Evolution of the Cytosolic Iron/Sulfur cluster Assembly machinery in Blastocystis sp. and other microbial eukaryotes

The Cytosolic Iron/Sulfur cluster Assembly (CIA) machinery is responsible for the assembly of cytosolic and nuclear iron/sulfur clusters, cofactors that are vital for all living cells. This machinery is uniquely found in eukaryotes and consists of at least eight proteins in opisthokont lineages such as animals and yeast. We sought to identify and characterize homologues of the CIA system proteins in the anaerobic stramenopile parasite Blastocystis sp. NandII strain. We identified transcripts encoding six of the components - Cia1, Cia2, MMS19, Nbp35, Nar1, and a putative Tah18 - and showed that the last three of them localized to the cytoplasm of the cell using immuno-fluorescence microscopy, immuno-electron microscopy and subcellular fractionation. We then used comparative genomic and phylogenetic approaches to investigate the evolutionary history of these proteins. While most Blastocystis homologues branch with their eukaryotic counterparts, the putative Blastocystis Tah18 seems to have a separate evolutionary origin and therefore possibly a different function. Furthermore, our phylogenomic analyses revealed that all eight CIA components described in opisthokonts originated before the diversification of extant eukaryotic lineages and were likely already present in the Last Eukaryotic Common Ancestor (LECA). Nbp35, Nar1 Cia1 and Cia2 proteins have been conserved during the subsequent evolutionary diversification of eukaryotes and are present in virtually all extant lineages, whereas the other CIA proteins have patchy phylogenetic distributions. Cia2 appears to be homologous to SufT, a component of the prokaryotic SUF system, making this the first reported evolutionary link between the CIA and any other Fe/S biogenesis pathway. All of our results suggest that the CIA machinery is an ubiquitous biosynthetic pathway in eukaryotes, but its apparent plasticity in composition raises questions regarding how it functions in non-model organisms and how it interfaces with various iron/sulfur cluster systems (i.e., ISC, NIF and/or SUF) found in eukaryotic cells

