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"Roth, Patrick"
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رحلتى إلى شابلن
كتاب \"رحلتي إلى شابلن\" يجسد قصة شغف وحماس إنه قصة تحكي عن حب حياة روث وعن تبجيله لمؤلف \"أضواء المدينة\" 1931 (شارلي شابلن الذي كان قد تعقيه من شاشة سينما متداعية في لوس انجلس وصولا إلى أمام منزله السويسري ليسلمه شخصيا رسالة بعد 22 سنة من رحلته إلى القدوة والمثال الموقر يسلك روث طريق الرحلة مرة أخرى ويستوعب خطوة خطوة سبب حماسته لـشابلن ويدرك أن هذا السبب يكمن في واقعة الملامسة بين المتشرد والفتاة العمياء بائعة الزهور السابقة الواقعة التي يتأكد له أنها تمثل \"اللحظة الأشد قدسية في قصة الفيلم\" ويعيد إحياءها في روايته مرة أخرى هكذا تتحول سردية \"رحلتي إلى شابلن\" نفسها إلى فيلم لــشابلن حيث يلعب الشاب دور المتشرد بينما يكون الراوي محرجا لهذه الذكرى.
BOOK
Biological activity of tumor-treating fields in preclinical glioma models
Glioblastoma is the most common and aggressive form of intrinsic brain tumor with a very poor prognosis. Thus, novel therapeutic approaches are urgently needed. Tumor-treating fields (TTFields) may represent such a novel treatment option. The aim of this study was to investigate the effects of TTFields on glioma cells, as well as the functional characterization of the underlying mechanisms. Here, we assessed the anti-glioma activity of TTFields in several preclinical models. Applying TTFields resulted in the induction of cell death in a frequency- and intensity-dependent manner in long-term glioma cell lines, as well as glioma-initiating cells. Cell death occurred in the absence of caspase activation, but involved autophagy and necroptosis. Severe alterations in cell cycle progression and aberrant mitotic features, such as poly- and micronucleation, preceded the induction of cell death. Furthermore, exposure to TTFields led to reduced migration and invasion, which are both biological hallmarks of glioma cells. The combination of TTFields with irradiation or the alkylating agent, temozolomide (TMZ), resulted in additive or synergistic effects, and the O
6
-methyl-guanine DNA methyltransferase status did not influence the efficacy of TTFields. Importantly, TMZ-resistant glioma cells were responsive to TTFields application, highlighting the clinical potential of this therapeutic approach. In summary, our results indicate that TTFields induce autophagy, as well as necroptosis and hamper the migration and invasiveness of glioma cells. These findings may allow for a more detailed clinical evaluation of TTFields beyond the clinical data available so far.
Journal Article
EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood
In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy — Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.Herein, the European Association of Neuro-Oncology (EANO) provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. These evidence-based guidelines incorporate major changes in diagnostic algorithms based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System as well as on evidence from recent large clinical trials.
Journal Article
Structure and mechanism of a phosphotransferase system glucose transporter
Glucose is the primary source of energy for many organisms and is efficiently taken up by bacteria through a dedicated transport system that exhibits high specificity. In
Escherichia coli
, the glucose-specific transporter IICB
Glc
serves as the major glucose transporter and functions as a component of the phosphoenolpyruvate-dependent phosphotransferase system. Here, we report cryo-electron microscopy (cryo-EM) structures of the glucose-bound IICB
Glc
protein. The dimeric transporter embedded in lipid nanodiscs was captured in the occluded, inward- and occluded, outward-facing conformations. Together with biochemical and biophysical analyses, and molecular dynamics (MD) simulations, we provide insights into the molecular basis and dynamics for substrate recognition and binding, including the gates regulating the binding sites and their accessibility. By combination of these findings, we present a mechanism for glucose transport across the plasma membrane. Overall, this work provides molecular insights into the structure, dynamics, and mechanism of the IICB
Glc
transporter in a native-like lipid environment.
Glucose is a key energy source for many organisms, efficiently transported in bacteria by specific systems. Here, the authors reveal cryo-EM structures of the glucose transporter IICB from E. coli, providing insights into its mechanism and dynamics.
