A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)2(dppz)]+, Ir1-Ir4, were rationally designed and synthesized, where the aryl group attached to the thienyl ring was p-CF3C6H4 or p-Me2NC6H4. These new Ir(III) complexes were assessed as photosensitizers to explore the structure-activity correlations for their potential use in biocompatible anticancer photodynamic therapy. When irradiated with blue light, the complexes exhibited high selective potency across several cancer cell lines predisposed to photodynamic therapy; the benzothiazole derivatives (Ir1 and Ir2) were the best performers, Ir2 being also activatable with green or red light. Notably, when irradiated, the complexes induced leakage of lysosomal content into the cytoplasm of HeLa cancer cells and induced oncosis-like cell death. The capability of the new Ir complexes to photoinduce cell death in 3D HeLa spheroids has also been demonstrated. The investigated Ir complexes can also catalytically photo-oxidate NADH and photogenerate 1O2 and/or •OH in cell-free media.
- MeSH
- antitumorózní látky * farmakologie MeSH
- benzothiazoly MeSH
- fotosenzibilizující látky farmakologie terapeutické užití MeSH
- fototoxická dermatitida * farmakoterapie MeSH
- iridium farmakologie MeSH
- komplexní sloučeniny * farmakologie MeSH
- lidé MeSH
- lyzozomy MeSH
- nádorové buněčné linie MeSH
- nádory * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: We report an analysis of minimal residual/detectable disease (MRD) as a predictor of outcome in previously untreated patients with follicular lymphoma (FL) from the randomized, multicenter GALLIUM (ClinicalTrials.gov identifier: NCT01332968) trial. PATIENTS AND METHODS: Patients received induction with obinutuzumab (G) or rituximab (R) plus bendamustine, or cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or cyclophosphamide, vincristine, prednisone (CVP) chemotherapy, followed by maintenance with the same antibody in responders. MRD status was assessed at predefined time points (mid-induction [MI], end of induction [EOI], and at 4-6 monthly intervals during maintenance and follow-up). Patients with evaluable biomarker data at diagnosis were included in the survival analysis. RESULTS: MRD positivity was associated with inferior progression-free survival (PFS) at MI (hazard ratio [HR], 3.03 [95% CI, 2.07 to 4.45]; P < .0001) and EOI (HR, 2.25 [95% CI, 1.53 to 3.32]; P < .0001). MRD response was higher after G- versus R-chemotherapy at MI (94.2% v 88.9%; P = .013) and at EOI (93.1% v 86.7%; P = .0077). Late responders (MI-positive/EOI-negative) had a significantly poorer PFS than early responders (MI-negative/EOI-negative; HR, 3.11 [95% CI, 1.75 to 5.52]; P = .00011). The smallest proportion of MRD positivity was observed in patients receiving bendamustine at MI (4.8% v 16.0% in those receiving CHOP; P < .0001). G appeared to compensate for less effective chemotherapy regimens, with similar MRD response rates observed across the G-chemo groups. During the maintenance period, more patients treated with R than with G were MRD-positive (R-CHOP, 20.7% v G-CHOP, 7.0%; R-CVP, 21.7% v G-CVP, 9.4%). Throughout maintenance, MRD positivity was associated with clinical relapse. CONCLUSION: MRD status can determine outcome after induction and during maintenance, and MRD negativity is a prerequisite for long-term disease control in FL. The higher MRD responses after G- versus R-based treatment confirm more effective tumor cell clearance.
