Complex Paterns of Monoclonal Ig Diversification in B-CLL Cells from Different Tissue Compartments.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5021-5021
Author(s):  
Evangelia M. Dimitriadou ◽  
Panayiotis Panayiotidis ◽  
Vasiliki Karali ◽  
Konstantinos Lilakos ◽  
Maria K. Angelopoulou ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Significant Proportion ◽  
Point Mutations ◽  
Base Point ◽  
Distinct Pattern ◽  
Clone Evolution ◽  
Pcr Products ◽  
Tissue Compartments ◽  
Detailed Picture

Abstract It has recently been demonstrated that a considerable subset of CLL patients (>50%) displays intraclonal diversification in their monoclonal Ig sequence, suggesting that the mechanism of ongoing somatic mutations is retained in a significant proportion of B CLL cells. The complexity of studying this phenomenon relies on the enclaved risk of misinterpreting superimposed mutations originating from experimental artifacts. We are still lacking a more detailed picture of inraclonal diversification regarding its frequency and developmental pattern in disease compartments other than blood. In order to clarify some of these questions, we analyzed a total of 675 Ig clones from 11 CLL patients. DNA was extracted from blood in 6 patients (1st group: pt.1 to 6) or from blood/marrow (BM)/lymph nodes (LN) obtained at the same in 5 patients (2nd group: pt.7-11). PCR was performed for 40 cycles with Taq Platinum polymerase and leader or FR1 VH1-6 primers and a consensus JH primer. Monoclonal PCR products were ligated to TA vector and 20 to 70 clones were sequenced. from both orientations. Polymerase mediated base error was 4.4x10−4 after 40 PCR cycles. Base differences observed in two or more clones out of 20, were verified twice and assigned as true intraclonal diversification. This was observed in 6 (pt 2, 6, 7, 9, 10, 11) out of 11 pts (54.5%). Pts 2, 6, 10, 11 were mutated and pt. 7, 9 unmutated in their Ig sequence. Intraclonal diversification was observed in pt. 2 and 6, whereas pt.7, 9, 10, 11 in the 2nd group, displayed intraclonal diversification in some or in all compartments. Base point mutations that were unique in one clone only were observed at the polymerase mediated error rate and were not verified by a second idependent experiment. In the 2nd group pt. 8 displayed lack of diversification both in blood and marrow. Pt.7 displayed diversification only in BM clones (2/64, 3.1%) but not in 71 blood derived or in 53 LN derived clones. Pt. 9 had diversified clones in blood only (2/26, 7.6%) and no diversified clones in 25 BM clones. Pt.10 had diversified clones both in blood and marrow with a distinct pattern: in blood (62 clones) 4 different patterns of diversification were observed in 54 clones (84%); 17/54 were evolving clones. In BM two of the 4 patterns of diversification present in blood were observed in 28/57 clones (51.7%); ten were evolving clones. In pt.11, no diversified clones were present in blood (50 clones) whereas marrow had 4/60 diversified clones (6,66%, two patterns of diversification) and LN had 20/40 diversified clones (50%, two patterns of diversification); 8/20 diversified were evolving clones. The patterns of diversification were different bettween LN and BM in this patient. Base changes in 110 diversified clones were in FRs rather than CDRs (16:1) and resulted in S(silent) rather than R(replacements), S/R 2:1. In conclusion, intraclonal diversification must be considered true if identical base substitutions are observed in minimum two clones. Pattern and frequency are not identical in B CLL cells from different sites (blood vs BM vs LN). Preferance of FRs v CDRs and SvR substitutions implies that diversification procces is not antigen driven. The presence of a functional mechanism of ongoing somatic mutations in leukemic clones and the ability of diversification to target with altered frequency/patterns various disease compartments implies a role of tissue millieu in CLL clone evolution.

