Dynamic blockage of radio propagation paths between the user equipment (UE) and the 5G New Radio (NR) Base Station (BS) induces abrupt rate fluctuations that may lead to sub-optimal performance of the Transmission Control Protocol (TCP) protocol. In this work, we characterize the effects of dynamic human blockage on TCP throughput at the 5G NR air interface. To this aim, we develop an analytical model that expresses the TCP throughput as a function of the round-trip time (RTT), environmental, and radio system parameters. Our results indicate that the blockage affects TCP throughput only when the RTT is comparable to the blocked and non-blocked state durations when the frequency of state changes is high. However, such conditions are not typical for dynamic body blockage environments allowing TCP to benefit from the high bandwidth of 5G NR systems fully.

• Klíčová slova
• 5G NR, TCP, analysis, blockage, mmWave,
• MeSH
• lidé MeSH
• lidské tělo * MeSH
• rádiové vlny * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH

BACKGROUND: We assessed the results and impact of blockage of utero-ovarian anastomoses (UOA) on clinical outcome in women treated by laparoscopic uterine artery occlusion for uterine fibroids. METHODS: Between 2004 and 2005, we prospectively analyzed the clinical data for 23 laparoscopic uterine artery occlusion cases combined with blockage of utero-ovarian anastomoses (Group A) and 67 laparoscopic uterine artery occlusion cases alone (Group B). RESULTS: Of these 23 patients with UOA (mean age, 36.7+/-2.8 years), 10 patients (43.4%) had anastomoses bilaterally and 13 patients (56.6%) had unilateral anastomoses. Mean fibroid size reduction after LUAO and anastomoses blockage was 32.5% from baseline (P<0.001). In patients with LUAO, the mean DF size after surgery was estimated at 38.7+/-19.2 mm, which translated to a mean fibroid size reduction of 30.6% from baseline (P<0.001). No case of clinical failure or recurrence was found in Group A patients with UOA (mean follow-up, 15.6 months), who were treated with combined surgery. At a mean clinical follow-up of 18.2 months (Group B), 6 patients (8.9%) elected to undergo further surgical intervention for clinical failure and recurrence, including 4 myomectomies and 2 hysterectomies. The statistical difference between groups was not significant (P=0.33). CONCLUSION: Laparoscopic blockage of utero-ovarian anastomoses combined with uterine artery occlusion is a safe, feasible surgical procedure in women with symptomatic fibroids. Combining the uterine artery occlusion and blockage of UO anastomoses may be a useful procedure for the decreasing rate of clinical failure and recurrence. This premise should be confirmed in a larger prospective multicenter study.

• MeSH
• dospělí MeSH
• krvácení při operaci MeSH
• leiomyom terapie   MeSH
• lidé MeSH
• nádory dělohy terapie   MeSH
• terapeutická embolizace * MeSH
• uterus krevní zásobení   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Current findings suggest a role for the angiotensin II (Ang II) signalling pathway in generation of reactive oxygen species and diabetes-induced cardiac complications. In this study we aimed to investigate the effect of angiotensin II type 1 (AT1) receptor blockage on some antioxidant enzymes such as glucose- 6-phosphate dehydrogenase (G6PD), 6-phoshogluconate dehydrogenase (6PGD), glutathione reductase (GR), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px), and catalase (CAT) in the heart of streptozotocin (STZ)-induced diabetic rats. The effect of AT1 receptor blocker, candesartan-cilexetil (5 mg/kg/day for 4 weeks) was studied. Diabetes caused hyperglycaemia (4-fold of control) with significant increases in G6PD, 6PGD, GR, GSH-PX, CAT and no effect on GST in heart tissues as compared to normal control rats. Treatment of STZ-induced diabetic rats with candesartan-cilexetil had significant beneficial effects on these parameters without any side effect on control rats. These results suggest that Ang II can take part in induction of oxidative stress in diabetic rat heart and that blockage of its activity by AT1 receptor blocker is potentially protective against diabetes-induced cellular damage.