- MeSH
- bendamustin hydrochlorid MeSH
- cyklofosfamid MeSH
- doxorubicin MeSH
- folikulární lymfom * MeSH
- galium * terapeutické užití MeSH
- lidé MeSH
- prednison MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- reziduální nádor farmakoterapie MeSH
- rituximab MeSH
- vinkristin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: Bismuth quadruple therapies (BQTs) including bismuth, a proton pump inhibitor (PPI) and two antibiotics have been shown to be highly effective for treating Helicobacter pylori infection even in areas of high bacterial antibiotic resistance. OBJECTIVE: To describe the time trends of use, effectiveness and safety of BQT in Europe using the European Registry on Helicobacter pylori Management (Hp-EuReg). DESIGN: Patients registered in the Hp-EuReg from 2013 to 2021 who had received BQT were included. The regimens prescribed, the number of eradication attempts, effectiveness, adherence and safety were analysed. The effectiveness was assessed by modified intention to treat (mITT). Time-trend and multivariate analyses were performed to determine variables that predicted treatment success. RESULTS: Of the 49 690 patients included in the Hp-EuReg, 15 582 (31%) had received BQT. BQT use increased from 8.6% of all treatments in 2013 to 39% in 2021. Single-capsule BQT-containing bismuth, metronidazole and tetracycline-plus a PPI (single-capsule BQT, ScBQT) was the most frequent treatment mode (43%). Schemes that obtained an effectiveness above 90% were the 10-day ScBQT and 14-day BQT using tetracycline plus metronidazole, or amoxicillin plus either clarithromycin or metronidazole. Only ScBQT achieved above 90% cure rates in all the geographical areas studied. Using the ScBQT scheme, adherence, the use of standard or high-dose PPIs, 14-day prescriptions and the use of BQT as first-line treatment were significantly associated with higher mITT effectiveness. CONCLUSION: The use of BQT increased notably in Europe over the study period. A 10-day ScBQT was the scheme that most consistently achieved optimal effectiveness. TRIAL REGISTRATION NUMBER: NCT02328131.
- MeSH
- amoxicilin terapeutické užití aplikace a dávkování MeSH
- antibakteriální látky * terapeutické užití škodlivé účinky aplikace a dávkování MeSH
- bismut * terapeutické užití aplikace a dávkování MeSH
- dospělí MeSH
- Helicobacter pylori * účinky léků MeSH
- infekce vyvolané Helicobacter pylori * farmakoterapie MeSH
- inhibitory protonové pumpy * terapeutické užití aplikace a dávkování škodlivé účinky MeSH
- klarithromycin terapeutické užití aplikace a dávkování MeSH
- kombinovaná farmakoterapie * MeSH
- lidé středního věku MeSH
- lidé MeSH
- metronidazol terapeutické užití aplikace a dávkování MeSH
- registrace * MeSH
- senioři MeSH
- tetracyklin terapeutické užití aplikace a dávkování MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- Geografické názvy
- Evropa MeSH
Herein, we describe and investigate biological activity of three octahedral ruthenium(II) complexes of the type [Ru(C∧N)(phen)2]+, RuL1-RuL3, containing a π-expansive cyclometalating substituted benzo[g]quinoxaline ligand (C∧N ligand) (phen = 1,10-phenanthroline). Compounds RuL1-RuL3 in cervical, melanoma, and colon human cancer cells exhibit high phototoxicity after irradiation with light (particularly blue), with the phototoxicity index reaching 100 for the complex RuL2 in most sensitive HCT116 cells. RuL2 accumulates in the cellular membranes. If irradiated, it induces lipid peroxidation, likely connected with photoinduced ROS generation. Oxidative damage to the fatty acids leads to the attenuation of the membranes, the activation of caspase 3, and the triggering of the apoptotic pathway, thus implementing membrane-localized photodynamic therapy. RuL2 is the first photoactive ruthenium-based complex capable of killing the hardly treatable colon cancer stem cells, a highly resilient subpopulation within a heterogeneous tumor mass, responsible for tumor recurrence and the metastatic progression of cancer.
- MeSH
- antitumorózní látky * farmakologie chemie chemická syntéza terapeutické užití MeSH
- apoptóza účinky léků MeSH
- buněčná membrána účinky léků metabolismus MeSH
- chinoxaliny * chemie farmakologie chemická syntéza MeSH
- fotochemoterapie * MeSH
- fotosenzibilizující látky * farmakologie chemie chemická syntéza terapeutické užití MeSH
- komplexní sloučeniny * farmakologie chemie chemická syntéza terapeutické užití MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové kmenové buňky * účinky léků patologie MeSH
- nádory tračníku * farmakoterapie patologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- ruthenium * chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.
