The efforts to utilize microflow liquid chromatography hyphenated to tandem mass spectrometry (μLC-MS/MS) for deep-scale proteomic analysis are still growing. In this work, two-dimensional LC separation and peptide derivatization by a tandem mass tag (TMT) were used to assess the capability of μLC-MS/MS to reveal protein changes associated with the severe chronic anthracycline cardiotoxicity phenotype in comparison with nanoflow liquid chromatography (nLC-MS/MS). The analysis of the control and anthracycline-treated rabbit myocardium by μLC-MS/MS and nLC-MS/MS allowed quantification of 3956 and 4549 proteins, respectively, with 84% of these proteins shared in both data sets. Both nLC-MS/MS and μLC-MS/MS revealed marked global proteome dysregulation in severe anthracycline cardiotoxicity, with a significant change in approximately 55% of all detected proteins. The μLC-MS/MS analysis allowed less compressed and more precise determination of the TMT channel ratio and correspondingly broader fold-change protein distribution than nLC-MS/MS. The total number of significantly changed proteins was higher in nLC-MS/MS (2498 vs 2183, 1900 proteins shared), whereas the opposite was true for a number of significantly changed proteins with a fold-change cutoff ≥ 2 (535 vs 820). The profound changes concerned mainly proteins of cardiomyocyte sarcomeres, costameres, intercalated discs, mitochondria, and extracellular matrix. In addition, distinct alterations in immune and defense response were found with a remarkable involvement of type I interferon signaling that has been recently hypothesized to be essential for anthracycline cardiotoxicity pathogenesis. Hence, μLC-MS/MS was found to be a sound alternative to nLC-MS/MS that can be useful for comprehensive mapping of global myocardial proteome alterations such as those associated with severe anthracycline cardiotoxicity.

• Publication type
• Journal Article MeSH

Recent findings on stress and anxiety in attention deficit hyperactivity disorder (ADHD) suggest that specific processes related to brain developmental disorganization could create a vulnerable background that increases sensitivity to stress stimuli from the psychosocial environment. These basic neurodevelopmental processes are closely related to the developmental mechanisms of primitive functions and their integration or disintegration. In this context, the psychopathological processes that manifest in ADHD are linked to the mechanisms of disturbed inhibitory functions that may cause incongruent neural interactions ("neural interference") between the more primitive functions and the higher levels of attentional and cognitive neural processes. These disturbed developmental processes may also determine increased sensitivity to stressful experiences that, in ADHD cases, could lead to the manifestations of various psychopathological symptoms such as disturbed attentional and motor functions, anxiety, and depression, among other cognitive and affective disturbances. These findings, based on previous research, suggest novel framework and hypothesis on how this neurodevelopment-based increased sensitivity to stress stimuli could manifest in the etiopathogenesis of ADHD in its relationship with cognitive, affective, and motor deficits.

• Publication type
• Journal Article MeSH
• Review MeSH

Development of dentition is a commonly studied process as a representative of the development of ectodermal derivates. A key step is the formation of a signaling center called the enamel knot (EK), which organizes tooth crown formation. In the mouse lower jaw, the anterior part of the tooth-forming region undergoes a series of complex events before the first molar primary EK can form more posteriorly and the tooth can progress through the cap stage. Although much is known about the molecular factors involved in tooth development, disentangling their specific roles is difficult. In this study, we circumvented this problem by isolating the posterior part of the tooth-forming region at embryonic day 13.5 and cultivating it in vitro. By treating them with molecules activating or inhibiting Sonic hedgehog (Shh) and fibroblast growth factor (Fgf) pathways, we demonstrate that Shh plays the role of an inhibitor of EK formation, and we suggest that the FGF pathways may have both positive and negative roles, as seen in hair. By RNA-sequencing of the cultivated isolates after 0, 16, or 24 h in vitro, respectively, we screened for genes whose expression varies with EK and cap formation and pointed to Cdkn2b and Sema3b as 2 promising candidates in this process.