The Porto European Cancer Research Summit 2021

Key stakeholders from the cancer research continuum met in May 2021 at the European Cancer Research Summit in Porto to discuss priorities and specific action points required for the successful implementation of the European Cancer Mission and Europe's Beating Cancer Plan (EBCP). Speakers presented a unified view about the need to establish high-quality, networked infrastructures to decrease cancer incidence, increase the cure rate, improve patient's survival and quality of life, and deal with research and care inequalities across the European Union (EU). These infrastructures, featuring Comprehensive Cancer Centres (CCCs) as key components, will integrate care, prevention and research across the entire cancer continuum to support the development of personalized/precision cancer medicine in Europe. The three pillars of the recommended European infrastructures – namely translational research, clinical/prevention trials and outcomes research – were pondered at length. Speakers addressing the future needs of translational research focused on the prospects of multiomics assisted preclinical research, progress in Molecular and Digital Pathology, immunotherapy, liquid biopsy and science data. The clinical/prevention trial session presented the requirements for next-generation, multicentric trials entailing unified strategies for patient stratification, imaging, and biospecimen acquisition and storage. The third session highlighted the need for establishing outcomes research infrastructures to cover primary prevention, early detection, clinical effectiveness of innovations, health-related quality-of-life assessment, survivorship research and health economics. An important outcome of the Summit was the presentation of the Porto Declaration, which called for a collective and committed action throughout Europe to develop the cancer research infrastructures indispensable for fostering innovation and decreasing inequalities within and between member states. Moreover, the Summit guidelines will assist decision making in the context of a unique EU-wide cancer initiative that, if expertly implemented, will decrease the cancer death toll and improve the quality of life of those confronted with cancer, and this is carried out at an affordable cost.Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. JT reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, DaiichiSankyo, F. Hoffmann‐La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc. And also educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). JT also declares institutional financial interest in form of financial support for clinical trials or contracted research for Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann‐La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen‐Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc, Spanish Association Against Cancer Scientific Foundation and Cancer Research UK. MB has received funding for his research projects and for educational grants to the University of Dresden by Bayer AG (2016‐2018), Merck KGaA (2014‐open) and Medipan GmbH (2014‐2018). He is on the supervisory board of HI‐STEM GmbH (Heidelberg) for the German Cancer Research Center (DKFZ, Heidelberg) and also member of the supervisory body of the Charité University Hospital, Berlin. As former chair of OncoRay (Dresden) and present CEO and Scientific Chair of the German Cancer Research Center (DKFZ, Heidelberg), he has been or is responsible for collaborations with a multitude of companies and institutions, worldwide. In this capacity, he has discussed potential projects and signed contracts for research funding and/or collaborations with industry and academia for his institute(s) and staff, including but not limited to pharmaceutical companies such as Bayer, Boehringer Ingelheim, Bosch, Roche and other companies such as Siemens, IBA, Varian, Elekta, Bruker, etc. In this role, he was/is also responsible for the commercial technology transfer activities of his institute(s), including the creation of start‐ups and licensing. This includes the DKFZ‐PSMA617 related patent portfolio [WO2015055318 (A1), ANTIGEN (PSMA)] and similar IP portfolios. MB confirms that, to the best of his knowledge, none of the above funding sources were involved in the preparation of this paper. BB has received research funding from 4D Pharma, Abbvie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi‐Sankyo, Eli Lilly, GSK, Inivata, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche‐Genentech, Sanofi, Takeda, Tolero Pharmaceuticals. FC declares consultancy role for: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi‐Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck‐Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre‐Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva. SF is a consulting or advisory board member at Bayer, Illumina, Roche; has received honoraria from Amgen, Eli Lilly, PharmaMar, Roche; has received research funding from AstraZeneca, Pfizer, PharmaMar, Roche; has received sponsorship of travel or accommodation expenses by Amgen, Eli Lilly, Illumina, PharmaMar, Roche. SG owns AstraZeneca stock and is a full‐time employee of AstraZeneca. PN has had an advisory role at Bayer, MSD Oncology, has received honoraria from Bayer, Novartis and MSD Oncology, and has had travel expenses paid by Novartis. JO has been an advisory board member at Roche, Novartis, Bayer, Merck, Eisai, Astrazeneca, Pierre Fabre Medicament and Bristol‐Myers Squibb. He has also received research funding by IPO Porto, Astrazeneca, Fundação para a Ciencia e a Tecnologia (FCT) and Liga Portuguesa Contra o Cancro (LPCC). AR is an employee of European Federation of Pharmaceutical Industries and Associations, Brussels, MSD International Business GmbH, Kriens, Switzerland[CvG1], and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA, who may own stock and/or hold stock options in the Company.RS serves as principal investigator of the ASCO TAPUR study. ASCO receives research grants from the following companies in support of the study: Astra‐Zeneca, Bayer, Boehringer‐Ingelheim, Bristol Myers Squibb, Genentech, Lilly, Merck, Pfizer, Seattle Genetics. Dr. Schilsky serves as a member of the managing board of Clariifi and as a consultant to Bryologyx, Cellworks Group, EQRx, and Scandion Oncology. The Netherlands Cancer Institute receives research support via EV from Roche, Astrazeneca, Eisai, Novartis, GSK, Clovis, BMS, MSD, Pfizer, Amgen, Bayer, Lilly, Janssen and Seagen. LZ is founder of everImmune, member of the board of directors of Transgene, member of the scientific advisory board of Transgene, EpiVax, Lytix Biopharma. LZ has also had research contracts with: Merus, Roche, Tusk, Kaleido, GSK, BMS, Incyte, Pileje, Innovate Pharma, and Transgene and has received honoraria by Transgene. All other authors have no conflicts of interest to declare. Regarding the design of innovative and adaptive clinical trials, two examples were illustrated: the first European multimodular, two‐part academic CCE‐endorsed Basket of Baskets (BoB) study, and the recently launched CCE Building Data Rich Clinical Trials (DART) Consortium, which is supported by EU’s Horizon 2020 research and innovation programme (Box 13 ). We are grateful for the support by Carolina Espina, International Agency for Research on Cancer; Christina von Gertten, European Academy of Cancer Sciences; Ana Augusta Silva, Portuguese Oncology Institute of Porto; and Teresa Tavares, Ministry of Science, Technology and Higher Education, Portugal for their excellent cooperation. Carmen Jeronimo, Portuguese Oncology Institute of Porto, collaborated in the presentation of Porto Comprehensive Cancer Center by Raquel Seruca

Epigenetic and transcriptional signatures of stable versus plastic differentiation of proinflammatory gd T cell subsets

Two distinct subsets of γδ T cells that produce interleukin 17 (IL-17) (CD27(-) γδ T cells) or interferon-γ (IFN-γ) (CD27(+) γδ T cells) develop in the mouse thymus, but the molecular determinants of their functional potential in the periphery remain unknown. Here we conducted a genome-wide characterization of the methylation patterns of histone H3, along with analysis of mRNA encoding transcription factors, to identify the regulatory networks of peripheral IFN-γ-producing or IL-17-producing γδ T cell subsets in vivo. We found that CD27(+) γδ T cells were committed to the expression of Ifng but not Il17, whereas CD27(-) γδ T cells displayed permissive chromatin configurations at loci encoding both cytokines and their regulatory transcription factors and differentiated into cells that produced both IL-17 and IFN-γ in a tumor microenvironment

Danger- and pathogen-associated molecular patterns recognition by pattern-recognition receptors and ion channels of the transient receptor potential family triggers the inflammasome activation in immune cells and sensory neurons.

