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Knowledge of fundamental differences between breast cancer subtypes has driven therapeutic advances; however, basal-like breast cancer (BLBC) remains clinically intractable. Because BLBC exhibits alterations in DNA repair enzymes and cell-cycle checkpoints, elucidation of factors enabling the genomic instability present in this subtype has the potential to reveal novel anti-cancer strategies. Here, we demonstrate that BLBC is especially sensitive to suppression of iron-sulfur cluster (ISC) biosynthesis and identify DNA polymerase epsilon (POLE) as an ISC-containing protein that underlies this phenotype. In BLBC cells, POLE suppression leads to replication fork stalling, DNA damage, and a senescence-like state or cell death. In contrast, luminal breast cancer and non-transformed mammary cells maintain viability upon POLE suppression but become dependent upon an ATR/CHK1/CDC25A/CDK2 DNA damage response axis. We find that CDK1/2 targets exhibit hyperphosphorylation selectively in BLBC tumors, indicating that CDK2 hyperactivity is a genome integrity vulnerability exploitable by targeting POLE.
Assuntos
Neoplasias da Mama/patologia , Carcinoma Basocelular/patologia , Quinase 2 Dependente de Ciclina/metabolismo , DNA Polimerase II/metabolismo , Instabilidade Genômica , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Animais , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Basocelular/genética , Carcinoma Basocelular/metabolismo , Ciclo Celular , Proliferação de Células , Quinase 2 Dependente de Ciclina/genética , Dano ao DNA , DNA Polimerase II/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Fosforilação , Proteínas de Ligação a Poli-ADP-Ribose/genética , Transdução de Sinais , Células Tumorais CultivadasRESUMO
The Tibetan Plateau, recognized as Earth's third pole and among the most responsive regions to climate shifts, profoundly influences regional and even global hydrological processes. Here, we discerned a significant weakening in the influence of temperature on the initiation of surface freeze-thaw cycle (the Start of Thawing, SOT), which can be ascribed to a multitude of climatic variables, with radiation emerging as the most pivotal factor. Additionally, we showed that the diminishing impact of warming on SOT yields amplified soil moisture within the root zone. This, in turn, fosters a greening third pole with increased leaf area index and solar-induced chlorophyll fluorescence. We further showed that current Earth system models failed to reproduce the linkage between weakened sensitivity and productivity under various shared socioeconomic pathways. Our findings highlight the dynamic shifts characterizing the influence of climate warming on spring freeze-thaw process and underscore the profound ecological implications of these changes in the context of future climate scenarios.
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Candida albicans is the most prevalent fungal pathogen associated with candidemia. Similar to other fungi, the complex life cycle of C. albicans has been challenging to study with high-resolution microscopy due to its small size. We employed ultrastructure expansion microscopy (U-ExM) to directly visualise sub-cellular structures at high resolution in the yeast and during its transition to hyphal growth. NHS-ester pan-labelling in combination with immunofluorescence (IF) via snapshots of various mitotic stages provided a comprehensive map of nucleolar and mitochondrial segregation dynamics and enabled the resolution of inner and outer plaque of spindle pole bodies (SPBs). Analyses of microtubules (MTs) and SPBs suggest that C. albicans displays side-by-side SPB arrangement with a short mitotic spindle and longer astral MTs (aMTs) at the pre-anaphase stage. Modifications to the established U-ExM protocol enabled the expansion of six other human fungal pathogens, revealing that the side-by-side SPB configuration is a plausible conserved feature shared by many fungal species. We highlight the power of U-ExM to investigate sub-cellular organisation at high resolution and low cost in poorly studied and medically relevant microbial pathogens.
