Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of plasma cells. The incidence of MM worldwide is increasing with greater than 140 000 people being diagnosed with MM per year. Whereas 5-year survival after a diagnosis of MM has improved from 28% in 1975 to 56% in 2012, the disease remains essentially incurable. In this review, we summarize our current understanding of MM including its epidemiology, genetics and biology. We will also provide an overview of MM management that has led to improvements in survival, including recent changes to diagnosis and therapies. Areas of unmet need include the management of patients with high-risk MM, those with reduced performance status and those refractory to standard therapies. Ongoing research into the biology and early detection of MM as well as the development of novel therapies, such as immunotherapies, has the potential to influence MM practice in the future.
- MeSH
- cyklin D1 genetika MeSH
- exozom genetika MeSH
- genetická predispozice k nemoci MeSH
- histondemethylasy genetika MeSH
- imunoterapie metody MeSH
- lidé MeSH
- míra přežití MeSH
- mnohočetný myelom diagnóza epidemiologie genetika terapie MeSH
- mutace MeSH
- nádorové biomarkery genetika MeSH
- plazmatické buňky imunologie patologie MeSH
- represorové proteiny genetika MeSH
- rizikové faktory MeSH
- transkripční elongační faktory genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
A precisely balanced activity of canonical Wnt signaling is essential for a number of biological processes and its perturbation leads to developmental defects or diseases. Here, we demonstrate that alternative isoforms of the KDM2A and KDM2B lysine demethylases have the ability to negatively regulate canonical Wnt signaling. These KDM2A and KDM2B isoforms (KDM2A-SF and KDM2B-SF) lack the N-terminal demethylase domain, but they still have the ability to bind to CpG islands in promoters and to interact with their protein partners via their other functional domains. We have observed that KDM2A-SF and KDM2B-SF bind to the promoters of axin 2 and cyclin D1, two canonical Wnt signaling target genes, and repress their activity. Moreover, KDM2A-SF and KDM2B-SF are both able to strongly repress a Wnt-responsive luciferase reporter. The transcriptional repression mediated by KDM2A-SF and KDM2B-SF, but also by KDM2A-LF, is dependent on their DNA binding domain, while the N-terminal demethylase domain is dispensable for this process. Surprisingly, KDM2B-LF is unable to repress both the endogenous promoters and the luciferase reporter. Finally, we show that both KDM2A-SF and KDM2B-SF are able to interact with TCF7L1, one of the transcriptional mediators of canonical Wnt signaling. KDM2A-SF and KDM2B-SF are thus likely to negatively affect the transcription of canonical Wnt signaling target genes by binding to their promoters and by interacting with TCF7L1 and other co-repressors.
- MeSH
- CpG ostrůvky MeSH
- cyklin D1 genetika metabolismus MeSH
- F-box proteiny genetika metabolismus MeSH
- HEK293 buňky MeSH
- Jumonjiho doména s histondemethylasami genetika metabolismus MeSH
- lidé MeSH
- lysin genetika metabolismus MeSH
- promotorové oblasti (genetika) * MeSH
- protein - isoformy MeSH
- protein 1 podobný transkripčnímu faktoru 7 genetika metabolismus MeSH
- regulace genové exprese * MeSH
- signální dráha Wnt * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The influence of cilostazol on learning and memory, and cyclin D1 expression in the cerebral cortex of rats with chronic cerebral ischemia were investigated. A chronic cerebral ischemia model was established using the permanent bilateral common carotid artery occlusion method (2VO), learning and memory capacity was detected using the Morris water maze, and expression changes in apoptosis regulating gene cyclin D1 were tested by RT-PCR. Results of the Morris water maze indicated that significant extensions were found in the escape latent period and swimming path of rats in the ischemia group (2VO group), learning and memory results in the cilostazol group was obviously superior compared to the 2VO group (P<0.05), and the expression of cyclin D1 was observed to increase in both the ischemia and cilostazol intervention groups at the 9th week of ischemia. A significant difference was observed, compared with the sham operation group (P<0.05), the expression level decreased in the ischemia group compared with the cilostazol group, and a significant difference was identified compared with the ischemia group (P<0.05). Cilostazol can reduce nerve function impairment and improve learning and memory functions by affecting changes in apoptosis regulating genes.
