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HemaSphere Apr 2024
PubMed: 38566805
DOI: 10.1002/hem3.67 -
PLoS Pathogens Apr 2024Lyme disease is a tick-borne infection caused by the spirochete Borrelia (Borreliella) burgdorferi. Borrelia species have highly fragmented genomes composed of a linear...
Lyme disease is a tick-borne infection caused by the spirochete Borrelia (Borreliella) burgdorferi. Borrelia species have highly fragmented genomes composed of a linear chromosome and a constellation of linear and circular plasmids some of which are required throughout the enzootic cycle. Included in this plasmid repertoire by almost all Lyme disease spirochetes are the 32-kb circular plasmid cp32 prophages that are capable of lytic replication to produce infectious virions called ϕBB-1. While the B. burgdorferi genome contains evidence of horizontal transfer, the mechanisms of gene transfer between strains remain unclear. While we know that ϕBB-1 transduces cp32 and shuttle vector DNA during in vitro cultivation, the extent of ϕBB-1 DNA transfer is not clear. Herein, we use proteomics and long-read sequencing to further characterize ϕBB-1 virions. Our studies identified the cp32 pac region and revealed that ϕBB-1 packages linear cp32s via a headful mechanism with preferential packaging of plasmids containing the cp32 pac region. Additionally, we find ϕBB-1 packages fragments of the linear chromosome and full-length plasmids including lp54, cp26, and others. Furthermore, sequencing of ϕBB-1 packaged DNA allowed us to resolve the covalently closed hairpin telomeres for the linear B. burgdorferi chromosome and most linear plasmids in strain CA-11.2A. Collectively, our results shed light on the biology of the ubiquitous ϕBB-1 phage and further implicates ϕBB-1 in the generalized transduction of diverse genes and the maintenance of genetic diversity in Lyme disease spirochetes.
Topics: Humans; Borrelia burgdorferi; Bacteriophages; Plasmids; Lyme Disease; Genomics; DNA
PubMed: 38558079
DOI: 10.1371/journal.ppat.1012122 -
International Heart Journal 2024Tyrosine kinase inhibitors (TKIs) are essential drugs for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Cardiovascular or...
Tyrosine kinase inhibitors (TKIs) are essential drugs for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Cardiovascular or arteriothrombotic adverse events have been reported in patients treated with TKIs. We report 3 cases of Ponatinib-related vasospastic angina, in which prophylactic administration of nitrates or calcium channel blockers was effective.
Topics: Humans; Coronary Vasospasm; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Imidazoles; Pyridazines
PubMed: 38556342
DOI: 10.1536/ihj.23-355 -
JAMA Network Open Mar 2024The reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQOL)....
IMPORTANCE
The reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQOL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the less than 15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry.
OBJECTIVES
To determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); to describe military service metrics of men with SCAs; and to compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis vs matched controls.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study used a case-control recruitment design to select biological males enrolled in the MVP biobank in the US Veterans Administration health care system from 2011 to 2022. Cases were participants with 47,XXY syndrome or 47,XYY syndrome, matched 1:5 with controls based on sex, age, and genetic ancestry. Data were analyzed from January 2022 to December 2023.
EXPOSURE
Genomic identification of an additional X or Y chromosome.
MAIN OUTCOMES AND MEASURES
Outcomes of interest included prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index; rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; and standardized mortality ratio.
RESULTS
Of 595 612 genotyped males in the MVP, 862 had an additional X chromosome (47,XXY) and 747 had an extra Y chromosome (47,XYY), with the highest prevalence among men with East Asian (47,XXY: 10 of 7313 participants; 47,XYY: 14 of 7313 participants) and European (47,XXY: 725 of 427 143 participants; 47,XYY: 625 of 427 143 participants) ancestry. Mean (SD) age at assessment was 61 (12) years, at which point 636 veterans (74.X%) with 47,XXY and 745 veterans (99%) with 47,XYY remained undiagnosed. Individuals with 47,XXY and 47,XYY had similar military service history, all-cause standardized mortality ratio, and age of death compared with matched controls. Individuals with SCA, compared with controls, had higher Charlson Comorbidity Index scores (47,XXY: mean [SD], 4.30 [2.72] vs controls: mean [SD], 3.90 [2.47]; 47,XYY: mean [SD], 4.45 [2.90] vs controls: mean [SD], 3.82 [2.50]) and health care utilization (eg, median [IQR] outpatient encounters per year: 47,XXY, 22.6 [11.8-37.8] vs controls, 16.8 [9.4-28]; 47,XYY: 21.4 [12.4-33.8] vs controls: 17.0 [9.4-28.2]), while several measures of HRQOL were lower (eg, mean [SD] self-reported physical function: 47,XXY: 34.2 [12] vs control mean [SD] 37.8 [12.8]; 47,XYY: 36.3 [11.6] vs control 37.9 [12.8]). Men with a clinical diagnosis of 47,XXY, compared with individuals without a clinical diagnosis, had higher health care utilization (eg, median [IQR] encounters per year: 26.6 [14.9-43.2] vs 22.2 [11.3-36.0]) but lower Charlson Comorbidity Index scores (mean [SD]: 3.7 [2.7] vs 4.5 [4.1]).