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Maintenance of epigenetic integrity relies on coordinated recycling and partitioning of parental histones and deposition of newly synthesized histones during DNA replication. This process depends upon a poorly characterized network of histone chaperones, remodelers, and binding proteins. Here we implicate the POLE3-POLE4 subcomplex of the leading-strand polymerase, Polε, in replication-coupled nucleosome assembly through its ability to selectively bind to histones H3-H4. Using hydrogen/deuterium exchange mass spectrometry and physical mapping, we define minimal domains necessary for interaction between POLE3-POLE4 and histones H3-H4. Biochemical analyses establish that POLE3-POLE4 is a histone chaperone that promotes tetrasome formation and DNA supercoiling in vitro. In cells, POLE3-POLE4 binds both newly synthesized and parental histones, and its depletion hinders helicase unwinding and chromatin PCNA unloading and compromises coordinated parental histone retention and new histone deposition. Collectively, our study reveals that POLE3-POLE4 possesses intrinsic H3-H4 chaperone activity, which facilitates faithful nucleosome dynamics at the replication fork.
Assuntos
DNA Polimerase III/genética , Replicação do DNA/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética/genética , Histonas/biossíntese , Nucleoproteínas/genética , Cromatina/genética , DNA Polimerase II/química , DNA Polimerase II/genética , DNA Polimerase III/química , Proteínas de Ligação a DNA/química , Chaperonas de Histonas/química , Chaperonas de Histonas/genética , Histonas/genética , Humanos , Chaperonas Moleculares/química , Chaperonas Moleculares/genética , Nucleoproteínas/química , Nucleossomos/química , Nucleossomos/genética , Proteínas de Ligação a Poli-ADP-Ribose/química , Proteínas de Ligação a Poli-ADP-Ribose/genética , Antígeno Nuclear de Célula em Proliferação/genética , Ligação ProteicaRESUMO
DNA polymerase ε (POLE) is a four-subunit complex and the major leading strand polymerase in eukaryotes. Budding yeast orthologs of POLE3 and POLE4 promote Polε processivity in vitro but are dispensable for viability in vivo. Here, we report that POLE4 deficiency in mice destabilizes the entire Polε complex, leading to embryonic lethality in inbred strains and extensive developmental abnormalities, leukopenia, and tumor predisposition in outbred strains. Comparable phenotypes of growth retardation and immunodeficiency are also observed in human patients harboring destabilizing mutations in POLE1. In both Pole4-/- mouse and POLE1 mutant human cells, Polε hypomorphy is associated with replication stress and p53 activation, which we attribute to inefficient replication origin firing. Strikingly, removing p53 is sufficient to rescue embryonic lethality and all developmental abnormalities in Pole4 null mice. However, Pole4-/-p53+/- mice exhibit accelerated tumorigenesis, revealing an important role for controlled CMG and origin activation in normal development and tumor prevention.
Assuntos
Carcinogênese/patologia , DNA Polimerase II/química , DNA Polimerase II/fisiologia , Replicação do DNA , Deficiências do Desenvolvimento/etiologia , Transtornos do Crescimento/etiologia , Leucopenia/etiologia , Animais , Carcinogênese/genética , Células Cultivadas , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Humanos , Recém-Nascido , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Proteína Supressora de Tumor p53/fisiologiaRESUMO
In cells, microtubules (MTs) assemble from α/ß-tubulin subunits at nucleation sites containing the γ-tubulin ring complex (γ-TuRC). Within the γ-TuRC, exposed γ-tubulin molecules act as templates for MT assembly by interacting with α/ß-tubulin. The vertebrate γ-TuRC is scaffolded by γ-tubulin-interacting proteins GCP2-6 arranged in a specific order. Interestingly, the γ-tubulin molecules in the γ-TuRC deviate from the cylindrical geometry of MTs, raising the question of how the γ-TuRC structure changes during MT nucleation. Recent studies on the structure of the vertebrate γ-TuRC attached to the end of MTs came to varying conclusions. In vitro assembly of MTs, facilitated by an α-tubulin mutant, resulted in a closed, cylindrical γ-TuRC showing canonical interactions between all γ-tubulin molecules and α/ß-tubulin subunits. Conversely, native MTs formed in a frog extract were capped by a partially closed γ-TuRC, with some γ-tubulin molecules failing to align with α/ß-tubulin. This review discusses these outcomes, along with the broader implications.
