- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
This article presents 2 cases of TFG::MET-rearranged mesenchymal tumor, an extremely rare molecular subset among an emerging group of mesenchymal neoplasms with kinase gene (NTRK, BRAF, RET and others) alterations. Both tumors were congenital, occurred in female patients and presented as huge masses on the trunk and thigh, measuring 18 and 20 cm in the largest dimension. Both cases showed identical areas with a distinctive triphasic morphology resembling fibrous hamartoma of infancy (FHI), consisting of haphazardly arranged ovoid to spindled cells traversed by variably cellular and hyalinized fascicles admixed with (most likely non-neoplastic) adipose tissue. In other areas, a high-grade infantile fibrosarcoma/malignant peripheral nerve sheath tumor-like (IFS/MPNST-like) morphology was present in both cases. While the first case co-expressed CD34 and S100 protein, the other case did not. When combined with the three previously reported MET-rearranged cases (of which two harbored TFG::MET fusion), 3/5 and 3/4 of MET-rearranged and TFG::MET fusion-associated tumors, respectively exhibited similar triphasic FHI-like low-grade morphology. This points toward the existence of a relatively distinct morphological subset among kinase-fusion-associated tumors which seems to be strongly associated with MET fusions. It seems some of these low-grade cases may transform into a high-grade variant with IFS/MPNST-like morphology as has been observed in other tumors with kinase gene fusions. While most cases seem to follow an indolent clinical course, the recognition of these tumors is clinically relevant as MET tyrosine kinase inhibitors might represent an effective treatment option for clinically aggressive or unresectable cases.
- MeSH
- fibrosarkom * genetika MeSH
- fúze genů MeSH
- lidé MeSH
- nádorové biomarkery genetika MeSH
- nádory kůže * MeSH
- nádory měkkých tkání * genetika patologie MeSH
- nádory z pojivové a měkké tkáně * MeSH
- neurofibrosarkom * MeSH
- proteiny genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: Blood bicarbonate concentration plays an important role for obstructive sleep apnea (OSA) patients to maintain acid-base balance. We investigated the association between arterial standard bicarbonate ([HCO3-]) and nocturnal hypoxia as well as comorbid hypertension in OSA. METHODS: A cross-sectional analysis of 3329 patients in the European Sleep Apnea Database (ESADA) was performed. Arterial blood gas analysis and lung function test were performed in conjunction with polysomnographic sleep studies. The 4% oxygen desaturation index (ODI), mean and minimum oxygen saturation (SpO2), and percentage of time with SpO2 below 90% (T90%) were used to reflect nocturnal hypoxic burden. Arterial hypertension was defined as a physician diagnosis of hypertension with ongoing antihypertensive medication. Hypertensive patients with SBP/DBP below or above 140/90 mmHg were classified as controlled-, uncontrolled hypertension, respectively. RESULTS: The [HCO3-] level was normal in most patients (average 24.0 ± 2.5 mmol/L). ODI, T90% increased whereas mean and minimum SpO2 decreased across [HCO3-] tertiles (ANOVA, p = 0.030, <0.001, <0.001, and <0.001, respectively). [HCO3-] was independently associated with ODI, mean SpO2, minimum SpO2, and T90% after adjusting for confounders (β value [95%CI]: 1.21 [0.88-1.54], -0.16 [-0.20 to -0.11], -0.51 [-0.64 to -0.37], 1.76 [1.48-2.04], respectively, all p < 0.001). 1 mmol/L elevation of [HCO3-] was associated with a 4% increased odds of uncontrolled hypertension (OR: 1.04 [1.01-1.08], p = 0.013). CONCLUSION: We first demonstrated an independent association between [HCO3-] and nocturnal hypoxic burden as well as uncontrolled hypertension in OSA patients. Bicarbonate levels as an adjunctive measure provide insight into the pathophysiology of hypertension in OSA.
