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Frontiers in Oncology 2020Large granular lymphocyte leukemia (LGLL) is a chronic proliferation of clonal cytotoxic lymphocytes, usually presenting with cytopenias and yet lacking a specific... (Review)
Review
Large granular lymphocyte leukemia (LGLL) is a chronic proliferation of clonal cytotoxic lymphocytes, usually presenting with cytopenias and yet lacking a specific therapy. The disease is heterogeneous, including different subsets of patients distinguished by LGL immunophenotype (CD8+ Tαβ, CD4+ Tαβ, Tγδ, NK) and the clinical course of the disease (indolent/symptomatic/aggressive). Even if the etiology of LGLL remains elusive, evidence is accumulating on the genetic landscape driving and/or sustaining chronic LGL proliferations. The most common gain-of-function mutations identified in LGLL patients are on and genes, which have been recently recognized as clonal markers and were included in the 2017 WHO classification of the disease. A significant correlation between mutations and symptomatic disease has been highlighted. At variance, mutations could have a different clinical impact based on the immunophenotype of the mutated clone. In fact, they are regarded as the signature of an aggressive clinical course with a poor prognosis in CD8+ T-LGLL and aggressive NK cell leukemia, while they are devoid of negative prognostic significance in CD4+ T-LGLL and Tγδ LGLL. Knowing the specific distribution of mutations helps identify the discrete mechanisms sustaining LGL proliferations in the corresponding disease subsets. Some patients equipped with wild type genes are characterized by less frequent mutations in different genes, suggesting that other pathogenetic mechanisms are likely to be involved. In this review, we discuss how the LGLL mutational pattern allows a more precise and detailed tumor stratification, suggesting new parameters for better management of the disease and hopefully paving the way for a targeted clinical approach.
PubMed: 32133291
DOI: 10.3389/fonc.2020.00152 -
Archives of Medical Science : AMS 2021Aging is a natural process involving dysfunction of multiple organs and is characterized by increased susceptibility to infections, cancer and autoimmune diseases. The...
INTRODUCTION
Aging is a natural process involving dysfunction of multiple organs and is characterized by increased susceptibility to infections, cancer and autoimmune diseases. The functionality of the immune system depends on the capacity of lymphocytes to proliferate in response to antigenic challenges, and telomere length has an important role regulating the number of cell divisions. The aim of this study was to determine the possible relationship between telomere length, interleukin 2 (IL-2) production, CD25 expression and proliferation of peripheral blood mononuclear cells (PBMCs) in aged men.
MATERIAL AND METHODS
Telomere length was measured by RT-PCR in PBMCs from young and aged men. IL-2 production and CD25 expression were determined by ELISA and flow cytometry, respectively. Cell proliferation was measured by CFSE dilution assays upon stimulation with concanavalin A (Con A).
RESULTS
PBMCs from aged men showed a shorter telomere length and a reduced capacity to proliferate , compared to young men. In contrast, no significant differences in the level of CD25 expression on T lymphocytes, and production of IL-2 were detected in both groups. In addition, no significant correlation was detected between levels of CD25 expression, IL-2 production, cell proliferation, and telomere length in aged men.
CONCLUSIONS
In aged men the telomere length shortening and the reduced T cell proliferation are not related to the capacity of IL-2 production and CD25 expression on T lymphocytes.
PubMed: 34025848
DOI: 10.5114/aoms.2019.87593 -
EvoDevo Jun 2022There are a wide range of developmental strategies in animal phyla, but most insights into adult body plan formation come from direct-developing species. For...
BACKGROUND
There are a wide range of developmental strategies in animal phyla, but most insights into adult body plan formation come from direct-developing species. For indirect-developing species, there are distinct larval and adult body plans that are linked together by metamorphosis. Some outstanding questions in the development of indirect-developing organisms include the extent to which larval tissue undergoes cell death during the process of metamorphosis and when and where the tissue that will give rise to the adult originates. How do the processes of cell division and cell death redesign the body plans of indirect developers? In this study, we present patterns of cell proliferation and cell death during larval body plan development, metamorphosis, and adult body plan formation, in the hemichordate Schizocardium californium (Cameron and Perez in Zootaxa 3569:79-88, 2012) to answer these questions.
RESULTS
We identified distinct patterns of cell proliferation between larval and adult body plan formation of S. californicum. We found that some adult tissues proliferate during the late larval phase prior to the start of overt metamorphosis. In addition, using an irradiation and transcriptomic approach, we describe a genetic signature of proliferative cells that is shared across the life history states, as well as markers that are unique to larval or juvenile states. Finally, we observed that cell death is minimal in larval stages but begins with the onset of metamorphosis.