• MeSH
• antagonisté receptorů pro angiotenzin * MeSH
• benzimidazoly farmakologie   MeSH
• bifenylové sloučeniny farmakologie   MeSH
• blokátory receptoru 1 pro angiotenzin II farmakologie   MeSH
• experimentální diabetes mellitus patofyziologie   MeSH
• glukosa-6-fosfátdehydrogenasa metabolismus   MeSH
• glutathionperoxidasa metabolismus   MeSH
• glutathionreduktasa metabolismus   MeSH
• glutathiontransferasa metabolismus   MeSH
• katalasa metabolismus   MeSH
• krysa rodu Rattus MeSH
• oxidační stres účinky léků   MeSH
• potkani Wistar MeSH
• tetrazoly farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antagonisté receptorů pro angiotenzin * MeSH
• benzimidazoly MeSH
• bifenylové sloučeniny MeSH
• blokátory receptoru 1 pro angiotenzin II MeSH
• candesartan cilexetil MeSH Prohlížeč
• glukosa-6-fosfátdehydrogenasa MeSH
• glutathionperoxidasa MeSH
• glutathionreduktasa MeSH
• glutathiontransferasa MeSH
• katalasa MeSH
• tetrazoly MeSH

Substrate inhibition is the most common deviation from Michaelis-Menten kinetics, occurring in approximately 25% of known enzymes. It is generally attributed to the formation of an unproductive enzyme-substrate complex after the simultaneous binding of two or more substrate molecules to the active site. Here, we show that a single point mutation (L177W) in the haloalkane dehalogenase LinB causes strong substrate inhibition. Surprisingly, a global kinetic analysis suggested that this inhibition is caused by binding of the substrate to the enzyme-product complex. Molecular dynamics simulations clarified the details of this unusual mechanism of substrate inhibition: Markov state models indicated that the substrate prevents the exit of the halide product by direct blockage and/or restricting conformational flexibility. The contributions of three residues forming the possible substrate inhibition site (W140A, F143L and I211L) to the observed inhibition were studied by mutagenesis. An unusual synergy giving rise to high catalytic efficiency and reduced substrate inhibition was observed between residues L177W and I211L, which are located in different access tunnels of the protein. These results show that substrate inhibition can be caused by substrate binding to the enzyme-product complex and can be controlled rationally by targeted amino acid substitutions in enzyme access tunnels.

• Publikační typ
• časopisecké články MeSH

Juvenile idiopathic arthritis (JIA) is a multifactorial autoimmune disease mediated by both adaptive and innate immunity. The role of neutrophils in the pathogenesis of autoimmune diseases is well-established; however, in JIA they are still markedly understudied. Here, we explored the neutrophil features and role of platelet-neutrophil aggregates in JIA patients and assessed the effect of TNF inhibitor (TNFi) therapy. We provide evidence of dysbalanced neutrophil subsets in JIA patients, with a shift towards immature and suppressive subpopulations that lack the cell-adhesion molecules. Correspondingly, patient sera contained high amounts of neutrophil- and platelet-related products. Transcriptomic analysis revealed neutrophil degranulation as the most affected process by TNFi therapy, which was mirrored by the decrease in degranulation products in the patient sera. Toll-like receptors -4, -7, and - 8 signaling pathways are particularly hyperresponsive in patients, but are strongly suppressed by TNFi. Overall, our study demonstrates augmented neutrophil and platelet responses in JIA patients.

• Klíčová slova
• Juvenile idiopathic arthritis, MMP8, Neutrophil, Neutrophil-platelet aggregates, Platelet, S100, TNF inhibitors,
• MeSH
• aktivace neutrofilů MeSH
• imunomodulace MeSH
• juvenilní artritida * MeSH
• lidé MeSH
• neutrofily MeSH
• trombocyty MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The mitochondrial rhomboid protease PARL regulates mitophagy by balancing intramembrane proteolysis of PINK1 and PGAM5. It has been implicated in the pathogenesis of Parkinson's disease, but its investigation as a possible therapeutic target is challenging in this context because genetic deficiency of PARL may result in compensatory mechanisms. To address this problem, we undertook a hitherto unavailable chemical biology strategy. We developed potent PARL-targeting ketoamide inhibitors and investigated the effects of acute PARL suppression on the processing status of PINK1 intermediates and on Parkin activation. This approach revealed that PARL inhibition leads to a robust activation of the PINK1/Parkin pathway without major secondary effects on mitochondrial properties, which demonstrates that the pharmacological blockage of PARL to boost PINK1/Parkin-dependent mitophagy is a feasible approach to examine novel therapeutic strategies for Parkinson's disease. More generally, this study showcases the power of ketoamide inhibitors for cell biological studies of rhomboid proteases.