Assuntos
Microtúbulos , Tubulina (Proteína) , Microtúbulos/metabolismo , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/química , Animais , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/químicaRESUMO
Systematic literature searches on POT1/POLE/BAP1 found that limited skin phenotypic characteristics have been documented in mutation carriers; 248 variants were annotated, and high-cluster variant regions associated with cutaneous melanoma were found in all three genes. Genotype-phenotype correlations can be used to identify patient disease predisposition based on mutation position and cluster regions.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Proteínas de Ligação a Telômeros/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Melanoma Maligno CutâneoRESUMO
Centrosomes are a functionally conserved feature of eukaryotic cells that play an important role in cell division. The conserved γ-tubulin complex organizes spindle and astral microtubules, which, in turn, separate replicated chromosomes accurately into daughter cells. Like DNA, centrosomes are duplicated once each cell cycle. Although in some cell types it is possible for cell division to occur in the absence of centrosomes, these divisions typically result in defects in chromosome number and stability. In single-celled organisms such as fungi, centrosomes [known as spindle pole bodies (SPBs)] are essential for cell division. SPBs also must be inserted into the membrane because fungi undergo a closed mitosis in which the nuclear envelope (NE) remains intact. This poorly understood process involves events similar or identical to those needed for de novo nuclear pore complex assembly. Here, we review how analysis of fungal SPBs has advanced our understanding of centrosomes and NE events.
Assuntos
Centrossomo/ultraestrutura , Regulação Fúngica da Expressão Gênica , Microtúbulos/ultraestrutura , Saccharomyces cerevisiae/genética , Schizosaccharomyces/genética , Corpos Polares do Fuso/ultraestrutura , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Centrossomo/metabolismo , Cromossomos Fúngicos/metabolismo , Cromossomos Fúngicos/ultraestrutura , Microtúbulos/genética , Microtúbulos/metabolismo , Mitose , Poro Nuclear/genética , Poro Nuclear/metabolismo , Poro Nuclear/ultraestrutura , Proteoma/genética , Proteoma/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/ultraestrutura , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Schizosaccharomyces/metabolismo , Schizosaccharomyces/ultraestrutura , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Corpos Polares do Fuso/genética , Corpos Polares do Fuso/metabolismo , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismoRESUMO
The frontal pole is implicated in humans in whether to exploit resources versus explore alternatives. Effective connectivity, functional connectivity, and tractography were measured between six human frontal pole regions and for comparison 13 dorsolateral and dorsal prefrontal cortex regions, and the 360 cortical regions in the Human Connectome Project Multi-modal-parcellation atlas in 171 HCP participants. The frontal pole regions have effective connectivity with Dorsolateral Prefrontal Cortex regions, the Dorsal Prefrontal Cortex, both implicated in working memory; and with the orbitofrontal and anterior cingulate cortex reward/non-reward system. There is also connectivity with temporal lobe, inferior parietal, and posterior cingulate regions. Given this new connectivity evidence, and evidence from activations and damage, it is proposed that the frontal pole cortex contains autoassociation attractor networks that are normally stable in a short-term memory state, and maintain stability in the other prefrontal networks during stable exploitation of goals and strategies. However, if an input from the orbitofrontal or anterior cingulate cortex that expected reward, non-reward, or punishment is received, this destabilizes the frontal pole and thereby other prefrontal networks to enable exploration of competing alternative goals and strategies. The frontal pole connectivity with reward systems may be key in exploit versus explore.
