242 results on '"Chang BH"'
Search Results
2. Pnpla3/Adiponutrin-Deficient Mice Maintain Normal Adipose Development and Liver Lipid Homeostasis.
- Author
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Chen, W, primary, Chang, BH, additional, Li, L, additional, and Chan, L, additional
- Published
- 2010
- Full Text
- View/download PDF
3. End-of-life spiritual care at a VA medical center: Chaplains' perspectives.
- Author
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Chang BH, Stein NR, Trevino K, Stewart M, Hendricks A, and Skarf LM.
- Abstract
Objective:Spiritual care is an essential component of quality palliative care. Recognizing the importance, the Department of Veterans Affairs (VA) mandates the inclusion of chaplains in a palliative care consult team (PCCT). The purpose of this study is to explain the process and content of spiritual care provided in a VA Medical Center from chaplains' perspectives.Method:Five Christian chaplains who provide care to patients at end of life were interviewed. Each interview was recorded and transcribed. Analysis based on the grounded theory was used to identify themes from each interview question.Results:The PCCT in this study appeared to have a strong referral and communication system in which every palliative care patient was seen by a chaplain and the care plan was discussed with an interdisciplinary team. Chaplains reported providing a range of services, which addressed religious, spiritual, emotional, family, and illness concerns. Chaplains were aware of the unique spiritual needs of veterans, including working through guilt for killing in war and requiring forgiveness. Chaplains' ideas for improvement of spiritual care services included increasing time to provide care, providing bereavement care and support to families, and adding chaplains with different religious backgrounds. Chaplains reported how their own spirituality influenced the care they provided.Significance of results:Spiritual care in the VA can include a range of services and should consider the unique needs of the veteran population. Future studies can build upon our findings from chaplains to learn about the perspectives of patients, family, and other healthcare providers of spiritual care. This information would allow identification of strengths of current spiritual care practices and areas for care improvement, and ultimately could improve the well-being of patients at the end of life. [ABSTRACT FROM AUTHOR]
- Published
- 2012
4. A model for integrating a mind/body approach to cardiac rehabilitation: outcomes and correlators.
- Author
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Casey A, Chang BH, Huddleston J, Virani N, Benson H, and Dusek JA
- Published
- 2009
- Full Text
- View/download PDF
5. The Combined Effect of Relaxation Response and Acupuncture on Quality of Life in Patients with HIV: A Pilot Study.
- Author
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Chang BH, Boehmer U, Zhao Y, and Sommers E
- Subjects
- *
THERAPEUTICS , *RELAXATION for health , *ACUPUNCTURE , *QUALITY of life , *HIV-positive persons , *AIDS patients - Abstract
Objectives: Treatment advances have transformed human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) into a chronic manageable disease; quality of life (QoL) has become an important health outcome. Some studies have shown the individual effects of acupuncture and the relaxation response (RR) in improving QoL of patients with HIV/AIDS. In light of the presumed shared features of acupuncture and the RR, we conducted a pilot study to examine the effects of adding the RR to usual acupuncture treatment on improving the QoL of HIV/AIDS patients. Design: Two-arm double-blind randomized controlled trial. Settings/location and subjects: We enrolled 119 patients with HIV/AIDS (mean age 46 years, 85% male) who had at least 1 of the highly prevalent HIV-related symptoms and who were receiving acupuncture treatment in an acupuncture clinic in Boston, MA. Intervention: We randomized patients into intervention (N = 58) and control (N = 61) groups. All participants received individualized acupuncture treatments prescribed by their acupuncturists. While receiving acupuncture treatment, the intervention group wore earphones to listen to tapes with instructions to elicit the RR followed by soft music that was routinely played in the clinic; the control group listened only to soft music. Outcome measures: Three (3) QoL scales: the Medical Outcomes Study HIV health survey, the Functional Assessment of HIV Infection, and the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being, measured at baseline, 4-week, 8-week, and 12-week follow-ups. Results: At the 12-week follow-up, the intervention group showed significant improvements in emotional (p = 0.0002), spiritual/peace (p = 0.02), physical (p = 0.003) and mental health (p = 0.0003) QoL from baseline. Results of mixed effects regression models indicated linear trends of improvement over time in these dimensions of QoL for the intervention group (p < 0.02). In the control group, the only significant improvement was observed in the emotional QoL (p < 0.01). The intervention group showed trends of greater improvements than the control group (p = 0.07 for 12-week physical health QoL). Conclusions: Data from this pilot trial suggested that adding the RR to acupuncture may enhance improvement in QoL of patients with HIV/AIDS. Further investigation on this putative synergistic effect is warranted. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
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6. Optimizing early phase clinical trial washout periods: a report from the Therapeutic Advances in Childhood Leukemia and Lymphoma consortium.
- Author
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Schafer ES, Rushing T, Crews KR, Annesley C, Colace SI, Kaiser N, Pommert L, Ramsey LB, Sabnis HS, Wong K, Chang BH, Cooper TM, Shah NN, Rheingold SR, Place AE, Chi YY, Bhojwani D, Wayne AS, and Bernhardt MB
- Subjects
- Humans, Child, United States, Patient Selection, National Cancer Institute (U.S.), Lymphoma therapy, Leukemia therapy, Clinical Trials as Topic
- Abstract
Background: The National Cancer Institute (NCI) issued a 2021 memorandum adopting the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) task force recommendations to broaden clinical study eligibility criteria. They recommended that washout periods be eliminated for most prior cancer therapy and when required to utilize evidence- and/or rationale-based criteria. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium responded to this guidance., Methods: A TACL task force reviewed the consortium's research portfolio, the relevant literature and guidance documents from ASCO-Friends, NCI, and US Food and Drug Administration to make expert consensus and evidence-based recommendations for modernizing, broadening, and codifying TACL-study washout periods while ensuring consistency with pediatric ethics, and federal regulations. TACL's screening log was reviewed to estimate the impact that updated washout periods would have on patient inclusivity and recruitment., Results: Over a 19-year period, 42 (14.6% of all screened ineligible patients [n = 287]) patients were identified as excluded from TACL early phase studies exclusively because of not meeting washout criteria. An additional 6 (2.1%) did not meet washout and at least 1 other exclusion criterion. A new TACL washout guidance document was developed and then adopted for use. Where washout criteria were not eliminated, rationale- and/or evidenced-based criteria were established with citation., Conclusion: In an effort to reduce unnecessary exclusion from clinical trials, TACL created rationale- and/or evidenced-based washout period standards largely following guidance from the NCI and ASCO-Friends recommendations. These new, expanded eligibility criteria are expected to increase access to TACL clinical trials while maintaining safety and scientific excellence., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
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7. Multi-Team Shared Expectations Tool (MT-SET): An Exercise to Improve Teamwork Across Health Care Teams.
- Author
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Marsteller JA, Rosen MA, Wyskiel R, Chang BH, Hsu YJ, Thompson DA, Kim G, Speck K, Ijagbemi M, Huang S, and Gurses AP
- Subjects
- Humans, Cooperative Behavior, Quality Improvement organization & administration, Workflow, Interdisciplinary Communication, Interprofessional Relations, Patient Care Team organization & administration, Communication, Patient Safety
- Abstract
Care transitions among high-intensity units caring for patients with complex needs are a critical yet undeveloped area of patient safety research. In addition, effective communication and coordination across disciplines remain elusive. This study introduces and tests the Multi-Team Shared Expectations Tool (MT-SET), an exercise that aims to engage health care teams in eliciting needs and establishing agreed-upon expectations teams and individuals within a multi-team system have of one another. We piloted the exercise within hospital-based workflows for oncology inpatients and later adopted it to elicit data on mutual needs and expectations of teams across units involved in patient transitions in two patient safety projects. Our studies demonstrated that the exercise identified common cross-unit coordination problems of delays in care, unwanted variations in care, and lack of standardized communication among units. It also revealed mismatched prioritization of each of these problems between specific unit types. The participants reported that the MT-SET helped establish positive relationships for building better cross-unit and cross-disciplinary teamwork and coordination. There is a need for systematic approaches to understand and facilitate cross-unit communication and coordination in care delivery and transitions. Future studies should broaden the application of the exercise to additional types of multi-unit and multidisciplinary teams and observe intervention ideas generated from the exercise, as well as their implementation., (Copyright © 2024 The Joint Commission. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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8. Clonally related benign cephalic histiocytosis, histiocytic sarcoma, and T-cell acute lymphoblastic leukemia: Expanding the spectrum of histiocytic transdifferentiation.
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Thellman JC, Fang MM, Neff T, Thomas G, Frerich C, Press R, Dhossche JM, White KP, Chang BH, and Raess PW
- Subjects
- Humans, Cell Transdifferentiation, Male, Female, Histiocytosis pathology, Histiocytic Sarcoma pathology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
- Published
- 2024
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9. Sgabd-2 plays specific role in immune response against biopesticide Metarhizium anisopliae in Aphis citricola.