CONCLUSION AND RELEVANCE
In this case-control study of men with 47,XXY and 47,XYY syndromes, prevalence of SCA was comparable with estimates in the general population. While these men had successfully served in the military, they had higher morbidity and reported poorer HRQOL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics.
Topics: Male; Humans; Female; Veterans; Prevalence; Case-Control Studies; Cross-Sectional Studies; Quality of Life; Sex Chromosome Aberrations; Aneuploidy; Morbidity; Sex Chromosomes; XYY Karyotype; Sex Chromosome Disorders
PubMed: 38551561
DOI: 10.1001/jamanetworkopen.2024.4113 -
Cambridge Prisms. Precision Medicine 2023Treatment and understanding of BCR::ABL1-positive leukaemias is a precision medicine success story. Our appreciation of the gene and resulting BCR::ABL1 oncoprotein in... (Review)
Review
Treatment and understanding of BCR::ABL1-positive leukaemias is a precision medicine success story. Our appreciation of the gene and resulting BCR::ABL1 oncoprotein in chronic myeloid leukaemia (CML) and Philadelphia chromosome-positive (Ph+) acute leukaemias, has led to treatment advances associated with exceptional improvements in patient outcomes with normal life expectancy for many patients with chronic phase (CP-)CML. However, despite these major therapeutic advances, the management of Ph+ leukaemias remains complex, with development of specific resistance mutations on treatment, as well as the need for lifelong therapy in most patients due to the persistence of CML stem cells despite prolonged tyrosine kinase inhibitors (TKIs) treatment. BCR::ABL1-specific TKIs are associated with chronic toxicities affecting quality-of-life in many patients but can also result in more serious pulmonary and cardiovascular complications. Dose optimisation is increasingly being used to manage side effects and maintain molecular response in CML patients. Here, we review the development of BCR::ABL1-specific TKIs from the discovery of imatinib in 1996 to the more recent second- and third-generation TKIs and emerging specifically targeting the ABL myristoyl pocket (STAMP) inhibitors. We will also evaluate the current evidence for treatment of BCR::ABL1-positive leukaemias, including TKI discontinuation in optimally responding CP-CML patients.
PubMed: 38550948
DOI: 10.1017/pcm.2023.9 -
Case Reports in Hematology 2024Evidence suggests that the earliest genetic events in the evolution of a cancer can predate diagnosis by several years or decades. In chronic myeloid leukemia (CML), the...
Evidence suggests that the earliest genetic events in the evolution of a cancer can predate diagnosis by several years or decades. In chronic myeloid leukemia (CML), the BCR::ABL1 fusion driver mutation can be present for an extended period before clinical disease manifests. The time between the BCR::ABL1 occurrence and symptom onset is referred to as the latency period. Though modeling studies predict this latency period is no more than ten years, it is still unclear how long it can be. We present a case of a patient referred for suspected CML. Both karyotype and FISH analysis identified the (9;22)(34;11.2) translocation resulting in the Philadelphia chromosome formation in 98.5% of cells analyzed. The patient responded to imatinib and achieved a sustained complete hematologic and cytogenetic remission. Clinical history revealed that the same patient presented eight years previously with anemia. Various non-neoplastic conditions were excluded, and a bone marrow biopsy was performed to rule out MDS. Cytogenetic analysis at that time revealed del(20) as the sole abnormality in all 20 cells analyzed. No treatment was given since the presence of isolated del(20) is not considered evidence of MDS in the absence of diagnostic morphologic criteria. Retrospective FISH analysis of archived bone marrow pellets from this previous specimen revealed the presence of BCR::ABL1 in 1.8% of cells. A clonal population of cells harboring the BCR::ABL1 fusion was unambiguously detected in this patient's archived bone marrow pellet obtained eight years before the current CML diagnosis. This case demonstrates that Carnoy's fixed nuclear pellets stored in cytogenetic laboratories are suitable for detecting driver mutations years before disease presentation. Such archived material may be useful for the retrospective studies needed to better understand the initiation and subsequent development of hematological malignancies. By identifying individuals who are at increased risk, it may be possible to initiate preventive measures or begin treatment at an earlier stage before disease progression.
