PURPOSE: Germline missense variants of unknown significance in cancer-related genes are increasingly being identified with the expanding use of next-generation sequencing. The ataxia telangiectasia-mutated (ATM) gene on chromosome 11 has more than 1,000 germline missense variants of unknown significance and is a tumor suppressor. We aimed to determine if rare germline ATM variants are more frequent in chronic lymphocytic leukemia (CLL) compared with other hematologic malignancies and if they influence the clinical characteristics of CLL. METHODS: We identified 3,128 patients (including 825 patients with CLL) in our hematologic malignancy clinic who had received clinical-grade sequencing of the entire coding region of ATM. We ascertained the comparative frequencies of germline ATM variants in categories of hematologic neoplasms, and, in patients with CLL, we determined whether these variants affected CLL-associated characteristics such as somatic 11q deletion. RESULTS: Rare germline ATM variants are present in 24% of patients with CLL, significantly greater than that in patients with other lymphoid malignancies (16% prevalence), myeloid disease (15%), or no hematologic neoplasm (14%). Patients with CLL with germline ATM variants are younger at diagnosis and twice as likely to have 11q deletion. The ATM variant p.L2307F is present in 3% of patients with CLL, is associated with a three-fold increase in rates of somatic 11q deletion, and is a hypomorph in cell-based assays. CONCLUSION: Germline ATM variants cluster within CLL and affect the phenotype of CLL that develops, implying that some of these variants (such as ATM p.L2307F) have functional significance and should not be ignored. Further studies are needed to determine whether these variants affect the response to therapy or account for some of the inherited risk of CLL.
- MeSH
- ATM protein * genetika MeSH
- chronická lymfatická leukemie * farmakoterapie MeSH
- lidé MeSH
- mutace MeSH
- nádorové supresorové proteiny genetika MeSH
- protein-serin-threoninkinasy genetika terapeutické užití MeSH
- proteiny buněčného cyklu genetika MeSH
- teleangiektatická ataxie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- ATM protein, human MeSH Prohlížeč
- ATM protein * MeSH
- nádorové supresorové proteiny MeSH
- protein-serin-threoninkinasy MeSH
- proteiny buněčného cyklu MeSH
The recombinant Outer surface protein A (rOspA) from Borrelia burgdorferi is a possible immunogen for protection of infected humans and animals against development of Lyme borreliosis (Lyme disease), a chronic tick-borne disease characterised by diverse dermatologic, neurologic, rheumatic, and cardiac manifestations. For several years, research and development have been directed towards a vaccine for the prevention of this debilitating disease. Numerous animal studies demonstrate that pre-existing antibodies against the outer surface proteins of B. burgdorferi can prevent infection and disease caused by this organism. In this communication, using recombinant DNA technology, genes from B. burgdorferi sensu stricto and B. afzelii were inserted into E. coli-expression vectors and the rOspA were produced. Our aim was to obtain rOspA protein in a purity and quantity desirable for immunization of experimental animals. rOspA is currently the most developed, molecularly-defined vaccine candidate for the prevention of Lyme borreliosis.
- MeSH
- antigeny povrchové biosyntéza izolace a purifikace MeSH
- bakteriální vakcíny biosyntéza izolace a purifikace MeSH
- Borrelia burgdorferi komplex imunologie MeSH
- Borrelia burgdorferi imunologie MeSH
- DNA vakcíny biosyntéza izolace a purifikace MeSH
- Escherichia coli MeSH
- genetické vektory MeSH
- lipoproteiny biosyntéza izolace a purifikace MeSH
- proteiny vnější bakteriální membrány biosyntéza izolace a purifikace MeSH
- vakcína proti lymeské nemoci biosyntéza MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antigeny povrchové MeSH
- bakteriální vakcíny MeSH
- DNA vakcíny MeSH
- lipoproteiny MeSH
- OspA protein MeSH Prohlížeč
- proteiny vnější bakteriální membrány MeSH
- vakcína proti lymeské nemoci MeSH
The aim of this work was isolation and purification of the major immunodominant protein, Outer surface protein C (OspC) of three members of the species group Borrelia burgdorferi, the causative agent of Lyme disease. Our aim was to obtain this protein in a quantity and purity sufficient for immunization of experimental animals. For optimalization of protein purification's yield we used immobilized metal ion affinity chromatography (IMAC) under different conditions. The greatest efficiency was achieved by using of HiTrap Chelating Column under native conditions.
- MeSH
- antigeny bakteriální biosyntéza izolace a purifikace MeSH
- DNA vakcíny biosyntéza izolace a purifikace MeSH
- Escherichia coli MeSH
- genetické vektory MeSH
- proteiny vnější bakteriální membrány biosyntéza izolace a purifikace MeSH
- vakcína proti lymeské nemoci biosyntéza izolace a purifikace MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antigeny bakteriální MeSH
- DNA vakcíny MeSH
- OspC protein MeSH Prohlížeč
- proteiny vnější bakteriální membrány MeSH
- vakcína proti lymeské nemoci MeSH
Chemokine-driven migration of inflammatory cells has been implicated in pathogenesis of atherosclerosis-associated conditions such as ischemic stroke and myocardial infarction. In this study, a candidate chemokine, monocyte chemoattractant protein (MCP)-1, was investigated in patients with both aforementioned manifestations of atheroslerotic inflammation. MCP-1 levels in serum were determined by ELISA in 40 healthy, control subjects (C), 40 patients with ischemic stroke (IS), and in 64 patients with myocardial infarction (MI). Statistical analysis utilised Mann-Whitney test, Fisher's exact test, and Spearman's rank correlation (P < .05). In comparison to control subjects (C; median/interquartile range: 239/126 pg/mL), MCP-1 serum levels were increased in both investigated patient cohorts (IS: 384/370, P < .001; MI: 360/200, P < .002). There was a substantial variability of MCP-1 serum levels, especially in the IS group. No relationship was observed between chemokine levels and atherosclerosis risk factors (hypertension, diabetes, smoking, and alcohol consumption), and MCP-1 was also not related to age or gender. Elevation of MCP-1 in circulation of patients with atherosclerosis-associated complications implicates this CC chemokine ligand (CCL)2 in inflammatory processes, which contribute to pathogenesis of myocardial infarction and ischemic stroke. Further investigations, including patient stratification, are however necessary to evaluate if MCP-1 can be utilised for clinical management of patients with these diseases.
