Explore the vast range of titles available.

The story behind one of the most significant archaeological discoveries of all time, explaining its significance for understanding human evolution and how it is shaping the thinking of the scientific community.

Gaucher disease (GD), an autosomal recessive lysosomal disorder, primarily affects the lysosomal enzyme β-glucocerebrosidase (GCase), leading to glucosylceramide accumulation in lysosomes. GD presents a wide spectrum of clinical manifestations. This study deploys immune-based proteomics and mass spectrometry-based metabolomics technologies to comprehensively investigate the biochemical landscape in 43 deeply phenotyped type 1 GD patients compared to 59 controls. Conventional and systems biology approaches have been used to analyze the data. The results show promising biological imprints. Elevated phosphatidylcholines in GD patients suggest altered lipid metabolism, potentially due to their increased synthesis. This points to endoplasmic reticulum stress and impaired lipid trafficking, commonly seen in lysosomal diseases. GD patients exhibit an inflammatory profile with elevated cytokines and autoimmune-like inflammation, even in treated patients, highlighting the complexity of GD-related immune imbalances. Mitochondrial dysfunction clues are found through increased oxidative stress markers and altered acylcarnitine profiles in GD patients, suggesting mitochondrial membrane dysfunction affecting carnitine-carrying capacity. Furthermore, platelet count, splenectomy, treatment, and clinical traits were associated with specific omics features, providing insights into GD’s clinical heterogeneity and potential diagnostic markers. Autophagy inhibition appears pivotal in GD, driving lipid synthesis, impaired mitochondrial function, and inflammation through chronic activation of mTORC1. Despite limitations like focusing on type 1 GD and using targeted omics approaches, this study provides valuable insights into GD metabolic and immune dysregulation. It lays the basis for future comprehensive investigations into GD manifestations with broader scope and molecular coverage. Key messages The study sheds light on metabolic and immune dysregulation in Gaucher disease. Gaucher disease patients showed elevated phosphatidylcholines, disrupted lipid metabolism, and inflammation profiles. Signs of mitochondrial dysfunction are evident in Gaucher disease patients, with autophagy inhibition significantly affecting lipid synthesis, mitochondrial function, and inflammation via chronic activation of mTORC1.

Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment. In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0·1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114. Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21–34). Molecular relapse-free survival for these patients was 61% (95% CI 57–64) at 6 months and 50% (46–54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1·14 [95% CI 1·05–1·23]; p=0·0010) and longer deep molecular response durations (1·13 [1·04–1·23]; p=0·0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1·13 [0·98–1·29]; p=0·08). TKI discontinuation was associated with substantial cost savings (an estimated €22 million). No serious adverse events were reported. Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure. ELN Foundation and France National Cancer Institute.

Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8 + T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8 + T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8 + T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a T cell response that most likely contributes to virus control in COVID-19 patients but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8 + T cells, but not CD4 + T cells, characterized by the simultaneous production of granzyme A and B as well as perforin within different effector CD8 + T cell subsets. PD-1-expressing CD8 + T cells also produced cytotoxic molecules during acute infection, indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years, the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8 + cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provide valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development. IMPORTANCE Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8 + T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8 + T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8 + T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients.

Mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa) channels are involved in myocardial ischemic preconditioning. Their role in sildenafil-induced cardioprotection is unknown. We investigated whether sildenafil-induced acute cardioprotection is mediated by activation of mBKCa channels in the rat heart in vitro. Male Wistar rats (n = 8 per group) were randomized and anesthetized with pentobarbital (90 mg/kg). Hearts were isolated, mounted on a Langendorff system and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. Hearts underwent 30 min of global ischemia followed by 60 min of reperfusion. At the end of the experiments infarct size was determined by TTC staining. In the control group rats were not further treated. Sildenafil (3 μM) was administered over 10 min before the beginning of ischemia. The mBKCa channel inhibitor paxilline (1 μM) was administered with and without sildenafil before the onset of ischemia. The pathway underlying sildenafil-induced cardioprotection was further investigated with the protein kinase G blocker KT5823 (1 μM). Myocardial cGMP concentration was measured by ELISA. Data (mean±SD) were analysed with a one and two-way analysis of variance as appropriate. In control animals infarct size was 52±8%. Sildenafil increased cGMP concentration and reduced infarct size to 35±6% (P<0.05 vs. control). Paxilline and KT5823 completely blocked sildenafil-induced cardioprotection (paxilline+sildenafil: 50±8%, KT5823+sildenafil: 45±8%; both P<0.05 vs. sildenafil). Functional heart parameters and coronary flow were not different between the study groups. This study shows that in male rats protein kinase G-dependent opening of mBKCa channels plays a pivotal role in sildenafil-induced cardioprotection.

