PURPOSE: Male breast cancer (MBC) is a rare, but increasingly common disease, and lacks prospective studies. Collaborative efforts are needed to understand and address MBC, including its prognosis, in different countries. METHODS: We retrospectively reviewed the clinical, histopathological, and molecular-genetic characteristics, treatments, and survival outcomes of MBC diagnosed between 2007 and 2017 in the Czech Republic. Prognostic factors of overall survival (OS), recurrence-free interval (RFi), and breast cancer-specific mortality (BCSM) were analyzed and indirectly compared to international data. RESULTS: We analyzed 256 patients with MBC (median age 66 years), including 12% with de novo metastatic (M1). Of 201 non-metastatic (M0) patients, 6% were <40 years old, 29% had stage I, 55% were cN0, and 54% underwent genetic testing. Overall, 97% of tumors had estrogen receptor expression ≥10%, 61% had high Ki67 index, 40% were high-grade (G3), and 68% were luminal B-like (HER2-negative). Systemic therapies included endocrine therapy (90%) and chemotherapy (53%). Few (5%) patients discontinued adjuvant endocrine therapy for reasons other than disease relapse or death. Patients treated with aromatase inhibitors alone had significantly shorter RFi (P < .001). OS, RFi, and BCSM were associated with disease stage, T stage, N stage, progesterone receptor expression, grade, and Ki67 index. Median OS reached 122 and 42 months in M0 and de novo M1 patients, respectively. CONCLUSION: Due to the rarity of MBC, this study highlights important findings from real clinical practice. Although the number of patients with MBC with unfavorable features was higher in this Czech dataset than in international studies, the prognosis remains consistent with real-world evidence.
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu u mužů * patologie mortalita terapie farmakoterapie MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Geografické názvy
- Česká republika MeSH
Gene inactivation of the cyclin-dependent kinase inhibitors p16INK4a, p15INK4b and p21WAF is frequently mediated by promoter gene methylation, whereas histone deacetylases (HDACs) control gene expression through their ability to deacetylate proteins. The effect of suberohydroxamic acid (SBHA) and 5-Aza-2'-deoxycytidine (Decitabine) (DAC) treatments on the transcription of CDKN2A, CDKN2B and CDKN1A genes, and their effects on molecular biological behavior were examined in two myeloma cell lines, RPMI8226 and U266, which differ in p53-functionality and IL-6 expression. In both tested myeloma cell lines, a non-methylated state of the CDKN2B gene promoter region was detected with normal gene expression, and the same level of p15INK4b protein was detected by immunocytochemical staining. Furthermore, in myeloma cells treated with SBHA and DAC alone, the expression of both p15INK4b and p21WAF was significantly upregulated in RPMI8226 cells (p53-functional, without IL-6 expression), whereas in the U266 cell line (p53 deleted, expressing IL-6) only p21WAF expression was significantly increased. Moreover, the analysis revealed that treatment with DAC induced DNMT3B enhancement in U266 cells. In conclusion, in myeloma cells with IL-6 expression, significantly increased DNMT3B expression indicated the tumorigenic consequences of 5-Aza-2'deoxycytidine treatment, which requires careful use in diseases involving epigenetic dysregulation, such as multiple myeloma (MM).