- Author
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Fan J, Jiang S, Zhang T, Gao H, Chang BH, Qiao X, and Han P
- Subjects
- Animals, Pest Control, Biological methods, Biological Control Agents, Insect Proteins genetics, Insect Proteins metabolism, Fungal Proteins genetics, Fungal Proteins metabolism, RNA Interference, Metarhizium pathogenicity, Aphids microbiology
- Abstract
Metarhizium anisopliae is an effective biopesticide for controlling Aphis citricola, which has developed resistance to many chemical pesticides. However, the powerful immune system of A. citricola has limited the insecticidal efficacy of M. anisopliae. The co-evolution between insects and entomogenous fungi has led to emergence of new antifungal immune genes, which remain incompletely understood. In this study, an important immune gene Sgabd-2 was identified from A. citricola through transcriptome analysis. Sgabd-2 gene showed high expression in the 4th instar nymph and adult stages, and was mainly distributed in the abdominal region of A. citricola. The recombinant protein (rSgabd-2) exhibited no antifungal activity but demonstrated clear agglutination activity towards the conidia of M. anisopliae. RNA interference of Sgabd-2 by dsRNA feeding resulted in decreased phenoloxidase (PO) activity and weakened defense for A. citricola against M. anisopliae. Simultaneous silence of GNBP-1 and Sgabd-2 effectively reduced the immunity of A. citricola against M. anisopliae more than the individual RNAi of GNBP-1 or Sgabd-2. Furthermore, a genetically engineered M. anisopliae expressing double-stranded RNA (dsSgabd-2) targeting Sgabd-2 in A. citricola successfully suppressed the expression of Sgabd-2 and demonstrated increased virulence against A. citricola. Our findings elucidated Sgabd-2 as a critical new antifungal immune gene and proposed a genetic engineering strategy to enhance the insecticidal virulence of entomogenous fungi through RNAi-mediated inhibition of pest immune genes., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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10. The genomic basis of childhood T-lineage acute lymphoblastic leukaemia.
- Author
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Pölönen P, Di Giacomo D, Seffernick AE, Elsayed A, Kimura S, Benini F, Montefiori LE, Wood BL, Xu J, Chen C, Cheng Z, Newman H, Myers J, Iacobucci I, Li E, Sussman J, Hedges D, Hui Y, Diorio C, Uppuluri L, Frank D, Fan Y, Chang Y, Meshinchi S, Ries R, Shraim R, Li A, Bernt KM, Devidas M, Winter SS, Dunsmore KP, Inaba H, Carroll WL, Ramirez NC, Phillips AH, Kriwacki RW, Yang JJ, Vincent TL, Zhao Y, Ghate PS, Wang J, Reilly C, Zhou X, Sanders MA, Takita J, Kato M, Takasugi N, Chang BH, Press RD, Loh M, Rampersaud E, Raetz E, Hunger SP, Tan K, Chang TC, Wu G, Pounds SB, Mullighan CG, and Teachey DT
- Subjects
- Child, Female, Humans, Male, Chromatin genetics, Chromatin metabolism, Enhancer Elements, Genetic genetics, Epigenomics, Gene Expression Regulation, Leukemic, Single-Cell Analysis, Transcriptome genetics, T-Lymphocytes cytology, T-Lymphocytes pathology, Genome, Human genetics, Genomics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour
1 that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation2,3 . Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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11. In vivo Targeting MEK and TNK2/SRC pathways in PTPN11 driven leukemia.
- Author
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Chang BH, Thiel-Klare K, and Tyner JW
- Abstract
PTPN11 encodes for a tyrosine phosphatase implicated in the pathogenesis of hematologic malignancies such as Juvenile Myelomonocytic Leukemia (JMML), Acute Myeloid Leukemia (AML), and Acute Lymphoblastic Leukemia (ALL). Since activating mutations of PTPN11 increase proliferative signaling and cell survival through the RAS/MAPK proliferative pathway there is significant interest in using MEK inhibitors for clinical benefit. Yet, single agent clinical activity has been minimal. Previously, we showed that PTPN11 is further activated by upstream tyrosine kinases TNK2/SRC, and that PTPN11-mutant JMML and AML cells are sensitive to TNK2 inhibition using dasatinib. In order to validate these findings, we adopted a genetically engineered mouse model of PTPN11 driven leukemia using the mouse strain 129S/Sv- Ptpn11
tm6Bgn /Mmucd crossed with B6.129P2- Lyz2tm1(cre)Ifo /J. The F1 progeny expressing Ptpn11D61Y within hematopoietic cells destined along the granulocyte-monocyte progenitor lineage developed a fatal myeloproliferative disorder characterized by neutrophilia and monocytosis, and infiltration of myeloid cells into the liver and spleen. Cohorts of Ptpn11D61Y expressing animals treated with combination of dasatinib and trametinib for an extended period of time was well tolerated and had a significant effect in mitigating disease parameters compared to single agents. Finally, a primary patient-derived xenograft model using a myeloid leukemia with PTPN11 F71L also displayed improved disease response to combination. Collectively, these studies point to combined therapies targeting MEK and TNK2/SRC as a promising therapeutic potential for PTPN11-mutant leukemias., Key Points: Combining MEK and TNK2/SRC inhibitors has therapeutic potential in PTPN11 mutant JMML and AML.- Published
- 2024
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12. FDG PET/CT Imaging 1 Week after a Single Dose of Pembrolizumab Predicts Treatment Response in Patients with Advanced Melanoma.
- Author
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Anderson TM, Chang BH, Huang AC, Xu X, Yoon D, Shang CG, Mick R, Schubert E, McGettigan S, Kreider K, Xu W, Wherry EJ, Schuchter LM, Amaravadi RK, Mitchell TC, and Farwell MD
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Treatment Outcome, Antineoplastic Agents, Immunological therapeutic use, Antineoplastic Agents, Immunological administration & dosage, Prospective Studies, Prognosis, Aged, 80 and over, Radiopharmaceuticals, Melanoma drug therapy, Melanoma pathology, Melanoma diagnostic imaging, Melanoma mortality, Positron Emission Tomography Computed Tomography methods, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized therapeutic use, Fluorodeoxyglucose F18 administration & dosage
- Abstract
Purpose: Immunologic response to anti-programmed cell death protein 1 (PD-1) therapy can occur rapidly with T-cell responses detectable in as little as one week. Given that activated immune cells are FDG avid, we hypothesized that an early FDG PET/CT obtained approximately 1 week after starting pembrolizumab could be used to visualize a metabolic flare (MF), with increased tumor FDG activity due to infiltration by activated immune cells, or a metabolic response (MR), due to tumor cell death, that would predict response., Patients and Methods: Nineteen patients with advanced melanoma scheduled to receive pembrolizumab were prospectively enrolled. FDG PET/CT imaging was performed at baseline and approximately 1 week after starting treatment. FDG PET/CT scans were evaluated for changes in maximum standardized uptake value (SUVmax) and thresholds were identified by ROC analysis; MF was defined as >70% increase in tumor SUVmax, and MR as >30% decrease in tumor SUVmax., Results: An MF or MR was identified in 6 of 11 (55%) responders and 0 of 8 (0%) nonresponders, with an objective response rate (ORR) of 100% in the MF-MR group and an ORR of 38% in the stable metabolism (SM) group. An MF or MR was associated with T-cell reinvigoration in the peripheral blood and immune infiltration in the tumor. Overall survival at 3 years was 83% in the MF-MR group and 62% in the SM group. Median progression-free survival (PFS) was >38 months (median not reached) in the MF-MR group and 2.8 months (95% confidence interval, 0.3-5.2) in the SM group (P = 0.017)., Conclusions: Early FDG PET/CT can identify metabolic changes in melanoma metastases that are potentially predictive of response to pembrolizumab and significantly correlated with PFS., (©2024 American Association for Cancer Research.)
- Published
- 2024
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13. Publisher Correction: NDUFS4 regulates cristae remodeling in diabetic kidney disease.
- Author
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Mise K, Long J, Galvan DL, Ye Z, Fan G, Sharma R, Serysheva II, Moore TI, Jeter CR, Anna Zal M, Araki M, Wada J, Schumacker PT, Chang BH, and Danesh FR
- Published
- 2024
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14. NDUFS4 regulates cristae remodeling in diabetic kidney disease.
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Mise K, Long J, Galvan DL, Ye Z, Fan G, Sharma R, Serysheva II, Moore TI, Jeter CR, Anna Zal M, Araki M, Wada J, Schumacker PT, Chang BH, and Danesh FR
- Subjects
- Male, Animals, Mice, Mitochondrial Membranes, Kidney, Mitochondria, Electron Transport Complex I genetics, Diabetic Nephropathies genetics, Diabetes Mellitus, Experimental genetics
- Abstract
The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that conditional male mice with genetic overexpression of Ndufs4 exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping protein STOML2 in linking NDUFS4 with improved cristae morphology. Together, we provide the evidence on the central role of NDUFS4 as a regulator of cristae remodeling and mitochondrial function in kidney podocytes. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD., (© 2024. The Author(s).)