CONCLUSIONS
Cell proliferation during the development of S. californicum has distinct patterns in the formation of larval and adult body plans. However, cell death is very limited in larvae and begins during the onset of metamorphosis and into early juvenile development in specific domains. The populations of cells that proliferated and gave rise to the larvae and juveniles have a genetic signature that suggested a heterogeneous pool of proliferative progenitors, rather than a set-aside population of pluripotent cells. Taken together, we propose that the gradual morphological transformation of S. californicum is mirrored at the cellular level and may be more representative of the development strategies that characterize metamorphosis in many metazoan animals.
PubMed: 35668535
DOI: 10.1186/s13227-022-00198-1 -
Stem Cell Research & Therapy Jan 2021Adult mammalian retinal stem cells (RSCs) readily proliferate, self-renew, and generate progeny that differentiate into all retinal cell types in vitro. RSC-derived...
BACKGROUND
Adult mammalian retinal stem cells (RSCs) readily proliferate, self-renew, and generate progeny that differentiate into all retinal cell types in vitro. RSC-derived progeny can be induced to differentiate into photoreceptors, making them a potential source for retinal cell transplant therapies. Despite their proliferative propensity in vitro, RSCs in the adult mammalian eye do not proliferate and do not have a regenerative response to injury. Thus, identifying and modulating the mechanisms that regulate RSC proliferation may enhance the capacity to produce RSC-derived progeny in vitro and enable RSC activation in vivo.
METHODS
Here, we used medium-throughput screening to identify small molecules that can expand the number of RSCs and their progeny in culture. In vitro differentiation assays were used to assess the effects of synthetic glucocorticoid agonist dexamethasone on RSC-derived progenitor cell fate. Intravitreal injections of dexamethasone into adult mouse eyes were used to investigate the effects on endogenous RSCs.
RESULTS
We discovered that high-affinity synthetic glucocorticoid agonists increase RSC self-renewal and increase retinal progenitor proliferation up to 6-fold without influencing their differentiation in vitro. Intravitreal injection of synthetic glucocorticoid agonist dexamethasone induced in vivo proliferation in the ciliary epithelium-the niche in which adult RSCs reside.
CONCLUSIONS
Together, our results identify glucocorticoids as novel regulators of retinal stem and progenitor cell proliferation in culture and provide evidence that GCs may activate endogenous RSCs.
Topics: Animals; Cell Differentiation; Cell Proliferation; Cell Self Renewal; Cells, Cultured; Glucocorticoids; Mice; Retina
PubMed: 33494791
DOI: 10.1186/s13287-021-02136-9 -
RSPO2 as Wnt signaling enabler: Important roles in cancer development and therapeutic opportunities.Genes & Diseases Mar 2024R-spondins are secretory proteins localized in the endoplasmic reticulum and Golgi bodies and are processed through the secretory pathway. Among the R-spondin family,... (Review)
Review
R-spondins are secretory proteins localized in the endoplasmic reticulum and Golgi bodies and are processed through the secretory pathway. Among the R-spondin family, RSPO2 has emanated as a novel regulator of Wnt signaling, which has now been acknowledged in numerous and studies. Cancer is an abnormal growth of cells that proliferates and spreads uncontrollably due to the accumulation of genetic and epigenetic factors that constitutively activate Wnt signaling in various types of cancer. Colorectal cancer (CRC) begins when cells in the colon and rectum follow an indefinite pattern of division due to aberrant Wnt activation as one of the key hallmarks. Decades-long progress in research on R-spondins has demonstrated their oncogenic function in distinct cancer types, particularly CRC. As a critical regulator of the Wnt pathway, it modulates several phenotypes of cells, such as cell proliferation, invasion, migration, and cancer stem cell properties. Recently, RSPO mutations, gene rearrangements, fusions, copy number alterations, and altered gene expression have also been identified in a variety of cancers, including CRC. In this review, we addressed the recent updates regarding the recurrently altered R-spondins with special emphasis on the RSPO2 gene and its involvement in potentiating Wnt signaling in CRC. In addition to the compelling physiological and biological roles in cellular fate and regulation, we propose that RSPO2 would be valuable as a potential biomarker for prognostic, diagnostic, and therapeutic use in CRC.
PubMed: 37692504
DOI: 10.1016/j.gendis.2023.01.013 -
Clinical & Translational Oncology :... May 2023Pancreatic cancer is a devastating and lethal malignancy. Our study investigated the effective mechanism of HNF4G on pancreatic cancer cell functions through the IGF2BP2...
OBJECTIVE
Pancreatic cancer is a devastating and lethal malignancy. Our study investigated the effective mechanism of HNF4G on pancreatic cancer cell functions through the IGF2BP2 transcription.