An increasing number of studies show that the activation of the innate immune system and inflammatory mechanisms play an important role in the pathogenesis of numerous diseases. The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Intracellular pathways, linking immune and inflammatory response to ion channel expression and function, have been recently identified. Among ion channels, the transient receptor potential (TRP) channels are a major family of non-selective cation-permeable channels that function as polymodal cellular sensors involved in many physiological and pathological processes.In this review, we summarize current knowledge of interactions between immune cells and PRRs and ion channels of TRP families with PAMPs and DAMPs to provide new insights into the pathogenesis of inflammatory diseases. TRP channels have been found to interfere with innate immunity via both nuclear factor-kB and procaspase-1 activation to generate the mature caspase-1 that cleaves pro-interleukin-1ß cytokine into the mature interleukin-1ß.Sensory neurons are also adapted to recognize dangers by virtue of their sensitivity to intense mechanical, thermal and irritant chemical stimuli. As immune cells, they possess many of the same molecular recognition pathways for danger. Thus, they express PRRs including Toll-like receptors 3, 4, 7, and 9, and stimulation by Toll-like receptor ligands leads to induction of inward currents and sensitization in TRPs. In addition, the expression of inflammasomes in neurons and the involvement of TRPs in central nervous system diseases strongly support a role of TRPs in inflammasome-mediated neurodegenerative pathologies. This field is still at its beginning and further studies may be required.Overall, these studies highlight the therapeutic potential of targeting the inflammasomes in proinflammatory, autoinflammatory and metabolic disorders associated with undesirable activation of the inflammasome by using specific TRP antagonists, anti-human TRP monoclonal antibody or different molecules able to abrogate the TRP channel-mediated inflammatory signals

Age at symptom onset and death and disease duration in genetic frontotemporal dementia : an international retrospective cohort study

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49\ub75 years (SD 10\ub70; onset) and 58\ub75 years (11\ub73; death) in the MAPT group, 58\ub72 years (9\ub78; onset) and 65\ub73 years (10\ub79; death) in the C9orf72 group, and 61\ub73 years (8\ub78; onset) and 68\ub78 years (9\ub77; death) in the GRN group. Mean disease duration was 6\ub74 years (SD 4\ub79) in the C9orf72 group, 7\ub71 years (3\ub79) in the GRN group, and 9\ub73 years (6\ub74) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0\ub745 between individual and parental age at onset, r=0\ub763 between individual and mean family age at onset, r=0\ub758 between individual and parental age at death, and r=0\ub769 between individual and mean family age at death) than in either the C9orf72 group (r=0\ub732 individual and parental age at onset, r=0\ub736 individual and mean family age at onset, r=0\ub738 individual and parental age at death, and r=0\ub740 individual and mean family age at death) or the GRN group (r=0\ub722 individual and parental age at onset, r=0\ub718 individual and mean family age at onset, r=0\ub722 individual and parental age at death, and r=0\ub732 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35\u201362, for age at onset; 61%, 47\u201373, for age at death), and even more by family membership (66%, 56\u201375, for age at onset; 74%, 65\u201382, for age at death). In the GRN group, only 2% (0\u201310) of the variability of age at onset and 9% (3\u201321) of that of age of death was explained by the specific mutation, whereas 14% (9\u201322) of the variability of age at onset and 20% (12\u201330) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11\u201326) of the variability of age at onset and 19% (12\u201329) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society

Alzheimer's Disease: SPECT and PET Tracers for Beta-Amyloid Imaging

The definite diagnosis of Alzheimer's disease (AD) is based on the detection of beta amyloid (A beta) plaques and neurofibrillary tangles (NFTs) - which are the pathological hallmarks of the disease- in the postmortem brains. Although regional Cerebral Blood Flow (rCBF) and Cerebral Glucose Metabolism (CGM) abnormalities have already been studied in AD patients with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET), the development of specific imaging agents for direct mapping of A beta plaques in the living brain, is a great challenge. A beta probes could significantly contribute to the early diagnosis of AD, the elucidation of the underlying neuropathological processes and the evaluation of anti-amyloid therapies which are currently under investigation. The development of SPECT and PET tracers for A beta imaging represents an active area in radiopharmaceutical design. A beta substantial number of potential A beta imaging radioligands have been designed and used in-vitro. They are either monoclonal antibodies to A beta and radiolabeled A beta peptides, or derivatives of histopathological stains such as Congo red (CR), chrysamine-G (CG) and Thioflavin T (TT). Though, only few of them, that display high binding affinity to A beta as well as sufficient brain penetration, have been used primarily in in-vivo studies and to a smaller degree on human subjects. Since A beta plaques are not homogenous and contain multiple binding sites that can accommodate structurally diverse compounds, they offer flexibility in designing various different probes, as potential amyloid imaging agents

Non-pharmacological Interventions for Agitation/aggressive Behaviour in Patients With Dementia: A Randomized Controlled Crossover Trial

Agitation/aggressive behaviour is a common behavioural and psychological symptom in people with dementia (PwD), occurring with a frequency of between 13-50.4% according to recent studies, and the rate increases as the severity of cognitive decline increases. The burden on caregivers is considerable. This trial is a randomized controlled crossover trial conducted in Greece. The following measures were used: the Mini-Mental State Examination, Addenbrooke\u27s Cognitive Examination Revised, Geriatric Depression Scale, Functional Rating Scale for Symptoms in Dementia and Neuropsychiatric Inventory. According to the results the most effective nonpharmacological intervention for reducing agitation/aggressive behaviour in PwD was music therapy, followed by aromatherapy and massage, and finally physical exercise