Less than 70 years ago, the vast majority of hematologic malignancies were untreatable diseases with fatal prognoses. The development of modern chemotherapy agents, which had begun after the Second World War, was markedly accelerated by the discovery of the structure of DNA and its role in cancer biology and tumor cell division. The path travelled from the first temporary remissions observed in children with acute lymphoblastic leukemia treated with single-agent antimetabolites until the first cures achieved by multi-agent chemotherapy regimens was incredibly short. Despite great successes, however, conventional genotoxic cytostatics suffered from an inherently narrow therapeutic index and extensive toxicity, which in many instances limited their clinical utilization. In the last decade of the 20th century, increasing knowledge on the biology of certain malignancies resulted in the conception and development of first molecularly targeted agents designed to inhibit specific druggable molecules involved in the survival of cancer cells. Advances in technology and genetic engineering enabled the production of structurally complex anticancer macromolecules called biologicals, including therapeutic monoclonal antibodies, antibody-drug conjugates and antibody fragments. The development of drug delivery systems (DDSs), in which conventional drugs were attached to various types of carriers including nanoparticles, liposomes or biodegradable polymers, represented an alternative approach to the development of new anticancer agents. Despite the fact that the antitumor activity of drugs attached to DDSs was not fundamentally different, the improved pharmacokinetic profiles, decreased toxic side effects and significantly increased therapeutic indexes resulted in their enhanced antitumor efficacy compared to conventional (unbound) drugs. Approval of the first immune checkpoint inhibitor for the treatment of cancer in 2011 initiated the era of cancer immunotherapy. Checkpoint inhibitors, bispecific T-cell engagers, adoptive T-cell approaches and cancer vaccines have joined the platform so far, represented mainly by recombinant cytokines, therapeutic monoclonal antibodies and immunomodulatory agents. In specific clinical indications, conventional drugs have already been supplanted by multi-agent, chemotherapy-free regimens comprising diverse immunotherapy and/or targeted agents. The very distinct mechanisms of the anticancer activity of new immunotherapy approaches not only call for novel response criteria, but might also change fundamental treatment paradigms of certain types of hematologic malignancies in the near future.
- MeSH
- Hematologic Neoplasms therapy MeSH
- Immunotherapy methods MeSH
- Humans MeSH
- Antibodies, Monoclonal therapeutic use MeSH
- Cancer Vaccines immunology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Human parvovirus B19 (B19V) is a ubiquitous human pathogen associated with a number of conditions, such as fifth disease in children and arthritis and arthralgias in adults. B19V is thought to evolve exceptionally rapidly among DNA viruses, with substitution rates previously estimated to be closer to those typical of RNA viruses. On the basis of genetic sequences up to ∼70 years of age, the most recent common ancestor of all B19V has been dated to the early 1800s, and it has been suggested that genotype 1, the most common B19V genotype, only started circulating in the 1960s. Here we present 10 genomes (63.9-99.7% genome coverage) of B19V from dental and skeletal remains of individuals who lived in Eurasia and Greenland from ∼0.5 to ∼6.9 thousand years ago (kya). In a phylogenetic analysis, five of the ancient B19V sequences fall within or basal to the modern genotype 1, and five fall basal to genotype 2, showing a long-term association of B19V with humans. The most recent common ancestor of all B19V is placed ∼12.6 kya, and we find a substitution rate that is an order of magnitude lower than inferred previously. Further, we are able to date the recombination event between genotypes 1 and 3 that formed genotype 2 to ∼5.0-6.8 kya. This study emphasizes the importance of ancient viral sequences for our understanding of virus evolution and phylogenetics.
- MeSH
- History, 19th Century MeSH
- History, 20th Century MeSH
- Erythema Infectiosum genetics history MeSH
- Phylogeny * MeSH
- Genome, Viral * MeSH
- Genotype * MeSH
- Humans MeSH
- Parvovirus B19, Human genetics MeSH
- Evolution, Molecular * MeSH
- Sequence Analysis, DNA * MeSH
- Check Tag
- History, 19th Century MeSH
- History, 20th Century MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Historical Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Endogenous retrovirus (ERV) sequences provide a rich source of information about the long-term interactions between retroviruses and their hosts. However, most ERVs are derived from a subset of retrovirus groups, while ERVs derived from certain other groups remain extremely rare. In particular, only a single ERV sequence has been identified that shows evidence of being related to an ancient Deltaretrovirus, despite the large number of vertebrate genome sequences now available. In this report, we identify a second example of an ERV sequence putatively derived from a past deltaretroviral infection, in the genomes of several species of horseshoe bats (Rhinolophidae). This sequence represents a fragment of viral genome derived from a single integration. The time of the integration was estimated to be 11-19 million years ago. This finding, together with the previously identified endogenous Deltaretrovirus in long-fingered bats (Miniopteridae), suggest a close association of bats with ancient deltaretroviruses.