- MeSH
- decitabin * farmakologie MeSH
- DNA-(cytosin-5-)methyltransferasa * genetika metabolismus MeSH
- epigeneze genetická * MeSH
- inhibitor p15 cyklin-dependentní kinasy genetika metabolismus MeSH
- inhibitor p16 cyklin-dependentní kinasy genetika metabolismus MeSH
- interleukin-6 genetika metabolismus MeSH
- lidé MeSH
- metylace DNA MeSH
- mnohočetný myelom * genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 genetika metabolismus MeSH
- proteiny buněčného cyklu genetika metabolismus MeSH
- umlčování genů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
A small library of 2-[(1H-indol-3-yl)methyl]-5-(alkylthio)-1,3,4-oxadiazoles was prepared, starting from indole-3-acetic acid methyl ester and its 5-methyl-substituted derivative. The synthetic route involved the formation of intermediate hydrazides, their condensation with carbon disulfide, and intramolecular cyclization to corresponding 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones. The latter were then S-alkylated, and in case of ester derivatives, they were further hydrolyzed into corresponding carboxylic acids. All 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones and their S-alkylated derivatives were then screened for their protective effects in vitro and in vivo. Methyl substitution on the indole ring and propyl, butyl, or benzyl substitution on sulfhydryl group-possessing compounds were revealed to protect Friedreich's ataxia fibroblasts against the effects of glutathione depletion induced by the γ-glutamylcysteine synthetase inhibitor, buthionine sulfoximine. Two of the active compounds also reproducibly increased the survival of Caenorhabditis elegans exposed to juglone-induced oxidative stress.
- MeSH
- acetáty chemická syntéza MeSH
- antioxidancia * chemická syntéza chemie farmakologie MeSH
- Caenorhabditis elegans MeSH
- Friedreichova ataxie farmakoterapie metabolismus patologie MeSH
- indoly * chemie farmakologie MeSH
- kultivované buňky MeSH
- kyseliny indoloctové chemie MeSH
- lidé MeSH
- oxadiazoly * chemická syntéza chemie farmakologie MeSH
- oxidační stres účinky léků MeSH
- thioketony * chemická syntéza chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Amides of betulinic acid with cystamine were synthesized to investigate their antimicrobial and antitumor activity, and their influence on the cell cycle and cell apoptosis. The former target amide (6) displayed cytotoxicity in CEM cell line after 72 h of treatment (IC50 = 3.0 ± 0.7 μM; TI = 20), and induced apoptosis by caspase-3/7 activation in CEM cells. The latter target amide (9) displayed antimicrobial activity against Streptococcus mutans (MIC 3.125 μM; MBC 3.125 μM) and Bacillus cereus (MIC 25 μM; MBC 25 μM). The achieved results demonstrate enhancing of their biological activity over that of the parent compounds. However, two intermediate compounds (2 and 7) displayed either considerable cytotoxicity (2; 7.5 ± 0.8 μM; TI = 10, against G361) or antimicrobial activity (7; both against Actinomyces odontolycus and Clostridium perfrigens with MIC 12.5 µM and MBC 12.5 µM). The experimental data were compared with the in silico calculated physico-chemical and ADME parameters of the target compounds, including successful intermediates.
- MeSH
- Actinomyces účinky léků MeSH
- amidy chemie farmakologie MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- Bacillus cereus účinky léků MeSH
- Clostridium účinky léků MeSH
- cystamin chemie farmakologie MeSH
- kultivované buňky MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární konformace MeSH
- proliferace buněk účinky léků MeSH
- Streptococcus mutans účinky léků MeSH
- triterpeny chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
Chitosan, v posledních letech intenzivně zkoumaný polymer polosyntetického původu, svými vlastnostmi poukazuje na řadu možných použití. Také v technologii léků nachází své uplatnění jako pomocná látka vyznačující se v závislosti na koncentraci pojivými, mukoadhezivními, viskozitu zvyšujícími nebo filmotvornými vlastnostmi. Pelety, sférické násobné lékové formy, umožňují díky svým jedinečným vlastnostem řešit řadu technologických i terapeutických problémů spojených s perorálním podáním léčiv. V našem experimentu jsme použili chitosan spolu s mikrokrystalickou celulosou pro přípravu matricových pelet s theofylinem. Peletizační technikou byla extruze-sferonizace. Sledoval se vliv rozdílné koncentrace chitosanu (25, 35, 45, 55, 65 a 70 %) se stupněm deacetylace 91 % na uvolňování léčivé látky v disolučních prostředích s různou hodnotou pH. Nejpomalejšího uvolňování theofylinu po dobu 3 hodin se dosáhlo ve fosforečnanovém pufru o pH 6,8 při použití chitosanu v koncentraci 25–35 %.