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Conectoma , Lobo Parietal , Humanos , Imageamento por Ressonância Magnética , Lobo Frontal/diagnóstico por imagem , Córtex Pré-Frontal/diagnóstico por imagem , Lobo TemporalRESUMO
Discrepancies in self-rated and observer-rated depression severity may underlie the basis for biological heterogeneity in depressive disorders and be an important predictor of outcomes and indicators to optimize intervention strategies. However, the neural mechanisms underlying this discrepancy have been understudied. This study aimed to examine the brain networks that represent the neural basis of the discrepancy between self-rated and observer-rated depression severity using resting-state functional MRI. To examine the discrepancy between self-rated and observer-rated depression severity, self- and observer-ratings discrepancy (SOD) was defined, and the higher and lower SOD groups were selected from depressed patients as participants showing extreme deviation. Resting-state functional MRI analysis was performed to examine regions with significant differences in functional connectivity in the two groups. The results showed that, in the higher SOD group compared to the lower SOD group, there was increased functional connectivity between the frontal pole and precuneus, both of which are subregions of the default mode network that have been reported to be associated with ruminative and self-referential thinking. These results provide insight into the association of brain circuitry with discrepancies between self- and observer-rated depression severity and may lead to more treatment-oriented diagnostic reclassification in the future.
Assuntos
Depressão , Lobo Frontal , Imageamento por Ressonância Magnética , Lobo Parietal , Humanos , Imageamento por Ressonância Magnética/métodos , Feminino , Masculino , Adulto , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Depressão/diagnóstico por imagem , Depressão/fisiopatologia , Depressão/psicologia , Pessoa de Meia-Idade , Adulto Jovem , Transtornos do Humor/diagnóstico por imagem , Transtornos do Humor/fisiopatologia , Transtornos do Humor/psicologia , Autorrelato , Vias Neurais/fisiopatologia , Vias Neurais/diagnóstico por imagem , Descanso , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Índice de Gravidade de Doença , Mapeamento Encefálico/métodosRESUMO
Vortex crystals are quasiregular arrays of like-signed vortices in solid-body rotation embedded within a uniform background of weaker vorticity. Vortex crystals are observed at the poles of Jupiter and in laboratory experiments with magnetized electron plasmas in axisymmetric geometries. We show that vortex crystals form from the free evolution of randomly excited two-dimensional turbulence on an idealized polar cap. Once formed, the crystals are long lived and survive until the end of the simulations (300 crystal-rotation periods). We identify a fundamental length scale, Lγ=(U/γ)1/3, characterizing the size of the crystal in terms of the mean-square velocity U of the fluid and the polar parameter γ=fp/a2p, with fp the Coriolis parameter at the pole and ap the polar radius of the planet.
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Gastric cancer results in great cancer mortality worldwide, and inducing ferroptosis dramatically improves the malignant phenotypes of gastric cancer. DNA polymerase epsilon subunit 2 (POLE2) plays indispensable roles in tumorigenesis; however, its involvement and molecular basis in ferroptosis and gastric cancer are not clear. Human gastric cancer cells were infected with lentiviral vectors to knock down or overexpress POLE2, and cell ferroptosis was detected. To further validate the involvement of nuclear factor erythroid 2-related factor 2 (NRF2) and glutathione peroxidase 4 (GPX4), lentiviral vectors were used. POLE2 expression was elevated in human gastric cancer cells and tissues and closely correlated with clinicopathological features in gastric cancer patients. POLE2 knockdown was induced, while POLE2 overexpression inhibited ferroptosis of human gastric cancer cells, thereby modulating the malignant phenotypes of gastric cancer. Mechanistic studies revealed that POLE2 overexpression elevated NRF2 expression and activity and subsequently activated GPX4, which then prevented lipid peroxidation and ferroptosis in human gastric cancer cells. In contrast, either NRF2 or GPX4 silence significantly prevented POLE2 overexpression-mediated inductions of cell proliferation, migration, invasion and inhibition of ferroptosis. POLE2 overexpression inhibits ferroptosis in human gastric cancer cells through activating NRF2/GPX4 pathway, and inhibiting POLE2 may be a crucial strategy to treat gastric cancer.