- MeSH
- bludiště - učení účinky léků MeSH
- chronická nemoc MeSH
- cilostazol farmakologie MeSH
- cyklin D1 biosyntéza genetika metabolismus MeSH
- ischemie mozku farmakoterapie genetika metabolismus patologie MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- mozková kůra účinky léků metabolismus MeSH
- neuroprotektivní látky farmakologie MeSH
- paměť účinky léků MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The patients with mantle cell lymphoma (MCL) have translocation t(11;14) associated with cyclin D1 overexpression. We observed that iron (an essential cofactor of dioxygenases including prolyl hydroxylases [PHDs]) depletion by deferoxamine blocked MCL cells' proliferation, increased expression of DNA damage marker γH2AX, induced cell cycle arrest and decreased cyclin D1 level. Treatment of MCL cell lines with dimethyloxalylglycine, which blocks dioxygenases involving PHDs by competing with their substrate 2-oxoglutarate, leads to their decreased proliferation and the decrease of cyclin D1 level. We then postulated that loss of EGLN2/PHD1 in MCL cells may lead to down-regulation of cyclin D1 by blocking the degradation of FOXO3A, a cyclin D1 suppressor. However, the CRISPR/Cas9-based loss-of-function of EGLN2/PHD1 did not affect cyclin D1 expression and the loss of FOXO3A did not restore cyclin D1 levels after iron chelation. These data suggest that expression of cyclin D1 in MCL is not controlled by ENGL2/PHD1-FOXO3A pathway and that chelation- and 2-oxoglutarate competition-mediated down-regulation of cyclin D1 in MCL cells is driven by yet unknown mechanism involving iron- and 2-oxoglutarate-dependent dioxygenases other than PHD1. These data support further exploration of the use of iron chelation and 2-oxoglutarate-dependent dioxygenase inhibitors as a novel therapy of MCL.
- MeSH
- aminokyseliny dikarboxylové farmakologie MeSH
- chelátory železa farmakologie MeSH
- cyklin D1 metabolismus MeSH
- deferoxamin farmakologie MeSH
- dioxygenasy antagonisté a inhibitory metabolismus MeSH
- down regulace účinky léků MeSH
- hydroxylace MeSH
- hypoxie buňky účinky léků MeSH
- inhibitory enzymů farmakologie MeSH
- kyseliny ketoglutarové farmakologie MeSH
- lidé MeSH
- lymfom z plášťových buněk enzymologie MeSH
- messenger RNA genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- poškození DNA MeSH
- prolyl-4-hydroxylasy HIF metabolismus MeSH
- protein FOXO3 genetika metabolismus MeSH
- železo nedostatek MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Chromosomal translocation t(11;14)(q13;q32) is a characteristic molecular marker of mantle cell lymphoma (MCL) and leads to the fusion of the immunoglobulin heavy chain enhancer-promoter with the cyclin D1 gene. Both aberrant cyclin D1 expression and underlying chromosomal aberration may be used as molecular targets for monitoring minimal residual disease (MRD). The present study aims to assess the usefulness of quantitative cyclin D1 gene expression compared to the standardised but more technologically demanding DNA-based method for immunoglobulin heavy chain (IGH) or t(11;14) clone-specific gene rearrangement quantification in a cohort of bone marrow (BM) and peripheral blood (PB) samples from patients with MCL. We simultaneously evaluated DNA-MRD and cyclin D1 expression levels in 234 samples from 57 patients. We observed that both in DNA-MRD positive and negative BM/PB pairs from the same time points the expression levels of cyclin D1 are lower in PB than in BM (median 19×, BM/PB range 0.41-352). The correlation of cyclin D1 transcript levels with DNA-MRD or with flow cytometry was good only in samples with a very high infiltration. In DNA-MRD-negative BM samples, we observed a significant heterogeneity of cyclin D1 expression (in the range of more than three orders of magnitude). This is in contrast to previous reports demonstrating the usefulness of cyclin D1 for MRD monitoring that did not use DNA-based method as a reference. In PB, the specificity of cyclin D1 expression was better due to a lower physiological background. In conclusion, we show that cyclin D1 is unsuitable for MRD monitoring in BM.