• MeSH
• Fibroblast Growth Factors physiology   MeSH
• Molar embryology   MeSH
• Mice MeSH
• Odontogenesis * physiology   genetics   MeSH
• Hedgehog Proteins physiology   metabolism   MeSH
• Signal Transduction MeSH
• Gene Expression Regulation, Developmental MeSH
• Tooth Crown * embryology   MeSH
• Dental Enamel * embryology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Schizophrenia is a psychiatric disorder with heterogeneous clinical manifestations and complex aetiology. Notably, the triple-network model proposes an interesting framework for investigating abnormal neurocircuit activity at rest in schizophrenia. The present study on 30 chronic schizophrenia individuals and 30 controls aimed to explore the differences in EEG resting state effective connectivity within a triple-network model using source-localization-based Directed Transfer Function. Our findings revealed multiband effective connectivity disturbances within default mode (DMN), central executive (CEN), and salience (SN) networks in schizophrenia. The most significant difference was manifested in a global DMN hyperconnectivity, accompanied by low-band hyperconnectivity and high-band hypoconnectivity in CEN, along with the aberrant information flows in SN. In conclusion, our study presents novel insights into schizophrenia neuropathology, with a particular emphasis on the reversed directionality in information flows between hubs of SN, DMN, and CEN. This may be suggested as a promising biomarker of schizophrenia.

• MeSH
• Default Mode Network * physiopathology   MeSH
• Adult MeSH
• Electroencephalography MeSH
• Connectome * methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Nerve Net * physiopathology   diagnostic imaging   MeSH
• Schizophrenia * physiopathology   diagnostic imaging   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: This study explored patient and clinician perspectives on a new fixed-dose combination of macitentan and tadalafil (M/T FDC) in a once-daily single tablet for treatment of pulmonary arterial hypertension (PAH). METHODS: Qualitative semi-structured interviews were conducted during the open-label period of the global, phase 3 A DUE clinical trial that evaluated M/T FDC. A subset of enrolled patients (N = 26) and site investigators (N = 18 clinicians) were interviewed. Patients received four tablets during double-blind treatment and could be in one of three arms (macitentan + placebo; tadalafil + placebo; M/T FDC + placebo) followed by M/T FDC (one tablet) during the open-label period. Patients and clinicians were asked to share their experience of pre-trial PAH medication, double-blind treatment, and open-label M/T FDC. Thematic analysis was conducted on blinded data. RESULTS: Patients preferred the M/T FDC tablet (open-label) over the four tablets during double-blind treatment. Patients were satisfied with M/T FDC, highlighting its positive impact on their psychological well-being, through reducing stress associated with managing multiple pills. All patients indicated that having a single, once-a-day pill for PAH was more convenient and associated with greater treatment adherence. Clinicians highlighted that their patients have a high daily pill burden for PAH and other comorbidities, and prefer treatments with an oral mode of administration that reduce the number of daily pills required. Clinicians felt that M/T FDC would be well received in clinical practice and potentially assist in implementing guideline-recommended combination treatment of PAH. CONCLUSIONS: In this qualitative analysis, all 26 patients and 18 clinicians provided positive feedback on M/T FDC treatment, which was consistent across countries. Reducing the number of pills needed to treat PAH, through use of single-tablet M/T FDC, is highly valued by patients and endorsed by clinicians, who both felt the single-tablet combination therapy could have a positive effect on patients' well-being and increase treatment adherence.

• MeSH
• Adaptive Clinical Trials as Topic MeSH
• Antihypertensive Agents * administration & dosage   therapeutic use   MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Drug Combinations MeSH
• Phosphodiesterase 5 Inhibitors administration & dosage   therapeutic use   MeSH
• Clinical Trials, Phase III as Topic MeSH
• Qualitative Research MeSH
• Middle Aged MeSH
• Humans MeSH
• Multicenter Studies as Topic MeSH
• Pulmonary Arterial Hypertension * drug therapy   MeSH
• Hypertension, Pulmonary * drug therapy   MeSH
• Pyrimidines * administration & dosage   therapeutic use   MeSH
• Randomized Controlled Trials as Topic MeSH
• Interviews as Topic MeSH
• Aged MeSH
• Patient Satisfaction MeSH
• Sulfonamides * administration & dosage   therapeutic use   MeSH
• Tablets MeSH
• Tadalafil * administration & dosage   therapeutic use   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Acinetobacter baumannii (AB) is an opportunistic pathogen with growing clinical relevance due to its increasing level of antimicrobial resistance in the last few decades. In the event of an AB hospital outbreak, fast detection and localization of the pathogen is crucial, to prevent its further spread. However, contemporary diagnostic tools do not always meet the requirements for rapid and accurate diagnosis. For this reason, we report here the possibility of using gallium-68 labeled siderophores, bacterial iron chelators, for positron emission tomography imaging of AB infections. In our study, we radiolabeled several siderophores and tested their in vitro uptake in AB cultures. Based on the results and the in vitro properties of studied siderophores, we selected two of them for further in vivo testing in infectious models. Both selected siderophores, ferrioxamine E and ferrirubin, showed promising in vitro characteristics. In vivo, we observed rapid pharmacokinetics and no excessive accumulation in organs other than the excretory organs in normal mice. We demonstrated that the radiolabeled siderophores accumulate in AB-infected tissue in three animal models: a murine model of myositis, a murine model of dorsal wound infection and a rat model of pneumonia. These results suggest that both siderophores radiolabeled with Ga-68 could be used for PET imaging of AB infection.