Background COVID-19 has developed into a worldwide pandemic which was accompanied by an «infodemic» consisting of much false and misleading information. To cope with these new challenges, health literacy plays an essential role. The aim of this paper is to present the findings of a trend study in Switzerland on corona-specific health literacy, the use of and trust in information sources during the COVID-19 pandemic, and their relationships. Methods Three online surveys each with approximately 1′020 individuals living in the German-speaking part of Switzerland (age ≥ 18 years) were conducted at different timepoints during the COVID-19 pandemic, namely spring, fall and winter 2020. For the assessment of corona-specific health literacy, a specifically developed instrument (HLS-COVID-Q22) was used. Descriptive, bivariate, and multivariate data analyses have been conducted. Results In general, a majority of the Swiss-German population reported sufficient corona-specific health literacy levels which increased during the pandemic: 54.6% participants in spring, 62.4% in fall and 63.3% in winter 2020 had sufficient corona-specific health literacy. Greatest difficulties concerned the appraisal of health information on the coronavirus. The most used information sources were television (used by 73.3% in spring, 70% in fall and 72.3% in winter) and the internet (used by 64.1, 64.8 and 66.5%). Although health professionals, health authorities and the info-hotline were rarely mentioned as sources for information on the coronavirus, respondents had greatest trust in them. On the other hand, social media were considered as the least trustworthy information sources. Respondents generally reporting more trust in the various information sources, tended to have higher corona-specific health literacy levels. Conclusions Sufficient health literacy is an essential prerequisite for finding, understanding, appraising, and applying health recommendations, particularly in a situation where there is a rapid spread of a huge amount of information. The population should be supported in their capability in appraising the received information and in assessing the trustworthiness of different information sources.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123 + epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections. Here, the authors identify interleukin-3 as a predictive marker for severity and outcome of SARS-CoV-2 infection in a multi-center, prospective study and find that patients with severe COVID-19 have reduced circulating plasmacytoid dendritic cell levels compared to non-severe COVID-19 patients.

The use of real-world data (RWD) for healthcare decision-making is complicated by concerns regarding whether RWD is fit-for-purpose or is of sufficient validity to support the creation of credible RWE. An efficient mechanism for screening the quality of RWD is needed as regulatory agencies begin to use real-world evidence (RWE) to inform decisions about treatment effectiveness and safety. First, we provide an overview of RWD and RWE. Data quality frameworks (DQFs) in the US and EU were examined, including their dimensions and subdimensions. There is some convergence of the conceptual DQFs on specific assessment criteria. Second, we describe a list of screening criteria for assessing the quality of RWD sources. The curation and analysis of RWD will continue to evolve in light of developments in digital health and artificial intelligence (AI). In conclusion, this paper provides a perspective on the utilization of RWD and RWE in healthcare decision-making. It covers the types and uses of RWD, data quality frameworks (DQFs), regulatory landscapes, and the potential impact of RWE, as well as the challenges and opportunities for the greater leveraging of RWD to create credible RWE.

Chronic Myeloid Leukemia (CML) is a model to investigate the impact of tumor intra-clonal heterogeneity in personalized medicine. Indeed, tyrosine kinase inhibitors (TKIs) target the BCR-ABL fusion protein, which is considered the major CML driver. TKI use has highlighted the existence of intra-clonal heterogeneity, as indicated by the persistence of a minority subclone for several years despite the presence of the target fusion protein in all cells. Epigenetic modifications could partly explain this heterogeneity. This review summarizes the results of DNA methylation studies in CML. Next-generation sequencing technologies allowed for moving from single-gene to genome-wide analyses showing that methylation abnormalities are much more widespread in CML cells. These data showed that global hypomethylation is associated with hypermethylation of specific sites already at diagnosis in the early phase of CML. The BCR-ABL-independence of some methylation profile alterations and the recent demonstration of the initial intra-clonal DNA methylation heterogeneity suggests that some DNA methylation alterations may be biomarkers of TKI sensitivity/resistance and of disease progression risk. These results also open perspectives for understanding the epigenetic/genetic background of CML predisposition and for developing new therapeutic strategies.