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Ferroptose , Neoplasias Gástricas , Humanos , Lentivirus , Fator 2 Relacionado a NF-E2 , Nucleotidiltransferases , Subunidades ProteicasRESUMO
BACKGROUND: During mitosis the cell depends on proper attachment and segregation of replicated chromosomes to generate two identical progeny. In cancers defined by overexpression or dysregulation of the MYC oncogene this process becomes impaired, leading to genomic instability and tumor evolution. Recently it was discovered that the chromatin regulator WDR5-a critical MYC cofactor-regulates expression of genes needed in mitosis through a direct interaction with the master kinase PDPK1. However, whether PDPK1 and WDR5 contribute to similar mitotic gene regulation in MYC-overexpressing cancers remains unclear. Therefore, to characterize the influence of WDR5 and PDPK1 on mitotic gene expression in cells with high MYC levels, we performed a comparative transcriptomic analysis in neuroblastoma cell lines defined by MYCN-amplification, which results in high cellular levels of the N-MYC protein. RESULTS: Using RNA-seq analysis, we identify the genes regulated by N-MYC and PDPK1 in multiple engineered CHP-134 neuroblastoma cell lines and compare them to previously published gene expression data collected in CHP-134 cells following inhibition of WDR5. We find that as expected N-MYC regulates a multitude of genes, including those related to mitosis, but that PDPK1 regulates specific sets of genes involved in development, signaling, and mitosis. Analysis of N-MYC- and PDPK1-regulated genes reveals a small group of commonly controlled genes associated with spindle pole formation and chromosome segregation, which overlap with genes that are also regulated by WDR5. We also find that N-MYC physically interacts with PDPK1 through the WDR5-PDPK1 interaction suggesting regulation of mitotic gene expression may be achieved through a N-MYC-WDR5-PDPK1 nexus. CONCLUSIONS: Overall, we identify a small group of genes highly enriched within functional gene categories related to mitotic processes that are commonly regulated by N-MYC, WDR5, and PDPK1 and suggest that a tripartite interaction between the three regulators may be responsible for setting the level of mitotic gene regulation in N-MYC amplified cell lines. This study provides a foundation for future studies to determine the exact mechanism by which N-MYC, WDR5, and PDPK1 converge on cell cycle related processes.
Assuntos
Genes myc , Neuroblastoma , Humanos , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Linhagem Celular Tumoral , Segregação de Cromossomos , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neuroblastoma/metabolismoRESUMO
The copackaging of mRNAs into biomolecular condensates called germ granules is a conserved strategy to posttranscriptionally regulate germline mRNAs. In Drosophila melanogaster, mRNAs accumulate in germ granules by forming homotypic clusters, aggregates containing multiple transcripts from the same gene. Nucleated by Oskar (Osk), homotypic clusters are generated through a stochastic seeding and self-recruitment process that requires the 3' untranslated region (UTR) of germ granule mRNAs. Interestingly, the 3' UTR belonging to germ granule mRNAs, such as nanos (nos), have considerable sequence variations among Drosophila species and we hypothesized that this diversity influences homotypic clustering. To test our hypothesis, we investigated the homotypic clustering of nos and polar granule component (pgc) in four Drosophila species and concluded that clustering is a conserved process used to enrich germ granule mRNAs. However, we discovered germ granule phenotypes that included significant changes in the abundance of transcripts present in species' homotypic clusters, which also reflected diversity in the number of coalesced primordial germ cells within their embryonic gonads. By integrating biological data with computational modeling, we found that multiple mechanisms underlie naturally occurring germ granule diversity, including changes in nos, pgc, osk levels and/or homotypic clustering efficacy. Furthermore, we demonstrated how the nos 3' UTR from different species influences nos clustering, causing granules to have â¼70% less nos and increasing the presence of defective primordial germ cells. Our results highlight the impact that evolution has on germ granules, which should provide broader insight into processes that modify compositions and activities of other classes of biomolecular condensate.
Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/genética , Drosophila melanogaster/genética , Proteínas de Drosophila/genética , Grânulos de Ribonucleoproteínas de Células Germinativas , Regiões 3' não Traduzidas , Células Germinativas , RNA Mensageiro/genéticaRESUMO
The budding and fission yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe have served as invaluable model organisms to study conserved fundamental cellular processes. Although super-resolution microscopy has in recent years paved the way to a better understanding of the spatial organization of molecules in cells, its wide use in yeasts has remained limited due to the specific know-how and instrumentation required, contrasted with the relative ease of endogenous tagging and live-cell fluorescence microscopy. To facilitate super-resolution microscopy in yeasts, we have extended the ultrastructure expansion microscopy (U-ExM) method to both S. cerevisiae and S. pombe, enabling a 4-fold isotropic expansion. We demonstrate that U-ExM allows imaging of the microtubule cytoskeleton and its associated spindle pole body, notably unveiling the Sfi1p-Cdc31p spatial organization on the appendage bridge structure. In S. pombe, we validate the method by monitoring the homeostatic regulation of nuclear pore complex number through the cell cycle. Combined with NHS-ester pan-labelling, which provides a global cellular context, U-ExM reveals the subcellular organization of these two yeast models and provides a powerful new method to augment the already extensive yeast toolbox. This article has an associated First Person interview with Kerstin Hinterndorfer and Felix Mikus, two of the joint first authors of the paper.
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Proteínas de Saccharomyces cerevisiae , Schizosaccharomyces , Humanos , Schizosaccharomyces/metabolismo , Saccharomyces cerevisiae/metabolismo , Microscopia , Proteínas de Saccharomyces cerevisiae/metabolismo , Corpos Polares do Fuso/metabolismoRESUMO
BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.
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Neoplasias Colorretais , DNA Polimerase III , DNA Polimerase II , Inibidores de Checkpoint Imunológico , Mutação , Proteínas de Ligação a Poli-ADP-Ribose , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Masculino , Feminino , Inibidores de Checkpoint Imunológico/uso terapêutico , Pessoa de Meia-Idade , Idoso , DNA Polimerase II/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , DNA Polimerase III/genética , Adulto , Instabilidade de Microssatélites , Idoso de 80 Anos ou mais , Reparo de Erro de Pareamento de DNARESUMO
Neuroimaging studies have consistently demonstrated concurrent activation of the human precuneus and temporal pole (TP), both during resting-state conditions and various higher-order cognitive functions. However, the precise underlying structural connectivity between these brain regions remains uncertain despite significant advancements in neuroscience research. In this study, we investigated the connectivity of the precuneus and TP by employing parcellation-based fiber micro-dissections in human brains and fiber tractography techniques in a sample of 1065 human subjects and a sample of 41 rhesus macaques. Our results demonstrate the connectivity between the posterior precuneus area POS2 and the areas 35, 36, and TG of the TP via the fifth subcomponent of the cingulum (CB-V) also known as parahippocampal cingulum. This finding contributes to our understanding of the connections within the posteromedial cortices, facilitating a more comprehensive integration of anatomy and function in both normal and pathological brain processes. PRACTITIONER POINTS: Our investigation delves into the intricate architecture and connectivity patterns of subregions within the precuneus and temporal pole, filling a crucial gap in our knowledge. We revealed a direct axonal connection between the posterior precuneus (POS2) and specific areas (35, 35, and TG) of the temporal pole. The direct connections are part of the CB-V pathway and exhibit a significant association with the cingulum, SRF, forceps major, and ILF. Population-based human tractography and rhesus macaque fiber tractography showed consistent results that support micro-dissection outcomes.
