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Proceedings of the National Academy of... Jul 2020Cell size is believed to influence cell growth and metabolism. Consistently, several studies have revealed that large cells have lower mass accumulation rates per unit...
Cell size is believed to influence cell growth and metabolism. Consistently, several studies have revealed that large cells have lower mass accumulation rates per unit mass (i.e., growth efficiency) than intermediate-sized cells in the same population. Size-dependent growth is commonly attributed to transport limitations, such as increased diffusion timescales and decreased surface-to-volume ratio. However, separating cell size- and cell cycle-dependent growth is challenging. To address this, we monitored growth efficiency of pseudodiploid mouse lymphocytic leukemia cells during normal proliferation and polyploidization. This was enabled by the development of large-channel suspended microchannel resonators that allow us to monitor buoyant mass of single cells ranging from 40 pg (small pseudodiploid cell) to over 4,000 pg, with a resolution ranging from ∼1% to ∼0.05%. We find that cell growth efficiency increases, plateaus, and then decreases as cell cycle proceeds. This growth behavior repeats with every endomitotic cycle as cells grow into polyploidy. Overall, growth efficiency changes 33% throughout the cell cycle. In contrast, increasing cell mass by over 100-fold during polyploidization did not change growth efficiency, indicating exponential growth. Consistently, growth efficiency remained constant when cell cycle was arrested in G Thus, cell cycle is a primary determinant of growth efficiency. As growth remains exponential over large size scales, our work finds no evidence for transport limitations that would decrease growth efficiency.
Topics: Animals; Biosensing Techniques; Cell Cycle; Cell Division; Cell Enlargement; Cell Line, Tumor; Cell Proliferation; Humans; Leukemia, Lymphoid; Mice; Microfluidic Analytical Techniques; Polyploidy
PubMed: 32581119
DOI: 10.1073/pnas.1922197117 -
PloS One 2020Relapse of chronic lymphocytic leukaemia and non-Hodgkin's lymphoma after standard of care treatment is common and new therapies are needed. The targeted alpha therapy...
Relapse of chronic lymphocytic leukaemia and non-Hodgkin's lymphoma after standard of care treatment is common and new therapies are needed. The targeted alpha therapy with 212Pb-NNV003 presented in this study combines cytotoxic α-particles from 212Pb, with the anti-CD37 antibody NNV003, targeting B-cell malignancies. The goal of this study was to explore 212Pb-NNV003 for treatment of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma in preclinical mouse models.An anti-proliferative effect of 212Pb-NNV003 was observed in both chronic lymphocytic leukaemia (MEC-2) and Burkitt's lymphoma (Daudi) cells in vitro. In biodistribution experiments, accumulation of 212Pb-NNV003 was 23%ID/g and 16%ID/g in Daudi and MEC-2 tumours 24 h post injection. In two intravenous animal models 90% of the mice treated with a single injection of 212Pb-NNV003 were alive 28 weeks post cell injection. Median survival times of control groups were 5-9 weeks. There was no significant difference between different specific activities of 212Pb-NNV003 with regards to therapeutic effect or toxicity. For therapeutically effective activities, a transient haematological toxicity was observed. This study shows that 212Pb-NNV003 is effective and safe in preclinical models of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma, warranting future clinical testing.
Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents, Immunological; Cell Line, Tumor; Cell Proliferation; Cetuximab; Female; Humans; Lead Radioisotopes; Leukemia, Lymphoid; Lymphoma, Non-Hodgkin; Mice; Mice, SCID; Radiometry; Tetraspanins
PubMed: 32187209
DOI: 10.1371/journal.pone.0230526 -
Immunology Aug 2014Immunological tolerance theory in chronic lymphocytic leukaemia (CLL): we suggest that B cells that express B-cell receptors (BCR) that recognize their own BCR epitopes... (Review)
Review
Immunological tolerance theory in chronic lymphocytic leukaemia (CLL): we suggest that B cells that express B-cell receptors (BCR) that recognize their own BCR epitopes are viewed by immune system as 'dangerous cells'. BCR autonomous signalling may induce constant receptor editing and mistakes in allelic exclusion. The fact that whole BCR recognizes a self-antigen or foreing antigen may be irrelevant in early B cell development. In early B cells, autonomous signalling induced by recognition of the BCR's own epitopes simulates an antigen-antibody engagement. In the bone marrow this interaction is viewed as recognition of self-molecules and induces receptor editing. In mature B cells autonomous signalling by the BCR may promote 'reversible anergy' and also may correct self-reactivity induced by the somatic hypermutation mechanisms in mutated CLL B cells. However, in unmutated CLL B cells, BCR autonomous signalling in addition to self-antigen recognition augments B cell activation, proliferation and genomic instability. We suggest that CLL originates from a coordinated normal immunologic tolerance mechanism to destroy self-reactive B cells. Additional genetic damage induced by tolerance mechanisms may immortalize self-reactive B cells and transform them into a leukemia.
Topics: B-Lymphocytes; Humans; Immune Tolerance; Leukemia, Lymphocytic, Chronic, B-Cell; Receptors, Antigen, B-Cell; Signal Transduction
PubMed: 24645778
DOI: 10.1111/imm.12285 -
Cytometry. Part B, Clinical Cytometry Jul 2021Pre-analytical and analytical errors can threaten the reliability of flow cytometry (FC) results. A potential solution to some of these is the use of dry, pre-mixed...
INTRODUCTION
Pre-analytical and analytical errors can threaten the reliability of flow cytometry (FC) results. A potential solution to some of these is the use of dry, pre-mixed antibodies, such as the ClearLLab 10C system. The purpose of the present study was to compare the diagnostic performance of the ClearLLab 10C B cell tube with that of our standard laboratory practice.
METHODS
We compared the diagnoses made with the ClearLLab 10C B cell tube (experimental strategy) with those made with standard laboratory practice (standard strategy). Samples were selected aiming for representation of the full spectrum of B cell disorders, with an emphasis on mature B cell malignancies, as well as healthy controls.
RESULTS
We included 116 samples (34 normal controls, 4 acute lymphoblastic leukemias, 54 mature lymphoproliferative disorders in peripheral blood and bone marrow, 3 myelomas, 6 bone marrow samples with involvement by lymphoma and 1 with elevated hematogone count, 14 lymph node samples, 1 cerebrospinal fluid, and 1 pleural effusion). There were two diagnostic errors (1.7%). The agreement between the two strategies in the percentage of CD19 cells and fluorescence intensity of CD5, CD19, CD20, CD200, and CD10 was very good.
CONCLUSIONS
In this study, the ClearLLab 10C B cell tube performed similarly to our standard laboratory practice to diagnose and classify mature B cell malignancies.
Topics: Antigens, CD; Antigens, CD19; Antigens, CD20; B-Lymphocytes; Female; Flow Cytometry; Humans; Immunophenotyping; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Lymphoma; Lymphoproliferative Disorders; Male; Neprilysin
PubMed: 32961011
DOI: 10.1002/cyto.b.21955 -
Journal of the American Veterinary... Apr 20212 male and 3 female adult bearded dragons () were evaluated at the North Carolina State University College of Veterinary Medicine's Exotic Animal Medicine Service...
CASE DESCRIPTION
2 male and 3 female adult bearded dragons () were evaluated at the North Carolina State University College of Veterinary Medicine's Exotic Animal Medicine Service between September 2018 and October 2019 because of severe lymphocytosis.
CLINICAL FINDINGS
All 5 bearded dragons had nonspecific clinical signs, including lethargy, poor appetite, ocular discharge, and weight loss. Clinicopathologic testing revealed extremely high lymphocyte counts with morphological findings consistent with lymphocytic leukemia.
TREATMENT AND OUTCOME
All 5 patients were treated with lomustine, prednisolone, and antimicrobials. In addition, 1 or 2 doses of L-asparaginase were administered when the drug was available. Partial remission was achieved in all 5 patients. One patient, after disease progression was documented, was treated with cyclophosphamide and achieved a second partial remission. One of the 5 patients was still alive and continuing to receive chemotherapy at the time of final follow-up 244 days after the initial diagnosis. Survival times (ie, times from initial diagnosis to euthanasia) for the other 4 patients were 57, 157, 330, and 416 days.