Journal Article
Simultaneous TGF-β and GITR pathway modulation promotes anti-tumor immunity in glioma
The immunosuppressive tumor microenvironment of glioblastoma limits the effectiveness of most immunotherapies. Transforming growth factor (TGF)-β signaling drives tumor progression and prevents effective T cell activity. Notably, both regulatory T cells (Tregs) and effector T cells within glioblastoma and other tumors express high levels of the immune checkpoint receptor, glucocorticoid-induced tumor necrosis factor receptor (GITR), which modulates T cell activation and function. Combining GITR agonism with TGF-β inhibition may therefore offer a compelling approach to restore anti-tumor immunity. We evaluated the combined effects of TGF-β inhibition and GITR modulation using two different GITR agonists in syngeneic mouse glioma models. GITR modulation enhanced T cell activation, as shown by increased cytokine secretion and effector T cell proliferation in vitro. Combining GITR modulation with TGF-β inhibition amplified these effects, resulting in significantly stronger immune cell-mediated tumor cell killing compared to single-agent treatments. Combination therapy improved survival of glioma-bearing mice, with a higher fraction of long-term survivors compared to monotherapy. Surviving mice resisted tumor re-challenge, indicating durable adaptive immunity. In summary, dual targeting of TGF-β and GITR pathways synergistically enhances anti-tumor immunity in glioblastoma. This novel combination strategy demonstrates clinical potential by addressing the limitations of existing immunotherapies and offering a promising approach for durable and effective glioblastoma treatment.
Journal Article
A phase Ib/II randomized, open-label drug repurposing trial of glutamate signaling inhibitors in combination with chemoradiotherapy in patients with newly diagnosed glioblastoma: the GLUGLIO trial protocol
Background
Glioblastoma is the most common and most aggressive malignant primary brain tumor in adults. Glioblastoma cells synthesize and secrete large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Moreover, neuronal networks interconnect with glioblastoma cell networks through glutamatergic neuroglial synapses, activation of which induces oncogenic calcium oscillations that are propagated
via
gap junctions between tumor cells. The primary objective of this study is to explore the efficacy of brain-penetrating anti-glutamatergic drugs to standard chemoradiotherapy in patients with glioblastoma.
Methods/design
GLUGLIO is a 1:1 randomized phase Ib/II, parallel-group, open-label, multicenter trial of gabapentin, sulfasalazine, memantine and chemoradiotherapy (Arm A) versus chemoradiotherapy alone (Arm B) in patients with newly diagnosed glioblastoma. Planned accrual is 120 patients. The primary endpoint is progression-free survival at 6 months. Secondary endpoints include overall and seizure-free survival, quality of life of patients and caregivers, symptom burden and cognitive functioning. Glutamate levels will be assessed longitudinally by magnetic resonance spectroscopy. Other outcomes of interest include imaging response rate, neuronal hyperexcitability determined by longitudinal electroencephalography, Karnofsky performance status as a global measure of overall performance, anticonvulsant drug use and steroid use. Tumor tissue and blood will be collected for translational research. Subgroup survival analyses by baseline parameters include segregation by age, extent of resection, Karnofsky performance status, O
6
-methylguanine DNA methyltransferase
(MGMT)
promotor methylation status, steroid intake, presence or absence of seizures, tumor volume and glutamate levels determined by MR spectroscopy. The trial is currently recruiting in seven centers in Switzerland.
Trial registration
NCT05664464. Registered 23 December 2022.