- MeSH
- cyklin D1 genetika metabolismus MeSH
- kostní dřeň metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfom z plášťových buněk diagnóza genetika patologie MeSH
- messenger RNA analýza MeSH
- monitorování fyziologických funkcí metody MeSH
- nádorové biomarkery analýza genetika MeSH
- regulace genové exprese u nádorů MeSH
- reziduální nádor MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
A BCL1 leukemia-cell-targeted polymer-drug conjugate with a narrow molecular weight distribution consisting of an N-(2-hydroxypropyl)methacrylamide copolymer carrier and the anticancer drug pirarubicin is prepared by controlled radical copolymerization followed by metal-free click chemistry. A targeting recombinant single chain antibody fragment (scFv) derived from a B1 monoclonal antibody is attached noncovalently to the polymer carrier via a coiled coil interaction between two complementary peptides. Two pairs of coiled coil forming peptides (abbreviated KEK/EKE and KSK/ESE) are used as linkers between the polymer-pirarubicin conjugate and the targeting protein. The targeted polymer conjugate with the coiled coil linker KSK/ESE exhibits 4× better cell binding activity and 2× higher cytotoxicity in vitro compared with the other conjugate. Treatment of mice with established BCL1 leukemia using the scFv-targeted polymer conjugate leads to a markedly prolonged survival time of the experimental animals compared with the treatment using the free drug and the nontargeted polymer-pirarubicin conjugate.
- MeSH
- akrylamidy chemie MeSH
- cílená molekulární terapie MeSH
- cyklin D1 antagonisté a inhibitory imunologie MeSH
- imunoglobuliny - fragmenty aplikace a dávkování imunologie MeSH
- imunokonjugáty aplikace a dávkování chemie MeSH
- leukemie imunologie patologie terapie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- monoklonální protilátky chemie imunologie MeSH
- myši MeSH
- nosiče léků aplikace a dávkování chemie MeSH
- peptidy chemie imunologie MeSH
- polymery aplikace a dávkování chemie MeSH
- syntetická chemie okamžité shody MeSH
- systémy cílené aplikace léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Ectomesenchymal chondromyxoid tumor (ECT) is a rare benign tumor of uncertain lineage, which almost exclusively affects the anterior tongue. Herein, we report 2 cases of ECT occurring in 58- and 56-year-old males on the right and on the left side of the dorsum of the anterior tongue, measuring 18 mm and 10 mm, respectively. Despite positive resection margin in one case, none of the tumors recurred during follow-up of 6 and 5 years. Microscopically, both tumors had lobular architecture with a mixture of solid, microcystic, and chondromyxoid areas. The tumor cells were polygonal or elongated and showed mild atypia in one case. Immunohistochemically, both tumors showed diffuse expression of vimentin and focal positivity of CD10 and of smooth muscle actin. Regarding neural tissue-related markers, there was nearly diffuse expression of CD56 and neuron-specific enolase and focal positivity of PGP 9.5 in both cases and variable expression of CD57, synaptophysin, glial fibrillary acidic protein, and S-100 protein. Interestingly, we observed diffuse expression of SOX10 in one case. In both tumors, diffuse strong nuclear expression of cyclin D1 was present, without CCND1/IGH translocation or CCND1 amplification. The EWSR1 gene rearrangement was not detected. To the best of our knowledge, expression of SOX10, which may support neural crest origin of this peculiar lesion, has not been reported in ECT. The significance of strong cyclin D1 expression remains to be further investigated.