- Published
- 2024
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15. Conditional hepatocyte ablation of PDIA1 uncovers indispensable roles in both APOB and MTTP folding to support VLDL secretion.
- Author
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Chen Z, Wang S, Pottekat A, Duffey A, Jang I, Chang BH, Cho J, Finck BN, Davidson NO, and Kaufman RJ
- Subjects
- Animals, Mice, Apolipoproteins B genetics, Apolipoproteins B metabolism, Molecular Chaperones genetics, Molecular Chaperones metabolism, Triglycerides metabolism, Hepatocytes metabolism, Lipoproteins, VLDL metabolism, Thymine Nucleotides
- Abstract
Objectives: The assembly and secretion of hepatic very low-density lipoprotein (VLDL) plays pivotal roles in hepatic and plasma lipid homeostasis. Protein disulfide isomerase A1 (PDIA1/P4HB) is a molecular chaperone whose functions are essential for protein folding in the endoplasmic reticulum. Here we investigated the physiological requirement in vivo for PDIA1 in maintaining VLDL assembly and secretion., Methods: Pdia1/P4hb was conditionally deleted in adult mouse hepatocytes and the phenotypes characterized. Mechanistic analyses in primary hepatocytes determined how PDIA1 ablation alters MTTP synthesis and degradation as well as altering synthesis and secretion of Apolipoprotein B (APOB), along with complementary expression of intact PDIA1 vs a catalytically inactivated PDIA1 mutant., Results: Hepatocyte-specific deletion of Pdia1/P4hb inhibited hepatic MTTP expression and dramatically reduced VLDL production, leading to severe hepatic steatosis and hypolipidemia. Pdia1-deletion did not affect mRNA expression or protein stability of MTTP but rather prevented Mttp mRNA translation. We demonstrate an essential role for PDIA1 in MTTP synthesis and function and show that PDIA1 interacts with APOB in an MTTP-independent manner via its molecular chaperone function to support APOB folding and secretion., Conclusions: PDIA1 plays indispensable roles in APOB folding, MTTP synthesis and activity to support VLDL assembly. Thus, like APOB and MTTP, PDIA1 is an obligatory component of hepatic VLDL production., Competing Interests: Declaration of competing interest There is no conflict of interest to be declared., (Copyright © 2024. Published by Elsevier GmbH.)
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- 2024
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16. Nivolumab Plus 5-Azacitidine in Pediatric Relapsed/Refractory Acute Myeloid Leukemia (AML): Phase I/II Trial Results from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium.
- Author
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Verma A, Chi YY, Malvar J, Lamble A, Chaudhury S, Agarwal A, Li HT, Liang G, Leong R, Brown PA, Kaplan J, Schafer ES, Slone T, Pauly M, Chang BH, Stieglitz E, Wayne AS, Hijiya N, and Bhojwani D
- Abstract
Improvements in survival have been made over the past two decades for childhood acute myeloid leukemia (AML), but the approximately 40% of patients who relapse continue to have poor outcomes. A combination of checkpoint-inhibitor nivolumab and azacitidine has demonstrated improvements in median survival in adults with AML. This phase I/II study with nivolumab and azacitidine in children with relapsed/refractory AML (NCT03825367) was conducted through the Therapeutic Advances in Childhood Leukemia & Lymphoma consortium. Thirteen patients, median age 13.7 years, were enrolled. Patients had refractory disease with multiple reinduction attempts. Twelve evaluable patients were treated at the recommended phase II dose (established at dose level 1, 3 mg/kg/dose). Four patients (33%) maintained stable disease. This combination was well tolerated, with no dose-limiting toxicities observed. Grade 3-4 adverse events (AEs) were primarily hematological. Febrile neutropenia was the most common AE ≥ grade 3. A trend to improved quality of life was noted. Increases in CD8+ T cells and reductions in CD4+/CD8+ T cells and demethylation were observed. The combination was well tolerated and had an acceptable safety profile in pediatric patients with relapsed/refractory AML. Future studies might explore this combination for the maintenance of remission in children with AML at high risk of relapse.
- Published
- 2024
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17. Outcomes of World Health Organization-defined Severe Respiratory Distress without Shock in Adults in Sub-Saharan Africa.
- Author
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Chang BH, Adakun SA, Auma MA, Banura P, Majwala A, Mbonde AA, McQuade ER, Ssekitoleko R, Conaway M, and Moore CC
- Subjects
- Adult, Humans, Africa South of the Sahara epidemiology, World Health Organization, Dyspnea, Respiratory Distress Syndrome therapy
- Published
- 2024
- Full Text
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18. ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS.
- Author
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Jin JC, Chen BY, Deng CH, Chen JN, Xu F, Tao Y, Hu CL, Xu CH, Chang BH, Wang Y, Fei MY, Liu P, Yu PC, Li ZJ, Li XY, Chen SB, Jiang YL, Chen XC, Zong LJ, Zhang JY, Ren YY, Xu FH, Liu Q, Huang XH, Guo J, He Q, Song LX, Zhou LY, Su JY, Xiao C, Zhang YM, Yan M, Zhang Z, Wu D, Chang CK, Li X, Wang L, and Wu LY
- Subjects
- Animals, Humans, Mice, Nerve Tissue Proteins genetics, Prognosis, Receptors, Immunologic genetics, Roundabout Proteins, Erythropoiesis genetics, Myelodysplastic Syndromes genetics
- Abstract
Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 ( ROBO1 ) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42 , a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1 -deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42 .
- Published
- 2023
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19. Clinical Correlates of Venetoclax-Based Combination Sensitivities to Augment Acute Myeloid Leukemia Therapy.
- Author
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Eide CA, Kurtz SE, Kaempf A, Long N, Joshi SK, Nechiporuk T, Huang A, Dibb CA, Taylor A, Bottomly D, McWeeney SK, Minnier J, Lachowiez CA, Saultz JN, Swords RT, Agarwal A, Chang BH, Druker BJ, and Tyner JW
- Subjects
- Humans, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Azacitidine pharmacology, Azacitidine therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use
- Abstract
The BCL2 inhibitor venetoclax combined with the hypomethylating agent azacytidine shows significant clinical benefit in a subset of patients with acute myeloid leukemia (AML); however, resistance limits response and durability. We prospectively profiled the ex vivo activity of 25 venetoclax-inclusive combinations on primary AML patient samples to identify those with improved potency and synergy compared with venetoclax + azacytidine (Ven + azacytidine). Combination sensitivities correlated with tumor cell state to discern three patterns: primitive selectivity resembling Ven + azacytidine, monocytic selectivity, and broad efficacy independent of cell state. Incorporation of immunophenotype, mutation, and cytogenetic features further stratified combination sensitivity for distinct patient subtypes. We dissect the biology underlying the broad, cell state-independent efficacy for the combination of venetoclax plus the JAK1/2 inhibitor ruxolitinib. Together, these findings support opportunities for expanding the impact of venetoclax-based drug combinations in AML by leveraging clinical and molecular biomarkers associated with ex vivo responses., Significance: By mapping drug sensitivity data to clinical features and tumor cell state, we identify novel venetoclax combinations targeting patient subtypes who lack sensitivity to Ven + azacytidine. This provides a framework for a taxonomy of AML informed by readily available sets of clinical and genetic features obtained as part of standard care. See related commentary by Becker, p. 437 . This article is featured in Selected Articles from This Issue, p. 419., (©2023 American Association for Cancer Research.)
- Published
- 2023
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20. Patient-Specific Targeting of the T-Cell Receptor Variable Region as a Therapeutic Strategy in Clonal T-Cell Diseases.
- Author
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Lucero OM, Lee JA, Bowman J, Johnson K, Sapparapu G, Thomas JK, Fan G, Chang BH, Thiel-Klare K, Eide CA, Okada C, Palazzolo M, Lind E, Kosaka Y, Druker BJ, Lydon N, and Bowers PM
- Subjects
- Humans, Mice, Animals, Rituximab, T-Lymphocytes immunology, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta immunology, Receptors, Antigen, T-Cell genetics, Lymphoma, T-Cell
- Abstract
Purpose: Targeted therapeutics are a goal of medicine. Methods for targeting T-cell lymphoma lack specificity for the malignant cell, leading to elimination of healthy cells. The T-cell receptor (TCR) is designed for antigen recognition. T-cell malignancies expand from a single clone that expresses one of 48 TCR variable beta (Vβ) genes, providing a distinct therapeutic target. We hypothesized that a mAb that is exclusive to a specific Vβ would eliminate the malignant clone while having minimal effects on healthy T cells., Experimental Design: We identified a patient with large granular T-cell leukemia and sequenced his circulating T-cell population, 95% of which expressed Vβ13.3. We developed a panel of anti-Vβ13.3 antibodies to test for binding and elimination of the malignant T-cell clone., Results: Therapeutic antibody candidates bound the malignant clone with high affinity. Antibodies killed engineered cell lines expressing the patient TCR Vβ13.3 by antibody-dependent cellular cytotoxicity and TCR-mediated activation-induced cell death, and exhibited specific killing of patient malignant T cells in combination with exogenous natural killer cells. EL4 cells expressing the patient's TCR Vβ13.3 were also killed by antibody administration in an in vivo murine model., Conclusions: This approach serves as an outline for development of therapeutics that can treat clonal T-cell-based malignancies and potentially other T-cell-mediated diseases. See related commentary by Varma and Diefenbach, p. 4024., (©2023 American Association for Cancer Research.)