- MeSH
- akrylamidy * MeSH
- aniliny terapeutické užití MeSH
- erbB receptory genetika MeSH
- indoly * MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- lidé MeSH
- mutace MeSH
- nádory centrálního nervového systému * diagnostické zobrazování farmakoterapie genetika MeSH
- nádory plic * farmakoterapie genetika patologie MeSH
- nemalobuněčný karcinom plic * farmakoterapie genetika patologie MeSH
- pemetrexed terapeutické užití MeSH
- platina terapeutické užití MeSH
- pyrimidiny * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
Portosinusoidální vaskulární choroba (PSVD) je málo rozpoznávané onemocnění jater podmíněné postižením malých cév. Diagnóza je definována souborem klinických a/nebo histopatologických kritérií, absolutní podmínkou je vyloučení cirhózy jater biopsií. Klinicky se PSVD obvykle manifestuje komplikací portální hypertenze, ta ale nemusí byt vyjádřena u všech nemocných. V článku popisujeme případ 71letého pacienta se známou, hematologicky nevysvětlenou a dále neprošetřenou splenomegalií, který byl vyšetřen pro těžkou symptomatickou mikrocytární anemii, pravděpodobně sekundární k portální hypertenzi, byť bez deklarovaných krvácivých projevů. Za hospitalizace byla provedena ligace velkých rizikových varixů jícnu, jiný zdroj anemizace prokázán nebyl. U pacienta byla vyloučena pre- nebo posthepatální etiologie portální hypertenze, elastografie jater byla ve fyziologických hodnotách, jaterní testy byly vyjma marginální izolované elevace gama-glutamyltransferázy v normě, funkce jater byla intaktní. V jaterní biopsii byl nález kompatibilní s diagnózou PSVD. U pacienta nebylo rozpoznáno žádné z asociovaných onemocnění, rovněž neužíval rizikovou medikaci, léčba tudíž spočívala pouze v řešení komplikací portální hypertenze, ambulantně byla dokončena eradikace jícnových varixů. Při terapii perorálním preparátem železa došlo k normalizaci hemoglobinu, fyziologické hodnoty přetrvávají i měsíce po ukončení substituční léčby, jaterní funkce je nadále v normě.
Portosinusoidal vascular disease (PSVD) is a rarely recognized liver condition caused by the involvement of small hepatic vessels. The diagnosis is established based on a set of clinical and/or histopathological criteria, with the absolute requirement of excluding liver cirrhosis through biopsy. Clinically, PSVD often presents with complications related to portal hypertension, although not all patients exhibit these signs. This article discusses the case of a 71-year-old patient with known splenomegaly, which had not been fully investigated and lacked a hematological explanation. The patient was evaluated for severe symptomatic microcytic anemia, likely secondary to portal hypertension, despite the absence of overt bleeding symptoms. During hospitalization, ligation of large, high-risk esophageal varices was performed, and no other sources of anemia were identified. Pre- or post-hepatic causes of portal hypertension were ruled out. Liver elastography results were within normal ranges, and liver function tests were normal except for a marginal isolated elevation of gamma-glutamyltransferase. Liver function remained intact. Liver biopsy findings were consistent with a diagnosis of PSVD. The patient did not have any identifiable associated conditions and was not taking any medications known to pose a risk. Therefore, treatment was focused solely on managing the complications of portal hypertension. Outpatient follow-up included the eradication of esophageal varices. Treatment with oral iron supplements led to the normalization of hemoglobin levels, which remained stable for months after the discontinuation of therapy, and liver function tests continued to be normal.