scholarly journals Somatic Mutations During an Immune Response inXenopusTadpoles

1995 ◽  
Vol 4 (3) ◽  
pp. 227-234 ◽  
Author(s):  
Melanie Wilson ◽  
Anne Marcuz ◽  
Louis Du Pasquier
Keyword(s):  
Immune Response ◽  
Somatic Mutations ◽  
Somatic Hypermutation ◽  
Point Mutations ◽  
Base Point ◽  
High Ratio ◽  
Cell Repertoire ◽  
Cdna Sequences ◽  
B Cell Repertoire ◽  
Reduced Rate

The tadpole B-cell repertoire is less diverse than that of the adult frog; their antibodies are of lower affinity and are less heterogenous. In order to determine whether this difference is due to a lack of or a reduced rate of somatic hypermutation, we analyzed and compared cDNA sequences utilizing VH1 elements with germline counterparts in isogenic LG7 tadpoles during an immune response. Indeed, tadpole VH1 sequences contained somatic mutations. There were zeo to 5 mutations per sequence, all single base-point mutations, with the high ratio of GC to AT base-pair alterations similar to that observed in adult frogs.

Update regarding anemia in heart failure

Medic ro ◽  
2020 ◽  
Vol 6 (1) ◽  
pp. 8-13
Author(s):  
Roxana Marcela Sânpălean ◽  
Dorina Nastasia Petra
Keyword(s):  
Heart Failure ◽  
Iron Deficiency ◽  
Multidisciplinary Team ◽  
Significant Proportion ◽  
Life Quality ◽  
Lower Number ◽  
Nutritional Deficiencies ◽  
Cardiac Morbidity ◽  
Appropriate Treatment

Heart failure (HF) is a burden for the healthcare system. The incidence will increase significantly due to the aging of po­pu­la­tion, which is associated with multiple comorbidities. Ane­mia and iron deficiency are common in patients with HF, their etiology being often multifactorial. The screening for anemia and iron deficiency is recommended as soon as pos­si­ble. There are often no targeted investigations, therefore a significant proportion of cases are underdiagnosed. The ma­nagement of patients may focus on identifying and correcting the cause. Anemia can occur due to nutritional deficiencies, infla­m­mation, renal failure, bone marrow dysfunction, neuro­hor­mo­nal activity, treatment and hemodilution. The appropriate the­ra­py for the patients with anemia and HF will contribute to the improvement of life quality. The only recommended iron product is ferric carboxymalose administered by in­tra­venous infusion. Under the appropriate treatment, the pa­tients showed an increase in effort tolerance, with an im­prove­ment in symptomatology and a lower number of hos­pi­ta­li­za­tion days. The management of these cases is handled by a multidisciplinary team consisting of a general prac­ti­tio­ner, a cardiologist and other specialists if the patient has other comorbidities. The role of the general practitioner is essential, as he can perform proper screening, prevention and management, developed by a multidisciplinary team, in order to reduce the cardiac morbidity and mortality.  

THE ROLE OF PHOSPHATIDYLINOSITOL-3-KINASE IN CARCINOGENESIS

2017 ◽  
Vol 63 (4) ◽  
pp. 545-556
Author(s):  
Natalya Oskina ◽  
Aleksandr Shcherbakov ◽  
Maksim Filipenko ◽  
Nikolay Kushlinskiy ◽  
L. Ovchinnikova
Keyword(s):  
Genetic Disease ◽  
Intracellular Signaling ◽  
Somatic Mutations ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Phosphatidylinositol 3 Kinase ◽  
Intracellular Signaling Pathway ◽  
Metabolic Activities ◽  
Carcinogenic Process

Currently it is established that cancer is a genetic disease and that somatic mutations are the initiators of the carcinogenic process. The PI3K/AKT/mTOR pathway is an important intracellular signaling pathway regulating the cell growth and metabolic activities. Aberrant activation of the PI3K pathway is commonly observed in many different cancers. In this review we analyze the genetic alterations of PI3K pathway in a variety of human malignancies and discuss their possible implications for diagnosis and therapy.

