Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) ...(n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.
It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep ...molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86
pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86
pDC (n=12). This suggested that low CD86
pDC might be predictive of TFR. Indeed, in a prospective analysis of 122 patients discontinuing their TKI within the EURO-SKI trial, the one-year relapse-free survival (RFS) was 30.1% (95% CI 15.6-47.9) for patients with >95 CD86
pDC per 10
lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with <95 CD86
pDC (hazard ratio (HR) 3.4, 95%
CI: 1.9-6.0; P<0.0001). Moreover, only patients with <95 CD86
pDC derived a significant benefit from longer (>8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86
pDC counts significantly correlated with leukemia-specific CD8
T
cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86
pDC counts have a higher risk of relapse after TKI discontinuation.
Geometric morphometrics offer effective methods to obtain information about shape and shape variability. In ostracodology, landmark-based methods are, however, not well established. To test the ...applicability of geometric morphometric analyses for ostracods, we investigated shape variation among recent and fossil populations of the genus Cytheridella using a combination of landmarks and semilandmarks. The study focuses on the species' intraspecific morphological variability on a supra-regional scale, comparing living populations from Florida, Yucatán, Colombia and Brazil. We performed Generalized least-squares Procrustes Analysis on 508 adult and juvenile specimens (valves) including stages A-1 to A-4. The analyses show that the primary pattern in shape variation is ontogenetic allometry, supporting a clear separation of adults and juveniles. Shape changes are relatively small during ontogeny from A-4 to A-1. Greatest modification of valve shape occurs during the last molt phase. Insufficient differentiation of sexes is caused by females with less developed brood pouches. Disentangling size- and non-size-dependent shape changes reveals regional differences between populations of the species C. ilosvayi and supports its taxonomic distinction from a fossil relative (C. danielopoli). The distribution of regional morphotypes of C. ilosvayi in Florida, Mexico, and Brazil are congruent with fly ways of water birds.
Information on strategies and practices in the search of missing persons with dementia is inconsistent which creates challenges for first responders, such as police, when they choose appropriate ...search and rescue approaches. The purpose of this study was to describe current strategies among police services in Ontario. Telephone interviews with police were conducted. Questions included what strategies were used for locating missing persons living with dementia, and what gaps exist in search practices. Participants described they used high- and low-tech solutions in search and rescue. They identified gaps in education and awareness, proactive strategies, resources, and funding. Information collected from the interviews was used to develop a practice guideline for police in partnership with the Alzheimer Society of Ontario.
This mini-review summarizes the present knowledge regarding central oxygen-chemosensitive sites with special emphasis on their function in regulating changes in cardiovascular and respiratory ...responses. These oxygen-chemosensitive sites are distributed throughout the brain stem from the thalamus to the medulla and may form an oxygen-chemosensitive network. The ultimate effect on respiratory or sympathetic activity presumably depends on the specific neural projections from each of these brain stem oxygen-sensitive regions as well as on the developmental age of the animal. Little is known regarding the cellular mechanisms involved in the chemotransduction process of the central oxygen sensors. The limited information available suggests some conservation of mechanisms used by other oxygen-sensing systems, e.g., carotid body glomus cells and pulmonary vascular smooth muscle cells. However, major gaps exist in our understanding of the specific ion channels and oxygen sensors required for transducing central hypoxia by these central oxygen-sensitive neurons. Adaptation of these central oxygen-sensitive neurons during chronic or intermittent hypoxia likely contributes to responses in both physiological conditions (ascent to high altitude, hypoxic conditioning) and clinical conditions (heart failure, chronic obstructive pulmonary disease, obstructive sleep apnea syndrome, hypoventilation syndromes). This review underscores the lack of knowledge about central oxygen chemosensors and highlights real opportunities for future research.
Cyclotides are head-to-tail cyclized peptides with a unique cystine-knot motif. Their structure provides exceptional resistance against enzymatic, chemical, or thermal degradation compared to other ...peptides. Peptide-based therapeutics promise high specificity, selectivity and lower immunogenicity, making them safer alternatives to small molecules or large biologicals. Cyclotides were researched due to their anti-cancer properties by inducing apoptosis in tumor cells in the past, but the impact of cyclotides on cytotoxic immune cells was poorly studied. Natural Killer (NK) cells are cytotoxic innate lymphoid cells and play an important role in the defense against infected, stressed and transformed cells. NK cells do not need prior sensitization and act in an antigen independent manner, holding promising potential in the field of immunotherapy. To investigate the effect of immunomodulatory cyclotides on NK cells, we evaluated several peptide-enriched plant extracts on NK cell mediated cytotoxicity. We observed that the extract samples derived from Carapichea ipecacuanha (Brot.) L. Andersson augments the killing potential of mouse NK cells against different tumor targets in vitro. Subsequent isolation of cyclotides from C. ipecacuanha extracts led to the identification of a primary candidate that enhances cytotoxicity of both mouse and human NK cells. The augmented killing is facilitated by the increased degranulation capacity of NK cells. In addition, we noted a direct toxic effect of caripe 8 on tumor cells, suggesting a dual therapeutic potential in cancer treatment. This study offers novel insights how natural peptides can influence NK cell cytotoxicity. These pre-clinical findings hold significant promise for advancing current immunotherapeutic approaches.