CLINICAL RELEVANCE
The present report represented the first description of lomustine as a primary chemotherapeutic agent for the treatment of lymphocytic leukemia in bearded dragons and provided information on response to treatment, adverse effects, and survival times.
Topics: Animals; Female; Leukemia, Lymphoid; Lizards; Male; North Carolina
PubMed: 33754817
DOI: 10.2460/javma.258.7.748 -
PloS One 2016Chronic lymphocytic leukemia (CLL) is extremely rare in Asian countries and there has been one report on genetic changes for 5 genes (TP53, SF3B1, NOTCH1, MYD88, and...
Chronic lymphocytic leukemia (CLL) is extremely rare in Asian countries and there has been one report on genetic changes for 5 genes (TP53, SF3B1, NOTCH1, MYD88, and BIRC3) by Sanger sequencing in Chinese CLL. Yet studies of CLL in Asian countries using Next generation sequencing have not been reported. We aimed to characterize the genomic profiles of Korean CLL and to find out ethnic differences in somatic mutations with prognostic implications. We performed targeted sequencing for 87 gene panel using next-generation sequencing along with G-banding and fluorescent in situ hybridization (FISH) for chromosome 12, 13q14.3 deletion, 17p13 deletion, and 11q22 deletion. Overall, 36 out of 48 patients (75%) harbored at least one mutation and mean number of mutation per patient was 1.6 (range 0-6). Aberrant karyotypes were observed in 30.4% by G-banding and 66.7% by FISH. Most recurrent mutation (>10% frequency) was ATM (20.8%) followed by TP53 (14.6%), SF3B1 (10.4%), KLHL6 (8.3%), and BCOR (6.25%). Mutations of MYD88 was associated with moderate adverse prognosis by multiple comparisons (P = 0.055). Mutation frequencies of MYD88, SAMHD1, EGR2, DDX3X, ZMYM3, and MED12 showed similar incidence with Caucasians, while mutation frequencies of ATM, TP53, KLHL6, BCOR and CDKN2A tend to be higher in Koreans than in Caucasians. Especially, ATM mutation showed 1.5 fold higher incidence than Caucasians, while mutation frequencies of SF3B1, NOTCH1, CHD2 and POT1 tend to be lower in Koreans than in Caucasians. However, mutation frequencies between Caucasians and Koreans were not significantly different statistically, probably due to low number of patients. Collectively, mutational profile and adverse prognostic genes in Korean CLL were different from those of Caucasians, suggesting an ethnic difference, while profile of cytogenetic aberrations was similar to those of Caucasians.
Topics: Adult; Aged; Aged, 80 and over; Asian People; Case-Control Studies; Chromosome Aberrations; Female; Genetic Loci; Genome, Human; Humans; Leukemia, Lymphoid; Male; Middle Aged; Mutation; Mutation Rate; Republic of Korea; White People
PubMed: 27959900
DOI: 10.1371/journal.pone.0167641 -
Anais Brasileiros de Dermatologia Apr 2016Bullous leukemia cutis is an uncommon clinical manifestation of cutaneous infiltration by leukemic cells, from B-cell chronic lymphocytic leukemia. We present the case...
Bullous leukemia cutis is an uncommon clinical manifestation of cutaneous infiltration by leukemic cells, from B-cell chronic lymphocytic leukemia. We present the case of a 67-year-old, female, chronic lymphocytic leukemia patient. She was taking chlorambucil and developed facial edema with erythema and warmth, misjudged as facial cellulitis. Two days later, she developed bullous lesions in the arms, legs, neck and face. The histopathology of facial and bullous lesions confirmed leukemia cutis. All lesions disappeared following the administration of rituximab combined with cycles of fludarabine and cyclophosphamide. Although soft tissue infections are common complications in patients undergoing chemotherapy, leukemia cutis can also resemble cellulitis.
