Metastasis, the spread of malignant cells from a primary tumour to distant sites, causes 90% of cancer-related deaths. The integrin ITGB3 has been previously described to play an essential role in ...breast cancer metastasis, but the precise mechanisms remain undefined. We have now uncovered essential and thus far unknown roles of ITGB3 in vesicle uptake. The functional requirement for ITGB3 derives from its interactions with heparan sulfate proteoglycans (HSPGs) and the process of integrin endocytosis, allowing the capture of extracellular vesicles and their endocytosis-mediated internalization. Key for the function of ITGB3 is the interaction and activation of focal adhesion kinase (FAK), which is required for endocytosis of these vesicles. Thus, ITGB3 has a central role in intracellular communication via extracellular vesicles, proposed to be critical for cancer metastasis.
Emerging evidence shows the crucial role of inflammation (particularly NF‐κB pathway) in the development and progression of myelofibrosis (MF), becoming a promising therapeutic target. Furthermore, ...tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias. Since recent studies have highlighted the role of miR‐146a, a negative regulator of the NF‐κB pathway, in the pathogenesis of MF; here we used miR‐146a−/− (KO) mice, a MF‐like model lacking driver mutations, to investigate whether pharmacological inhibition of JAK/STAT and/or NF‐κB pathways may reverse the myelofibrotic phenotype of these mice. Specifically, we tested the JAK1/2 inhibitor, ruxolitinib; the NF‐κB inhibitor via IKKα/β, BMS‐345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2/IRAK1), pacritinib. Although all treatments decreased spleen size and partially recovered its architecture, only NF‐κB inhibition, either using BMS‐345541 (alone or in combination) or pacritinib, resulted in a reduction of extramedullary hematopoiesis, bone marrow (BM) fibrosis and osteosclerosis, along with an attenuation of the exacerbated inflammatory state (via IL‐1β and TNFα). However, although dual inhibitor improved anemia and reversed thrombocytopenia, the combined therapy worsened anemia by inducing BM hypoplasia. Both therapeutic options reduced NF‐κB and JAK/STAT signaling in a context of JAK2V617F‐driven clonal hematopoiesis. Additionally, combined treatment reduced both COL1A1 and IL‐6 production in an in vitro model mimicking JAK2‐driven fibrosis. In conclusion, NF‐κB inhibition reduces, in vitro and in vivo, disease burden and BM fibrosis, which could provide benefits in myelofibrosis patients.
We used miR‐146a−/− (KO) mice, a MF‐like model lacking driver mutations, to investigate whether pharmacological inhibition of JAK/STAT and/or NF‐κB pathways may reverse the myelofibrotic phenotype of these mice. Specifically, we tested the JAK1/2 inhibitor, ruxolitinib; the NF‐κB inhibitor via IKKα/β, BMS‐345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2/IRAK1), pacritinib. Although all treatments decreased spleen size and partially recovered its architecture, only NF‐κB inhibition, either using BMS‐345541 (alone or in combination) or pacritinib, resulted in a reduction of extramedullary hematopoiesis, bone marrow (BM) fibrosis and osteosclerosis, along with an attenuation of the exacerbated inflammatory state (via IL‐1β and TNFα). However, whereas dual inhibitor improved anemia and reversed thrombocytopenia, the combined therapy worsened anemia by inducing BM hypoplasia. Additionally, combined treatment reduced both COL1A1 and IL‐6 production in an in vitro model mimicking JAK2‐driven fibrosis. In summary, NF‐κB inhibition reduces, in vitro and in vivo, disease burden, and BM fibrosis, which could provide benefits in myelofibrosis patients
Targeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding ...the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo3,4-bpyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these kinases, EB1 only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the specific DFD motif. This novel mode of action appears to be superior to the ATP-competitive inhibitors, which render the protein in a pseudo-active state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.
New diquat derivatives based on 1,2,3triazolo1,5‐apyridine and 1,2,3triazolo1,5‐aquinoline have been synthesized in excellent yields. To evaluate the effect of the alkyl bridge length, ethane and ...propane dibromo alkane substrates were used for their synthesis. Theoretical calculations predicted a very small energetic barrier between the two possible enantiomers P (Ra) and M (Sa), which makes them very difficult to resolve. Thermal denaturation studies, UV/Visible spectroscopy, and fluorescence titrations with ct‐DNA evidenced the intercalation of the quinoline derivatives in DNA.
Electrostatic interactions: New diquat derivatives based on 1,2,3triazolo1,5‐apyridine and 1,2,3triazolo1,5‐aquinoline have been synthesized in excellent yields. To evaluate the effect of the alkyl bridge length, ethane and propane dibromo alkane substrates were used for their synthesis (see scheme).