- MeSH
- hydrogenuhličitany MeSH
- hypertenze * epidemiologie komplikace MeSH
- hypoxie komplikace MeSH
- kyslík MeSH
- lidé MeSH
- obstrukční spánková apnoe * MeSH
- průřezové studie MeSH
- syndromy spánkové apnoe * komplikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Quantifying intraspecific and interspecific trait variability is critical to our understanding of biogeography, ecology and conservation. But quantifying such variability and understanding the importance of intraspecific and interspecific variability remain challenging. This is especially true of large geographic scales as this is where the differences between intraspecific and interspecific variability are likely to be greatest. Our goal is to address this research gap using broad-scale citizen science data to quantify intraspecific variability and compare it with interspecific variability, using the example of bird responses to urbanization across the continental United States. Using more than 100 million observations, we quantified urban tolerance for 338 species within randomly sampled spatial regions and then calculated the standard deviation of each species' urban tolerance. We found that species' spatial variability in urban tolerance (i.e. standard deviation) was largely explained by the variability of urban cover throughout a species' range (R2 = 0.70). Variability in urban tolerance was greater in species that were more tolerant of urban cover (i.e. the average urban tolerance throughout their range), suggesting that generalist life histories are better suited to adapt to novel anthropogenic environments. Overall, species differences explained most of the variability in urban tolerance across spatial regions. Together, our results indicate that (1) intraspecific variability is largely predicted by local environmental variability in urban cover at a large spatial scale and (2) interspecific variability is greater than intraspecific variability, supporting the common use of mean values (i.e. collapsing observations across a species' range) when assessing species-environment relationships. Further studies, across different taxa, traits and species-environment relationships are needed to test the role of intraspecific variability, but nevertheless, we recommend that when possible, ecologists should avoid using discrete categories to classify species in how they respond to the environment.
BACKGROUND: In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available. METHODS: We randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05. RESULTS: At a median follow-up of 29.6 months, zanubrutinib was found to be superior to ibrutinib with respect to progression-free survival among 652 patients (hazard ratio for disease progression or death, 0.65; 95% confidence interval, [CI], 0.49 to 0.86; P = 0.002), as assessed by the investigators; the results were similar to those as assessed by an independent-review committee. At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, a TP53 mutation, or both, those who received zanubrutinib had longer progression-free survival than those who received ibrutinib (hazard ratio for disease progression or death, 0.53; 95% CI, 0.31 to 0.88); progression-free survival across other major subgroups consistently favored zanubrutinib. The percentage of patients with an overall response was higher in the zanubrutinib group than in the ibrutinib group. The safety profile of zanubrutinib was better than that of ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death. CONCLUSIONS: In patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE ClinicalTrials.gov number, NCT03734016.).
- MeSH
- antitumorózní látky * škodlivé účinky terapeutické užití MeSH
- chronická lymfatická leukemie * farmakoterapie MeSH
- lidé MeSH
- nemoci srdce * chemicky indukované MeSH
- progrese nemoci MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
Transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling has fundamental roles in the regulation of the stem cell niche for both embryonic and adult stem cells. In zebrafish, male germ stem cell niche is regulated by follicle-stimulating hormone (Fsh) through different members of the TGF-β superfamily. On the other hand, the specific roles of TGF-β and BMP signaling pathways are unknown in the zebrafish male germ stem cell niche. Considering this lack of information, the present study aimed to investigate the pharmacological inhibition of TGF-β (A83-01) and BMP (DMH1) signaling pathways in the presence of recombinant zebrafish Fsh using testicular explants. We also reanalyzed single cell-RNA sequencing (sc-RNA-seq) dataset from adult zebrafish testes to identify the testicular cellular sites of smad expression, and to understand the physiological significance of the changes in smad transcript levels after inhibition of TGF-β or BMP pathways. Our results showed that A83-01 potentiated the pro-stimulatory effects of Fsh on spermatogonial differentiation leading to an increase in the proportion area occupied by differentiated spermatogonia with concomitant reduction of type A undifferentiated (Aund) spermatogonia. In agreement, expression analysis showed lower mRNA levels for the pluripotency gene pou5f3, and increased expression of dazl (marker of type B spermatogonia and spermatocyte) and igf3 (pro-stimulatory growth factor) following the co-treatment with TGF-β inhibitor and Fsh. Contrariwise, the inhibition of BMP signaling nullified the pro-stimulatory effects of Fsh, resulting in a reduction of differentiated spermatogonia and increased proportion area occupied by type Aund spermatogonia. Supporting this evidence, BMP signaling inhibition increased the mRNA levels of pluripotency genes nanog and pou5f3, and decreased dazl levels when compared to control. The sc-RNA-seq data unveiled a distinctive pattern of smad expression among testicular cells, primarily observed in spermatogonia (smad 2, 3a, 3b, 8), spermatocytes (smad 2, 3a, 8), Sertoli cells (smad 1, 3a, 3b), and Leydig cells (smad 1, 2). This finding supports the notion that inhibition of TGF-β and BMP signaling pathways may predominantly impact cellular components within the spermatogonial niche, namely spermatogonia, Sertoli, and Leydig cells. In conclusion, our study demonstrated that TGF-β and BMP signaling pathways exert antagonistic roles in the zebrafish germ stem cell niche. The members of the TGF-β subfamily are mainly involved in maintaining the undifferentiated state of spermatogonia, while the BMP subfamily promotes spermatogonial differentiation. Therefore, in the complex regulation of the germ stem cell niche by Fsh, members of the BMP subfamily (pro-differentiation) should be more predominant in the niche than those belonging to the TGF-β (anti-differentiation). Overall, these findings are not only relevant for understanding the regulation of germ stem cell niche but may also be useful for expanding in vitro the number of undifferentiated spermatogonia more efficiently than using recombinant hormones or growth factors.