METHODS
HNF4G and IGF2BP2 expressions in pancreatic cancer were examined. The relationship between HNF4G expression and pancreatic cancer patients' clinicopathological characteristics was evaluated. After interfering with HNF4G expression in pancreatic cancer cells, the cell proliferative, migratory, and invasive capabilities were evaluated. Also, the expression of proliferation-related gene PCNA and migration and invasion-related gene MMP2 was determined. The binding relation between HNF4G and HNF4G promoter was forecasted and testified. A tumorigenesis assay in nude mice was performed to detect the HNF4G interference's effect on the subcutaneous tumorigenic capacity of pancreatic cancer cells.
RESULTS
HNF4G and IGF2BP2 expressions were up-regulated in pancreatic cancer. Specifically, interfering with HNF4G inhibited PANC-1 cell proliferative, invasive and migratory behaviors, and decreased PCNA and MMP2 expression. Mechanistically, HNF4G as a transcription factor could specifically bind to IGF2BP2 and promote its expression. Rescue assay findings showed that IGF2BP2 overexpression could reverse the inhibiting effect of HNF4G interference on pancreatic cancer cells. For the in vivo finding, interfering HNF4G expression retarded the subcutaneous tumorigenic ability of pancreatic cancer cells.
CONCLUSION
We summarize that HNF4G as a transcription factor regulates IGF2BP2 expression to promote pancreatic cancer cell proliferation and migration capacities.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Matrix Metalloproteinase 2; Mice, Nude; Pancreatic Neoplasms; Proliferating Cell Nuclear Antigen; Transcription Factors
PubMed: 36607591
DOI: 10.1007/s12094-022-03048-7 -
Journal of B.U.ON. : Official Journal... 2021To investigate the expressions of CD44 non-small cell lung cancer cells, proliferating cell nuclear antigen (PCNA) and multidrug resistance-associated protein 1 (MRP1)...
PURPOSE
To investigate the expressions of CD44 non-small cell lung cancer cells, proliferating cell nuclear antigen (PCNA) and multidrug resistance-associated protein 1 (MRP1) in the lung cancer tissues and their effects on the proliferation and invasion abilities in vitro of lung cancer cell line 95D.
METHODS
138 lung cancer tissues and 127 adjacent normal tissues were collected from lung cancer patients after operation in Shandong Provincial Third Hospital from January 2015 to December 2017. CD44 siRNA (experimental CD44 group), PCNA siRNA (experimental PCNA group) and MRP1 siRNA (experimental MRP1 group) were transfected into human lung cancer 95D cells, and a negative control group (cells transfected with miR-Native Control) and a blank group (untransfected cells) were established. MTT assay was used for detecting the proliferation of cells, and Transwell chamber was used for detecting their invasion ability.
RESULTS
The relative expressions of CD44, PCNA and MRP1 in the lung cancer tissues were higher than those in the adjacent tissues (p<0.050). At 24th h, the cell survival rate in the experimental MRP1 group was lower than that in the experimental PCNA group (p<0.050); At 48th the cell survival rate in the experimental MRP1 group was higher than that in the experimental CD44 group (p<0.050). At 72th h, the cell survival rate in the experimental PCNA group was significantly higher than that in the experimental CD44 group and the experimental MRP1 group (p<0.05). The cell invasion number in the experimental CD44 group, the experimental PCNA group and the experimental MRP1 group were significantly lower than cells in the negative control group and blank group (p<0.05).
CONCLUSION
CD44, PCNA and MRP1, which may be involved in the regulation of the proliferation and invasion abilities of lung cancer cells, may serve as new molecular targeting markers for the diagnosis and treatment of lung cancer.
Topics: Cell Line, Tumor; Cell Proliferation; Female; Humans; Hyaluronan Receptors; Lung Neoplasms; Multidrug Resistance-Associated Proteins; Proliferating Cell Nuclear Antigen
PubMed: 33721434
DOI: No ID Found -
Scientific Reports Jan 2021Generating the proliferation of differentiated normal adult human hepatocytes is a major challenge and an expected central step in understanding the microenvironmental...
Generating the proliferation of differentiated normal adult human hepatocytes is a major challenge and an expected central step in understanding the microenvironmental conditions that regulate the phenotype of human hepatocytes in vitro. In this work, we described optimized 3D culture conditions of primary human hepatocytes (PHH) to trigger two waves of proliferation and we identified matrix stiffness and cell-cell interactions as the main actors necessary for this proliferation. We demonstrated that DNA replication and overexpression of cell cycle markers are modulate by the matrix stiffness while PHH cultured in 3D without prior cellular interactions did not proliferate. Besides, we showed that PHH carry out an additional cell cycle after transient inhibition of MAPK MER1/2-ERK1/2 signaling pathway. Collagen cultured hepatocytes are organized as characteristic hollow spheroids able to maintain survival, cell polarity and hepatic differentiation for long-term culture periods of at least 28 days. Remarkably, we demonstrated by transcriptomic analysis and functional experiments that proliferating cells are mature hepatocytes with high detoxication capacities. In conclusion, the advanced 3D model described here, named Hepoid, is particularly relevant for obtaining normal human proliferating hepatocytes. By allowing concomitant proliferation and differentiation, it constitutes a promising tool for many pharmacological and biotechnological applications.