• MeSH
• Acinetobacter baumannii * MeSH
• Acinetobacter Infections * diagnostic imaging   microbiology   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Positron-Emission Tomography * methods   MeSH
• Gallium Radioisotopes * chemistry   MeSH
• Siderophores * chemistry   pharmacokinetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

INTRODUCTION: Familial risk of lung cancer (LC) is at the level of many common cancers (ca 2.0) but as cigarette smoking is the main cause of LC, it has remained undefined to what extent smoking contributes to the familial risk. We take advantage of the natural experiment of divorce. In Sweden, it has been customary that children stay with their mother after divorce. We thus hypothesize that only maternal half-siblings share the childhood environment to the same extent than full siblings. METHODS: We used Swedish nation-wide data on family structures and cancers up to year 2021 to determined LC risk (standardized incidence ratio, SIR with 95% confidence intervals) in maternal and paternal half-siblings and in full siblings. RESULTS: Familial risk for LC in maternal half-siblings was 2.21 (1.76-2.77) which was not different from that of full siblings 2.23 (2.22-2.44). For paternal half-siblings the risk was 1.56 (1.21-2.01). For adenocarcinoma the risks were for full siblings 2.36 (2.23-2.51), for maternal half-siblings 2.55 (1.93-3.35) and for paternal half-siblings 1.33 (0.94-1.87). CONCLUSIONS: The results showed that familial risk for LC was equal in full siblings and in maternal half-siblings; the risks for paternal half-siblings were lower and for adenocarcinoma significantly lower than those for full siblings. The results suggest that smoking is a major contributor to familial risk of LC in this setting. Smoking starts at an early age and anti-smoking campaigns should target childhood environment for prevention of smoking initiation.

• MeSH
• Adult MeSH
• Incidence MeSH
• Smoking adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mothers MeSH
• Lung Neoplasms * epidemiology   etiology   prevention & control   MeSH
• Fathers MeSH
• Risk Factors MeSH
• Aged MeSH
• Siblings * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Sweden MeSH

BACKGROUND: Profiling studies in small-cell lung cancer (SCLC) have mainly focused on primary tumors, omitting the potential molecular changes that might occur during lymphatic metastasis formation. Here, we assessed the molecular discordance between primary SCLCs and corresponding lymph node (LN) metastases in the light of subtype distribution and expression of clinically relevant proteins. METHODS: Comparative profiling of 32 surgically resected primary SCLCs and their LN metastases was achieved by RNA expression analysis and immunohistochemistry (IHC). In addition to subtype markers (ASCL1, NEUROD1, POU2F3, and YAP1), the expression of nine cancer-specific proteins was evaluated. RESULTS: The selected clinically relevant molecules showed no significant differences in their RNA expression profile when assessing the primary tumors and their corresponding LN metastases. Nevertheless, IHC analyses revealed significantly higher DLL3 expression in the primary tumors than in the LN metastases (P = 0.008). In contrast, NEUROD1 expression was significantly lower in the primary tumors (versus LN metastases, P < 0.001). No statistically significant difference was found by IHC analysis in the case of other clinically relevant proteins. Concerning SCLC molecular subtypes, a change in subtype distribution was detected in 21 cases. Phenotype switching from neuroendocrine (NE) subtypes toward non-NE lesions and from non-NE landscape toward NE subtypes were both detected. CONCLUSIONS: Although the molecular landscape of SCLC LN metastases largely resembles that of the tumor of origin, key differences exist in terms of DLL3 and NEUROD1 expression, and in subtype distribution. These diagnostic pitfalls should be considered when establishing the tumors' molecular profile for future clinical trials solely based on LN biopsies.