- Published
- 2023
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21. The non-cell-autonomous function of ID1 promotes AML progression via ANGPTL7 from the microenvironment.
- Author
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Fei MY, Wang Y, Chang BH, Xue K, Dong F, Huang D, Li XY, Li ZJ, Hu CL, Liu P, Wu JC, Yu PC, Hong MH, Chen SB, Xu CH, Chen BY, Jiang YL, Liu N, Zhao C, Jin JC, Hou D, Chen XC, Ren YY, Deng CH, Zhang JY, Zong LJ, Wang RJ, Gao FF, Liu H, Zhang QL, Wu LY, Yan J, Shen S, Chang CK, Sun XJ, and Wang L
- Subjects
- Animals, Mice, Bone Marrow metabolism, Disease Models, Animal, Tumor Microenvironment, Humans, Angiopoietin-Like Protein 7 genetics, Angiopoietin-Like Protein 7 metabolism, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Inhibitor of Differentiation Protein 1 metabolism
- Abstract
The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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22. The transcription factor ChREBP links mitochondrial lipidomes to mitochondrial morphology and progression of diabetic kidney disease.
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Li L, Long J, Mise K, Poungavrin N, Lorenzi PL, Mahmud I, Tan L, Saha PK, Kanwar YS, Chang BH, and Danesh FR
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- Animals, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Gene Expression Regulation, Kidney metabolism, Lipidomics, Transcription Factors genetics, Transcription Factors metabolism, Diabetes Mellitus metabolism, Diabetic Nephropathies metabolism
- Abstract
A substantial body of evidence has established the contributions of both mitochondrial dynamics and lipid metabolism to the pathogenesis of diabetic kidney disease (DKD). However, the precise interplay between these two key metabolic regulators of DKD is not fully understood. Here, we uncover a link between mitochondrial dynamics and lipid metabolism by investigating the role of carbohydrate-response element-binding protein (ChREBP), a glucose-responsive transcription factor and a master regulator of lipogenesis, in kidney podocytes. We find that inducible podocyte-specific knockdown of ChREBP in diabetic db/db mice improves key biochemical and histological features of DKD in addition to significantly reducing mitochondrial fragmentation. Because of the critical role of ChREBP in lipid metabolism, we interrogated whether and how mitochondrial lipidomes play a role in ChREBP-mediated mitochondrial fission. Our findings suggest a key role for a family of ether phospholipids in ChREBP-induced mitochondrial remodeling. We find that overexpression of glyceronephosphate O-acyltransferase, a critical enzyme in the biosynthesis of plasmalogens, reverses the protective phenotype of ChREBP deficiency on mitochondrial fragmentation. Finally, our data also points to Gnpat as a direct transcriptional target of ChREBP. Taken together, our results uncover a distinct mitochondrial lipid signature as the link between ChREBP-induced mitochondrial dynamics and progression of DKD., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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23. Disseminated fungal disease caused by Magnusiomyces clavatus in a pediatric cancer patient: Case report and review of the literature.
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Mitchell PG, Chang BH, and Walker LW
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- Child, Humans, Antifungal Agents therapeutic use, Mycoses drug therapy, Saccharomycetales, Neoplasms drug therapy
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- 2023
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24. NDUFS4 Regulates Cristae Remodeling in Diabetic Kidney Disease.
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Mise K, Long J, Galvan DL, Ye Z, Fan G, Serysheva II, Moore TI, Wada J, Schumacker PT, Chang BH, and Danesh FR
- Abstract
The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generated diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model to investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that these conditional mice exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping proteins in linking NDUFS4 with improved cristae morphology. Taken together, we discover the central role of NDUFS4 as a powerful regulator of cristae remodeling, respiratory supercomplexes assembly, and mitochondrial ultrastructure in vitro and in vivo . We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD., Competing Interests: Competing interests The authors declare no competing interests.
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- 2023
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25. Carbon emissions and the rising effect of trade openness and foreign direct investment: Evidence from a threshold regression model.
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Derindag OF, Maydybura A, Kalra A, Wong WK, and Chang BH
- Abstract
The relationship between carbon emissions, foreign trade openness, and FDI has been studied in prior studies. The previous studies, however, did not examine the link by focusing on carbon emissions in India's industrial sectors. Using carbon emission intensity as a threshold variable and a threshold regression model, we add to the existing studies by assessing the influence of India's industrial sector on carbon emissions. According to the study's findings, there are three threshold effects of foreign direct investment and foreign trade openness on industrial carbon emissions. FDI harms industrial carbon emissions, as it has a characteristically declining and then rising effect coefficient on industrial carbon emissions. Foreign trade openness, however, affects carbon emissions both positively and negatively. Foreign trade openness encourages carbon emission in sectors of the economy with lower carbon emission intensity. However, it also partially constrains it for sectors with high carbon emission intensity. The number of employees, technological innovation, GDP per capita, and economic activity intensity significantly influence carbon emissions in India's industrial sector. This study can extend further in other countries using the recent innovative methodologies., Competing Interests: The authors declare no competing interests.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., (© 2023 Published by Elsevier Ltd.)
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- 2023
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26. Subunit vaccines with a saponin-based adjuvant boost humoral and cellular immunity to MERS coronavirus.
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Chang CC, Algaissi A, Lai CC, Chang CK, Lin JS, Wang YS, Chang BH, Chang YC, Chen WT, Fan YQ, Peng BH, Chao CY, Tzeng SR, Liang PH, Sung WC, Hu AY, Chang SC, and Chang MF
- Subjects
- Animals, Mice, Humans, Antibodies, Neutralizing, Antibodies, Viral, Dipeptidyl Peptidase 4, Immunity, Cellular, Mice, Transgenic, Adjuvants, Immunologic, Recombinant Proteins, Vaccines, Subunit, Spike Glycoprotein, Coronavirus, Middle East Respiratory Syndrome Coronavirus, Viral Vaccines, Coronavirus Infections
- Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) outbreaks have constituted a public health issue with drastic mortality higher than 34%, necessitating the development of an effective vaccine. During MERS-CoV infection, the trimeric spike protein on the viral envelope is primarily responsible for attachment to host cellular receptor, dipeptidyl peptidase 4 (DPP4). With the goal of generating a protein-based prophylactic, we designed a subunit vaccine comprising the recombinant S1 protein with a trimerization motif (S1-Fd) and examined its immunogenicity and protective immune responses in combination with various adjuvants. We found that sera from immunized wild-type and human DPP4 transgenic mice contained S1-specific antibodies that can neutralize MERS-CoV infection in susceptible cells. Vaccination with S1-Fd protein in combination with a saponin-based QS-21 adjuvant provided long-term humoral as well as cellular immunity in mice. Our findings highlight the significance of the trimeric S1 protein in the development of MERS-CoV vaccines and offer a suitable adjuvant, QS-21, to induce robust and prolonged memory T cell response., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ming-Fu Chang reports financial support was provided by Ministry of Science & Technology of Taiwan. Ming-Fu Chang reports a relationship with Ministry of Science & Technology of Taiwan that includes: funding grants. Ming-Fu Chang has patent NA pending to NA. 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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27. Patients with Down syndrome can be included in early phase clinical trials- a report from the T2016-003 Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) study.
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Gossai N, Bhojwani D, Schafer ES, Chang BH, Pommert L, Verma A, Malvar J, Chi YY, Hitzler J, Burke MJ, and Rabin KR
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- Humans, Down Syndrome complications, Down Syndrome drug therapy, Leukemia drug therapy, Leukemia pathology, Lymphoma drug therapy
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- 2023
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28. Transplantation and immigration: Comparing infectious complications and outcomes between foreign-born and US-born kidney transplant recipients in Minnesota.
