Interest in the biodegradation mechanisms and environmental fate of hydrophobic organic compounds (HOC) such as polycyclic aromatic hydrocarbons (PAHs) is motivated by their ubiquity in the ...environment, their persistence and their potentially deleterious effect on human health. Due to their high hydrophobicity, PAH tend to interact with non-aqueous phases and natural organic matter and, as a consequence, are poorly bioavailable for microbial degradation. Here, a novel calorimetric approach was developed and successfully tested in order to gain real time information on the kinetics and the physiology of PAH bioconversion in aqueous systems. Anthracene-degrading soil bacterium
Mycobacterium frederiksbergense LB501T was exposed to a pulsed titration of dissolved anthracene and the resulting thermal reaction monitored. The heat flux signals of the biodegradation of 180
ng anthracene were interpreted in terms of the Michaelis-Menten kinetics and the parameters
K
A and
r
A
max
of anthracene degradation were derived. The comparison with a conventional method shows the suitability of isothermal titration calorimetry (ITC) to extract kinetic degradation parameters of organic trace pollutants from simple ITC experiments.
Background Alzheimer's disease (AD) is often preceded by stages of cognitive impairment, namely subjective cognitive decline (SCD) and mild cognitive impairment (MCI). While cerebrospinal fluid (CSF) ...biomarkers are established predictors of AD, other non-invasive candidate predictors include personality traits, anxiety, and depression, among others. These predictors offer non-invasive assessment and exhibit changes during AD development and preclinical stages.Methods In a cross-sectional design, we comparatively evaluated the predictive value of personality traits (Big Five), geriatric anxiety and depression scores, resting-state functional magnetic resonance imaging activity of the default mode network, apoliprotein E (ApoE) genotype, and CSF biomarkers (tTau, pTau181, A beta 42/40 ratio) in a multi-class support vector machine classification. Participants included 189 healthy controls (HC), 338 individuals with SCD, 132 with amnestic MCI, and 74 with mild AD from the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE).ResultsMean predictive accuracy across all participant groups was highest when utilizing a combination of personality, depression, and anxiety scores. HC were best predicted by a feature set comprised of depression and anxiety scores and participants with AD were best predicted by a feature set containing CSF biomarkers. Classification of participants with SCD or aMCI was near chance level for all assessed feature sets.Conclusion Our results demonstrate predictive value of personality trait and state scores for AD. Importantly, CSF biomarkers, personality, depression, anxiety, and ApoE genotype show complementary value for classification of AD and its at-risk stages.
Enhanced glycolysis (Warburg effect) driven by the BRAF oncogene, dysregulated GAPDH expression, and activation of the PI3K/AKT/mTOR signaling pathway may significantly contribute to the ...resistance-targeted therapy of BRAF-mutated melanomas. Therefore, we aimed to study for the first time the anti-tumor activity of the GAPDH inhibitor GP-2250 in BRAF-mutated melanoma cell lines and benign melanocytes. We employed three melanoma cell lines and one primary melanocyte cell line (Ma-Mel-61a, Ma-Mel-86a, SH-4 and ATCC-PCS-200-013, respectively), which were exposed to different GP-2250 doses. GP-2250’s effects on cell proliferation and viability were evaluated by means of the BrdU and MTT assays, respectively. The RealTime-Glo Annexin V Apoptosis and Necrosis Assay was performed for the evaluation of apoptosis and necrosis induction. RT-PCR and western blotting were implemented for the determination of AKT and STAT3 gene and protein expression analyses, respectively. The melanoma cell lines showed a dose-dependent response to GP-2250 during BrDU and MTT testing. The RealTime-Glo Annexin V assay revealed the heterogenous impact of GP-2250 on apoptosis as well as necrosis. With respect to the melanoma cell lines Ma-Mel-86a and SH-4, the responses and dosages were comparable to those used for the MTT viability assay. Using the same dose range of GP-2250 administered to melanoma cells, however, we observed neither the noteworthy apoptosis nor necrosis of GP-2250-treated benign melanocytes. The gene expression profiles in the melanoma cell lines for AKT and STAT3 were heterogenous, whereby AKT as well as STAT3 gene expression were most effectively downregulated using the highest GP-2250 doses. Immunoblotting revealed that there was a time-dependent decrease in protein expression at the highest GP-2250 dose used, whereas a time- as well as dose-dependent AKT decrease was predominantly observed in Ma-Mel-61a. The STAT3 protein expression of Ma-Mel-86a and SH-4 was reduced in a time-dependent pattern at lower and moderate doses. STAT3 expression in Ma-Me-61a was barely altered by GP-2250. In conclusion, GP-2250 has anti-neoplastic effects in BRAF-mutated melanoma cell lines regarding tumor cell viability, proliferation, and apoptosis/necrosis. GP-2250 is able to downregulate the gene and protein expression of aberrant tumorigenic pathways in melanoma cell lines. Since GP-2250 is a GAPDH inhibitor, the substance may be a promising combination therapy for tumors presenting the Warburg effect, such as melanoma.
In multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE), dysfunction of the blood–brain barrier (BBB) leads to edema formation within the central nervous ...system. The molecular mechanisms of edema formation in EAE/MS are poorly understood. We hypothesized that edema formation is due to imbalanced water transport across the BBB caused by a disturbed crosstalk between BBB endothelium and astrocytes. Here, we demonstrate at the light microscopic and ultrastructural level, the loss of polarized localization of the water channel protein aquaporin-4 (AQP4) in astrocytic endfeet surrounding microvessels during EAE. AQP4 was found to be redistributed over the entire astrocytic cell surface and lost its arrangement in orthogonal arrays of intramembranous particles as seen in the freeze-fracture replica. In addition, immunostaining for the astrocytic extracellular matrix receptor β-dystroglycan disappeared from astroglial membranes in the vicinity of inflammatory cuffs, whereas immunostaining for the dystroglycan ligands agrin and laminin in the perivascular basement membrane remained unchanged. Our data suggest that during EAE, loss of β-dystroglycan-mediated astrocyte foot process anchoring to the basement membrane leads to loss of polarized AQP4 localization in astrocytic endfeet, and thus to edema formation in EAE.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severely debilitating condition which markedly restricts activity and function of affected people. Since the beginning of the COVID-19 ...pandemic ME/CFS related to post-acute COVID-19 syndrome (PACS) can be diagnosed in a subset of patients presenting with persistent fatigue 6 months after a mostly mild SARS-CoV-2 infection by fulfillment of the Canadian Consensus Criteria (CCC 2003). Induction of autoimmunity after viral infection is a mechanism under intensive investigation. In patients with ME/CFS, autoantibodies against thyreoperoxidase (TPO), beta-adrenergic receptors (ß2AR), and muscarinic acetylcholine receptors (MAR) are frequently found, and there is evidence for effectiveness of immunomodulation with B cell depleting therapy, cyclophosphamide, or intravenous immunoglobulins (IVIG). Preliminary studies on the treatment of ME/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement. However, evidence from placebo-controlled trials is currently missing.
In this double-blinded, randomized, sham-controlled, exploratory trial the therapeutic effect of five cycles of IA every other day in patients with ME/CFS, including patients with post-acute COVID-19 chronic fatigue syndrome (PACS-CFS), will be evaluated using the validated Chalder Fatigue Scale, a patient-reported outcome measurement. A total of 66 patients will be randomized at a 2:1 ratio: 44 patients will receive IA (active treatment group) and 22 patients will receive a sham apheresis (control group). Moreover, safety, tolerability, and the effect of IA on patient-reported outcome parameters, biomarker-related objectives, cognitive outcome measurements, and physical parameters will be assessed. Patients will be hospitalized at the clinical site from day 1 to day 10 to receive five IA treatments and medical visits. Four follow-up visits (including two visits at site and two visits via telephone call) at month 1 (day 30), 2 (day 60), 4 (day 120), and 6 (day 180; EOS, end of study visit) will take place.