• MeSH
• Immunohistochemistry MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphatic Metastasis * pathology   MeSH
• Small Cell Lung Carcinoma * surgery   pathology   genetics   MeSH
• Biomarkers, Tumor genetics   MeSH
• Lung Neoplasms * pathology   surgery   genetics   MeSH
• Aged MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

BACKGROUND: Despite extensive research on physical activity behaviour (PAB), consensus is lacking on related terms and definitions, thereby hindering the ability to compare findings between studies and to develop reliable assessment tools. This study therefore aimed to establish consensus on the definitions of key PAB determinants. METHODS: First, an international expert steering committee was established, comprising members of the European Cooperation in Science and Technology (COST) action "DEterminants of Physical ActivitieS in Settings" (DE-PASS). Recently published review-level studies were used to identify key determinants of PAB. Two independent reviewers systematically reviewed the literature to catalogue the range of definitions used for key determinants of PAB (steps 1-2). A two-round modified Delphi survey was conducted online from February to September 2023, to determine the optimal definition for each determinant. In round 1, experts selected the most suitable definition for each of the 41 initially identified determinants. In round 2, experts ranked the appropriateness of the definition selected from round 1 on a 5-point Likert scale. Consensus was defined a priori as ≥ 75% agreement on the definition (i.e., ratings of ≥ 4 points). A professional English language expert ensured concise, coherent wording and high-quality editing of the definitions (steps 3-6). RESULTS: Eighty-five experts in PAB research participated in round 1, and sixty-nine experts in round 2. Consensus of definitions was achieved for 39 of the 41 determinants (88.4%-98.6% agreement). The consensus threshold was not achieved for two determinants: genetic profile and regulation (69.6%) and backyard access/size (73.9%). CONCLUSIONS: The findings of this study offer a consensus-based set of definitions for 39 key determinants of PAB. These definitions can be used homogenously in academic research on physical activity.

• MeSH
• Exercise * MeSH
• Delphi Technique * MeSH
• Consensus * MeSH
• Humans MeSH
• Health Behavior MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Epitranscriptomics, the study of RNA modifications such as N6-methyladenosine (m6A), provides a novel layer of gene expression regulation with implications for numerous biological processes, including cellular adaptation to hypoxia. Hypoxia-inducible factor-1 (HIF-1), a master regulator of the cellular response to low oxygen, plays a critical role in adaptive and pathological processes, including cancer, ischemic heart disease, and metabolic disorders. Recent discoveries accent the dynamic interplay between m6A modifications and HIF-1 signaling, revealing a complex bidirectional regulatory network. While the roles of other RNA modifications in HIF-1 regulation remain largely unexplored, emerging evidence suggests their potential significance. MAIN BODY: This review examines the reciprocal regulation between HIF-1 and epitranscriptomic machinery, including m6A writers, readers, and erasers. HIF-1 modulates the expression of key m6A components, while its own mRNA is regulated by m6A modifications, positioning HIF-1 as both a regulator and a target in this system. This interaction enhances our understanding of cellular hypoxic responses and opens avenues for clinical applications in treating conditions like cancer and ischemic heart disease. Promising progress has been made in developing selective inhibitors targeting the m6A-HIF-1 regulatory axis. However, challenges such as off-target effects and the complexity of RNA modification dynamics remain significant barriers to clinical translation. CONCLUSION: The intricate interplay between m6A and HIF-1 highlights the critical role of epitranscriptomics in hypoxia-driven processes. Further research into these regulatory networks could drive therapeutic innovation in cancer, ischemic heart disease, and other hypoxia-related conditions. Overcoming challenges in specificity and off-target effects will be essential for realizing the potential of these emerging therapies.

• MeSH
• Adenosine analogs & derivatives   metabolism   MeSH
• Epigenesis, Genetic * MeSH
• Hypoxia-Inducible Factor 1 * metabolism   genetics   MeSH
• Humans MeSH
• RNA Processing, Post-Transcriptional MeSH
• Gene Expression Regulation MeSH
• Signal Transduction MeSH
• Transcriptome MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH