Induction of autophagy represents an effective survival strategy for nutrient-deprived or stressed cancer cells. Autophagy contributes to the modulation of communication within the tumor microenvironment. Here, we conducted a study of the metabolic and signaling implications associated with autophagy induced by glutamine (Gln) and serum starvation and PI3K/mTOR inhibitor and autophagy inducer NVP-BEZ235 (BEZ) in the head and neck squamous cell carcinoma (HNSCC) cell line FaDu. We compared the effect of these different types of autophagy induction on ATP production, lipid peroxidation, mitophagy, RNA cargo of extracellular vesicles (EVs), and EVs-associated cytokine secretome of cancer cells. Both BEZ and starvation resulted in a decline in ATP production. Simultaneously, Gln starvation enhanced oxidative damage of cancer cells by lipid peroxidation. In starved cells, there was a discernible fragmentation of the mitochondrial network coupled with an increase in the presence of tumor susceptibility gene 101 (TSG101) on the mitochondrial membrane, indicative of the sorting of mitochondrial cargo into EVs. Consequently, the abundance of mitochondrial RNAs (mtRNAs) in EVs released by FaDu cells was enhanced. Notably, mtRNAs were also detectable in EVs isolated from the serum of both HNSCC patients and healthy controls. Starvation and BEZ reduced the production of EVs by cancer cells, yet the characteristic molecular profile of these EVs remained unchanged. We also found that alterations in the release of inflammatory cytokines constitute a principal response to autophagy induction. Importantly, the specific mechanism driving autophagy induction significantly influenced the composition of the EVs-associated cytokine secretome.
- MeSH
- adenosintrifosfát * metabolismus MeSH
- autofagie * účinky léků MeSH
- dlaždicobuněčné karcinomy hlavy a krku metabolismus genetika patologie MeSH
- extracelulární vezikuly * metabolismus účinky léků MeSH
- glutamin * metabolismus MeSH
- lidé MeSH
- mitochondrie metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory hlavy a krku metabolismus patologie genetika MeSH
- oxidační stres * MeSH
- RNA mitochondriální * metabolismus genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The failure of intracellular zinc accumulation is a key process in prostate carcinogenesis. Although prostate cancer cells can accumulate zinc after long-term exposure, chronic zinc oversupply may accelerate prostate carcinogenesis or chemoresistance. Because cancer progression is associated with energetically demanding cytoskeletal rearrangements, we investigated the effect of long-term zinc presence on biophysical parameters, ATP production, and EMT characteristics of two prostate cancer cell lines (PC-3, 22Rv1). Prolonged exposure to zinc increased ATP production, spare respiratory capacity, and induced a response in PC-3 cells, characterized by remodeling of vimentin and a shift of cell dry mass density and caveolin-1 to the perinuclear region. This zinc-induced remodeling correlated with a greater tendency to maintain actin architecture despite inhibition of actin polymerization by cytochalasin. Zinc partially restored epithelial characteristics in PC-3 cells by decreasing vimentin expression and increasing E-cadherin. Nevertheless, the expression of E-cadherin remained lower than that observed in predominantly oxidative, low-invasive 22Rv1 cells. Following long-term zinc exposure, we observed an increase in cell stiffness associated with an increased refractive index in the perinuclear region and an increased mitochondrial content. The findings of the computational simulations indicate that the mechanical response cannot be attributed exclusively to alterations in cytoskeletal composition. This observation suggests the potential involvement of an additional, as yet unidentified, mechanical contributor. These findings indicate that long-term zinc exposure alters a group of cellular parameters towards an invasive phenotype, including an increase in mitochondrial number, ATP production, and cytochalasin resistance. Ultimately, these alterations are manifested in the biomechanical properties of the cells.
- Publikační typ
- časopisecké články MeSH
Prevence a léčba krvácení nebo trombózy je u pacientů s jaterní cirhózou spojena s řadou úskalí, zažitých představ a zavedených stereotypů. V odborné veřejnosti přetrvává falešné paradigma, že změny hemostázy provázející jaterní cirhózu mají apriori krvácivý charakter. Ve skutečnosti se spolu s jaterním onemocněním vyvíjí nová hemostatická rovnováha. Problém je, že je křehká a snadno se vlivem vnitřních pohnutek nebo vnějších zásahů bortí. Výsledkem může být krvácení stejně jako trombóza. K těmto neblahým důsledkům mohou přispět i neadekvátní lékařské intervence vedené ve snaze upravit patologické výsledky koagulačních testů nebo trombocytopenii. Předložené doporučení pro klinickou praxi bylo vypracováno s cílem poskytnout praktické pokyny pro interpretaci výsledků laboratorních vyšetření hemostázy a počtu destiček, resp. shrnout současné názory na hemostázu u jaterní cirhózy, pravidla úpravy trombocytopenie a změn v koagulačním systému před invazivními výkony a pravidla tromboprofylaxe u hospitalizovaných pacientů. Hlavním východiskem je doporučení Evropské asociace pro studium jater „Clinical Practice Guidelines on prevention and management of bleeding and thrombosis in patients with cirrhosis“.
Prevention and treatment of bleeding or thrombosis in patients with liver cirrhosis is associated with a number of pitfalls, perceived ideas and established stereotypes. A false paradigm persists in the professional community that changes in haemostasis accompanying liver cirrhosis are a priori bleeding. In fact, a new haemostatic balance develops along with liver disease. The problem is that it is fragile and easily disrupted by internal drives or external interventions. The result can be bleeding as well as thrombosis. Inadequate medical interventions conducted in an attempt to correct pathological coagulation abnormalities or thrombocytopenia may contribute to these unfortunate consequences. The present guideline for clinical practice was developed to provide practical guidelines for the interpretation of the results of laboratory tests of haemostasis and platelet count, to summarize current views on haemostasis in liver cirrhosis, rules for the correction of thrombocytopenia and changes in the coagulation system before invasive procedures as well as rules for thromboprophylaxis in hospitalized patients. The main starting point is the recommendation of the European Association for the Study of the Live "Clinical Practice Guidelines on prevention and management of bleeding and thrombosis in patients with cirrhosis".
- MeSH
- hemostáza * účinky léků MeSH
- hodnocení rizik metody MeSH
- inhibitory agregace trombocytů terapeutické užití MeSH
- jaterní cirhóza * komplikace MeSH
- krvácení při operaci * ošetřování prevence a kontrola MeSH
- lidé MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- trombocytopenie etiologie terapie MeSH
- trombotická příhoda farmakoterapie MeSH
- vyšetření krevní srážlivosti metody MeSH
- Check Tag
- lidé MeSH
Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of ≥50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts ≥30 × 109/L and ≥50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals. This trial is registered at www.clinicaltrials.gov as #NCT03395210 and www.clinicaltrialsregister.eu as EudraCT 2017-004012-19.
- MeSH
- idiopatická trombocytopenická purpura * farmakoterapie chemicky indukované MeSH
- krvácení chemicky indukované MeSH
- lidé MeSH
- receptory Fc MeSH
- thrombopoetin terapeutické užití MeSH
- trombocytopenie * chemicky indukované MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
AIMS: To evaluate antibody response to mRNA vaccine, identify subgroups with poor response and to determine long-term antibody durability in hematological patients. MATERIALS AND METHODS: We have vaccinated 292 patients with all hematological malignancies with a third dose of mRNA COMIRNATY vaccine with a 12-month follow-up period in our center in Ostrava, Czech Republic. RESULTS: Antibody response for the whole cohort exceeded 74% through the whole 12-month follow-up. Lowest seroconversion was observed in CLL cohort (20/41, 48.8%), patients who received anti-CD20 therapy < 6 months before vaccination (8/30, 26.7%) and BTK inhibitors (3/6, 50.0%). On the contrary, patients with chronic myeloproliferative neoplasms and acute leukemia performed comparably with healthy population (33/33; 100% and 12/13; 92.3%, respectively). We have seen better results if the time interval between anti-CD20 therapy and additional vaccine dose was longer than 6 months (5/8 patients achieved seroconversion on 4th booster dose after previous failure). Also, 36 patients received a 4th dose of vaccine as a booster with measurable increase in protective antibodies in 50% (18/36). CONCLUSIONS: Additional doses show promise for a well-timed revaccination even in poor responders. To our knowledge, no study comparable to our work in terms of follow-up length, vaccine consistency or variety of hematological malignancies and/or treatment has been reported yet. Our findings shed more light on long-term antibody response to mRNA vaccines against SARS-CoV-2 in patients with hematological cancer and bring important data for the evaluation of possible vaccine failure and scheduling of subsequent doses.
- MeSH
- časové faktory MeSH
- COVID-19 * prevence a kontrola imunologie MeSH
- dospělí MeSH
- hematologické nádory * imunologie terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mRNA vakcíny MeSH
- následné studie MeSH
- protilátky virové * krev imunologie MeSH
- SARS-CoV-2 * imunologie MeSH
- sekundární imunizace * MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- vakcíny proti COVID-19 * imunologie aplikace a dávkování MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: Acquired haemophilia (AH) is a serious autoimmune haematological disease caused by the production of auto-antibodies against coagulation factor VIII. In some patients, AH is associated with a concomitant malignancy. In case of surgical intervention, AH poses a high risk of life-threatening bleeding. CASE SUMMARY: A 60-year-old female patient with multiple recurrences of non-muscle invasive bladder cancer underwent transurethral tumour resection. A severe haematuria developed postoperatively warranting two endoscopic revisions; however, no clear source of bleeding was identified in the bladder. Subsequent haematological examination established a diagnosis of AH. Treatment with factor VIII inhibitor bypass activity and immunosuppressive therapy was initiated immediately. The patient responded well to the therapy and was discharged from the hospital 21 d after the primary surgery. At the 38-mo follow-up, both AH and bladder cancer remained in complete remission. CONCLUSION: AH is a rare, life-threatening haematological disease. AH should be considered in patients with persistent severe haematuria or other bleeding symptoms, especially if combined with isolated activated partial thromboplastin time prolongation.
- Publikační typ
- kazuistiky MeSH
- MeSH
- epistaxe * etiologie prevence a kontrola terapie MeSH
- hereditární hemoragická teleangiektazie * diagnóza patologie MeSH
- lidé MeSH
- sekundární prevence klasifikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