- MeSH
- ateroskleróza imunologie MeSH
- cévní mozková příhoda * krev imunologie MeSH
- chemokin CCL2 * krev MeSH
- infarkt myokardu * krev imunologie MeSH
- ischemie mozku * krev imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- rizikové faktory MeSH
- senioři MeSH
- statistika jako téma MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- chemokin CCL2 * MeSH
OBJECTIVE: In systemic sclerosis (SSc), constitutive expression of the proinflammatory and fibrogenic cytokine interleukin 1alpha (IL-1alpha) by dermal fibroblasts from the affected skin has been observed. We investigated the association of a single-nucleotide polymorphism at position -889 in the IL-1alpha gene in patients with SSc. METHODS: Genotyping of IL-1alpha-889 polymorphism was performed in 46 patients with SSc and in 150 healthy controls by polymerase chain reaction with sequence-specific primers. All subjects were unrelated Slovak Caucasians. RESULTS: In SSc patients, carriers of the IL-1alpha-889 T allele were significantly overrepresented in comparison with controls (63.0% vs 42.0%; p = 0.01, OR 2.3, 95% CI 1.2-4.6). The frequency of the IL-1alpha-889 T allele was increased in SSc patients (38.0%) in comparison with controls (25.7%; p = 0.02). CONCLUSION: The IL-1alpha-889 polymorphism, previously shown to predispose to increased IL-1 protein expression, may be involved in susceptibility to SSc.
- MeSH
- genetická predispozice k nemoci MeSH
- genotyp MeSH
- interleukin-1 genetika MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé MeSH
- studie případů a kontrol MeSH
- systémová sklerodermie genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- interleukin-1 MeSH
In this study, messenger RNA (mRNA) expression for novel T lymphocyte chemoattractants, leukotactin-1, macrophage inflammatory protein (MIP)-3 alpha and MIP-3 beta was investigated in bronchoalveolar lavage fluid (BALF) cells from patients with sarcoidosis, a T cell-mediated disease with typical CD4+ lymphocyte alveolitis. Of these three chemokines, only MIP-3 beta mRNA was upregulated in sarcoidosis, and therefore, protein levels of this chemokine, its pharmacologic regulation, and association with disease clinical course were explored. MIP-3 beta protein concentrations were elevated in BALF from sarcoid patients compared with control subjects (p = 0.001) and in patients with chest X-ray stage II chemokine protein levels were increased compared with stage I (p = 0.003). MIP-3 beta protein was associated predominantly with alveolar macrophages and correlated with BALF lymphocytes and T cell subsets. mRNA expression for the MIP-3 beta receptor, CC chemokine receptor 7, was increased in sarcoidosis and correlated with MIP-3 beta protein levels. MIP-3 beta mRNA and protein expression in BALF cells was suppressed by dexamethasone and cyclosporine A in vitro. In conclusion, MIP-3 beta is implicated in T lymphocyte recruitment in sarcoidosis, is associated with disease progression, and is downregulated by drugs used for sarcoidosis treatment. This novel chemokine, therefore, represents a candidate for studies of sarcoidosis pathobiologic mechanisms.
- MeSH
- aktivace lymfocytů účinky léků imunologie MeSH
- alveolární makrofágy účinky léků imunologie MeSH
- bronchoalveolární lavážní tekutina chemie MeSH
- chemokin CCL19 MeSH
- chemokin CCL20 MeSH
- chemokiny CC analýza genetika imunologie MeSH
- cyklosporin imunologie terapeutické užití MeSH
- dexamethason imunologie terapeutické užití MeSH
- dospělí MeSH
- down regulace účinky léků MeSH
- exprese genu * účinky léků genetika imunologie MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- makrofágové zánětlivé proteiny analýza genetika imunologie MeSH
- messenger RNA analýza MeSH
- plicní sarkoidóza krev farmakoterapie imunologie patologie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- progrese nemoci MeSH
- receptory CCR6 MeSH
- receptory chemokinů * MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- stupeň závažnosti nemoci MeSH
- T-lymfocyty účinky léků imunologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- CCL19 protein, human MeSH Prohlížeč
- CCL20 protein, human MeSH Prohlížeč
- CCR6 protein, human MeSH Prohlížeč
- chemokin CCL19 MeSH
- chemokin CCL20 MeSH
- chemokiny CC MeSH
- cyklosporin MeSH
- dexamethason MeSH
- makrofágové zánětlivé proteiny MeSH
- messenger RNA MeSH
- receptory CCR6 MeSH
- receptory chemokinů * MeSH