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Ordaya EE, Shaughnessy M, Elkin B, Husmann RL, Stauffer JC, Luengas EM, Chang BH, Tessier KM, Walker PF, and Stauffer WM
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- Humans, Emigration and Immigration, Graft Rejection epidemiology, Graft Rejection prevention & control, Minnesota epidemiology, Retrospective Studies, Transplant Recipients, Kidney Transplantation adverse effects, Latent Infection
- Abstract
Background: Foreign-born kidney transplant recipients (FBKTRs) are at increased risk for reactivation of latent infections that may impact outcomes. We aimed to compare the etiology of infections and outcomes between FBKTR and United States KTRs (USKTR)., Methods: We performed a retrospective study of patients who underwent kidney transplantation between January 1, 2014 and December 31, 2018 at two transplant centers in Minnesota. Frequency and etiology of infections as well as outcomes (graft function, rejection, and patient survival) at 1-year post-transplant between FBKTR and USKTR were compared., Results: Of the 573 transplant recipients, 124 (21.6%) were foreign-born and 449 (78.4%) US-born. At least one infection occurred in 411 (71.7%) patients (38.2% bacterial, 55% viral, 9.4% fungal). Viral infections were more frequent in FBKTR, particularly BK viremia (38.7% vs. 21.2%, p < .001). No statistical differences were found for bacterial or fungal infections; no parasitic infections were identified in either group. No geographically-restricted infections were noted aside from a single case of Madura foot in a FBKTR. Rejection episodes were more common in USKTR (p = .037), but stable/improving graft function (p = .976) and mortality (p = .451) at 1-year posttransplantation were similar in both groups. After adjusting for covariates, previous transplantation was associated with a higher number of infections (IRR 1.35, 95% confidence intervals 1.05-1.73, p = .020)., Conclusion: Although viral infections were more frequent in FBKTR, overall frequency and etiology of most infections and outcomes were similar between FBKTR and USKTR suggesting that comprehensive transplant care is providing timely prevention, diagnosis, and treatment of latent infections in FBKTR., (© 2023 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)
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- 2023
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29. Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma.
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Li XY, Wu JC, Liu P, Li ZJ, Wang Y, Chen BY, Hu CL, Fei MY, Yu PC, Jiang YL, Xu CH, Chang BH, Chen XC, Zong LJ, Zhang JY, Fang Y, Sun XJ, Xue K, Wang L, Chen SB, Jiang SY, Gui AL, Yang L, Gu JJ, Yu BH, Zhang QL, and Wang L
- Subjects
- Animals, Mice, Humans, Rituximab therapeutic use, Pimozide therapeutic use, Ubiquitin-Specific Proteases genetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology, Lymphoma, Non-Hodgkin drug therapy
- Abstract
The patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL., (© 2022. The Author(s).)
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- 2023
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30. Fetal Hepatomegaly.
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Park J, Ondusko DS, Chang BH, Edwards EA, Doan S, Gatter K, Hajjali I, and Kim A
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- Humans, Female, Pregnancy, Hepatomegaly diagnostic imaging, Hepatomegaly etiology, Fetus, Prenatal Care
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- 2022
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31. Integrative analysis of drug response and clinical outcome in acute myeloid leukemia.
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Bottomly D, Long N, Schultz AR, Kurtz SE, Tognon CE, Johnson K, Abel M, Agarwal A, Avaylon S, Benton E, Blucher A, Borate U, Braun TP, Brown J, Bryant J, Burke R, Carlos A, Chang BH, Cho HJ, Christy S, Coblentz C, Cohen AM, d'Almeida A, Cook R, Danilov A, Dao KT, Degnin M, Dibb J, Eide CA, English I, Hagler S, Harrelson H, Henson R, Ho H, Joshi SK, Junio B, Kaempf A, Kosaka Y, Laderas T, Lawhead M, Lee H, Leonard JT, Lin C, Lind EF, Liu SQ, Lo P, Loriaux MM, Luty S, Maxson JE, Macey T, Martinez J, Minnier J, Monteblanco A, Mori M, Morrow Q, Nelson D, Ramsdill J, Rofelty A, Rogers A, Romine KA, Ryabinin P, Saultz JN, Sampson DA, Savage SL, Schuff R, Searles R, Smith RL, Spurgeon SE, Sweeney T, Swords RT, Thapa A, Thiel-Klare K, Traer E, Wagner J, Wilmot B, Wolf J, Wu G, Yates A, Zhang H, Cogle CR, Collins RH, Deininger MW, Hourigan CS, Jordan CT, Lin TL, Martinez ME, Pallapati RR, Pollyea DA, Pomicter AD, Watts JM, Weir SJ, Druker BJ, McWeeney SK, and Tyner JW
- Subjects
- Cell Differentiation, Cohort Studies, Humans, Receptors, Cell Surface genetics, Transcriptome, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML., Competing Interests: Declaration of interests C.E.T. receives research support from Notable Labs and serves as a scientific liaison for AstraZeneca. J.E.M. receives research funding from Gilead Pharmaceutical and serves on a scientific advisory board for Ionis Pharmaceuticals. M.W.D. serves on the advisory boards and/or as a consultant for Novartis, Incyte, and BMS and receives research funding from BMS and Gilead. C.S.H. receives research funding from Sellas. T.L.L. consults for Jazz Pharmaceuticals and receives research funding from Tolero, Gilead, Prescient, Ono, Bio-Path, Mateon, Genentech/Roche, Trovagene, AbbVie, Pfizer, Celgene, Imago, Astellas, Karyopharm, Seattle Genetics, and Incyte. D.A.P. receives research funding from Pfizer and Agios and served on advisory boards for Pfizer, Celyad, Agios, Celgene, AbbVie, Argenx, Takeda, and Servier. B.J.D. serves on the advisory boards for Aileron Therapeutics, Aptose, Blueprint Medicines, Cepheid, EnLiven Therapeutics, Gilead, GRAIL, Iterion Therapeutics, Nemucore Medical Innovations, the Novartis CML Molecular Monitoring Steering Committee, Recludix Pharma, the RUNX1 Research Program, ALLCRON Pharma, VB Therapeutics, Vincerx Pharma, and the Board of Directors for Amgen, and receives research funding from EnLiven and Recludix. B.J.D. is principal investigator or co-investigator on Novartis, BMS, and Pfizer clinical trials. His institution, OHSU, has contracts with these companies to pay for patient costs, nurse and data manager salaries, and institutional overhead, but he does not derive salary, nor does his laboratory receive funds, from these contracts. J.W.T. has received research support from Acerta, Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Kronos, Meryx, Petra, Schrodinger, Seattle Genetics, Syros, Takeda, and Tolero and serves on the advisory board for Recludix Pharma. The authors certify that all compounds tested in this study were chosen without input from any of our industry partners. A subset of findings from this manuscript have been included in a pending patent application., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2022
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32. Associating drug sensitivity with differentiation status identifies effective combinations for acute myeloid leukemia.
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Kurtz SE, Eide CA, Kaempf A, Long N, Bottomly D, Nikolova O, Druker BJ, McWeeney SK, Chang BH, Tyner JW, and Agarwal A
- Subjects
- Cell Differentiation, Humans, Immunophenotyping, Proto-Oncogene Proteins c-bcl-2 metabolism, p38 Mitogen-Activated Protein Kinases, Leukemia, Myeloid, Acute genetics
- Abstract
Using ex vivo drug screening of primary patient specimens, we identified the combination of the p38 MAPK inhibitor doramapimod (DORA) with the BCL2 inhibitor venetoclax (VEN) as demonstrating broad, enhanced efficacy compared with each single agent across 335 acute myeloid leukemia (AML) patient samples while sparing primary stromal cells. Single-agent DORA and VEN sensitivity was associated with distinct, nonoverlapping tumor cell differentiation states. In particular, increased monocytes, M4/M5 French-American-British classification, and CD14+ immunophenotype tracked with sensitivity to DORA and resistance to VEN but were mitigated with the combination. Increased expression of MAPK14 and BCL2, the respective primary targets of DORA and VEN, were observed in monocytic and undifferentiated leukemias, respectively. Enrichment for DORA and VEN sensitivities was observed in AML with monocyte-like and progenitor-like transcriptomic signatures, respectively, and these associations diminished with the combination. The mechanism underlying the combination's enhanced efficacy may result from inhibition of p38 MAPK-mediated phosphorylation of BCL2, which in turn enhances sensitivity to VEN. These findings suggest exploiting complementary drug sensitivity profiles with respect to leukemic differentiation state, such as dual targeting of p38 MAPK and BCL2, offers opportunity for broad, enhanced efficacy across the clinically challenging heterogeneous landscape of AML., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2022
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33. Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium.
