Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic ...alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the
gene (
= 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies (
= 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and
-deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways.
loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.
Aging results in chronic systemic inflammation that can alter neuroinflammation of the brain. Specifically, microglia shift to a pro-inflammatory phenotype predisposing them to hyperactivation upon ...stimulation by peripheral immune signals. It is proposed that certain nutrients can delay brain aging by preventing or reversing microglial hyperactivation. Butyrate, a short-chain fatty acid (SCFA) produced primarily by bacterial fermentation of fiber in the colon, has been extensively studied pharmacologically as a histone deacetylase inhibitor and serves as an attractive therapeutic candidate, as butyrate has also been shown to be anti-inflammatory and improve memory in animal models. In this study, we demonstrate that butyrate can attenuate pro-inflammatory cytokine expression in microglia in aged mice. It is still not fully understood, however, if an increase in butyrate-producing bacteria in the gut as a consequence of a diet high in soluble fiber could affect microglial activation during aging. Adult and aged mice were fed either a 1% cellulose (low fiber) or 5% inulin (high fiber) diet for 4 weeks. Findings indicate that mice fed inulin had an altered gut microbiome and increased butyrate, acetate, and total SCFA production. In addition, histological scoring of the distal colon demonstrated that aged animals on the low fiber diet had increased inflammatory infiltrate that was significantly reduced in animals consuming the high fiber diet. Furthermore, gene expression of inflammatory markers, epigenetic regulators, and the microglial sensory apparatus (i.e., the sensome) were altered by both diet and age, with aged animals exhibiting a more anti-inflammatory microglial profile on the high fiber diet. Taken together, high fiber supplementation in aging is a non-invasive strategy to increase butyrate levels, and these data suggest that an increase in butyrate through added soluble fiber such as inulin could counterbalance the age-related microbiota dysbiosis, potentially leading to neurological benefits.
Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger ...and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific (ETS)-fusion-negative tumors defined by mutations in epigenetic regulators, as well as alterations in pathways not previously implicated in prostate cancer, such as the spliceosome pathway. We find that the incidence of significantly mutated genes (SMGs) follows a long-tail distribution, with many genes mutated in less than 3% of cases. We identify a total of 97 SMGs, including 70 not previously implicated in prostate cancer, such as the ubiquitin ligase CUL3 and the transcription factor SPEN. Finally, comparing primary and metastatic prostate cancer identifies a set of genomic markers that may inform risk stratification.
Getting genetic ancestry right for science and society Lewis, Anna C F; Molina, Santiago J; Appelbaum, Paul S ...
Science (American Association for the Advancement of Science),
04/2022, Letnik:
376, Številka:
6590
Journal Article
Recenzirano
We must embrace a multidimensional, continuous view of ancestry and move away from continental ancestry categories.
Protists, which are single-celled eukaryotes, critically influence the ecology and chemistry of marine ecosystems, but genome-based studies of these organisms have lagged behind those of other ...microorganisms. However, recent transcriptomic studies of cultured species, complemented by meta-omics analyses of natural communities, have increased the amount of genetic information available for poorly represented branches on the tree of eukaryotic life. This information is providing insights into the adaptations and interactions between protists and other microorganisms and macroorganisms, but many of the genes sequenced show no similarity to sequences currently available in public databases. A better understanding of these newly discovered genes will lead to a deeper appreciation of the functional diversity and metabolic processes in the ocean. In this Review, we summarize recent developments in our understanding of the ecology, physiology and evolution of protists, derived from transcriptomic studies of cultured strains and natural communities, and discuss how these novel large-scale genetic datasets will be used in the future.
Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, although in microsatellite-stable tumors this association is of uncertain clinical utility. ...Here we uniformly analyzed whole-exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy, including radiographic response, across multiple cancer types to examine additional tumor genomic features that contribute to selective response. Our analyses identified genomic correlates of response beyond mutational burden, including somatic events in individual driver genes, certain global mutational signatures, and specific HLA-restricted neoantigens. However, these features were often interrelated, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. This study lays a path forward in analyzing large clinical cohorts in an integrated and multifaceted manner to enhance the ability to discover clinically meaningful predictive features of response to immune checkpoint blockade.
Abstract
Background
Aedes
-borne disease risk is increasing in tropical and sub-tropical regions across the globe. While
Aedes
-borne disease continues to disproportionally affect low- and ...middle-income countries, parts of high-income countries, such as the Torres Strait region in Australia are also at risk. The Torres Strait is a group of islands located between Cape York Peninsula in far north Queensland, Australia and Papua New Guinea. The Torres Strait has both
Aedes albopictus and Aedes aegypti
and is close to Papua New Guinea where dengue fever is endemic. Managing
Aedes-borne
disease risk requires a range of strategies, including community participation. Existing research shows that high-income countries tend to favour government-led (top-down) informing approaches when engaging communities in
Aedes
mosquito management. Little is known about the factors that influence the choice of community participation approaches in
Aedes
mosquito management particularly in a high-income country setting, such as Australia. This research contributes to filling this knowledge gap by exploring the community participation approaches used in
Aedes
mosquito management and the factors influencing these choices in the Torres Strait.