Chitosan, an intensively studied semisynthetic polymer, has many possible uses due to its special parameters. Chitosan is also presently useful as an excipient in pharmaceutical industry due to its binding, mucoadhesive, viscosity-increasing and film-coating properties which depend on its concentration. Pellets, spherical multiple dosage forms, make possible to solve a lot of problems with oral administration of drugs thanks to its unique properties. In our experiment, matrix pellets containing theophyllin were made by extrusion/spheronisation method. Microcrystalline cellulose and chitosan with 91% degree of deacetylation in concentrations of 25, 35, 45, 55, 65 and 70% were used as matrix-forming excipients. The influence of chitosan concentration on liberation of drug was observed in media with different pH values. The most prolonged theophyllin release (3 hours) was achieved in phosphate buffer of pH 6.8 and chitosan concentration of 25–35%.
Pellets are currently a very popular dosage form for oral application. They can be prepared by several pelletization techniques. Extrusion/spheronization, commonly used in the pharmaceutical industry, and modern agglomeration in a rotoprocessor were the methods chosen for pellet preparation in our study. Theophylline (in 10% to 65% concentration) was the model drug, lactose monohydrate was used as filler, microcrystalline cellulose Avicel PH 101 was thespheronization enhancer, and the wetting agent was purified water. Both techniques led to the formation of pellets of appropriate shape and mechanical properties. Pellets of a higher density, hardness, lower friability, and slightly slower dissolution profiles were obtained by extrusion/spheronization. This method of pelletization also led to production of particles with narrower size distribution and bigger yield of pellets with the requested size.
Systémy dopravující léčivo do tlustého střeva mají význam při léčbě zánětlivých střevních onemocnění (ulcerativní kolitida, Crohnova nemoc), některých nádorů, střevních chorob infekčního původu a onemocnění závisejících na cirkadiálních rytmech, jako je například astma, angina pectoris či artritida, kdy se záměrně využívá časové prodlevy mezi aplikací léku a absorpcí léčiva. Oblast tlustého střeva je možným místem vstupu peptidů, bílkovin, nukleotidů a vakcín do systémové cirkulace, protože se zde díky lokální nepřítomnosti trávicích enzymů tyto látky neštěpí. Směrování léčiv do tlustého střeva umožňuje přímou léčbu v místě onemocnění a snížení potřebné dávky léčiva. Protože se léčivo se do systémové cirkulace nevstřebává, snižují se významně systémové vedlejší nežádoucí účinky. Systémy dopravující léčiva do tlustého střeva využívají specifických podmínek v gastrointestinálním traktu (GIT), jako je rozdílné pH v různých úsecích trávicího traktu, dlouhá doba průchodu gastrointestinálním traktem, zvýšený střevní tlak a přítomnost bakteriální mikroflóry v těchto oblastech.
Colonic drug delivery systems are useful for the treatment of inflammatory bowel diseases (ulcerative colitis, Crohn's disease), some carcinomas, gastrointestinal infections and diseases that are sensitive to circadian rhythms, such as asthma, angina pectoris and arthritis, where an intention time delay in the absorption of the drug is required. The colon region is a site for the entry of peptides, proteins, nucleotides and vaccines into the systemic circulation due to local absence of digestive enzymes. Colonic drug targeting ensures direct treatment at the disease site and a possible reduction in the administered dose. A drug is not absorbed into the systemic circulation, so the associated systemic adverse effects are reduced. Colonic drug delivery systems are based on exploitation of characteristics that are unique to the gastrointestinal tract (GIT), such as pH gradient along the GIT, long transit time through the GIT, increased intraluminal pressure and a presence of bacterial microflora in these regions.
- MeSH
- aplikace orální MeSH
- biodegradace účinky léků MeSH
- lidé MeSH
- nosiče léků farmakokinetika terapeutické užití MeSH
- polysacharidy farmakologie MeSH
- systémy cílené aplikace léků metody trendy MeSH
- tlusté střevo enzymologie metabolismus účinky léků MeSH
- způsoby aplikace léků MeSH
- Check Tag
- lidé MeSH