- Author
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Pommert L, Schafer ES, Malvar J, Gossai N, Florendo E, Pulakanti K, Heimbruch K, Stelloh C, Chi YY, Sposto R, Rao S, Huynh VT, Brown P, Chang BH, Colace SI, Hermiston ML, Heym K, Hutchinson RJ, Kaplan JA, Mody R, O'Brien TA, Place AE, Shaw PH, Ziegler DS, Wayne A, Bhojwani D, and Burke MJ
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Child, Cytarabine, Decitabine therapeutic use, Humans, Vorinostat, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Lymphoma drug therapy
- Abstract
Survival outcomes for relapsed/refractory pediatric acute myeloid leukemia (R/R AML) remain dismal. Epigenetic changes can result in gene expression alterations which are thought to contribute to both leukemogenesis and chemotherapy resistance. We report results from a phase I trial with a dose expansion cohort investigating decitabine and vorinostat in combination with fludarabine, cytarabine, and G-CSF (FLAG) in pediatric patients with R/R AML [NCT02412475]. Thirty-seven patients enrolled with a median age at enrollment of 8.4 (range, 1-20) years. There were no dose limiting toxicities among the enrolled patients, including two patients with Down syndrome. The recommended phase 2 dose of decitabine in combination with vorinostat and FLAG was 10 mg/m
2 . The expanded cohort design allowed for an efficacy evaluation and the overall response rate among 35 evaluable patients was 54% (16 complete response (CR) and 3 complete response with incomplete hematologic recovery (CRi)). Ninety percent of responders achieved minimal residual disease (MRD) negativity (<0.1%) by centralized flow cytometry and 84% (n = 16) successfully proceeded to hematopoietic stem cell transplant. Two-year overall survival was 75.6% [95%CI: 47.3%, 90.1%] for MRD-negative patients vs. 17.9% [95%CI: 4.4%, 38.8%] for those with residual disease (p < .001). Twelve subjects (34%) had known epigenetic alterations with 8 (67%) achieving a CR, 7 (88%) of whom were MRD negative. Correlative pharmacodynamics demonstrated the biologic activity of decitabine and vorinostat and identified specific gene enrichment signatures in nonresponding patients. Overall, this therapy was well-tolerated, biologically active, and effective in pediatric patients with R/R AML, particularly those with epigenetic alterations., (© 2022 Wiley Periodicals LLC.)- Published
- 2022
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34. Schwann Cells Accelerate Osteogenesis via the Mif/CD74/FOXO1 Signaling Pathway In Vitro.
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Li JQ, Jiang HJ, Su XY, Feng L, Zhan NZ, Li SS, Chen ZJ, Chang BH, Cheng PZ, Yang L, and Pei GX
- Abstract
Schwann cells have been found to promote osteogenesis by an unclear molecular mechanism. To better understand how Schwann cells accelerate osteogenesis, RNA-Seq and LC-MS/MS were utilized to explore the transcriptomic and metabolic response of MC3T3-E1 to Schwann cells. Osteogenic differentiation was determined by ALP staining. Lentiviruses were constructed to alter the expression of Mif (macrophage migration inhibitory factor) in Schwann cells. Western blot (WB) analysis was employed to detect the protein expression. The results of this study show that Mif is essential for Schwann cells to promote osteogenesis, and its downstream CD74/FOXO1 is also involved in the promotion of Schwann cells on osteogenesis. Further, Schwann cells regulate amino acid metabolism and lipid metabolism in preosteoblasts. These findings unveil the mechanism for Schwann cells to promote osteogenesis where Mif is a key factor., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Jun-Qin Li et al.)
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- 2022
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35. Exchange rate response to economic policy uncertainty: evidence beyond asymmetry.
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Chang BH, Derindag OF, Hacievliyagil N, and Canakci M
- Abstract
Recent studies have examined the relationship between economic policy uncertainty and exchange rate. We contribute to this literature by considering the effect of minor positive and major positive changes as well as minor negative and major negative changes in the economic policy uncertainties on the exchange rates. In this regard, we use a recently developed multiple asymmetric threshold nonlinear ARDL model along with Granger causality in quantile test. Our estimates support the asymmetric effect in three countries only when an asymmetric ARDL model is used. However, these estimates support asymmetric effects for all the sample countries when the multiple asymmetric threshold nonlinear ARDL model is used. Moreover, the effect varies across various quantiles when Granger causality in quantile test is used. Overall, the extended model helps us to examine more minutely the impact of EPU and GEPU on the exchange rate in G7 countries. The results of this study can be useful for the central banks to devise appropriate policies to intervene in the foreign exchange market., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)
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- 2022
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36. Asymmetric effect of COVID-19 pandemic on E7 stock indices: Evidence from quantile-on-quantile regression approach.
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Hashmi SM, Chang BH, and Rong L
- Abstract
Various studies have been conducted to examine the effect of COVID-19 on stock prices. However, these studies failed to examine the effect across quantile distributions of both dependent and independent variables. This study pays particular attention to the emerging 7 countries and examines the effect of the novel coronavirus 2019 (COVID-19) pandemic on stock prices. We use quantile unit root and quantile cointegration tests to examine the integrating properties of COVID-19 cases and deaths with stock prices and use quantile-on-quantile regression (QQR) to examine the relationship across quantile distributions of both dependent and independent variables. Quantile cointegration estimates indicate that stock prices are integrated with COVID-19 cases whereas QQR estimates indicate a weak positive relationship at the upper quantiles of stock prices, and a strong negative effect is found at the lower quantiles of stock prices. Policy implications are recommended based on the findings of this study., (© 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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37. Aurora A kinase as a target for therapy in TCF3-HLF rearranged acute lymphoblastic leukemia.
- Author
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Leonard J, Wolf JS, Degnin M, Eide CA, LaTocha D, Lenz K, Wilmot B, Mullighan CG, Loh M, Hunger SP, Druker BJ, Loriaux MM, Tyner JW, and Chang BH
- Subjects
- Basic Helix-Loop-Helix Transcription Factors, Humans, Oncogene Proteins, Fusion genetics, Translocation, Genetic, Aurora Kinase A genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Published
- 2021
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38. Synbiotic Intervention with an Adlay-Based Prebiotic and Probiotics Improved Diet-Induced Metabolic Disturbance in Mice by Modulation of the Gut Microbiota.
- Author
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Chiou WC, Chang BH, Tien HH, Cai YL, Fan YC, Chen WJ, Chu HF, Chen YH, and Huang C
- Subjects
- Adipose Tissue, Animal Feed analysis, Animals, Bacteria classification, Bacteria genetics, Body Weight, Dyslipidemias, Insulin Resistance, Male, Mice, Obesity chemically induced, Diet, High-Fat adverse effects, Dysbiosis chemically induced, Gastrointestinal Microbiome drug effects, Prebiotics, Probiotics, Synbiotics
- Abstract
Metabolic syndrome and its associated conditions, such as obesity and type 2 diabetes mellitus (T2DM), are a major public health issue in modern societies. Dietary interventions, including microbiota-directed foods which effectively modulate the gut microbiome, may influence the regulation of obesity and associated comorbidities. Although research on probiotics and prebiotics has been conducted extensively in recent years, diets with the use of synbiotics remain relatively unexplored. Here, we investigated the effects of a novel synbiotic intervention, consisting of an adlay seed extrusion cooked (ASEC)-based prebiotic and probiotic ( Lactobacillus paracasei and Bacillus coagulans ) on metabolic disorders and microbial dysbiosis in high-fat diet (HFD)-induced obese mice. The ASEC-based synbiotic intervention helped improve HFD-induced body weight gain, hyperlipidemia, impaired glucose tolerance, insulin resistance, and inflammation of the adipose and liver tissues. In addition, data from fecal metagenomics indicated that the ASEC-based synbiotic intervention fostered reconstitution of gut bacterial diversity and composition in HFD-induced obese mice. In particular, the ASEC-based synbiotic intervention increased the relative abundance of families Ruminococcaceae and Muribaculaceae and order Bacteroidales and reduced that of families Lactobacillaceae , Erysipelotrichaceae , and Streptococcaceae in HFD-induced obese mice. Collectively, our results suggest that delayed dietary intervention with the novel ASEC-based synbiotic ameliorates HFD-induced obesity, metabolic disorders, and dysbiosis.
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- 2021
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39. PGC1α is required for the renoprotective effect of lncRNA Tug1 in vivo and links Tug1 with urea cycle metabolites.
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Li L, Long J, Mise K, Galvan DL, Overbeek PA, Tan L, Kumar SV, Chan WK, Lorenzi PL, Chang BH, and Danesh FR
- Subjects
- Animals, Arginase metabolism, Diabetic Nephropathies genetics, Diabetic Nephropathies pathology, Disease Progression, Gene Deletion, Mice, Inbred C57BL, Mice, Knockout, Mitochondria metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha deficiency, Podocytes metabolism, RNA, Long Noncoding genetics, Mice, Kidney metabolism, Metabolome, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Protective Agents metabolism, RNA, Long Noncoding metabolism, Urea metabolism
- Abstract
lncRNA taurine-upregulated gene 1 (Tug1) is a promising therapeutic target in the progression of diabetic nephropathy (DN), but the molecular basis of its protection remains poorly understood. Here, we generate a triple-mutant diabetic mouse model coupled with metabolomic profiling data to interrogate whether Tug1 interaction with peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) is required for mitochondrial remodeling and progression of DN in vivo. We find that, compared with diabetic conditional deletion of Pgc1α in podocytes alone (db/db; Pgc1α
Pod-f/f ), diabetic Pgc1α knockout combined with podocyte-specific Tug1 overexpression (db/db; TugPodTg ; Pgc1αPod-f/f ) reverses the protective phenotype of Tug1 overexpression, suggesting that PGC1α is required for the renoprotective effect of Tug1. Using unbiased metabolomic profiling, we find that altered urea cycle metabolites and mitochondrial arginase 2 play an important role in Tug1/PGC1α-induced mitochondrial remodeling. Our work identifies a functional role of the Tug1/PGC1α axis on mitochondrial metabolic homeostasis and urea cycle metabolites in experimental models of diabetes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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40. Factors and Outcomes Related to the Use of Guideline-Recommended Antibiotics in Patients With Neutropenic Fever at the Uganda Cancer Institute.