Display omitted
•Extracts or purified peptides derived from plants can enhance the activity of cytotoxic NK cells.•A cyclotide derived from Carapichea ipecacuanha, known as caripe 8, boosts the functionality of both mouse and human NK cells.•Additionally to its effect on NK cells, caripe 8 directly induces tumor cell death.
Objective
To compare direct and indirect costs and quality of life (QoL) of pediatric and adult patients with Dravet syndrome (DS), with drug‐resistant epilepsy (DRE) and in seizure remission (SR), ...and their caregivers, in Germany.
Methods
Questionnaire responses from 93 DS patients and their caregivers were matched by age and gender with responses from 93 DRE and 93 SR patients collected in independent studies, and were compared across main components of QoL, direct costs (patient visits, medication use, care level, medical equipment, and ancillary treatments), and indirect costs (quitting job, reduced working hours, missed days).
Results
Mean total direct costs were highest for DS patients (€4864 median €3564 vs €3049 median €1506 for DRE excluding outliers, P = 0.01; and €1007 median €311, P < 0.001 for SR). Total lost productivity over 3 months was highest among caregivers of pediatric DS (€4757, median €2841), compared with those of DRE (€1541, P < 0.001; median €0) and SR patients (€891, P < 0.001; median €0). The proportions of caregivers in employment were similar across groups (62% DS, 63% DRE, and 63% SR) but DS caregivers were more likely to experience changes to their working situation, such as quitting their job (40% DS vs 16% DRE and 9% SR, P < 0.001 in both comparisons). KINDL scores were significantly lower for DS patients (62 vs 74 and 72, P < 0.001 in both comparisons), and lower than for the average German population (77). Pediatric caregiver EQ‐5D scores across all cohorts were comparable with population norms, but more DS caregivers experienced moderate to severe depressive symptoms (24% vs 11% and 5%). Mean Beck Depression Inventory (BDI‐II) score was significantly higher in DS caregivers than either of the other groups (P < 0.001).
Significance
This first comparative study of Dravet syndrome to difficult‐to‐treat epilepsy and to epilepsy patients in seizure remission emphasizes the excess burden of DS in components of QoL and direct costs. The caregivers of DS patients have a greater impairment of their working lives (indirect costs) and increased depression symptoms.
Closely related species are often assumed to be functionally similar. Phylogenetic information is thus widely used to infer functional diversity and assembly of communities. In contrast, evolutionary ...processes generating functional similarity of phylogenetically distinct taxa are rarely addressed in this context.
To investigate the impact of convergent evolution on functional diversity (FD) and phylogenetic diversity (PD), we reconstructed the phylogenetic structure of carabid trophic groups. We then analyzed the mandible shapes using geometric morphometrics to link specialization in functional morphology with feeding specialization among herbivores, generalist carnivores, and specialized consumers of Collembola.
Our results show that carabid feeding groups are paraphyletic. Herbivory evolved at least twice and specialization to Collembola predation at least three times. Species within feeding groups share a remarkably similar mandible morphology, which evolved convergently. While specialized mandibles of herbivores and collembolan specialists represent an adaptation to their main food source, the particular mandible morphologies do not necessarily reflect the degree of food specialization within feeding groups. Only a few species with a specialized herbivorous mandible may occasionally feed on animals, but the range of specific food resources in generalist carnivore species is large, despite an almost identical mandible shape.
Thus, convergent evolution in specialized feeding groups reverses the relationship between PD and functional similarity compared with generalist carnivores. We conclude that phylogenetic relationship is a poor proxy of FD in carabids. Moreover, the inconsistencies between relatedness, morphological adaptation, and ecological function require caution in the characterization of functional groups. Rather than assuming general relationships between PD and FD, we suggest integrating the analysis of evolutionary processes into functional community analyses.
In this study, we demonstrate that in carabids feeding groups and their morphological adaptations to the main food resource evolved multiple times convergently. Therefore, in carabids there is no clear relationship between phylogenetic distance and functional similarity. We further show that morphological specialization does not explain ecological specialization and many species are specialized generalists.
ABSTRACT
Gastropoda are an exceptionally successful group with a rich and diverse fossil record. They have conquered land and freshwater habitats multiple times independently and have dispersed ...across the entire globe. Since they are important constituents of fossil assemblages, they are often used for palaeoecological reconstruction, biostratigraphic correlations, and as model groups to study morphological and taxonomic evolution. While marine faunas and their evolution have been a common subject of study, the freshwater component of the fossil record has attracted much less attention, and a global overview is lacking. Here, I review the fossil record of freshwater gastropods on a global scale, ranging from their origins in the late Palaeozoic to the Pleistocene. As compiled here, the global fossil record of freshwater Gastropoda includes 5182 species in 490 genera, 44 families, and 12 superfamilies over a total of ~340 million years. Following a slow and poorly known start in the late Palaeozoic, diversity slowly increased during the Mesozoic. Diversity culminated in an all‐time high in the Neogene, relating to diversification in numerous long‐lived (ancient) lakes in Europe. I summarise well‐documented and hypothesised freshwater colonisation events and compare the patterns found in freshwater gastropods to those in land snails. Furthermore, I discuss potential preservation and sampling biases, as well as the main drivers underlying species diversification in fresh water on a larger scale. In that context, I particularly highlight the importance of long‐lived lakes as islands and archives of evolution and expand a well‐known concept in ecology and evolution to a broader spectrum: scale‐independent ecological opportunity.
PDF