Role of key point Mutations in Receptor Binding Domain of SARS-CoV-2 Spike Glycoprotein

2020 ◽  
Vol 20 ◽  
Author(s):  
Bipin Singh
Keyword(s):  
Receptor Binding ◽  
Point Mutations ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Spike Glycoprotein ◽  
Angiotensin Converting Enzyme 2 ◽  
Recent Outbreak ◽  
Novel Coronavirus ◽  
Genomic Similarity

: The recent outbreak of novel coronavirus (SARS-CoV-2 or 2019-nCoV) and its worldwide spread is posing one of the major threats to human health and the world economy. It has been suggested that SARS-CoV-2 is similar to SARSCoV based on the comparison of the genome sequence. Despite the genomic similarity between SARS-CoV-2 and SARSCoV, the spike glycoprotein and receptor binding domain in SARS-CoV-2 shows the considerable difference compared to SARS-CoV, due to the presence of several point mutations. The analysis of receptor binding domain (RBD) from recently published 3D structures of spike glycoprotein of SARS-CoV-2 (Yan, R., et al. (2020); Wrapp, D., et al. (2020); Walls, A. C., et al. (2020)) highlights the contribution of a few key point mutations in RBD of spike glycoprotein and molecular basis of its efficient binding with human angiotensin-converting enzyme 2 (ACE2).

scholarly journals Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shumaila Sayyab ◽  
Anders Lundmark ◽  
Malin Larsson ◽  
Markus Ringnér ◽  
Sara Nystedt ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Large Scale ◽  
Somatic Mutations ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Point Mutations ◽  
Driver Genes ◽  
Protein Coding ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Evolutionary Trajectories

AbstractThe mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.

scholarly journals Efficacy of Phytocannabinoids in Epilepsy Treatment: Novel Approaches and Recent Advances

2021 ◽  
Vol 18 (8) ◽  
pp. 3993
Author(s):  
Aaron M. Farrelly ◽  
Styliani Vlachou ◽  
Konstantinos Grintzalis
Keyword(s):  
Therapeutic Potential ◽  
Significant Proportion ◽  
Future Research ◽  
Specific Reference ◽  
Undesirable Side Effect ◽  
Treatment Resistant ◽  
Current Review ◽  
Epilepsy Treatment ◽  
Clinical Environments

Epilepsy is a neurological disorder mainly characterised by recurrent seizures that affect the entire population diagnosed with the condition. Currently, there is no cure for the disease and a significant proportion of patients have been deemed to have treatment-resistant epilepsy (TRE). A patient is deemed to have TRE if two or more antiepileptic drugs (AEDs) fail to bring about seizure remission. This inefficacy of traditional AEDs, coupled with their undesirable side effect profile, has led to researchers considering alternative forms of treatment. Phytocannabinoids have long served as therapeutics with delta-9-THC (Δ9-THC) receiving extensive focus to determine its therapeutic potential. This focus on Δ9-THC has been to the detriment of analysing the plethora of other phytocannabinoids found in the cannabis plant. The overall aim of this review is to explore other novel phytocannabinoids and their place in epilepsy treatment. The current review intends to achieve this aim via an exploration of the molecular targets underlying the anticonvulsant capabilities of cannabidiol (CBD), cannabidavarin (CBDV), delta-9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG). Further, this review will provide an exploration of current pre-clinical and clinical data as it relates to the aforementioned phytocannabinoids and the treatment of epilepsy symptoms. With specific reference to epilepsy in young adult and adolescent populations, the exploration of CBD, CBDV, Δ9-THCV and CBG in both preclinical and clinical environments can guide future research and aid in the further understanding of the role of phytocannabinoids in epilepsy treatment. Currently, much more research is warranted in this area to be conclusive.

scholarly journals Prostate cancer and the human papilloma virus: causative association, role of vaccines, and the impact of the COVID-19 pandemic

2021 ◽  
Author(s):  
Naomi Morka ◽  
Joseph M. Norris ◽  
Mark Emberton ◽  
Daniel Kelly
Keyword(s):  
Prostate Cancer ◽  
Human Papilloma Virus ◽  
Hpv Vaccination ◽  
Significant Proportion ◽  
Vaccine Uptake ◽  
Papilloma Virus ◽  
Vaccination Campaigns ◽  
The Impact ◽  
Hpv Vaccine Uptake