- MeSH
- antihypertenziva terapeutické užití MeSH
- hypochromní anemie diagnóza farmakoterapie MeSH
- jaterní žilní okluze * diagnóza terapie MeSH
- karvedilol terapeutické užití MeSH
- lidé MeSH
- portální hypertenze * diagnóza farmakoterapie MeSH
- senioři MeSH
- splenomegalie MeSH
- železo terapeutické užití MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
Investigating microorganisms in metal-enriched environments holds the potential to revolutionize the sustainable recovery of critical metals such as lanthanides (Ln3+). We observe Hyphomicrobium spp. as part of a Fe2+/Mn2+-oxidizing consortia native to the ferruginous bottom waters of a Ln3+-enriched lake in Czechia. Notably, one species shows similarities to recently discovered bacteria expressing proteins with picomolar Ln3+ affinity. This finding was substantiated by developing an in-silico ionic competition model and recombinant expression of a homolog protein (Hm-LanM) from Hyphomicrobium methylovorum. Biochemical assays validate Hm-LanM preference for lighter Ln3+ ions (from lanthanum to gadolinium). This is comparable to established prototypes. Bioinformatics analyses further uncover additional H. methylovorum metabolic biomolecules in genomic proximity to Hm-LanM analogously dependent on Ln3+, including an outer membrane receptor that binds Ln3+-chelating siderophores. These combined observations underscore the remarkable strategy of Hyphomicrobium spp. for thriving in relatively Ln3+ enriched zones of metal-polluted environments.
Andjelkovic, Marija, Peter Paal, Susi Kriemler, Kaste Mateikaite-Pipiriene, Alison Rosier, Beth Beidleman, Mia Derstine, Jacqueline Pichler Hefti, David Hillebrandt, Lenka Horakova, Dominique Jean, and Linda E. Keyes. Nutrition in women at high altitude: a scoping review-UIAA Medical Commission recommendations. High Alt Med Biol. 25:9-15, 2024. Background: Nutritional concerns such as food composition, energy intake, and nutrient absorption are essential for performance at high altitude and may differ between men and women. We performed a scoping review to summarize what is currently known on nutrition for women during short-term, high-altitude, physically active sojourns. Methods: The UIAA Medical Commission convened an international team to review women's health issues at high altitude and to publish updated recommendations. Pertinent literature from PubMed and Cochrane was identified by keyword search combinations (including nutrition, metabolism, energy composition, micronutrients) with additional publications found by hand search. Results: We found 7,165 articles, of which 13 original articles assessed nutritional aspects in physically active women on short-term high-altitude sojourns, with other articles found by hand search. We summarize the main findings. Conclusions: Data on women's nutrition at altitude are very limited. Reduction in energy intake plus increased energy expenditure at high altitude can lead to unbalanced nutrition, negatively influencing high-altitude adaptation and physical performance. Therefore, adequate dietary and fluid intake is essential to maintaining energy balance and hydration at high altitude in women as in men. Iron supplementation should be considered for women with iron depletion before travel.
- MeSH
- dieta * MeSH
- lidé MeSH
- nadmořská výška * MeSH
- železo MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Recent research has highlighted the pivotal role of lipoxygenases in modulating ferroptosis and immune responses by catalyzing the generation of lipid peroxides. However, the limitations associated with protein enzymes, such as poor stability, low bioavailability, and high production costs, have motivated researchers to explore biomimetic materials with lipoxygenase-like activity. Here, we report the discovery of lipoxygenase-like two-dimensional (2D) MoS2nanosheets capable of catalyzing lipid peroxidation and inducing ferroptosis. The resulting catalytic products were successfully identified using mass spectrometry and a luminescent substrate. Unlike native lipoxygenases, MoS2 nanosheets exhibited exceptional catalytic activity at extreme pH, high temperature, high ionic strength, and organic solvent conditions. Structure-activity relationship analysis indicates that sulfur atomic vacancy sites on MoS2 nanosheets are responsible for their catalytic activity. Furthermore, the lipoxygenase-like activity of MoS2 nanosheets was demonstrated within mammalian cells and animal tissues, inducing distinctive ferroptotic cell death. In summary, this research introduces an alternative to lipoxygenase to regulate lipid peroxidation in cells, offering a promising avenue for ferroptosis induction.
- MeSH
- biomimetické materiály chemie farmakologie metabolismus MeSH
- disulfidy * chemie metabolismus MeSH
- ferroptóza * účinky léků MeSH
- katalýza MeSH
- lidé MeSH
- lipoxygenasa * metabolismus chemie MeSH
- molybden chemie metabolismus MeSH
- myši MeSH
- nanostruktury chemie MeSH
- peroxidace lipidů MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