- MeSH
- Chiroptera classification virology MeSH
- Deltaretrovirus classification genetics MeSH
- Endogenous Retroviruses classification genetics MeSH
- Phylogeny MeSH
- Genome genetics MeSH
- Genomics MeSH
- Terminal Repeat Sequences genetics MeSH
- Evolution, Molecular MeSH
- Recombination, Genetic MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Růstový hormon byl v klinické praxi poprvé použit před 60 lety. Tehdy šlo o extrakt z kadaverózních lidských hypofýz. Před 30 lety byl poprvé uveden na trh autentický rekombinantní růstový hormon, který bylo možné produkovat v potenciálně neomezených množstvích, což umožnilo zkoumat nové oblasti jeho využití. V současné době je léčba růstovým hormonem schválena v Evropě pro sedm indikačních oblastí, šest pediatrických a jednu v dospělosti. V roce 2016 bylo v České republice léčeno růstovým hormonem 2 058 dětí a dospívajících. Růstový hormon se podává formou každodenní subkutánní injekce, což může být pro některé rodiny obtížné. Vývoj proto směřuje ke vzniku depotní molekuly s optimálně zachovanou účinností při aplikaci nanejvýš jednou týdně. Přes řadu překážek je již několik molekul ve fázi klinického zkoušení. Současně genetické poznatky posledního desetiletí otevřely nový pohled na řízení růstu. Do centra pozornosti při zkoumání regulace růstu se dostává chondrocyt růstové ploténky, konečný efektor tělesného růstu. Výzkum regulace růstu postupně otevírá nový pohled na klasifikaci růstových poruch, což zřejmě v příštích letech povede k přehodnocení indikací pro léčbu růstovým hormonem podle etiologické diagnózy.
The first clinical administration of growth hormone was reported 60 years ago, using extract of human cadaverous pituitary glands. The authentic recombinant growth hormone was launched 30 years ago which allowed its potentially unlimited production and initiated research of novel indications. Currently, growth hormone is an approved medication in seven therapeutic areas, six in paediatric medicine and one in adults. In the Czech Republic, growth hormone used to be administered to 2058 children and adolescents in 2016. As the schedule of daily SC injections may be burdening for some families, the manufacturers aim to develop a long-acting molecule for once weekly or even less frequent administration, with maintained optimal efficacy. Despite persistent difficulties, several long-acting molecules are at different phases of clinical trials. The recent genetic discoveries opened new insights into the regulation of human growth, highlighting the role of growth plate chondrocyte as the final effector of growth. This leads to stepwise re-classification of growth disorders and may directly impact indications for growth hormone therapy according to aetiological diagnosis within the oncoming years.
- MeSH
- Chondrocytes MeSH
- Creutzfeldt-Jakob Syndrome prevention & control transmission MeSH
- Child MeSH
- Insulin-Like Growth Factor I drug effects MeSH
- Delayed-Action Preparations administration & dosage MeSH
- Humans MeSH
- Adolescent MeSH
- Growth Disorders drug therapy MeSH
- Growth Hormone * history economics therapeutic use MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
Fabryho choroba (rovněž označovaná jako Fabryho -Andersonova choroba, či deficience alfa- galaktosidázy A, deficit ceramid trihexosidázy, OMIM 301500) je vzácné geneticky podmínění onemocnění, které bylo popsáno již před více než 100 lety (1898) na základě své klinicky nápadné kožní manifestace. Není náhodou, že do povědomí lékařské komunity vešla nejprve pod názvem, který zdůrazňoval zejména velmi nápadný aspekt týkající se kožních projevů – a sice angiokeratoma corporis diffusum. Tento mnohočetný výskyt drobných angiokeratomů ale není jedinou manifestací, se kterou se dermatolog může ve své praxi setkat. Správné a časné rozpoznání těchto klasických příznaků dermatologem může mít zásadní význam pro další osud pacienta, protože jako u mnoha jiných monogenních onemocnění je v současné době možno defektní genový produkt substituovat rekombinantně připravenými enzymy.
Fabry disease (also referred as Fabry-Andrerson disease, alpha-galactosidase A deficiency, ceramide-trihexosidase deficiency, OMIM 301500) is a rare genetic disease, which was described more than one century ago (1898) based on typical clinical manifestation. The very first name „angiokeratoma corporis diffusum“ was coined due to the most visible cutaneous manifestation. However, this is not the only and exclusive dermatological feature in this condition. Early and correct recognition of symptoms of multi-systemic disease might have and direct impact on life of patient. Similarly to several other monogenic diseases, the defective gene product can be replaced by recombinant enzymes.