- Author
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Gulleen EA, Adams SV, Chang BH, Falk L, Hazard R, Kabukye J, Scala J, Liu C, Phipps W, Abrahams O, and Moore CC
- Abstract
Background: Neutropenic fever (NF) is associated with significant morbidity and mortality for patients receiving cancer treatment in sub-Saharan Africa (sSA). However, the antibiotic management of NF in sub-Saharan Africa has not been well described. We evaluated the timing and selection of antibiotics for patients with NF at the Uganda Cancer Institute (UCI)., Methods: We conducted a retrospective chart review of adults with acute leukemia admitted to UCI from 1 January 2016 to 31 May 2017, who developed NF. For each NF event, we evaluated the association of clinical presentation and demographics with antibiotic selection as well as time to both initial and guideline-recommended antibiotics. We also evaluated the association between ordered antibiotics and the in-hospital case fatality ratio (CFR)., Results: Forty-nine NF events occurred among 39 patients. The time to initial antibiotic order was <1 day. Guideline-recommended antibiotics were ordered for 37 (75%) NF events. The median time to guideline-recommended antibiotics was 3 days. Fever at admission, a documented physical examination, and abdominal abnormalities were associated with a shorter time to initial and guideline-recommended antibiotics. The in-hospital CFR was 43%. There was no difference in in-hospital mortality when guideline-recommended antibiotics were ordered as compared to when non-guideline or no antibiotics were ordered (hazard ratio, 0.51 [95% confidence interval {CI}, .10-2.64] and 0.78 [95% CI, .20-2.96], respectively)., Conclusions: Patients with acute leukemia and NF had delayed initiation of guideline-recommended antibiotics and a high CFR. Prospective studies are needed to determine optimal NF management in sub-Saharan Africa, including choice of antibiotics and timing of antibiotic initiation., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
- Published
- 2021
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41. Concomitant use of a dual Src/ABL kinase inhibitor eliminates the in vitro efficacy of blinatumomab against Ph+ ALL.
- Author
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Leonard JT, Kosaka Y, Malla P, LaTocha D, Lamble A, Hayes-Lattin B, Byrd K, Druker BJ, Tyner JW, Chang BH, and Lind E
- Subjects
- B-Lymphocytes, Dasatinib pharmacology, Humans, Imatinib Mesylate pharmacology, Imidazoles pharmacology, Interferon-gamma Release Tests, Jurkat Cells, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) metabolism, Mutation, Missense, Neoplasm Proteins physiology, Phosphorylation drug effects, Point Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma enzymology, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Protein Processing, Post-Translational drug effects, Proto-Oncogene Proteins c-abl genetics, Pyridazines pharmacology, Pyrimidines pharmacology, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes enzymology, T-Lymphocytes metabolism, Tumor Cells, Cultured, src-Family Kinases physiology, Antibodies, Bispecific pharmacology, Antineoplastic Agents pharmacology, Fusion Proteins, bcr-abl antagonists & inhibitors, Lymphocyte Activation drug effects, Neoplasm Proteins antagonists & inhibitors, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-abl antagonists & inhibitors, T-Lymphocytes immunology, src-Family Kinases antagonists & inhibitors
- Abstract
Blinatumomab is currently approved for use as a single agent in relapsed and refractory acute lymphoblastic leukemia (ALL). Cytotoxicity is mediated via signaling through the T-cell receptor (TCR). There is now much interest in combining blinatumomab with targeted therapies, particularly in Philadelphia chromosome-positive ALL (Ph+ ALL). However, some second- and third-generation ABL inhibitors also potently inhibit Src family kinases that are important in TCR signaling. We combined ABL inhibitors and dual Src/ABL inhibitors with blinatumomab in vitro from both healthy donor samples and primary samples from patients with Ph+ ALL. Blinatumomab alone led to both T-cell proliferation and elimination of target CD19+ cells and enhanced production of interferon-γ (IFN-γ). The addition of the ABL inhibitors imatinib or nilotinib to blinatumomab did not inhibit T-cell proliferation or IFN-γ production. However, the addition of dasatinib or ponatinib inhibited T-cell proliferation and IFN-γ production. Importantly, there was no loss of CD19+ cells treated with blinatumomab plus dasatinib or ponatinib in healthy samples or samples with a resistant ABL T315I mutation by dasatinib in combination with blinatumomab. These in vitro findings bring pause to the excitement of combination therapies, highlighting the importance of maintaining T-cell function with targeted therapies., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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42. In Regard to Wong et al.
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Scarpelli DB, Murphy B, Chang BH, Nemecek E, and Jaboin JJ
- Subjects
- Humans, Lymphoma, Whole-Body Irradiation
- Published
- 2020
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43. Oil prices and E7 stock prices: an asymmetric evidence using multiple threshold nonlinear ARDL model.
- Author
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Chang BH
- Subjects
- Brazil, China, India, Indonesia, Mexico, Russia, Turkey, Carbon Dioxide analysis
- Abstract
For examining the short-run and long-run asymmetric effect of oil prices on stock prices, recent literature uses standard nonlinear autoregressive distributed lag model. However, this model decomposes oil price series into partial sum of positive and negative changes only and fails to examine the effect of extreme changes in the oil price series on stock prices. This study, therefore, extends the existing literature by focusing on the emerging seven countries, i.e., Brazil, India, Russia, China, Mexico, Indonesia, and Turkey, and uses multiple threshold nonlinear ARDL model. This extended model helps to examine the asymmetric effect of extremely small to extremely large changes in the oil price series on stock prices. The estimates from standard nonlinear ARDL model indicate that, in the short run, oil prices significantly and asymmetrically affect stock prices in the context of Russia, Indonesia, and India only, whereas in the long run, insignificant effect is found for all sample countries. On the contrary, multiple threshold nonlinear ARDL model supports asymmetric effect in long run and short run for all sample countries where this effect is stronger in short run. Moreover, all diagnostic tests indicate that this extended model enjoys a better fit and is more stable than the traditional models. The findings, based on this model, provide deeper insights on the relationship between oil prices and stock prices and can be used for investors, policymakers, and other stakeholders.
- Published
- 2020
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44. Role for carbohydrate response element-binding protein (ChREBP) in high glucose-mediated repression of long noncoding RNA Tug1.
- Author
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Long J, Galvan DL, Mise K, Kanwar YS, Li L, Poungavrin N, Overbeek PA, Chang BH, and Danesh FR
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Cell Line, Tumor, Glucose genetics, Histone Deacetylase 1 genetics, Histone Deacetylase 1 metabolism, Humans, Mice, RNA, Long Noncoding genetics, Repressor Proteins genetics, Repressor Proteins metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Gene Expression Regulation, Glucose metabolism, Podocytes metabolism, RNA, Long Noncoding biosynthesis, Transcription, Genetic
- Abstract
Long noncoding RNAs (lncRNAs) have been shown to play key roles in a variety of biological activities of the cell. However, less is known about how lncRNAs respond to environmental cues and what transcriptional mechanisms regulate their expression. Studies from our laboratory have shown that the lncRNA Tug1 (taurine upregulated gene 1) is crucial for the progression of diabetic kidney disease, a major microvascular complication of diabetes. Using a combination of proximity labeling with the engineered soybean ascorbate peroxidase (APEX2), ChIP-qPCR, biotin-labeled oligonucleotide pulldown, and classical promoter luciferase assays in kidney podocytes, we extend our initial observations in the current study and now provide a detailed analysis on a how high-glucose milieu downregulates Tug1 expression in podocytes. Our results revealed an essential role for the transcription factor carbohydrate response element binding protein (ChREBP) in controlling Tug1 transcription in the podocytes in response to increased glucose levels. Along with ChREBP, other coregulators, including MAX dimerization protein (MLX), MAX dimerization protein 1 (MXD1), and histone deacetylase 1 (HDAC1), were enriched at the Tug1 promoter under high-glucose conditions. These observations provide the first characterization of the mouse Tug1 promoter's response to the high-glucose milieu. Our findings illustrate a molecular mechanism by which ChREBP can coordinate glucose homeostasis with the expression of the lncRNA Tug1 and further our understanding of dynamic transcriptional regulation of lncRNAs in a disease state., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Long et al.)
- Published
- 2020
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45. Simultaneous kinase inhibition with ibrutinib and BCL2 inhibition with venetoclax offers a therapeutic strategy for acute myeloid leukemia.