- MeSH
- cyklin D1 analýza biosyntéza MeSH
- hybridizace in situ fluorescenční MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mezenchymom diagnóza patologie MeSH
- myxom diagnóza patologie MeSH
- nádorové biomarkery analýza MeSH
- nádory jazyka diagnóza patologie MeSH
- transmisní elektronová mikroskopie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- Klíčová slova
- ribociklib, ribociclib, studie MONALEESA-2,
- MeSH
- aminopyridiny terapeutické užití MeSH
- analýza přežití MeSH
- antitumorózní látky terapeutické užití MeSH
- cyklin D1 MeSH
- cyklin-dependentní kinasa 4 antagonisté a inhibitory MeSH
- cyklin-dependentní kinasa 6 antagonisté a inhibitory MeSH
- letrozol MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu * farmakoterapie MeSH
- nitrily terapeutické užití MeSH
- puriny terapeutické užití MeSH
- retinoblastomový protein antagonisté a inhibitory MeSH
- senioři MeSH
- triazoly terapeutické užití MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: We conducted a large international study to estimate fractions of head and neck cancers (HNCs) attributable to human papillomavirus (HPV-AFs) using six HPV-related biomarkers of viral detection, transcription, and cellular transformation. METHODS: Formalin-fixed, paraffin-embedded cancer tissues of the oral cavity (OC), pharynx, and larynx were collected from pathology archives in 29 countries. All samples were subject to histopathological evaluation, DNA quality control, and HPV-DNA detection. Samples containing HPV-DNA were further subject to HPV E6*I mRNA detection and to p16(INK4a), pRb, p53, and Cyclin D1 immunohistochemistry. Final estimates of HPV-AFs were based on HPV-DNA, HPV E6*I mRNA, and/or p16(INK4a) results. RESULTS: A total of 3680 samples yielded valid results: 1374 pharyngeal, 1264 OC, and 1042 laryngeal cancers. HPV-AF estimates based on positivity for HPV-DNA, and for either HPV E6*I mRNA or p16(INK4a), were 22.4%, 4.4%, and 3.5% for cancers of the oropharynx, OC, and larynx, respectively, and 18.5%, 3.0%, and 1.5% when requiring simultaneous positivity for all three markers. HPV16 was largely the most common type. Estimates of HPV-AF in the oropharynx were highest in South America, Central and Eastern Europe, and Northern Europe, and lowest in Southern Europe. Women showed higher HPV-AFs than men for cancers of the oropharynx in Europe and for the larynx in Central-South America. CONCLUSIONS: HPV contribution to HNCs is substantial but highly heterogeneous by cancer site, region, and sex. This study, the largest exploring HPV attribution in HNCs, confirms the important role of HPVs in oropharyngeal cancer and drastically downplays the previously reported involvement of HPVs in the other HNCs.
- MeSH
- cyklin D1 analýza MeSH
- DNA virů izolace a purifikace MeSH
- dospělí MeSH
- genotyp MeSH
- imunohistochemie MeSH
- infekce papilomavirem komplikace virologie MeSH
- inhibitor p16 cyklin-dependentní kinasy analýza MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidský papilomavirus 16 izolace a purifikace MeSH
- mezinárodní spolupráce MeSH
- nádorové biomarkery analýza MeSH
- nádorový supresorový protein p53 analýza MeSH
- nádory hlavy a krku virologie MeSH
- nádory orofaryngu chemie virologie MeSH
- Papillomaviridae genetika izolace a purifikace MeSH
- prediktivní hodnota testů MeSH
- průřezové studie MeSH
- senioři MeSH
- slinné proteiny bohaté na prolin analýza MeSH
- spinocelulární karcinom chemie virologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