- MeSH
- alpha-Galactosidase blood MeSH
- Angiokeratoma etiology MeSH
- Fabry Disease * diagnosis physiopathology therapy MeSH
- Humans MeSH
- Skin Neoplasms etiology MeSH
- Rare Diseases MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Lidské papilomaviry (human papillomavirus, HPV) jsou nejvýznamnějším příčinným faktorem vzniku karcinomu děložního hrdla, ale i dalších maligních a benigních lézí ženského i mužského genitálu a částečně i dalších oblastí přechodu dlaždicového a cylindrického epitelu (skvamokolumnární junkce). Zabránění získání této infekce je pak ve svém důsledku primární prevencí všech těchto lézí včetně karcinomu děložního hrdla. Donedávna bylo možné přenosu a infikování HPV zabránit pouze sexuální abstinencí a bariérovými kontracepčními pomůckami, ovšem s vědomím toho, že viry jsou přenosné i při nekoitálních aktivitách. Posledních deset let máme možnost primární prevence očkováním kvadrivalentní, bivalentní a nejnověji též nonavalentní vakcínou proti HPV. Všechny charakterizuje vysoká účinnost proti typům HPV obsaženým v daných vakcínách a jejich bezpečnost.
Human papillomaviruses (HPV) are the most important causes of cervical cancer but also other carcinomas and non-malignant lessions especially of women's and men's genital area. But not only. Prevention of HPV infection is the primary prevention of all HPV-associated lessions. Rules of safety sex are very important but HPV could be transfer also by noncoital activities. Ten years ago clinical history of HPV vaccination has started by quadrivalent vaccine. In 2015 it was graduated by nonavalent vaccine. All HPV vaccines are characterized by high efficacy against including types of HPV and also high safety.
- MeSH
- Alphapapillomavirus immunology pathogenicity drug effects MeSH
- Papillomavirus Infections * epidemiology genetics complications transmission MeSH
- Humans MeSH
- Adolescent MeSH
- Anus Neoplasms pathology prevention & control virology MeSH
- Head and Neck Neoplasms pathology prevention & control virology MeSH
- Genital Neoplasms, Male prevention & control virology MeSH
- Genital Neoplasms, Female pathology prevention & control virology MeSH
- Immunization Schedule MeSH
- Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18 therapeutic use MeSH
- Papillomavirus Vaccines therapeutic use MeSH
- Check Tag
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Female MeSH
The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.
- MeSH
- Genetic Carrier Screening MeSH
- Adult MeSH
- Founder Effect * MeSH
- Haplotypes MeSH
- Nuclear Proteins genetics MeSH
- Cohort Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Mutation * MeSH
- DNA Repair MeSH
- DNA Damage MeSH
- Cell Cycle Proteins genetics MeSH
- Reproduction genetics MeSH
- Nijmegen Breakage Syndrome ethnology genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic MeSH
- Slovakia MeSH
Článek shrnuje zkušenosti s aplikací biologické léčby u autoimunitních zánětlivých revmatických onemocnění. Dosavadní konvenční léčba, která například u revmatoidní artritidy znamenala většinou aplikaci methotrexátu v kombinaci s glukokortikoidy, sice byla účinná, ale žádoucího stavu, tzn. navození remise, bylo dosaženo jen zřídka a jen velmi málo tato terapie ovlivňovala strukturální progresi onemocnění. Velký pokrok přinesla biologická léčba, která u 3/4 pacientů s nedostatečným efektem methotrexátu dociluje odpovědi a zlepšení klinického stavu. V současné době je k dispozici pro léčbu revmatoidní artritidy 8 biologických léků, přičemž 5 inhibuje anti-TNF a 3 mají jiný mechanismus účinku. U psoriatické artritidy jsou kromě anti-TNF blokátorů dostupné ještě blokátor IL-17 (secukinumab), blokátor IL-12 a 23 (ustekinumab) a inhibitor fosfodiesterázy 4 (apremilast). Pro léčbu ankylozující spondylitidy je registrován secukinumab. Anti-TNF léčba je relativně bezpečná, ale vzácně se mohou vyskytnout i závažné nežádoucí účinky. Jde především závažnější infekce, oportunní infekce a tuberkulózu. Objevují se také případy alergických reakcí a lokální nesnášenlivosti. Zvýšený výskyt lymfomů se nepotvrdil. Pravděpodobné je minimální zvýšení rizika kožních, melanomových i nemelanomových nádorů. Poměr účinnost/riziko však zůstává vysoce pozitivní.
