Publications by authors named "Duong Vu"

76 Publications

-ITD Allelic Burden and Acute Promyelocytic Leukemia Risk Stratification.

Biology (Basel) 2021 Mar 21;10(3). Epub 2021 Mar 21.

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

The significance of -ITD in acute promyelocytic leukemia (APL) is not well-established. We performed a bi-center retrospective study of 138 APL patients, 59 (42.8%) of whom had -ITD. APL patients with -ITD had higher baseline white blood cell counts (WBCs) ( < 0.001), higher hemoglobin, ( = 0.03), higher aspartate aminotransferase ( = 0.001), lower platelets ( = 0.004), lower fibrinogen ( = 0.003), and higher incidences of disseminated intravascular coagulation ( = 0.005), M3v variant morphology ( < 0.001), and the bcr3 isoform ( < 0.001). -ITD was associated with inferior post-consolidation complete remission (CR) ( = 0.02) and 5-year overall survival (OS) of 79.7%, compared to 94.4% for -WT (wild-type) ( = 0.02). -ITD was strongly associated with baseline WBCs ≥ 25 × 10/L (odds ratio (OR): 54.4; 95% CI: 10.4-286.1; < 0.001). High -ITD allelic burdens correlated with high-risk (HR) Sanz scores and high WBCs, with every 1% increase in allelic burden corresponding to a 0.6 × 10/L increase in WBC. HR APL was associated with a 38.5% increase in allelic burden compared with low-risk (LR) APL (95% CI: 19.8-57.2; < 0.001). Our results provide additional evidence that -ITD APL is a distinct subtype of APL that warrants further study to delineate potential differences in therapeutic approach.
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http://dx.doi.org/10.3390/biology10030243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003857PMC
March 2021

Human milk banks in the response to COVID-19: a statement of the regional human milk bank network for Southeast Asia and beyond.

Int Breastfeed J 2021 03 29;16(1):29. Epub 2021 Mar 29.

Alive & Thrive Southeast Asia/FHI 360, Manila, Philippines.

Background: The World Health Organization (WHO) recommendations on infant feeding in the context of COVID-19 uphold standing recommendations for breastfeeding, non-separation, and skin-to-skin contact, including the use of donor human milk when mother's own milk is not available. INSUFFICIENT GUIDANCE ON THE USE OF DONOR HUMAN MILK AND THE ROLE OF HUMAN MILK BANKS IN THE PANDEMIC RESPONSE: COVID-19 clinical management guidelines in seven countries in Southeast Asia are not aligned with WHO recommendations despite the lack of evidence of transmission through either breastmilk or breastfeeding. The use of safe donor human milk accessed through human milk banks is also insufficiently recommended, even in countries with an existing human milk bank, leading to a gap in evidence-based management of COVID-19. This highlights long-standing challenges as well as opportunities in the safe, equitable, and resilient implementation of human milk banks in the region.

Conclusions: This statement reflects the expert opinion of the Regional Human Milk Bank Network for Southeast Asia and Beyond on the need to revisit national guidelines based on the best evidence for breastfeeding during the COVID-19 pandemic, to incorporate human milk bank services in national obstetric and newborn care guidelines for COVID-19 where possible, and to ensure that operations of human milk banks are adapted to meet the needs of the current pandemic and to sustain donor human milk supply in the long-term. The Network also recommends sustained engagement with the global human milk bank community.
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http://dx.doi.org/10.1186/s13006-021-00376-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006108PMC
March 2021

Increased body mass index is a risk factor for acute promyelocytic leukemia.

EJHaem 2021 02 6;2(1):33-39. Epub 2021 Jan 6.

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.

Introduction: Obesity has become increasingly prevalent worldwide and is a risk factor for many malignancies. We studied the correlation between body mass index (BMI) and the incidence of acute promyelocytic leukemia (APL), non-APL acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and control hospitalized patients without leukemia in the same community.

Methods: Multi-center, retrospective analysis of 71,196 patients: APL (n=200), AML (n=437), ALL (n=103), non-leukemia hospitalized (n=70,456) admitted to University of Maryland and Johns Hopkins Cancer Centers, and University of Maryland Medical Center.

Results: Patients with APL had a significantly higher unadjusted mean and median BMI (32.5 kg/m and 30.3 kg/m) than those with AML (28.3 kg/m and 27.1 kg/m), ALL (29.3 kg/m and 27.7 kg/m), and others (29.3 kg/m and 27.7 kg/m) (p<0.001). Log-transformed BMI multivariable models demonstrated that APL patients had a significantly higher adjusted mean BMI by 3.7 kg/m (p<0.001) or approximately 10% (p<0.01) compared to the other groups, when controlled for sex, race, and age.

Conclusions: This study confirms that when controlled for sex, age, and race there is an independent association of higher BMI among patients with APL compared to patients with ALL, AML, and hospitalized individuals without leukemia in the same community.
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http://dx.doi.org/10.1002/jha2.163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943182PMC
February 2021

Phylogeny of D. Fang and Implications for Character Evolution and Conservation.