- Author
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Eide CA, Kurtz SE, Kaempf A, Long N, Agarwal A, Tognon CE, Mori M, Druker BJ, Chang BH, Danilov AV, and Tyner JW
- Subjects
- Adenine analogs & derivatives, Animals, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cell Line, Tumor, Humans, Mice, Piperidines, Sulfonamides pharmacology, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Leukemia, Myeloid, Acute drug therapy, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Sulfonamides therapeutic use
- Abstract
Acute myeloid leukemia (AML) results from the enhanced proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Using an ex vivo functional screening assay, we identified that the combination of the BTK inhibitor ibrutinib and BCL2 inhibitor venetoclax (IBR + VEN), currently in clinical trials for chronic lymphocytic leukemia (CLL), demonstrated enhanced efficacy on primary AML patient specimens, AML cell lines, and in a mouse xenograft model of AML. Expanded analyses among a large cohort of hematologic malignancies (n = 651 patients) revealed that IBR + VEN sensitivity associated with selected genetic and phenotypic features in both CLL and AML specimens. Among AML samples, 11q23 MLL rearrangements were highly sensitive to IBR + VEN. Analysis of differentially expressed genes with respect to IBR + VEN sensitivity indicated pathways preferentially enriched in patient samples with reduced ex vivo sensitivity, including IL-10 signaling. These findings suggest that IBR + VEN may represent an effective therapeutic option for patients with AML.
- Published
- 2020
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46. Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study.
- Author
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Burke MJ, Kostadinov R, Sposto R, Gore L, Kelley SM, Rabik C, Trepel JB, Lee MJ, Yuno A, Lee S, Bhojwani D, Jeha S, Chang BH, Sulis ML, Hermiston ML, Gaynon P, Huynh V, Verma A, Gardner R, Heym KM, Dennis RM, Ziegler DS, Laetsch TW, Oesterheld JE, Dubois SG, Pollard JA, Glade-Bender J, Cooper TM, Kaplan JA, Farooqi MS, Yoo B, Guest E, Wayne AS, and Brown PA
- Subjects
- Adolescent, Adult, Asparaginase administration & dosage, Bortezomib administration & dosage, Child, Child, Preschool, Decitabine administration & dosage, Dexamethasone administration & dosage, Doxorubicin administration & dosage, Female, Follow-Up Studies, Humans, Infant, Male, Mitoxantrone administration & dosage, Neoplasm Recurrence, Local pathology, Pilot Projects, Polyethylene Glycols administration & dosage, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Salvage Therapy methods, Survival Rate, Vincristine administration & dosage, Vorinostat administration & dosage, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasm Recurrence, Local drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Purpose: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution., Patients and Methods: We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial., Results: The most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia ( n = 1); seizure, somnolence, and delirium ( n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia ( n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects., Conclusions: Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690., (©2020 American Association for Cancer Research.)
- Published
- 2020
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47. Growth Performance and Enzymatic Response of the Grasshopper, Calliptamus abbreviatus (Orthoptera: Acrididae), to Six Plant-Derived Compounds.
- Author
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Wang Y, Huang X, Chang BH, and Zhang Z
- Subjects
- Animals, Female, Nymph enzymology, Nymph growth & development, Random Allocation, Diet, Grasshoppers enzymology, Grasshoppers growth & development, Insecticides classification
- Abstract
Plant-derived compounds are sources of biopesticides for the control of insect pests. We compared the growth performance and enzymatic response of the grasshopper Calliptamus abbreviatus Ikonn to six plant-derived compounds (rutin, quercetin, nicotine, matrine, azadirachtin, and rotenone) in laboratory and field trials. When exposed to the six compounds, C. abbreviatus had significantly reduced growth and survival. All the compounds significantly induced an elevated level of reactive oxygen species, indicating oxidative damage. The activity of detoxifying enzymes, including cytochrome P450s, carboxylesterase, glutathione-S-transferase, and UDP-glucuronosyltransferase, and the antioxidant enzymes, including superoxide dismutase, catalase, and peroxidase, all significantly increased after exposure to the six compounds. These data suggest that the six plant-derived compounds had negative effects on C. abbreviatus. Of the six compounds, matrine, azadirachtin, and rotenone were more toxic to C. abbreviatus, followed by nicotine, quercetin, and rutin. These results show the potential of these compounds as botanical pesticides, which can be applied for the biological control of the grasshopper C. abbreviatus., (© The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America.)
- Published
- 2020
- Full Text
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48. Phenotypic and Transcriptomic Response of the Grasshopper Oedaleus asiaticus (Orthoptera: Acrididae) to Toxic Rutin.
- Author
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Huang X, Lv S, Zhang Z, and Chang BH
- Abstract
Rutin, a widely distributed phytochemical flavonoid, can be used to control insect pests. In this study, we studied the growth performance of the grasshopper Oedaleus asiaticus Bey-Bienko given xenobiotic rutin using feeding experiments and transcriptomic analysis. O. asiaticus had reduced body size, lower survival rate, and reduced growth performance when fed with xenobiotic rutin. Rutin-fed nymphs had large variation in gene expression profiles, with a total of 308 genes significantly upregulated and 287 genes downregulated. The upregulated genes were significantly enriched in stress resistance-, immune-, and detoxification-related biological processes and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Downregulated genes mainly involved cuticle biosynthesis and nutrition metabolism-related pathways. The quantitative real-time PCR (qRT-PCR) analysis of 15 candidate genes also produced results consistent with the transcriptome data. These results suggested that grasshoppers' capacity for biosynthesis and nutrition metabolism decreased, and stress resistance and metabolized capacity to toxic substances were significantly induced when O. asiaticus was fed on xenobiotic rutin. Rutin, as a phytotoxin, had detrimental effects and induced changes in gene expression profiles for O. asiaticus . This study can provide a molecular basis and offer future opportunities for the development of rutin-related insecticides and their application to grasshopper control., (Copyright © 2020 Huang, Lv, Zhang and Chang.)
- Published
- 2020
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49. Reducing Three Infections Across Cardiac Surgery Programs: A Multisite Cross-Unit Collaboration.
- Author
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Chang BH, Hsu YJ, Rosen MA, Gurses AP, Huang S, Xie A, Speck K, Marsteller JA, and Thompson DA
- Subjects
- Humans, Infection Control methods, Intensive Care Units organization & administration, Safety Management organization & administration, Cardiac Surgical Procedures standards, Catheter-Related Infections prevention & control, Cross Infection prevention & control, Patient Safety standards, Pneumonia, Ventilator-Associated prevention & control
- Abstract
Using a pre-post design, this study examined the impact of a multifaceted program to simultaneously improve 3 health care-associated infections and patient safety culture throughout the cardiac surgery service line in 11 hospitals. Interventions included the Comprehensive Unit-based Safety Program to improve safety culture and evidence-based bundles to prevent central line-associated bloodstream infection (CLABSI), surgical site infection (SSI), and ventilator-associated pneumonia (VAP). CLABSIs and SSIs showed a downward trend over 2 years, then the rates returned to levels similar to baseline in the third year. VAP rate changes were difficult to interpret because of the VAP definition change. Patient safety culture domain "hospital management support" showed significant improvement, but feedback and communication about errors and staffing declined. Simultaneous implementation of multiple interventions across units is challenging. The findings highlight the importance of sustainment efforts and suggest future work should anticipate both positive and negative change in safety culture dimensions.
- Published
- 2020
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50. Replication timing alterations in leukemia affect clinically relevant chromosome domains.
- Author
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Rivera-Mulia JC, Sasaki T, Trevilla-Garcia C, Nakamichi N, Knapp DJHF, Hammond CA, Chang BH, Tyner JW, Devidas M, Zimmerman J, Klein KN, Somasundaram V, Druker BJ, Gruber TA, Koren A, Eaves CJ, and Gilbert DM
- Subjects
- Animals, B-Lymphocytes immunology, B-Lymphocytes metabolism, B-Lymphocytes pathology, Biomarkers, Central Nervous System Neoplasms secondary, Computational Biology methods, Disease Models, Animal, Disease Progression, Disease Susceptibility, Female, Gene Expression Profiling, Genetic Variation, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Heterografts, Humans, Immunophenotyping, Leukemia mortality, Male, Mice, Mice, Knockout, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Chromosomes genetics, DNA Replication Timing, Leukemia genetics, Leukemia pathology
- Abstract
Human B-cell precursor acute lymphoid leukemias (BCP-ALLs) comprise a group of genetically and clinically distinct disease entities with features of differentiation arrest at known stages of normal B-lineage differentiation. We previously showed that BCP-ALL cells display unique and clonally heritable, stable DNA replication timing (RT) programs (ie, programs describing the variable order of replication and subnuclear 3D architecture of megabase-scale chromosomal units of DNA in different cell types). To determine the extent to which BCP-ALL RT programs mirror or deviate from specific stages of normal human B-cell differentiation, we transplanted immunodeficient mice with quiescent normal human CD34+ cord blood cells and obtained RT signatures of the regenerating B-lineage populations. We then compared these with RT signatures for leukemic cells from a large cohort of BCP-ALL patients with varied genetic subtypes and outcomes. The results identify BCP-ALL subtype-specific features that resemble specific stages of B-cell differentiation and features that seem to be associated with relapse. These results suggest that the genesis of BCP-ALL involves alterations in RT that reflect biologically significant and potentially clinically relevant leukemia-specific epigenetic changes., (© 2019 by The American Society of Hematology.)
- Published
- 2019
- Full Text
- View/download PDF
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