Although ME/CFS including PACS-CFS causes an immense individual, social, and economic burden, we lack efficient therapeutic options. The present study aims to investigate the efficacy of immunoadsorption and to contribute to the etiological understanding and establishment of diagnostic tools for ME/CFS.
Registration Number: NCT05710770 . Registered on 02 February 2023.
(
), also known as
(
), represents an oncogenic driver and has been effectively targeted in breast and gastric cancer. Recently, next-generation sequencing (NGS) discovered
as a promising therapeutic ...target in metastatic colorectal cancer (mCRC), where it is altered in 3-5% of patients, but no therapies are currently approved for this use. Herein, we present the experience of a single center in diagnosing actionable genetic
alterations using NGS and utilizing the latest therapeutic options. Between October 2019 and December 2022, a total of 107 patients with advanced CRC underwent molecular analysis, revealing actionable
mutations in two patients and
amplifications in two other patients. These findings correlated with immunohistochemical (IHC) staining. Of these four patients, two were treated with trastuzumab-deruxtecan (T-DXd). We present two exemplary cases of patients with actionable
alterations to demonstrate the effectiveness of T-DXd in heavily pretreated
-positive mCRC patients and the need for early molecular profiling. To fully exploit the potential of this promising treatment, earlier molecular profiling and the initiation of targeted therapies are essential.
KCNA2 IgG autoimmunity in neuropsychiatric diseases Arlt, Friederike A.; Miske, Ramona; Machule, Marie-Luise ...
Brain, behavior, and immunity,
March 2024, 2024-03-00, 20240301, Letnik:
117
Journal Article
Recenzirano
Odprti dostop
•KCNA2 autoimmunity is diverse ranging from dementia to seizures and encephalitis.•Patients can respond to immunotherapy, in particular if initiated early.•CSF KCNA2 autoantibodies are associated ...with cognitive impairment.•KCNA2 IgGs react with intracellular epitopes and reach their targets in vivo.•IgG3 and IgG1 autoantibodies predominate and target distinct CNS and PNS structures.
Autoantibodies against the potassium voltage-gated channel subfamily A member 2 (KCNA2) have been described in a few cases of neuropsychiatric disorders, but their diagnostic and pathophysiological role is currently unknown, imposing challenges to medical practice.
We retrospectively collected comprehensive clinical and paraclinical data of 35 patients with KCNA2 IgG autoantibodies detected in cell-based and tissue-based assays. Patients’ sera and cerebrospinal fluid (CSF) were used for characterization of the antigen, clinical-serological correlations, and determination of IgG subclasses.
KCNA2 autoantibody-positive patients (n = 35, median age at disease onset of 65 years, range of 16–83 years, 74 % male) mostly presented with cognitive impairment and/or epileptic seizures but also ataxia, gait disorder and personality changes. Serum autoantibodies belonged to IgG3 and IgG1 subclasses and titers ranged from 1:32 to 1:10,000. KCNA2 IgG was found in the CSF of 8/21 (38 %) patients and in the serum of 4/96 (4.2 %) healthy blood donors. KCNA2 autoantibodies bound to characteristic anatomical areas in the cerebellum and hippocampus of mammalian brain and juxtaparanodal regions of peripheral nerves but reacted exclusively with intracellular epitopes. A subset of four KCNA2 autoantibody-positive patients responded markedly to immunotherapy alongside with conversion to seronegativity, in particular those presenting an autoimmune encephalitis phenotype and receiving early immunotherapy. An available brain biopsy showed strong immune cell invasion. KCNA2 autoantibodies occurred in less than 10 % in association with an underlying tumor.
Our data suggest that KCNA2 autoimmunity is clinically heterogeneous. Future studies should determine whether KCNA2 autoantibodies are directly pathogenic or develop secondarily. Early immunotherapy should be considered, in particular if autoantibodies occur in CSF or if clinical or diagnostic findings suggest ongoing inflammation. Suspicious clinical phenotypes include autoimmune encephalitis, atypical dementia, new-onset epilepsy and unexplained epileptic seizures.