Pak J Biol Sci 2021 Jan;24(1):1-12

Background And Objective: Alpinia, the largest genus of Zingiberaceae, includes ca. 250 species. The A. coriandriodora D. Fang was recognized for Vietnamese flora. However, the systematic position of this species within Alpinia genus was unclear. The study aimed to understand the phylogenetic placement of A. coriandriodora based on the molecular data and interpret evolution of the key morphological characters.

Materials And Methods: The phylogenetic analysis were conducted by using the combined dataset of two DNA regions by both Maximum Likelihood (ML) and Bayesian Inference (BI) methods. Seven morphological characters were selected for morphological character evolution and the analysis was performed in Mesquite.

Results: Alpinia coriandriodora was supported closely related to southern Chinese species of Alpinia. Morphological character optimizations suggest that the presence/absence of tomentum in leaf, inflorescence rachis and ovary is an important character for the taxonomy of Alpinia. The character evolution analyses indicated that panicle is ancestral character in Alpinia. The A. coriandriodora shares different evolutionary histories based on our character re-construction to most members of Southeast Asian Alpinia. The presence of filament is supposed to be an adaptation to the pollination by insects for species of Alpinia.

Conclusion: The present study revealed the molecular phylogenetic relationship of A. coriandriodora within Alpinia. The presence of filament could be an adaptation to the pollination by insects for species of Alpinia. Some reasonable conservation strategies are proposed to protect the species including maintenance of the plant's natural habitats, seeds or seedlings collection for germplasm storage and artificial breeding using biotechnology.
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http://dx.doi.org/10.3923/pjbs.2021.1.12DOI Listing
January 2021

Venous thromboembolism incidence and risk factors in adults with acute lymphoblastic leukemia treated with and without pegylated E. coli asparaginase-containing regimens.

Cancer Chemother Pharmacol 2021 Mar 7. Epub 2021 Mar 7.

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.

Purpose: Asparaginases, key agents in treatment of acute lymphoblastic leukemia (ALL), are associated with venous thromboembolism (VTE). While risks of short-acting asparaginase-related VTE is well-known, we studied VTE incidence and risk factors in adult ALL patients treated with and without long-acting pegylated asparaginase (PegA).

Methods: Single-center, retrospective analysis of 89 ALL patients treated with (n = 61) or without (n = 28) PegA at Greenebaum Comprehensive Cancer Center. Reviewed patient and disease characteristics, treatment, and VTE incidence.

Results: VTE during treatment occurred in 31 patients (35%), and was associated with PegA (p = 0.001) and Philadelphia chromosome negativity (p = 0.002). Among PegA recipients, VTE was associated with a significantly higher mean body mass index (BMI) of 31.3 kg/m (p = 0.037), and was more common with pre-T/T cell compared to pre-B/B cell ALL (68.2% vs. 33.3%, p = 0.009). Antithrombin-III (ATIII) levels were measured for 26 patients; 16 (61.5%) were < 50%. Of those, 8 (50%) experienced VTE, while 3 of 10 (30%) patients with ATIII levels ≥ 50% experienced VTE. VTE occurred in 7 of 13 (54%) of patients who received ATIII repletion. There was a trend toward a higher incidence of VTE in the PegA group among patients with non-O compared to O blood type (55.9% vs. 33.3%, p = 0.079) as well as those with a higher hemoglobin at diagnosis (9.3 vs 8.1 g/dL, p = 0.056).

Conclusion: This study confirms PegA as a risk factor for VTE in patients with ALL. Risk factors among those receiving PegA include higher BMI and pre-T/T cell ALL. ATIII repletion was not shown to be protective against VTE. There was a higher incidence of VTE in patients who received PegA with non-O compared to O blood type, but the precise correlation is uncertain.
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http://dx.doi.org/10.1007/s00280-021-04252-yDOI Listing
March 2021

The identification of novel immunogenic antigens as potential Shigella vaccine components.

Genome Med 2021 Jan 15;13(1). Epub 2021 Jan 15.

Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Level 5, Jeffery Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AW, UK.

Background: Shigella is a major diarrheal pathogen for which there is presently no vaccine. Whole genome sequencing provides the ability to predict and derive novel antigens for use as vaccines. Here, we aimed to identify novel immunogenic Shigella antigens that could serve as Shigella vaccine candidates, either alone, or when conjugated to Shigella O-antigen.

Methods: Using a reverse vaccinology approach, where genomic analysis informed the Shigella immunome via an antigen microarray, we aimed to identify novel immunogenic Shigella antigens. A core genome analysis of Shigella species, pathogenic and non-pathogenic Escherichia coli, led to the selection of 234 predicted immunogenic Shigella antigens. These antigens were expressed and probed with acute and convalescent serum from microbiologically confirmed Shigella infections.

Results: Several Shigella antigens displayed IgG and IgA seroconversion, with no difference in sero-reactivity across by sex or age. IgG sero-reactivity to key Shigella antigens was observed at birth, indicating transplacental antibody transfer. Six antigens (FepA, EmrK, FhuA, MdtA, NlpB, and CjrA) were identified in in vivo testing as capable of producing binding IgG and complement-mediated bactericidal antibody.

Conclusions: These findings provide six novel immunogenic Shigella proteins that could serve as candidate vaccine antigens, species-specific carrier proteins, or targeted adjuvants.
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http://dx.doi.org/10.1186/s13073-020-00824-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809897PMC
January 2021

Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial.