PubMed: 38550770
DOI: 10.1155/2024/2127657 -
World Journal of Oncology Apr 2024Asciminib is approved for treating patients with chronic-phase chronic myeloid leukemia who were previously treated with two or more tyrosine kinase inhibitors or those...
BACKGROUND
Asciminib is approved for treating patients with chronic-phase chronic myeloid leukemia who were previously treated with two or more tyrosine kinase inhibitors or those with mutation. However, the mechanisms underlying asciminib resistance remain unclear.
METHODS
In this study, we established a new asciminib-resistant cell line. We examined gene mutation analysis and the effects of conventional chronic myelogenous leukemia inhibitors.
RESULTS
Direct sequencing revealed and mutations in asciminib-resistant cells. Ponatinib and omacetaxine were effective against asciminib-resistant cells.
CONCLUSIONS
and mutations are extremely resistant to asciminib. Ponatinib and omacetaxine show potential for treating asciminib-resistant chronic myeloid leukemia.
PubMed: 38545482
DOI: 10.14740/wjon1818 -
Pharmaceuticals (Basel, Switzerland) Mar 2024Older adults who are diagnosed with acute lymphoblastic leukemia (ALL) and are treated with chemotherapy generally have poor outcomes. Blinatumomab is a CD19/CD3...
Older adults who are diagnosed with acute lymphoblastic leukemia (ALL) and are treated with chemotherapy generally have poor outcomes. Blinatumomab is a CD19/CD3 bispecific T-cell engager that has been approved for the treatment of B-cell ALL in the relapsed/refractory setting or in patients with minimal residual disease (MRD) positivity. We previously reported on a small cohort of older adults with newly diagnosed Philadelphia chromosome negative B-cell ALL who were treated with blinatumomab monotherapy in the first line setting. This is a long-term follow up of those patients and their clinical courses. All five patients achieved complete remission (CR) after one cycle of blinatumomab, and three were MRD-negative. Two patients completed three cycles of blinatumomab, two patients completed four cycles of blinatumomab, and one patient completed 17 cycles of blinatumomab total. In the last four years, four of these patients had relapsed disease requiring additional therapy. Two patients are alive after 61 months and 57 months since their first cycle of blinatumomab. Two of the patients died at 10 months and one died at 20 months. Here we describe the long-term clinical courses of these patients.
PubMed: 38543121
DOI: 10.3390/ph17030335 -
Turkish Journal of Haematology :... May 2024
Topics: Humans; Janus Kinase 2; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Philadelphia Chromosome; Male; Mutation; Female
PubMed: 38528751
DOI: 10.4274/tjh.galenos.2024.2023.0467 -
Molecular Cell Apr 2024The topological state of chromosomes determines their mechanical properties, dynamics, and function. Recent work indicated that interphase chromosomes are largely free...
The topological state of chromosomes determines their mechanical properties, dynamics, and function. Recent work indicated that interphase chromosomes are largely free of entanglements. Here, we use Hi-C, polymer simulations, and multi-contact 3C and find that, by contrast, mitotic chromosomes are self-entangled. We explore how a mitotic self-entangled state is converted into an unentangled interphase state during mitotic exit. Most mitotic entanglements are removed during anaphase/telophase, with remaining ones removed during early G1, in a topoisomerase-II-dependent process. Polymer models suggest a two-stage disentanglement pathway: first, decondensation of mitotic chromosomes with remaining condensin loops produces entropic forces that bias topoisomerase II activity toward decatenation. At the second stage, the loops are released, and the formation of new entanglements is prevented by lower topoisomerase II activity, allowing the establishment of unentangled and territorial G1 chromosomes. When mitotic entanglements are not removed in experiments and models, a normal interphase state cannot be acquired.
Topics: DNA Topoisomerases, Type II; Chromosomes; Mitosis; Interphase; Polymers
PubMed: 38521067
DOI: 10.1016/j.molcel.2024.02.025