Topics: Aged; Antineoplastic Agents, Alkylating; Cellulitis; Cyclophosphamide; Diagnosis, Differential; Facial Dermatoses; Female; Humans; Immunohistochemistry; Leukemia, Lymphoid; Leukemic Infiltration; Skin Diseases, Vesiculobullous
PubMed: 27192532
DOI: 10.1590/abd1806-4841.20164557 -
British Journal of Haematology Jul 2013Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL) is one of the more common forms of B cell malignancy. Although the condition has a variable clinical... (Review)
Review
Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL) is one of the more common forms of B cell malignancy. Although the condition has a variable clinical course, the trend is towards eventual relapse and the disease is considered incurable. Whilst the majority of the circulating CD5-positive neoplastic B cells are arrested in the G0 phase of the cell cycle, those in the bone marrow and lymphoid tissues proliferate at a rate of 0·1-1% of the entire clone per day. This proliferation is supported by the tissue microenvironment, which has been shown to induce upregulation of anti-apoptotic proteins and enhance the survival of the neoplastic cells. Microenvironmental factors are also thought to be important in tumour relapse and resistance to therapy. This review outlines the main signalling pathways involved in these tumour cell-stromal interactions, and includes potential therapeutic strategies based on the manipulation of key components within the CLL microenvironment.
Topics: Antineoplastic Agents; Apoptosis; Cell Movement; Gene Expression Regulation, Leukemic; Humans; Immunologic Factors; Leukemia, Lymphocytic, Chronic, B-Cell; Receptors, Antigen, B-Cell; Signal Transduction; Tumor Microenvironment
PubMed: 23617880
DOI: 10.1111/bjh.12344 -
Blood Jul 1983We compared the effect of adenosine and adenosine analogues on the phytohemagglutinin-induced proliferative response of blood lymphocytes from normal subjects and...
We compared the effect of adenosine and adenosine analogues on the phytohemagglutinin-induced proliferative response of blood lymphocytes from normal subjects and patients with chronic lymphocytic leukemia. As measured by the inhibition of thymidine or leucine incorporation, adenosine was more toxic to chronic lymphocytic leukemia (CLL) than to normal lymphocytes. This difference was not affected by the removal of adherent cells. The patients' B lymphocytes were more susceptible to adenosine toxicity than normal B lymphocytes. Similar responses were noted in T lymphocytes from both sources. Differential susceptibility was also observed with deoxyadenosine and adenosine analogues, including 5'deoxyadenosine. Uridine rescue from adenosine toxicity was observed for normal and CLL lymphocytes. In the presence of uridine, there was no difference in the residual inhibition of CLL as compared to normal lymphocytes. Intact CLL lymphocytes metabolized 14C-adenosine at a much lower rate than normal lymphocytes. While it appears that the greater toxicity of adenosine to CLL lymphocytes reflects the impaired catabolism of this nucleoside by these cells, evidence is presented that this is not the only mechanism underlying the differential susceptibility. These results may serve as the basis for further pharmacologic investigations of adenosine and adenosine deaminase inhibitors in chronic lymphocytic leukemia.
Topics: Adenosine; B-Lymphocytes; Deoxyadenosines; Humans; Leucine; Leukemia, Lymphoid; Phytohemagglutinins; Thymidine; Vidarabine
PubMed: 6602634
DOI: No ID Found -
Gene Expression 2015The first transgenic mouse of the TCL1 oncogene was described more than 15 years ago, and since then, the overexpression of the gene in T- and B-cells in vivo has been... (Review)
Review
The first transgenic mouse of the TCL1 oncogene was described more than 15 years ago, and since then, the overexpression of the gene in T- and B-cells in vivo has been extensively studied to reveal the molecular details in the pathogenesis of some lymphocytic leukemias. This review discusses the main features of the original TCL1 models and the different lines of research successively developed with particular attention to genetically compound mice and the therapeutic applications in drug development.
Topics: Animals; B-Lymphocytes; Disease Models, Animal; Drug Discovery; Humans; Leukemia, Lymphoid; Mice; Mice, Transgenic; Proto-Oncogene Proteins; T-Lymphocytes
PubMed: 25700368
DOI: 10.3727/105221615X14181438356256