• MeSH
• endopeptidasy MeSH
• lidé MeSH
• metaloproteasy genetika   metabolismus   MeSH
• mitochondriální proteiny metabolismus   MeSH
• mitofagie MeSH
• Parkinsonova nemoc * farmakoterapie   MeSH
• proteasy * MeSH
• proteinkinasy metabolismus   MeSH
• ubikvitinligasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endopeptidasy MeSH
• metaloproteasy MeSH
• mitochondriální proteiny MeSH
• PARL protein, human MeSH Prohlížeč
• proteasy * MeSH
• proteinkinasy MeSH
• ubikvitinligasy MeSH

Supraphysiological levels of IL-7 induce increase counts of pre-B cells, naive T cells and memory phenotype CD8+ T cells. Immunocomplexes of IL-7 and αIL-7 mAb M25 (IL-7/M25) were described as IL-7 superagonist in vivo. Thus, treatment of mice with IL-7/M25 remarkably increases the size of the T cell pool. We decided to use IL-7/M25 in order to expand the T cell population prior to the administration of αCTLA-4 and αPD-1 mAbs in tumor-bearing mice and in turn boost the immunotherapy based on a combination of CTLA-4 and PD-1 blockage. We found that just four doses of IL-7/M25 increased the absolute numbers of splenocytes approximately fivefold and significantly shifted the CD4+:CD8+ T cell ratio in favor of CD8+ T cells. There was also a substantive increase in relative counts of memory phenotype CD8+ T cells (approximately threefold) within CD8+ T cells but a significant decrease (approximately 30%) in relative counts of Treg cells within CD4+ T cells. All these data suggest that IL-7/M25 offer a suitable approach to potentiate tumor immunotherapy through CTLA-4 and PD-1 blockage. Unexpectedly, IL-7/M25 significantly abrogated the antitumor activity of αCTLA-4 plus αPD-1 mAbs in the following mouse tumor models: MC-38 and CT26 colon carcinoma and B16F10 melanoma. This paradoxical effect of IL-7/M25 on the antitumor activity of CTLA-4 and PD-1 blockage was not mediated via either increased levels of IL-10 or TGF-β in the sera or increased counts of IL-10-producing B or T cells in the spleen of mice injected with IL-7/M25. Thus, our work shows that caution should be exercised when combining two immunotherapy approaches together.

• Klíčová slova
• Antitumor activity, CTLA-4, IL-7, IL-7 immunocomplexes, Immunotherapy, PD-1,
• MeSH
• antigen CTLA-4 imunologie   MeSH
• antigeny CD279 imunologie   MeSH
• antitumorózní látky imunologie   MeSH
• CD4-pozitivní T-lymfocyty imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• imunoterapie metody   MeSH
• interleukin-10 imunologie   MeSH
• interleukin-7 imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom imunologie   MeSH
• modely nemocí na zvířatech MeSH
• monoklonální protilátky imunologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory tračníku imunologie   MeSH
• regulační T-lymfocyty imunologie   MeSH
• transformující růstový faktor beta imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• antigeny CD279 MeSH
• antitumorózní látky MeSH
• CTLA4 protein, human MeSH Prohlížeč
• IL7 protein, human MeSH Prohlížeč
• interleukin-10 MeSH
• interleukin-7 MeSH
• monoklonální protilátky MeSH
• PDCD1 protein, human MeSH Prohlížeč
• transformující růstový faktor beta MeSH

The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.

• MeSH
• antitumorózní látky farmakologie   MeSH
• buněčný cyklus účinky léků   MeSH
• dihydroorotátdehydrogenasa MeSH
• indazoly farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• nádory farmakoterapie   enzymologie   genetika   metabolismus   MeSH
• oxidoreduktasy působící na CH-CH vazby antagonisté a inhibitory   chemie   genetika   metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• proteolýza účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antitumorózní látky MeSH
• dihydroorotátdehydrogenasa MeSH
• indazoly MeSH
• inhibitory enzymů MeSH
• nádorový supresorový protein p53 MeSH
• oxidoreduktasy působící na CH-CH vazby MeSH

Venetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which call for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient-derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL2L11/BIM status.

• MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• benzothiazoly MeSH
• bicyklické sloučeniny heterocyklické * farmakologie   terapeutické užití   MeSH
• chemorezistence * MeSH
• isochinoliny MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protein bcl-X * metabolismus   antagonisté a inhibitory   MeSH
• protein BCL2L11 * metabolismus   genetika   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   antagonisté a inhibitory   MeSH
• sulfonamidy * farmakologie   terapeutické užití   MeSH
• synergismus léků MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• A-1155463 MeSH Prohlížeč
• antitumorózní látky MeSH
• BCL2L1 protein, human MeSH Prohlížeč
• benzothiazoly MeSH
• bicyklické sloučeniny heterocyklické * MeSH
• isochinoliny MeSH
• protein bcl-X * MeSH
• protein BCL2L11 * MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• sulfonamidy * MeSH
• venetoclax MeSH Prohlížeč

• Publikační typ
• tisková chyba MeSH