Journal Article
High‐throughput proteomic analysis of FFPE tissue samples facilitates tumor stratification
Formalin‐fixed, paraffin‐embedded (FFPE), biobanked tissue samples offer an invaluable resource for clinical and biomarker research. Here, we developed a pressure cycling technology (PCT)‐SWATH mass spectrometry workflow to analyze FFPE tissue proteomes and applied it to the stratification of prostate cancer (PCa) and diffuse large B‐cell lymphoma (DLBCL) samples. We show that the proteome patterns of FFPE PCa tissue samples and their analogous fresh‐frozen (FF) counterparts have a high degree of similarity and we confirmed multiple proteins consistently regulated in PCa tissues in an independent sample cohort. We further demonstrate temporal stability of proteome patterns from FFPE samples that were stored between 1 and 15 years in a biobank and show a high degree of the proteome pattern similarity between two types of histological regions in small FFPE samples, that is, punched tissue biopsies and thin tissue sections of micrometer thickness, despite the existence of a certain degree of biological variations. Applying the method to two independent DLBCL cohorts, we identified myeloperoxidase, a peroxidase enzyme, as a novel prognostic marker. In summary, this study presents a robust proteomic method to analyze bulk and biopsy FFPE tissues and reports the first systematic comparison of proteome maps generated from FFPE and FF samples. Our data demonstrate the practicality and superiority of FFPE over FF samples for proteome in biomarker discovery. Promising biomarker candidates for PCa and DLBCL have been discovered. Here, we report a pressure cycling technology‐SWATH data‐independent acquisition mass spectrometry workflow to reproducibly analyze punched and sectioned formalin‐fixed, paraffin‐embedded (FFPE) tissue proteomes in high‐throughput fashion. A FFPE tissue biobank can be thereby converted into a digital biobank of comprehensive tissue proteome archives which could be mined perpetually for clinical and biomarker research.
Journal Article
Factors associated with low health-related quality of life in persons with multiple sclerosis: A quantile-based segmentation approach
Improving health-related quality of life (HRQoL) is an important disease management goal in persons with Multiple Sclerosis (PwMS). HRQoL decreases with increasing age and prolonged disease duration; other factors remain less understood.
To identify associations of multiple sclerosis (MS) disease characteristics and symptom burden with low HRQoL.
Using the Swiss MS Registry, we applied quantile regression adjusted for age and MS disease duration to determine 25th (low HRQoL) and 75th (high HRQoL) percentiles of the EuroQol-5-Dimension (EQ-5D) distribution for PwMS. We compared PwMS across HRQoL groups by analyzing differences in sociodemographics, symptom burden, MS risk factors, gait impairment, and the MS Severity Score (MSSS), all measured at the same time as HRQoL. The analyses included descriptive methods, multivariable multinomial regression, and simultaneous quantile regression as a sensitivity analysis.
We included 1697 PwMS with median age and time-to-diagnosis of 49 and 9 years. Multivariable regression revealed low HRQoL to be associated with receiving invalidity insurance benefits, reporting depression, muscle weakness, memory problems, pain, and severe gait impairment. The analysis for individuals with available MSSS (n = 937) showed an increasing probability of low HRQoL with higher MSSS.
Our segmentation method identified symptom burden and MS severity as factors associated with low HRQoL. Pharmacological and non-pharmacological MS symptom management, especially for depression, fatigue, pain, and muscle weakness, may warrant increased attention to preserve or improve HRQoL.
Journal Article
Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma
The outcome of patients with anaplastic gliomas varies considerably. Whether a molecular classification of anaplastic gliomas based on large-scale genomic or epigenomic analyses is superior to histopathology for reflecting distinct biological groups, predicting outcomes and guiding therapy decisions has yet to be determined. Epigenome-wide DNA methylation analysis, using a platform which also allows the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas, and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering of DNA methylation patterns revealed two main groups correlated with
IDH
status: CpG island methylator phenotype (CIMP) positive (77.5 %) or negative (22.5 %). CIMP
pos
(
IDH
mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q. CIMP
neg
(
IDH
wild type) tumors showed hallmark copy-number alterations of glioblastomas, and clustered together with CIMP
neg
glioblastomas without forming separate groups based on WHO grade. Notably, there was no molecular evidence for a distinct biological entity representing anaplastic oligoastrocytoma. Tumor classification based on CIMP and 1p/19q status was significantly associated with survival, allowing a better prediction of outcome than the current histopathological classification: patients with CIMP
pos
tumors with 1p/19q codeletion (CIMP-codel) had the best prognosis, followed by patients with CIMP
pos
tumors but intact 1p/19q status (CIMP-non-codel). Patients with CIMP
neg
anaplastic gliomas (GBM-like) had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped by
IDH
and 1p/19q status into three molecular groups that show clear links to underlying biology and a significant association with clinical outcome in a prospective trial cohort.
Journal Article