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Imagem de Tensor de Difusão , Macaca mulatta , Vias Neurais , Lobo Parietal , Lobo Temporal , Humanos , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/fisiologia , Lobo Temporal/anatomia & histologia , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/fisiologia , Lobo Parietal/anatomia & histologia , Animais , Imagem de Tensor de Difusão/métodos , Masculino , Adulto , Feminino , Vias Neurais/diagnóstico por imagem , Vias Neurais/anatomia & histologia , Vias Neurais/fisiologia , Adulto Jovem , Axônios/fisiologia , Conectoma , Substância Branca/diagnóstico por imagem , Substância Branca/anatomia & histologia , Substância Branca/fisiologia , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiologia , Giro do Cíngulo/anatomia & histologiaRESUMO
Measurements of net primary productivity (NPP) and litter decomposition from tropical peatlands are severely lacking, limiting our ability to parameterise and validate models of tropical peatland development and thereby make robust predictions of how these systems will respond to future environmental and climatic change. Here, we present total NPP (i.e., above- and below-ground) and decomposition data from two floristically and structurally distinct forested peatland sites within the Pastaza Marañón Foreland Basin, northern Peru, the largest tropical peatland area in Amazonia: (1) a palm (largely Mauritia flexuosa) dominated swamp forest and (2) a hardwood dominated swamp forest (known as 'pole forest', due to the abundance of thin-stemmed trees). Total NPP in the palm forest and hardwood-dominated forest (9.83 ± 1.43 and 7.34 ± 0.84 Mg C ha-1 year-1, respectively) was low compared with values reported for terra firme forest in the region (14.21-15.01 Mg C ha-1 year-1) and for tropical peatlands elsewhere (11.06 and 13.20 Mg C ha-1 year-1). Despite the similar total NPP of the two forest types, there were considerable differences in the distribution of NPP. Fine root NPP was seven times higher in the palm forest (4.56 ± 1.05 Mg C ha-1 year-1) than in the hardwood forest (0.61 ± 0.22 Mg C ha-1 year-1). Above-ground palm NPP, a frequently overlooked component, made large contributions to total NPP in the palm-dominated forest, accounting for 41% (14% in the hardwood-dominated forest). Conversely, Mauritia flexuosa litter decomposition rates were the same in both plots: highest for leaf material, followed by root and then stem material (21%, 77% and 86% of mass remaining after 1 year respectively for both plots). Our results suggest potential differences in these two peatland types' responses to climate and other environmental changes and will assist in future modelling studies of these systems.
Mediciones de la productividad primaria neta (PPN) y la descomposición de materia orgánica de las turberas tropicales son escasas, lo que limita nuestra capacidad para parametrizar y validar modelos de desarrollo de las turberas tropicales y, en consecuencia, realizar predicciones sólidas sobre la respuesta de estos sistemas ante futuros cambios ambientales y climáticos. En este estudio, presentamos datos de PPN total (es decir, biomasa aérea y subterránea) y descomposición de la materia orgánica colectada en dos turberas boscosas con características florísticas y estructurales contrastantes dentro de la cuenca Pastaza Marañón al norte del Perú, el área de turberas tropicales más grande de la Amazonia: (1) un bosque pantanoso dominado por palmeras (principalmente Mauritia flexuosa) y (2) un bosque pantanosos dominado por árboles leñosos de tallo delgado (conocido como 'varillal hidromórfico'). La PPN total en el bosque de palmeras y el varillal hidromórfico (9,83 ± 1,43 y 7,34 ± 0,84 Mg C ha1 año1 respectivamente) fue baja en comparación con los valores reportados para los bosques de tierra firme en la región (14,2115,01 Mg C ha1 año1) y para turberas tropicales en otros lugares (11,06 y 13,20 Mg C ha1 año1). A pesar de que la PPN total fue similar en ambos tipos de bosque, hubo diferencias considerables en la distribución de la PPN. La PPN de las raíces finas fue siete veces mayor en el bosque de palmeras (4,56 ± 1,05 Mg C ha1 año1) que en el varillal hidromórfico (0,61 ± 0,22 Mg C ha1 año1). La PPN de la biomasa aérea de las palmeras, un componente ignorado frecuentemente, contribuyó en gran medida a la PPN total del bosque de palmeras, representando el 41% (14% en el varillal hidromórfico). Por el contrario, la tasa de descomposición de materia orgánica de Mauritia flexuosa fue la misma en ambos sitios: la más alta corresponde a la hojarasca, seguida por las raíces y luego el tallo (21%, 77% y 86% de la masa restante después de un año, respectivamente para ambos sitios). Nuestros resultados sugieren diferencias potenciales en la respuesta de estos dos tipos de turberas al clima y otros cambios ambientales, y ayudarán en futuros estudios de modelamiento de estos sistemas.
Assuntos
Florestas , Peru , Áreas Alagadas , Solo/química , Folhas de Planta/metabolismo , Clima TropicalRESUMO
Endometrioid endometrial carcinoma (EEC) stands as a prevalent gynecologic malignancy in developed regions. However, predicting relapse cases remains challenging, necessitating the identification of a novel biomarker for EEC relapse. The assessment of tumor mutational burden (TMB) is pivotal for immunotherapy in EEC patients. However, both whole-exome sequencing (WES) and targeted sequencing encountered application-related difficulties. In light of this, standardized and simplified techniques for TMB measurement are imperative. In this study, we employed WES on 25 EEC patients (12 relapsed cases and 13 non-relapsed cases) who accepted hysterectomy surgery (CHCAMS cohort). We additionally obtained a total of 391 tumor samples with clinicopathological features from TCGA website to broaden the study cohort. In the CHCAMS cohort, the TTN mutant group showed shorter progression-free survival (p < 0.001) and overall survival (p < 0.001) than TTN wild-type group. Additionally, we discovered that the number of TTN mutations per sample was significantly linked with TMB-WES in CHCAMS cohort and TCGA cohort (p < 0.05). And the number of TTN mutations per sample in POLE mutant group was greater than in the POLE wild-type group (p < 0.0001). In conclusion, TTN mutation may serve as a biomarker for EEC prognosis. TTN mutation is also associated with WES-TMB, and could be a simplified TMB measurement technique.
Assuntos
Carcinoma Endometrioide , Conectina , Neoplasias do Endométrio , Mutação , Humanos , Feminino , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/mortalidade , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/mortalidade , Pessoa de Meia-Idade , Conectina/genética , Biomarcadores Tumorais/genética , Idoso , Prognóstico , Sequenciamento do Exoma/métodos , AdultoRESUMO
The Cancer Genome Atlas (TCGA) Research Network described 4 molecular subgroups of endometrial carcinomas with different outcome: 1) POLE ultramutated endometrioid carcinomas which have an indolent behavior; 2) microsatellite instability hypermutated endometrioid carcinomas associated with intermediate prognosis; 3) copy-number low endometrioid carcinomas also with intermediate prognosis; and 4) copy-number high predominantly serous (non-endometrioid) but also serous-like endometrioid carcinomas, almost always carrying TP53 mutations, with poor clinical outcome. After 10 years of comprehensive analysis, it appears that the only real contribution of TCGA to the clinical management of these patients would be limited to the infrequent high-grade, early-stage endometrioid carcinomas with POLE exonuclease domain mutations, as these patients could benefit from a de-escalating treatment; knowledge about the other three subgroups has not changed significantly. The copy-number low (or non-specific genetic profile) which is the most frequent subgroup, is a mixture subgroup where investigators are currently trying to establish prognostic markers; for example, unexpected variations in a relatively small percentage of cases (i.e., CTNNB1 mutated or p53 aberrant low-grade and low-stage endometrioid carcinomas associated with unfavorable prognosis). On the other hand, TCGA has underlined that a small number of grade 3 endometrioid carcinomas, all TP53 mutated, overlap with copy-number high serous carcinomas. Recently, TCGA molecular subgroups have been integrated into the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging classification which incorporates other non-anatomic parameters like histotype, tumor grade, and lymphovascular space invasion. The result is a complicated and non-intuitive classification that makes its clinical application difficult and does not facilitate correspondence with the 2009 FIGO staging.