Cancer is a rapidly evolving, multifactorial disease that accumulates numerous genetic and epigenetic alterations. This results in molecular and phenotypic heterogeneity within the tumor, the ...complexity of which is further amplified through specific interactions between cancer cells. We aimed to dissect the molecular mechanisms underlying the cooperation between different clones.
We produced clonal cell lines derived from the MDA-MB-231 breast cancer cell line, using the UbC-StarTrack system, which allowed tracking of multiple clones by color: GFP C3, mKO E10 and Sapphire D7. Characterization of these clones was performed by growth rate, cell metabolic activity, wound healing, invasion assays and genetic and epigenetic arrays. Tumorigenicity was tested by orthotopic and intravenous injections. Clonal cooperation was evaluated by medium complementation, co-culture and co-injection assays.
Characterization of these clones in vitro revealed clear genetic and epigenetic differences that affected growth rate, cell metabolic activity, morphology and cytokine expression among cell lines. In vivo, all clonal cell lines were able to form tumors; however, injection of an equal mix of the different clones led to tumors with very few mKO E10 cells. Additionally, the mKO E10 clonal cell line showed a significant inability to form lung metastases. These results confirm that even in stable cell lines heterogeneity is present. In vitro, the complementation of growth medium with medium or exosomes from parental or clonal cell lines increased the growth rate of the other clones. Complementation assays, co-growth and co-injection of mKO E10 and GFP C3 clonal cell lines increased the efficiency of invasion and migration.
These findings support a model where interplay between clones confers aggressiveness, and which may allow identification of the factors involved in cellular communication that could play a role in clonal cooperation and thus represent new targets for preventing tumor progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Studies on older patients have established notable conceptual changes in the etiopathogenesis of acute coronary syndrome (ACS), but little is known about this disease in young patients (<45 years). ...Of special interest is thromboinflammation, key at onset, evolution and therapy of cardiovascular pathology. Therefore, we explored whether ACS at an early age is a thromboinflammatory disease by analyzing NETs and rs2431697 of miR-146a (a miRNA considered as a brake of TLR/NF-kB pathway), elements previously related to higher rates of recurrence in atrial fibrillation and sepsis. We included 359 ACS patients (<45 years) and classified them for specific analysis into G1 (collected during the hospitalization of the first event), G2 and G3 (retrospectively collected from patients with or without ACS recurrence, respectively). cfDNA and citH3−DNA were quantified, and rs2431697 was genotyped. Analysis in the overall cohort showed a moderate but significant correlation between cfDNA and citH3−DNA and Killip−Kimball score. In addition, patients with citH3−DNA > Q4 more frequently had a history of previous stroke (6.1% vs. 1.6%). In turn, rs2431697 did not confer increased risk for the onset of ACS, but T carriers had significantly higher levels of NET markers. By groups, we found that cfDNA levels were similarly higher in all patients, but citH3−DNA was especially higher in G1, suggesting that in plasma, this marker may be attenuated over time. Finally, patients from G2 with the worst markers (cfDNA and citH3−DNA > Q2 and T allele) had a two-fold increased risk of a new ischemic event at 2-year follow-up. In conclusion, our data confirm that ACS is younger onset with thromboinflammatory disease. In addition, these data consolidate rs2431697 as a silent proinflammatory factor predisposing to NETosis, and to a higher rate of adverse events in different cardiovascular diseases.
we assessed the accuracy of the QMon-20 oscillometric upper-arm cuff device professional for office blood pressure (BP) in general population according to the Association for the Advancement of ...Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Universal Standard (ISO 81060-2:2018).
Subjects were recruited according to AAMI/ ESH/ISO Universal Standard in general population using the same arm sequential BP measurement method. Two cuffs of the test device were used for arm circumference 22-31 (medium) and 32-42 cm (large).
One-hundred and fourteen subjects were recruited and 106 were analyzed. For validation criterion 1, the mean ± SD of the differences between the test device and reference BP readings was 0.8 ± 5.4/-0.5 ± 4.2 mmHg (systolic/ diastolic). For criterion 2, the SD of the mean BP differences between the test device and reference BP per subject was 4.34/3.48 mmHg (systolic/diastolic).
The QMon-20 oscillometric device for office BPs measurement fulfilled all the requirements of the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018) in general population and can be recommended for clinical use.
Isolated single chains of the coordination polymer Cd(6‐MCP)2 · 2H2On (6‐MCP = 6‐mercaptopurinate) (see Figure and inside cover) have been prepared by ultrasonic dispersion, ultracentrifugation, and ...deposition on a treated mica surface, and their mechanical and electrical properties studied. The observed insulating behaviour of the chains has been confirmed using density functional theory calculations.
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