The publication is summarizing application of biological DMARDs in autoimmune inflammatory rheumatic diseases. Up to now conventional therapy, which for example in rheumatoid arthritis was application of methotrexate (MTx) in combination with glucocorticoids, was effective, but the remission as a target was achieved in small proportion of patients and also there was little effect on structural progression of diseases. Biological therapy was great advance because response was achieved in ? patients who failed MTx. At present time 8 biological drugs are available. 5 are inhibitors of TNFα and 3 have different move of action. In psoriatic arthritis are beside TNF blockers available blocker of IL 17 (secukinumab, ustekinumab, apremilast). For ankylosing spondylitis is registered secukinumab. Anti-TNF therapy is relative safe but rarely serious adverse events can occur. The most important are serious infections, opportunistic infections and tuberculosis. Other adverse event includes allergic reactions and local intolerance. Increase incidence of lymphomas was not confirmed. There is probably minimal increased risk of skin melanoma and non-melanoma tumors. Benefit/risk ratio is still very positive. National registry of biological therapy ATTRA was founded 15 years ago and includes patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis. In June 2016 over all 6800 patients with those diagnoses was included and actually 5194 have been treated. In registry patients are regularly followed for activity, efficacy of the drug and other events. Results of registry are sent payers for evaluations of pharmacologic parameters.
- Keywords
- registr ATTRA,
- MeSH
- Abatacept administration & dosage therapeutic use MeSH
- Adalimumab administration & dosage therapeutic use MeSH
- Spondylitis, Ankylosing diagnosis drug therapy MeSH
- Antirheumatic Agents administration & dosage therapeutic use MeSH
- Autoimmune Diseases diagnosis MeSH
- Biological Therapy * MeSH
- Biosimilar Pharmaceuticals administration & dosage therapeutic use MeSH
- Etanercept administration & dosage therapeutic use MeSH
- Antibodies, Monoclonal, Humanized administration & dosage therapeutic use MeSH
- Combined Modality Therapy MeSH
- Humans MeSH
- Methotrexate administration & dosage therapeutic use MeSH
- Arthritis, Psoriatic diagnosis drug therapy MeSH
- Registries standards MeSH
- Rheumatic Diseases * diagnosis drug therapy classification MeSH
- Arthritis, Rheumatoid diagnosis drug therapy MeSH
- Rituximab administration & dosage therapeutic use MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
Telomerase and telomerase-generated telomeric DNA sequences are widespread throughout eukaryotes, yet they are not universal. Neither telomerase nor the simple DNA repeats associated with telomerase have been found in some plant and animal species. Telomerase was likely lost from Diptera before the divergence of Diptera and Siphonaptera, some 260 million years ago. Even so, Diptera is one of the most successful animal orders, making up 11% of known animal species. In addition, many species of Coleoptera and Hemiptera seem to lack canonical telomeric repeats at their chromosome ends. These and other insects that appear to lack canonical terminal repeat sequences account for another 10-15% of animal species. Conversely, the silk moth Bombyx mori maintains canonical telomeric sequences at its chromosome ends but seems to lack a functional telomerase. We speculate that a telomere-specific capping complex that recognizes the telomeric repeats and protects chromosome ends is the determining factor in maintaining canonical telomeric sequences and that telomerase is an early and efficacious mechanism for satisfying the needs of capping complex. There are alternate mechanisms for maintaining chromosome ends that do not depend on telomerase, such as recombination found in some human cancer cells and yeast mutants. These mechanisms may maintain the canonical telomeric repeats or allow the terminal sequence to evolve when specificity of the capping complex for terminal repeat sequences is weak.
- MeSH
- Gene Deletion * MeSH
- Insecta enzymology genetics MeSH
- Homologous Recombination MeSH
- Terminal Repeat Sequences MeSH
- Evolution, Molecular * MeSH
- Telomerase genetics MeSH
- Telomere metabolism MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Biologická léčiva, která často označujeme i jako cílená léčiva, před třiceti lety otevřela novou éru ve farmakoterapii. Jejich zavedení do klinické praxe ve významné míře zlepšilo úspěšnost léčby a prognózu nemocných s dosud neléčitelnými onemocněními. V současnosti biologická léčiva čerpají 30 % z celkových nákladů na léčiva. V našem článku představujeme problematiku biologických léčiv. Věnujeme se jejich definici, výrobnímu procesu, charakteristickým vlastnostem, rozdělení, mechanismu účinku a klinickému použití v obecné rovině.
Biological drugs, often referred to as targeted therapies, ushered in a new era in pharmacological therapy 30 years ago. Their introduction into clinical practice has significantly improved the success rates of therapy and prognosis of patients with conditions refractory to treatment thus far. At present, biological drugs account for 30 % of total pharmacotherapy costs. Our paper examines various aspects of biological drugs, discussing their definition, manufacturing process, characteristic properties, classification, mode of action, and their use in clinical practice in general