- MeSH
- buněčná diferenciace genetika MeSH
- dánio pruhované * genetika MeSH
- folikuly stimulující hormon farmakologie metabolismus MeSH
- messenger RNA genetika MeSH
- pyrazoly * MeSH
- spermatogeneze genetika MeSH
- spermatogonie * metabolismus MeSH
- testis metabolismus MeSH
- thiosemikarbazony * MeSH
- transformující růstový faktor beta metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Arousing events influence retrieval success, with a number of studies supporting a context-dependent effect of arousal on episodic memory retrieval. An improvement in speed and accuracy of episodic memories is observed when negative arousal is attached to them. In contrast, enhancing effects of negative arousal have not been reported to improve semantic memory retrieval. Episodic and semantic memory are highly interactive and yet differ based on their embedded contextual content. Although differences in brain activity exist between episodic and semantic memory, the two types of memory retrieval are part of a common long-term memory system. Considering the shared processes between episodic and semantic memory, the objectives of the current study were twofold: i) to examine, employing a novel paradigm, whether performance on episodic and semantic memory retrieval would be influenced differently by varying levels of arousal, between negative and neutral valence; and ii) to explore the neural patterns underlying these processes. Forty-seven healthy young adults were recruited and completed the experiment in the MRI scanner. The results demonstrated a negative arousal effect on the brain circuitry subserving both memory conditions as well as on behavioural performance, as indicated by better accuracy and faster reaction times. The study provides an insight into the role of negative arousal in memory processes and contributes to our understanding of the interplay between cognitive and emotional factors in memory modulation. Our work also highlights the highly interactive nature of episodic and semantic memory, and emphasises the importance in understanding how negative arousal interacts with the contextual content of a memory, on a behavioural and neurofunctional level.
- MeSH
- arousal MeSH
- emoce MeSH
- epizodická paměť * MeSH
- lidé MeSH
- mapování mozku MeSH
- mladý dospělý MeSH
- mozek * diagnostické zobrazování MeSH
- rozpomínání MeSH
- sémantika MeSH
- Check Tag
- lidé MeSH
- mladý dospělý MeSH
- Publikační typ
- časopisecké články MeSH
A cross countries in Europe, health policy is seeking to adapt to the post-pandemic 'permacrisis', where high demands on the healthcare workforce and shortages continue and combine with climate change, and war. The success of these efforts depends on the capacities of the healthcare workforce. This study aims to compare health policy responses to strengthen the capacities of the healthcare workforce and to explore the underpinning dynamics between health systems, policy actors and health policies. The study draws on a qualitative, comparative analysis of Austria, the Czech Republic, Denmark, Germany, Italy and the Netherlands. The findings suggest that policy responses at the national level focused on hospitals and absorptive capacities, while policy responses at local/regional levels also included general practice and adaptive capacities. There were only few examples of policies directed at transformative capacities. The underling dynamics were shaped by health systems, where individual parts are closely connected, by embeddedness in specific service delivery and areas, and by power dynamics. In conclusion, sub-national health policy responses emerge as key to effective responses to the post-pandemic permacrisis, where health professions are central policy actors. Sub-national health policy responses build on existing power relations, but also have the potential to transcend these power relations.
- MeSH
- COVID-19 * MeSH
- lidé MeSH
- poskytování zdravotní péče MeSH
- pracovní síly MeSH
- psychická odolnost * MeSH
- zdravotní politika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Geografické názvy
- Evropa MeSH
Monitoring of the patient supported with a temporary mechanical circulatory support (tMCS) is crucial in achieving the best possible outcome. Monitoring is a continuous and labour-intensive process, as cardiogenic shock (CS) patients can rapidly deteriorate and may require new interventions within a short time period. Echocardiography and invasive haemodynamic monitoring form the cornerstone of successful tMCS support. During monitoring, it is particularly important to ensure that adequate end-organ perfusion is achieved and maintained. Here, we provide a comprehensive overview of best practices for monitoring the CS patient supported by a micro-axial flow pump, veno-arterial extracorporeal membrane oxygenation, and both devices simultaneously (ECMELLA approach). It is a complex process that encompasses device control, haemodynamic control and stabilization, monitoring of interventions, and assessment of end-organ function. The combined, continuous, and preferably protocol-based approach of echocardiography, evaluation of biomarkers, end-organ assessment, and haemodynamic parameters is crucial in assessing this critically ill CS patient population.
- Publikační typ
- časopisecké články MeSH