AbstractProstate cancer affects a significant proportion of men worldwide. Evidence from genetic and clinical studies suggests that there may be a causal association between prostate cancer and the human papilloma virus (HPV). As HPV is a vaccine-preventable pathogen, the possibility of a role in prostate cancer causation may reinforce the importance of effective HPV vaccination campaigns. This is of particular relevance in light of the COVID-19 pandemic, which may have considerable effects on HPV vaccine uptake and distribution.

scholarly journals Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
M. Janusz Mezynski ◽  
Angela M. Farrelly ◽  
Mattia Cremona ◽  
Aoife Carr ◽  
Clare Morgan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Lines ◽  
Somatic Mutations ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Erbb Family ◽  
Gastric Tumour ◽  
Pi3k Signalling ◽  
Trial Setting

Abstract Background Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Methods Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Results Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM–1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05). Conclusions PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

Role of somatic mutations and chromosomal aberrations in the prognosis of uveal melanoma in a Spanish patient cohort

2021 ◽  
Author(s):  
Paula Silva‐Rodríguez ◽  
Manuel Bande ◽  
Daniel Fernández‐Díaz ◽  
Nerea Lago‐Baameiro ◽  
María Pardo ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Chromosomal Aberrations ◽  
Somatic Mutations ◽  
Spanish Patient ◽  
Patient Cohort

Block of Human Heart hH1 Sodium Channels by the Enantiomers of Bupivacaine

2000 ◽  
Vol 93 (4) ◽  
pp. 1022-1033 ◽  
Author(s):  
Carla Nau ◽  
Sho-Ya Wang ◽  
Gary R. Strichartz ◽  
Ging Kuo Wang
Keyword(s):  
Human Heart ◽  
Point Mutations ◽  
Cell Voltage ◽  
Site Directed Mutagenesis ◽  
Na Channel ◽  
Amino Acid Residues ◽  
Na Channels ◽  
State Dependent ◽  
Positively Charged

Background S(-)-bupivacaine reportedly exhibits lower cardiotoxicity but similar local anesthetic potency compared with R(+)-bupivacaine. The bupivacaine binding site in human heart (hH1) Na+ channels has not been studied to date. The authors investigated the interaction of bupivacaine enantiomers with hH1 Na+ channels, assessed the contribution of putatively relevant residues to binding, and compared the intrinsic affinities to another isoform, the rat skeletal muscle (mu1) Na+ channel. Methods Human heart and mu1 Na+ channel alpha subunits were transiently expressed in HEK293t cells and investigated during whole cell voltage-clamp conditions. Using site-directed mutagenesis, the authors created point mutations at positions hH1-F1760, hH1-N1765, hH1-Y1767, and hH1-N406 by introducing the positively charged lysine (K) or the negatively charged aspartic acid (D) and studied their influence on state-dependent block by bupivacaine enantiomers. Results Inactivated hH1 Na+ channels displayed a weak stereoselectivity with a stereopotency ratio (+/-) of 1.5. In mutations hH1-F1760K and hH1-N1765K, bupivacaine affinity of inactivated channels was reduced by approximately 20- to 40-fold, in mutation hH1-N406K by approximately sevenfold, and in mutations hH1-Y1767K and hH1-Y1767D by approximately twofold to threefold. Changes in recovery of inactivated mutant channels from block paralleled those of inactivated channel affinity. Inactivated hH1 Na+ channels exhibited a slightly higher intrinsic affinity than mu1 Na+ channels. Conclusions Differences in bupivacaine stereoselectivity and intrinsic affinity between hH1 and mu1 Na+ channels are small and most likely of minor clinical relevance. Amino acid residues in positions hH1-F1760, hH1-N1765, and hH1-N406 may contribute to binding of bupivacaine enantiomers in hH1 Na+ channels, whereas the role of hH1-Y1767 remains unclear.

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