Methods
16 semi-structured interviews were conducted with local government and state government agencies working in
Aedes
mosquito management in the Torres Strait. Six key mosquito management plans and policies were also reviewed. Thematic analysis was used to identify, analyse and attribute meaning from the data collected.
Results
A range of community participation approaches were used within the two main
Aedes
mosquito management programs (
Aedes albopictus
Elimination Program and the Torres Strait Island Regional Council, Environmental Health Program) in the Torres Strait. These approaches included door-to-door inspections, awareness raising strategies, and community clean-up events. Approaches were chosen for reasons related to regulations, attitude and beliefs, and resourcing.
Conclusions
This study revealed the use of both top-down and bottom-up approaches to engaging the community in
Aedes
mosquito management in the Torres Strait. These findings contribute to a better understanding of why bottom-up approaches are used, which is valuable for shaping future policy decisions. This study also provides suggestions on ways to enhance community participation in the Torres Strait, which could also be considered in other similar tropical regions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract In this article, we review the original findings from MRI and autopsy studies that demonstrated brain iron status is insufficient in individuals with restless legs syndrome (RLS). The ...concept of deficient brain iron status is supported by proteomic studies from cerebrospinal fluid (CSF) and from the clinical findings where intervention with iron, either dietary or intravenous, can improve RLS symptoms. Therefore, we include a section on peripheral iron status and how peripheral status may influence both the RLS symptoms and treatment strategy. Given the impact of iron in RLS, we have evaluated genetic data to determine if genes are directly involved in iron regulatory pathways. The result was negative. In fact, even the HFE mutation C282Y could not be shown to have a protective effect. Lastly, a consistent finding in conditions of low iron is increased expression of proteins in the hypoxia pathway. Although there is lack of clinical data that RLS patients are hypoxic, there are intriguing observations that environmental hypoxic conditions worsen RLS symptoms; in this chapter we review very compelling data for activation of hypoxic pathways in the brain in RLS patients. In general, the data in RLS point to a pathophysiology that involves decreased acquisition of iron by cells in the brain. Whether the decreased ability is genetically driven, activation of pathways (eg, hypoxia) that are designed to limit cellular uptake is unknown at this time; however, the data strongly support a functional rather than structural defect in RLS, suggesting that an effective treatment is possible.
The resilience of regeneration in vertebrates is not very well understood. Yet understanding if tissues can regenerate after repeated insults, and identifying limitations, is important for ...elucidating the underlying mechanisms of tissue plasticity. This is particularly challenging in tissues, such as the nervous system, which possess a large number of terminally differentiated cells and often exhibit limited regeneration in the first place. However, unlike mammals, which exhibit very limited regeneration of spinal cord tissues, many non-mammalian vertebrates, including lampreys, bony fishes, amphibians, and reptiles, regenerate their spinal cords and functionally recover even after a complete spinal cord transection. It is well established that lampreys undergo full functional recovery of swimming behaviors after a single spinal cord transection, which is accompanied by tissue repair at the lesion site, as well as axon and synapse regeneration. Here we begin to explore the resilience of spinal cord regeneration in lampreys after a second spinal transection (re-transection). We report that by all functional and anatomical measures tested, lampreys regenerate after spinal re-transection just as robustly as after single transections. Recovery of swimming, synapse and cytoskeletal distributions, axon regeneration, and neuronal survival were nearly identical after spinal transection or re-transection. Only minor differences in tissue repair at the lesion site were observed in re-transected spinal cords. Thus, regenerative potential in the lamprey spinal cord is largely unaffected by spinal re-transection, indicating a greater persistent regenerative potential than exists in some other highly regenerative models. These findings establish a new path for uncovering pro-regenerative targets that could be deployed in non-regenerative conditions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
High-income countries (HICs) in sub-tropical and tropical regions are at an increasing risk of Aedes mosquito-borne disease (MBD) outbreaks such as dengue fever. As the Aedes mosquito ...predominately lives and breeds in and around people’s homes, community participation in MBD management is an important part of preventing MBD outbreaks. Historically, government-led strategies have dominated community participation efforts as opposed to strategies co-designed or led by the community. A scoping review was conducted to describe the community participation and empowering approaches used in Aedes mosquito management specifically in HICs, and to identify any reported outcomes of these methods. A systematic search of peer-reviewed literature using electronic databases Medline (OVID), Web of Science, Scopus and ProQuest—Science and Technology as well as grey literature, found 19 studies that matched the review criteria. The review findings highlight a lack of empirical evidence to inform participatory and empowering approaches to mosquito management in HICs. Moreover, the rationale for using predominantly government-led approaches is not clear. Further research is required to better understand best approaches and barriers to employing empowering approaches in mosquito management in HICs.
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