Epigenetic mechanisms, which modulate gene expression, are becoming increasingly important in the research on anorexia nervosa (AN). Patients with AN have difficulties with the perception of hunger ...even though hormones like high ghrelin and low leptin signal the need for energy intake. Given the prominent role of the growth hormone secretagogue receptor (GHS-R1a) and the leptin receptor (LEPR) in appetite regulation, a dysregulation of the receptors’ expression levels, possibly resulting from altered DNA promoter methylation, may contribute to the pathophysiology of AN. Such alterations could be secondary effects of undernutrition (state markers) or biological processes that may play an antecedent, possibly causal, role in the pathophysiology (trait markers). Therefore, the objective of this study was to examine DNA promoter methylation of the GHS-R1a and LEPR gene promoter regions and investigate whether methylation levels are associated with AN symptoms. We studied medication-free underweight patients with acute AN as well as weight-recovered patients and normal-weight, healthy female control subjects. While DNA methylation of the LEPR gene was similar across groups, GHS-R1a promoter methylation was increased in underweight AN compared to healthy controls – a finding which can be interpreted within the framework of the “ghrelin-resistance” hypothesis in AN. The results of the current study suggest for the first time a potential epigenetic mechanism underlying altered GHS-R1a sensitivity or altered ghrelin signaling in acutely underweight AN. If a ghrelin-centered model of AN can be verified, a next step could be the search for a dietary or psychopharmacological modulation at the ghrelin receptor, potentially via epigenetic mechanisms.
•DNA promoter methylation of ghrelin receptor gene is increased in acute anorexia.•Epigenetic alteration of the ghrelin receptor gene in anorexia is a state-related effect.•DNA promoter methylation of leptin receptor gene is unaltered in anorexia patients.•Epigenetic mechanisms might contribute to altered GHS-R1a sensitivity in anorexia.
Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severely debilitating condition which markedly restricts activity and function of affected people. Since the beginning of ...the COVID-19 pandemic ME/CFS related to post-acute COVID-19 syndrome (PACS) can be diagnosed in a subset of patients presenting with persistent fatigue 6 months after a mostly mild SARS-CoV-2 infection by fulfillment of the Canadian Consensus Criteria (CCC 2003). Induction of autoimmunity after viral infection is a mechanism under intensive investigation. In patients with ME/CFS, autoantibodies against thyreoperoxidase (TPO), beta-adrenergic receptors (ss2AR), and muscarinic acetylcholine receptors (MAR) are frequently found, and there is evidence for effectiveness of immunomodulation with B cell depleting therapy, cyclophosphamide, or intravenous immunoglobulins (IVIG). Preliminary studies on the treatment of ME/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement. However, evidence from placebo-controlled trials is currently missing. Methods In this double-blinded, randomized, sham-controlled, exploratory trial the therapeutic effect of five cycles of IA every other day in patients with ME/CFS, including patients with post-acute COVID-19 chronic fatigue syndrome (PACS-CFS), will be evaluated using the validated Chalder Fatigue Scale, a patient-reported outcome measurement. A total of 66 patients will be randomized at a 2:1 ratio: 44 patients will receive IA (active treatment group) and 22 patients will receive a sham apheresis (control group). Moreover, safety, tolerability, and the effect of IA on patient-reported outcome parameters, biomarker-related objectives, cognitive outcome measurements, and physical parameters will be assessed. Patients will be hospitalized at the clinical site from day 1 to day 10 to receive five IA treatments and medical visits. Four follow-up visits (including two visits at site and two visits via telephone call) at month 1 (day 30), 2 (day 60), 4 (day 120), and 6 (day 180; EOS, end of study visit) will take place. Discussion Although ME/CFS including PACS-CFS causes an immense individual, social, and economic burden, we lack efficient therapeutic options. The present study aims to investigate the efficacy of immunoadsorption and to contribute to the etiological understanding and establishment of diagnostic tools for ME/CFS. Trial registration Registration Number: NCT05710770. Registered on 02 February 2023. Keywords: Chronic fatigue syndrome, Myalgic encephalomyelitis, Post-acute COVID-19 syndrome, Long-COVID, Immunoadsorption, Autoimmunity, PROMIS, Biomarker
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