Nat Med 2020 12 26;26(12):1852-1858. Epub 2020 Oct 26.

The Ohio State University, Columbus, OH, USA.

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient's leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.
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http://dx.doi.org/10.1038/s41591-020-1089-8DOI Listing
December 2020

Genomic Serotyping, Clinical Manifestations, and Antimicrobial Resistance of Nontyphoidal Gastroenteritis in Hospitalized Children in Ho Chi Minh City, Vietnam.

J Clin Microbiol 2020 11 18;58(12). Epub 2020 Nov 18.

Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), University of Cambridge, Cambridge, United Kingdom

Nontyphoidal (NTS) are among the most common etiological agents of diarrheal diseases worldwide and have become the most commonly detected bacterial pathogen in children hospitalized with diarrhea in Vietnam. Aiming to better understand the epidemiology, serovar distribution, antimicrobial resistance (AMR), and clinical manifestation of NTS gastroenteritis in Vietnam, we conducted a clinical genomics investigation of NTS isolated from diarrheal children admitted to one of three tertiary hospitals in Ho Chi Minh City. Between May 2014 and April 2016, 3,166 children hospitalized with dysentery were recruited into the study; 478 (∼15%) children were found to be infected with NTS by stool culture. Molecular serotyping of the 450 generated genomes identified a diverse collection of serogroups (B, C1, C2 to C3, D1, E1, G, I, K, N, O, and Q); however, serovar Typhimurium was the most predominant serovar, accounting for 41.8% (188/450) of NTS isolates. We observed a high prevalence of AMR to first-line treatments recommended by WHO, and more than half (53.8%; 242/450) of NTS isolates were multidrug resistant (MDR; resistant to ≥3 antimicrobial classes). AMR gene detection positively correlated with phenotypic AMR testing, and resistance to empirical antimicrobials was associated with a significantly longer hospitalization (0.91 days; 0.04). Our work shows that genome sequencing is a powerful epidemiological tool to characterize the serovar diversity and AMR profiles in NTS. We propose a revaluation of empirical antimicrobials for dysenteric diarrhea and endorse the use of whole-genome sequencing for sustained surveillance of NTS internationally.
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http://dx.doi.org/10.1128/JCM.01465-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685882PMC
November 2020

Agranulocytosis Following COVID-19 Recovery.

Cureus 2020 Jul 29;12(7):e9463. Epub 2020 Jul 29.

Hematology and Medical Oncology, University of Maryland Medical Center, Baltimore, USA.

Clinicians have continued to report on the clinical behavior and characteristics of patients with coronavirus disease 2019 (COVID-19) as our knowledge of the virus continues to mature. Herein, we report the case of a 39-year-old male with multiple comorbidities who became critically ill with COVID-19 infection, requiring mechanical ventilation and vasopressors, and then developed agranulocytosis following clinical improvement and resolution of symptoms of COVID infection. The period of agranulocytosis coincided with the development of thrombocytosis, and following resolution of agranulocytosis, the platelet count also normalized, suggesting a possible related mechanism. Interestingly, the patient was treated with TBO-filgrastim 480 mcg daily with a rapid reconstitution of neutrophils. While the mechanism of agranulocytosis remains unknown, we report, to our knowledge, the first known case of agranulocytosis following COVID-19 infection and its successful treatment with granulocyte colony-stimulating factor.
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http://dx.doi.org/10.7759/cureus.9463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455389PMC
July 2020

Applications of Mesoporous Silica-Encapsulated Gold Nanorods Loaded Doxorubicin in Chemo-photothermal Therapy.

ACS Omega 2020 Aug 7;5(32):20231-20237. Epub 2020 Aug 7.

Department of Physics, Le Quy Don Technical University, Cau Giay, Hanoi 10000, Vietnam.

We investigate the chemo-photothermal effects of gold nanorods (GNRs) coated using mesoporous silica (mSiO) loading doxorubicin (DOX). When the mesoporous silica layer is embedded by doxorubicin drugs, a significant change in absorption spectra enables to quantify the drug loading. We carried out photothermal experiments on saline and livers of mice having GNRs@mSiO and GNRs@mSiO-DOX. We also injected the gold nanostructures into many tumor-implanted mice and used laser illumination on some of them. By measuring the weight and size of tumors, the distinct efficiency of photothermal therapy and chemotherapy on treatment is determined. We experimentally confirm the accumulation of gold nanostructures in the liver.
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http://dx.doi.org/10.1021/acsomega.0c01939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439364PMC
August 2020

Convolutional neural networks improve fungal classification.

Sci Rep 2020 07 28;10(1):12628. Epub 2020 Jul 28.

Westerdijk Fungal Biodiversity Institute, Uppsalalaan 8, 3584CT, Utrecht, The Netherlands.

Sequence classification plays an important role in metagenomics studies. We assess the deep neural network approach for fungal sequence classification as it has emerged as a successful paradigm for big data classification and clustering. Two deep learning-based classifiers, a convolutional neural network (CNN) and a deep belief network (DBN) were trained using our recently released barcode datasets. Experimental results show that CNN outperformed the traditional BLAST classification and the most accurate machine learning based Ribosomal Database Project (RDP) classifier on datasets that had many of the labels present in the training datasets. When classifying an independent dataset namely the "Top 50 Most Wanted Fungi", CNN and DBN assigned less sequences than BLAST. However, they could assign much more sequences than the RDP classifier. In terms of efficiency, it took the machine learning classifiers up to two seconds to classify a test dataset while it was 53 s for BLAST. The result of the current study will enable us to speed up the taxonomic assignments for the fungal barcode sequences generated at our institute as ~ 70% of them still need to be validated for public release. In addition, it will help to quickly provide a taxonomic profile for metagenomics samples.
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http://dx.doi.org/10.1038/s41598-020-69245-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387343PMC
July 2020

Unambiguous identification of fungi: where do we stand and how accurate and precise is fungal DNA barcoding?

IMA Fungus 2020 10;11:14. Epub 2020 Jul 10.

International Commission on the Taxonomy of Fungi, Champaign, IL USA.

True fungi () and fungus-like organisms (e.g. , ) constitute the second largest group of organisms based on global richness estimates, with around 3 million predicted species. Compared to plants and animals, fungi have simple body plans with often morphologically and ecologically obscure structures. This poses challenges for accurate and precise identifications. Here we provide a conceptual framework for the identification of fungi, encouraging the approach of integrative (polyphasic) taxonomy for species delimitation, i.e. the combination of genealogy (phylogeny), phenotype (including autecology), and reproductive biology (when feasible). This allows objective evaluation of diagnostic characters, either phenotypic or molecular or both. Verification of identifications is crucial but often neglected. Because of clade-specific evolutionary histories, there is currently no single tool for the identification of fungi, although DNA barcoding using the internal transcribed spacer (ITS) remains a first diagnosis, particularly in metabarcoding studies. Secondary DNA barcodes are increasingly implemented for groups where ITS does not provide sufficient precision. Issues of pairwise sequence similarity-based identifications and OTU clustering are discussed, and multiple sequence alignment-based phylogenetic approaches with subsequent verification are recommended as more accurate alternatives. In metabarcoding approaches, the trade-off between speed and accuracy and precision of molecular identifications must be carefully considered. Intragenomic variation of the ITS and other barcoding markers should be properly documented, as phylotype diversity is not necessarily a proxy of species richness. Important strategies to improve molecular identification of fungi are: (1) broadly document intraspecific and intragenomic variation of barcoding markers; (2) substantially expand sequence repositories, focusing on undersampled clades and missing taxa; (3) improve curation of sequence labels in primary repositories and substantially increase the number of sequences based on verified material; (4) link sequence data to digital information of voucher specimens including imagery. In parallel, technological improvements to genome sequencing offer promising alternatives to DNA barcoding in the future. Despite the prevalence of DNA-based fungal taxonomy, phenotype-based approaches remain an important strategy to catalog the global diversity of fungi and establish initial species hypotheses.
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http://dx.doi.org/10.1186/s43008-020-00033-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353689PMC
July 2020

Favorable outcomes of acute leukemias of ambiguous lineage treated with hyperCVAD: a multi-center retrospective study.

Ann Hematol 2020 Sep 17;99(9):2119-2124. Epub 2020 Jul 17.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Acute leukemias of ambiguous lineage (ALAL) are rare hematologic malignancies with poor outcomes. Retrospective studies have suggested that acute lymphoblastic leukemia (ALL) regimens are more effective than acute myeloid leukemia (AML) regimens. We retrospectively examined the effectiveness of the widely-used adult ALL regimen hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyperCVAD) as initial therapy in patients with ALAL at five academic institutions. Twenty-five patients were identified, including 23 with mixed phenotype acute leukemia (MPAL) and two with acute undifferentiated leukemia. Five of 8 tested (63%) had FLT3-ITD and 3 of 25 (12%) were Philadelphia chromosome-positive. The complete remission (CR) rate was 76%, with CR with incomplete count recovery (CRi) in an additional 8%, for an overall response rate of 84%. Median number of cycles to CR/CRi was 1. There were no deaths in the first 30 days. Of the 21 patients achieving CR or CRi, 14 (66%) proceeded to allogeneic hematopoietic stem cell transplantation. With a median follow-up time of 31.6 months, median overall survival for the entire cohort was not reached, and the estimated 2-year survival was 63%. HyperCVAD can be considered an effective and tolerable front-line regimen for patients with ALAL, and warrants further prospective study.
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http://dx.doi.org/10.1007/s00277-020-04179-zDOI Listing
September 2020

(4)-Morpholinothiosemicarbazide-Modified Cellulose: Synthesis, Structure, Kinetics, Thermodynamics, and Ni(II) Removal Studies.

ACS Omega 2020 Jun 19;5(25):15229-15239. Epub 2020 Jun 19.

Faculty of Chemistry, Ho Chi Minh City University of Education, Ho Chi Minh City 700000 Vietnam.

In this study, cellulose extracted from straw was modified using (4)-morpholinothiosemicarbazide to generate a novel adsorbent as a chelate-complex-based material. The effects of pH, time, temperature, and mass ratios of KIO: cellulose on the yield of the oxidation were analyzed using iodometric titration and photometric methods. The accuracy and precision of the above two methods were evaluated using Student and Fisher statistical distribution. The structure of the material was characterized by Fourier-transform infrared spectroscopy, thermogravimetric analysis, X-ray diffraction, scanning electron microscopy, and Brunauer-Emmett-Teller surface area analysis. The kinetic order of Ni(II) adsorption was dependent on the concentration of Ni(II). The surface response design enabled to optimize the condition for Ni(II) adsorption at 58 °C, pH of 4.98, within 106 min. The maximum Ni(II) adsorption capacity was 90 mg g. This kind of adsorbent can be reused at least five times without a significant decrease in its adsorption efficiency.
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http://dx.doi.org/10.1021/acsomega.0c01234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331069PMC
June 2020

Novel multiplex real-time PCR assays reveal a high prevalence of diarrhoeagenic Escherichia coli pathotypes in healthy and diarrhoeal children in the south of Vietnam.

BMC Microbiol 2020 07 3;20(1):192. Epub 2020 Jul 3.

Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID) Department of Medicine, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AW, UK.

Background: Diarrhoeagenic Escherichia coli (DEC) infections are common in children in low-middle income countries (LMICs). However, detecting the various DEC pathotypes is complex as they cannot be differentiated by classical microbiology. We developed four multiplex real-time PCR assays were to detect virulence markers of six DEC pathotypes; specificity was tested using DEC controls and other enteric pathogens. PCR amplicons from the six E. coli pathotypes were purified and amplified to be used to optimize PCR reactions and to calculate reproducibility. After validation, these assays were applied to clinical samples from healthy and diarrhoeal Vietnamese children and associated with clinical data.

Results: The multiplex real-time PCRs were found to be reproducible, and specific. At least one DEC variant was detected in 34.7% (978/2815) of the faecal samples from diarrhoeal children; EAEC, EIEC and atypical EPEC were most frequent Notably, 41.2% (205/498) of samples from non-diarrhoeal children was positive with a DEC pathotype. In this population, only EIEC, which was detected in 34.3% (99/289) of diarrhoeal samples vs. 0.8% (4/498) non-diarrhoeal samples (p < 0.001), was significantly associated with diarrhoea. Multiplex real-time PCR when applied to clinical samples is an efficient and high-throughput approach to DEC pathotypes.

Conclusions: This approach revealed high carriage rates of DEC pathotypes among Vietnamese children. We describe a novel diagnostic approach for DEC, which provides baseline data for future surveillance studies assessing DEC burden in LMICs.
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http://dx.doi.org/10.1186/s12866-020-01878-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333254PMC
July 2020

Teenage mutant neutrophilic precursors: Leukemia cutis with IDH2 mutation on enasidenib therapy.

Leuk Res 2020 09 25;96:106406. Epub 2020 Jun 25.

Department of Medicine, Division of Hematology / Oncology, University of Maryland School of Medicine, Baltimore, MD, United States.

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http://dx.doi.org/10.1016/j.leukres.2020.106406DOI Listing
September 2020

SPHN - Development and Usability Testing of an Electronic General Consent Prototype.

Stud Health Technol Inform 2020 Jun;270:1151-1155

Department of Clinical Research, University and University Hospital Basel, Basel.

Background: According to the Swiss Law on Research in Humans, the reuse of routinely collected genetic and non-genetic data and samples from patients for research purposes requires the consent of patients. Unfortunately, the so far established paper-based processes are intrinsically linked to the hospital admission process, labour intensive and not yielding the targeted return rates. Therefore, the overall goal of the presented SPHN project is to increase patient reach by providing hospitals with a patient-centric, user-friendly and admission-independent electronic general consent pathway. As part of the project, feasibility of different digital pathways was evaluated in a usability testing.

Methods: Based on a nationwide harmonised template, a mobile centric progressive web application was developed by the Department of Clinical Research Basel. Usability of the application and according user journeys were evaluated at all partner hospitals. Two options of giving consent were explored using 1) patients' smartphones without any involvement of hospital personnel and 2) a hospital device (tablet) with explicit confirmation of patient identity by hospital personnel. Participant signatures were captured as a picture of a handwritten signature on paper taken with the camera of the smartphone or tablet. Usability issues and feedback of participants were documented directly after usability testing.

Results: In total, 122 users agreed to participate in the usability testing using a tablet or smartphone. The general consent request workflow on the smartphone or tablet was regarded as user friendly and easy to navigate by 96% of all participants. However, capturing a picture of a handwritten signature resulted in usability issues in multiple cases, i.e. due to missing pen or paper.

Conclusion: Usability testing of our prototype application showed a broad acceptance of participants regarding the use of mobile electronic devices to give general consent. Therefore, we believe that easy-to-use digital general consent processes provide effective means to increase the patient pool for health-related research. Further discussions with legislative bodies are required to find patient centric, feasible and legally acceptable solutions in the specific case of electronic general consent for the near future.
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http://dx.doi.org/10.3233/SHTI200343DOI Listing
June 2020

Frontline Blinatumomab in Older Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

Pharmaceuticals (Basel) 2020 Jun 16;13(6). Epub 2020 Jun 16.

Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Outcomes of acute lymphoblastic leukemia (ALL) in older adults treated with chemotherapy are poor. The CD19/CD3 bispecific T-cell engager (BiTE) antibody blinatumomab is approved for refractory, relapsed or minimal/measurable residual disease (MRD)-positive B-cell ALL, but there is little experience in the upfront setting, including in older patients. We retrospectively analyzed outcomes of blinatumomab monotherapy in five newly diagnosed Philadelphia chromosome-negative B-cell ALL patients over 70 years. Three had cytokine release syndrome, treated with dexamethasone and/or tocilizumab, and four patients had neurotoxicity, treated with dexamethasone, without blinatumomab interruption. All five achieved complete remission (CR) after cycle one, three with undetectable MRD. All five were alive at 8 to 15 months. Three remained in MRD-negative CR. Two relapsed after cycle 3, one with extramedullary disease. In our small cohort of patients over 70 years, blinatumomab was safe initial therapy and produced a high response rate.
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http://dx.doi.org/10.3390/ph13060124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345996PMC
June 2020

Comparative Genomic Analysis of Capsule-Producing Black Yeasts and , Potential Agents of Disseminated Mycoses.

Front Microbiol 2020 8;11:586. Epub 2020 Apr 8.

Research Center for Medical Mycology, Peking University, Beijing, China.

The two black yeasts and that are clinically considered as the most virulent species potentially causing disseminated infections are both producing extracellular capsule-like material, are compared. In this study, 10 genomes of and strains, including both clinical and environmental isolates, were selected based on phylogenetic analysis, physiology tests and virulence tests, sequenced on the Illumina MiSeq sequencer and annotated. Comparison of genome data were performed between intraspecific and interspecific strains. We found capsule-associated genes were however not consistently present in both species by the comparative genomics. The prevalent clinical species, , has small genomes containing significantly less virulence-associated genes than , and also than saprobic relatives. Gene OG0012246 and Myb-like DNA-binding domain and SANT/Myb domain, restricted to two strains from human brain, was shared with the neurotropic species . This study indicated that different virulence profiles existed in the two capsule-producing black yeasts, and the absence of consistent virulence-associated profiles supports the hypothesis that black yeasts are opportunists rather than primary pathogens. The results also provide the key virulence genes and drive the continuing research forward pathogen-host interactions to explore the pathogenesis.
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http://dx.doi.org/10.3389/fmicb.2020.00586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179667PMC
April 2020

Universal patterns in passenger flight departure delays.

Sci Rep 2020 04 23;10(1):6890. Epub 2020 Apr 23.

Boston University, Center for Polymer Studies and Department of Physics, Boston, MA, 02215, United States.

Departure delays are a major cause of economic loss and inefficiency in the growing industry of passenger flights. A departure delay of a current flight is inevitably affected by the late arrival of the flight immediately preceding it with the same aircraft. We seek to understand the mechanisms of such propagated delays, and to obtain universal metrics by which to evaluate an airline's operational effectiveness in delay alleviation. Here we use big data collected by the American Bureau of Transportation Statistics to design models of flight delays. Offering two dynamic models of delay propagation, we divided all carriers into two groups exhibiting a shifted power law or an exponentially truncated shifted power law delay distribution, revealing two universal delay propagation classes. Three model parameters, extracted directly from dual data mining, help characterize each airline's operational efficiency in delay mitigation. Therefore, our modeling framework provides the crucially lacking evaluation indicators for airlines, potentially contributing to the mitigation of future departure delays.
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http://dx.doi.org/10.1038/s41598-020-62871-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181864PMC
April 2020

A sequential two-stage dose escalation study of eltrombopag in patients with myelodysplastic syndrome and thrombocytopenia after hypomethylating agent failure.

Leuk Lymphoma 2020 08 19;61(8):1901-1907. Epub 2020 Apr 19.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Thrombocytopenia occurs frequently in patients with myelodysplastic syndromes (MDS), and the survival of patients after failure of hypomethylating agents (HMAs) is poor. We conducted a trial of eltrombopag in patients with MDS, MDS/myeloproliferative neoplasm (MPN) or acute myeloid leukemia (AML) with 20-30% myeloblasts after HMA failure and mean baseline platelet count ≤ 50 × 10/L. Eltrombopag was escalated from 50 mg daily up to 200 mg daily. The primary objective was to determine the maximally tolerated dose (MTD). 37 patients were enrolled, and MTD was not reached. Responses were observed in 9 patients (24%), 2 achieving marrow CR with hematologic improvement (HI), 1 marrow CR without HI, and 6 HI. Median overall survival was 7.5 months. Eltrombopag was well-tolerated and yielded modest responses in heavily treated, predominantly higher-risk MDS patients after HMA failure. Future studies should focus on determining characteristics that predict response.
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http://dx.doi.org/10.1080/10428194.2020.1751841DOI Listing
August 2020

Comparison of High-Dose Cytarabine, Mitoxantrone, and Pegaspargase (HAM-pegA) to High-Dose Cytarabine, Mitoxantrone, Cladribine, and Filgrastim (CLAG-M) as First-Line Salvage Cytotoxic Chemotherapy for Relapsed/Refractory Acute Myeloid Leukemia.

J Clin Med 2020 Feb 16;9(2). Epub 2020 Feb 16.

Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA.

Currently, no standard of care exists for the treatment of relapsed or refractory acute myeloid leukemia (AML). We present our institutional experience with using either CLAG-M or HAM-pegA, a novel regimen that includes pegaspargase. This is a retrospective comparison of 34 patients receiving CLAG-M and 10 receiving HAM-pegA as first salvage cytotoxic chemotherapy in the relapsed or refractory setting. Composite complete response rates were 47.1% for CLAG-M and 90% for HAM-pegA ( = 0.027). Event-free survival was significantly different in favor of HAM-pegA ( = 0.045), though overall survival was similar between groups. There were no significant differences in toxicities experienced by patients treated with the two regimens, including adverse events of special interest related to pegaspargase (venous thromboembolism, hemorrhage, hepatotoxicity, pancreatitis, and hypersensitivity reactions). HAM-pegA is a novel regimen for relapsed or refractory AML that resulted in improved response rates and similar toxicities compared to CLAG-M.
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http://dx.doi.org/10.3390/jcm9020536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074083PMC
February 2020

A phase 1 study of the antibody-drug conjugate brentuximab vedotin with re-induction chemotherapy in patients with CD30-expressing relapsed/refractory acute myeloid leukemia.

Cancer 2020 03 20;126(6):1264-1273. Epub 2019 Dec 20.

Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.

Background: Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody-drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re-induction chemotherapy for patients with CD30-expressing R/R AML.

Methods: Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7.

Results: There were no dose-limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease-free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion.

Conclusions: The combination of BV with MEC was found to be safe in patients with CD30-expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777).

Lay Summary: The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.
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http://dx.doi.org/10.1002/cncr.32657DOI Listing
March 2020

Jumping translocations of chromosome 1q occurring by a multi-stage process in an acute myeloid leukemia progressed from myelodysplastic syndrome with a mutation.

Mol Cytogenet 2019 19;12:47. Epub 2019 Nov 19.

1Department of Pathology, University of Maryland School of Medicine, Baltimore, MD USA.

Background: Jumping translocations (JTs) are rare chromosome rearrangements characterized by re-localization of one donor chromosome to multiple recipient chromosomes. Here, we describe an acute myeloid leukemia (AML) that progressed from myelodysplastic syndrome (MDS) in association with acquisition of 1q JTs. The sequence of molecular and cytogenetic changes in our patient may provide a mechanistic model for the generation of JTs in leukemia.

Case Presentation: A 68-year-old man presented with pancytopenia. Bone marrow aspirate and biopsy showed a hypercellular marrow with multilineage dysplasia, consistent with MDS, with no increase in blasts. Karyotype and MDS fluorescence in situ hybridization (FISH) panel were normal. Repeat bone marrow aspirate and biopsy after 8 cycles of azacitidine, with persistent pancytopenia, showed no changes in morphology, and karyotype was again normal. Myeloid mutation panel showed mutations in , , , and . Three years after diagnosis, he developed AML with myelodysplasia-related changes. Karyotype was abnormal, with unbalanced 1q JTs to the short arms of acrocentric chromosomes 14 and 21, leading to gain of 1q.

Conclusions: Our patient had MDS with pathogenic mutations of the , , , and genes and developed 1q JTs at the time of progression from MDS to AML. Our data suggest that the formation of 1q JTs involves multiple stages and may provide a mechanistic model for the generation of JTs in leukemia.
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http://dx.doi.org/10.1186/s13039-019-0460-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862801PMC
November 2019

Peripheral blood blast rate of clearance is an independent predictor of clinical response and outcomes in acute myeloid leukaemia.

Br J Haematol 2020 03 5;188(6):881-887. Epub 2019 Dec 5.

Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.

The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB-RC) was calculated for treatment-naive AML patients (n = 164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis. PBB-RC was defined as the percentage of the absolute PBB count on the day of diagnosis that was cleared with each day of therapy, on average, until D14 or day of PBB clearance. Each 5% increase in PBB-RC approximately doubled the likelihood of D14BM clearance (OR = 1·81; 95% CI: 1·24-2·64, P < 0·005). PBB-RC was also associated with improved CR rates (OR per 5% = 1·97; 95% CI: 1·27-3·01, P < 0·005) and overall survival (OS) [hazard ratio (HR) per 5% = 0·67; 95% CI: 0·52-0·87]. African American patients had poorer OS adjusted for PBB-RC (HR = 2·18; 95% CI: 1·13-4·23), while race was not associated with D14BM or CR rate. PBB-RC during induction chemotherapy is predictive of D14BM clearance, CR, and OS, and can therefore serve as a prognostic marker for clinical outcomes in AML.
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http://dx.doi.org/10.1111/bjh.16261DOI Listing
March 2020

Dissecting the molecular evolution of fluoroquinolone-resistant Shigella sonnei.

Nat Commun 2019 10 23;10(1):4828. Epub 2019 Oct 23.

The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

Shigella sonnei increasingly dominates the international epidemiological landscape of shigellosis. Treatment options for S. sonnei are dwindling due to resistance to several key antimicrobials, including the fluoroquinolones. Here we analyse nearly 400 S. sonnei whole genome sequences from both endemic and non-endemic regions to delineate the evolutionary history of the recently emergent fluoroquinolone-resistant S. sonnei. We reaffirm that extant resistant organisms belong to a single clonal expansion event. Our results indicate that sequential accumulation of defining mutations (gyrA-S83L, parC-S80I, and gyrA-D87G) led to the emergence of the fluoroquinolone-resistant S. sonnei population around 2007 in South Asia. This clone was then transmitted globally, resulting in establishments in Southeast Asia and Europe. Mutation analysis suggests that the clone became dominant through enhanced adaptation to oxidative stress. Experimental evolution reveals that under fluoroquinolone exposure in vitro, resistant S. sonnei develops further intolerance to the antimicrobial while the susceptible counterpart fails to attain complete resistance.
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http://dx.doi.org/10.1038/s41467-019-12823-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811581PMC
October 2019

A Prospective Study of Peritransplant Sorafenib for Patients with FLT3-ITD Acute Myeloid Leukemia Undergoing Allogeneic Transplantation.

Biol Blood Marrow Transplant 2020 02 21;26(2):300-306. Epub 2019 Sep 21.

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.

FLT3-ITD-mutated acute myeloid leukemia (AML) remains a therapeutic challenge. FLT3 inhibition in the setting of minimal residual disease and a new immune system via allogeneic transplantation offers a promise of improved survival for these patients. We performed a prospective study of patients with FLT3-ITD AML undergoing allogeneic transplant that was conducted to evaluate the safety, tolerability, and outcome of sorafenib administered peritransplant. Sorafenib dosing was individualized, starting at 200 mg twice a day (BID), and titrated based on tolerability or toxicities until a tolerable dose was identified. Forty-four patients, with a median age of 52 years, undergoing allogeneic transplant were started on sorafenib in the peritransplant period (21 pretransplant). The median duration of post-transplant follow-up was 27.6 months (range, 5.2 to 60.4). Overall survival was 76% at both 24 and 36 months. Event-free survival at 24 and 36 months was 74% and 64%, respectively. Ten patients died in the post-transplant period, with 6 deaths due to relapsed leukemia and 4 from transplant-associated toxicity. Tolerable doses ranged from 200 mg every other day to 400 mg BID with similar exposure. Correlative studies evaluating FLT3 inhibition via a plasma inhibitory activity assay showed consistent inhibition of FLT3 at all tolerability-determined dosing levels. Sorafenib is well tolerated in the peritransplant setting irrespective of the conditioning intensity or the donor source. Our findings indicate that sorafenib dosing can be individualized in the post-transplantation setting according to patient tolerability. This approach results in effective in vivo FLT3 inhibition and yields encouraging survival results.
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http://dx.doi.org/10.1016/j.bbmt.2019.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001148PMC
February 2020

Phyllosticta citricarpa and sister species of global importance to Citrus.

Mol Plant Pathol 2019 12 11;20(12):1619-1635. Epub 2019 Sep 11.

Westerdijk Fungal Biodiversity Institute, Utrecht, Netherlands.

Several Phyllosticta species are known as pathogens of Citrus spp., and are responsible for various disease symptoms including leaf and fruit spots. One of the most important species is P. citricarpa, which causes a foliar and fruit disease called citrus black spot. The Phyllosticta species occurring on citrus can most effectively be distinguished from P. citricarpa by means of multilocus DNA sequence data. Recent studies also demonstrated P. citricarpa to be heterothallic, and reported successful mating in the laboratory. Since the domestication of citrus, different clones of P. citricarpa have escaped Asia to other continents via trade routes, with obvious disease management consequences. This pathogen profile represents a comprehensive literature review of this pathogen and allied taxa associated with citrus, focusing on identification, distribution, genomics, epidemiology and disease management. This review also considers the knowledge emerging from seven genomes of Phyllosticta spp., demonstrating unknown aspects of these species, including their mating behaviour.

Taxonomy: Phyllosticta citricarpa (McAlpine) Aa, 1973. Kingdom Fungi, Phylum Ascomycota, Class Dothideomycetes, Order Botryosphaeriales, Family Phyllostictaceae, Genus Phyllosticta, Species citricarpa.

Host Range: Confirmed on more than 12 Citrus species, Phyllosticta citricarpa has only been found on plant species in the Rutaceae.

Disease Symptoms: P. citricarpa causes diverse symptoms such as hard spot, virulent spot, false melanose and freckle spot on fruit, and necrotic lesions on leaves and twigs.

Useful Websites: DOE Joint Genome Institute MycoCosm portals for the Phyllosticta capitalensis (https://genome.jgi.doe.gov/Phycap1), P. citriasiana (https://genome.jgi.doe.gov/Phycit1), P. citribraziliensis (https://genome.jgi.doe.gov/Phcit1), P. citrichinaensis (https://genome.jgi.doe.gov/Phcitr1), P. citricarpa (https://genome.jgi.doe.gov/Phycitr1, https://genome.jgi.doe.gov/Phycpc1), P. paracitricarpa (https://genome.jgi.doe.gov/Phy27169) genomes. All available Phyllosticta genomes on MycoCosm can be viewed at https://genome.jgi.doe.gov/Phyllosticta.
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http://dx.doi.org/10.1111/mpp.12861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859488PMC
December 2019

Characteristics and outcomes of therapy-related myeloid neoplasms after treatment for multiple myeloma.

Leuk Lymphoma 2019 12 8;60(14):3577-3580. Epub 2019 Jul 8.

Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1080/10428194.2019.1633639DOI Listing
December 2019