06 to 1.21), 1.28 (95% CI = 1.02 to 1.58), and 0.87 (95% CI = 0.74 to 1.01) and for nonseminoma were 1.05 (95% CI = 0.67 to 1.56), 1.25 (95% CI = 1.08 to 1.43), and 0.80 (95% CI = 0.70 to 0.92), respectively. Thirty-year cumulative incidences of solid-SMN after radiotherapy, chemotherapy, and surgery alone were 16.9% (95% CI = 15.7% to 18.1%), 10.1% (95% CI = 8.8% to 11.5%), and 8.8% (95% CI = 7.8% to 9.9%), respectively (P < .0001). Increased leukemia risks after chemotherapy (SIR = 2.68, 95% CI = 1.70 to 4.01) were driven by statistically significant sevenfold excesses of acute myeloid leukemia 1 to 10 years after TC diagnosis. Risks for lymphoma and plasma cell dyscrasias were not elevated. Conclusions: We report statistically significant excesses of solid-SMN affecting 1 in 6 TCS 30 years after radiotherapy, and 2.7-fold risks of leukemias after chemotherapy, mostly acute myeloid leukemia. Efforts to minimize chemotherapy and radiotherapy exposures for TC should continue. TCS should be counseled about cancer prevention and screening.