Topics: Cell Communication; Cell Culture Techniques; Cell Cycle; Cell Differentiation; Cell Polarity; Cell Proliferation; Cell Survival; Cells, Cultured; Collagen; DNA Replication; Elasticity; Hepatocytes; Humans; MAP Kinase Signaling System; Spheroids, Cellular
PubMed: 33436872
DOI: 10.1038/s41598-020-80019-4 -
The International Journal of... 2021Using autogenous grafts in mucogingival surgeries is related to postoperative morbidity and limited tissue availability, and thus xenogeneic matrices are increasingly...
Increasing the Thickness of the Collagen Xenogeneic Matrix Prevents Early Matrix Degradation and Improves the Proliferation, Adhesion, and Viability of Human Gingival Fibroblasts and Mesenchymal Stem Cells.
Using autogenous grafts in mucogingival surgeries is related to postoperative morbidity and limited tissue availability, and thus xenogeneic matrices are increasingly used. This in vitro study evaluated the influence of xenogeneic collagen matrix thickness on cell adhesion, morphology, viability, proliferation, and matrix degradation. Matrices were divided into three groups: SLC: single layer of Lumina Coat, as commercially available (2-mm thickness); DLC: double layer of SLC (Lumina Coat); and MG: single layer of Mucograft, as commercially available (4-mm thickness). SEM was used to evaluate the matrix surface topographies. To evaluate the cell viability, proliferation, adhesion, and morphology, human gingival fibroblasts (HGF) and stem cells from human exfoliated deciduous teeth (SHED) were used. Cell viability was evaluated through MTS colorimetric method evaluating HGF and SHED on days 1, 3, and 7. Cell proliferation was assessed by PicoGreen assay, evaluating HGF and SHED on days 3 and 7. Sample degradation was evaluated on days 1, 3, 7, 14, 21, 28, and 35. All groups were biocompatible for HGF and SHED, showing viabilities > 70% on days 1, 3, and 7. DCL promoted HGF viabilities similar to MG (P = .2828) and the highest SHED viability (P < .0001) on day 1. DLC also demonstrated HGF and SHED proliferations higher than the positive control (MG; P < .05) on day 7. SLC was completely degraded on day 14, while DLC and MG presented 48.41% and 20.52% of their initial mass, respectively, on day 35. Increasing the matrix thickness improved HGF and SHED viability and proliferation and prevented early matrix degradation. DLC demonstrated better results than SLC and MG concerning matrix degradation and HGF and SHED viability and proliferation.
Topics: Cell Proliferation; Cells, Cultured; Collagen; Fibroblasts; Humans; Mesenchymal Stem Cells
PubMed: 34328477
DOI: 10.11607/prd.5366 -
Journal of Gastroenterology and... Apr 2021Two intertwined compartments coexisting in nonpolypoid conventional (i.e. tubular or villous) adenomas are highlighted in this review: one built of dysplastic tissue on... (Review)
Review
Two intertwined compartments coexisting in nonpolypoid conventional (i.e. tubular or villous) adenomas are highlighted in this review: one built of dysplastic tissue on top and the other portraying crypts with irregular, corrupted shapes, albeit lined with normal epithelium, below. The latter compartment has remained unattended in the literature. Recently, however, the histologic characteristics of the nondysplastic compartment in nonpolypoid conventional adenomas were closely examined, and some of its biological attributes were unveiled. Studies with the proliferation marker ki67 showed that the crypts with irregular, corrupted shapes in the nondysplastic compartment displayed haphazardly distributed proliferating cell-domains. Given that the proliferating cells are generated by stem cells, the relocation of proliferating cell-domains in those crypts seems to be the result of a reorganization of the stem cells within the crypts. The abnormal distribution of proliferating cells, the finding of p53-upregulated cells, and of crypts in asymmetric fission suggest that the crypts in that compartment are histo-biologically altered, probably somatically mutated. This new information might contribute to unravel the riddle of crypto-histogenesis of nonpolypoid conventional adenomas of the colon. More research along these lines is necessary, before the biology of the crypts in the nondysplastic compartment can be fully translated into molecular terms.
Topics: Adenoma; Cell Proliferation; Colonic Neoplasms; Humans; Intestinal Mucosa; Ki-67 Antigen; Neoplastic Stem Cells; Tumor Suppressor Protein p53; Up-Regulation
PubMed: 32757480
DOI: 10.1111/jgh.15210