Longitudinal examination of perfusion and angiogenesis markers in primary colorectal tumors shows distinct signatures for metronomic and maximum-tolerated dose strategies
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus (mouse)
SUBMITTER:
PROVIDER: S-BIAD323 | bioimages |
REPOSITORIES: bioimages
Similar Datasets
Project description:Three subregions of the amygdala receive monosynaptic projections from the olfactory bulb, making them part of the primary olfactory cortex. These primary olfactory areas are located at the anterior-medial aspect of the amygdala and include the medial amygdala (MeA), cortical amygdala (CoA), and the periamygdaloid complex (PAC). The vast majority of research on the amygdala has focused on the larger basolateral and basomedial subregions, which are known to be involved in implicit learning, threat responses, and emotion. Fewer studies have focused on the MeA, CoA, and PAC, with most conducted in rodents. Therefore, our understanding of the functions of these amygdala subregions is limited, particularly in humans. Here, we first conducted a review of existing literature on the MeA, CoA, and PAC. We then used resting-state fMRI and unbiased k-means clustering techniques to show that the anatomical boundaries of human MeA, CoA, and PAC accurately parcellate based on their whole-brain resting connectivity patterns alone, suggesting that their functional networks are distinct, relative both to each other and to the amygdala subregions that do not receive input from the olfactory bulb. Finally, considering that distinct functional networks are suggestive of distinct functions, we examined the whole-brain resting network of each subregion and speculated on potential roles that each region may play in olfactory processing. Based on these analyses, we speculate that the MeA could potentially be involved in the generation of rapid motor responses to olfactory stimuli (including fight/flight), particularly in approach/avoid contexts. The CoA could potentially be involved in olfactory-related reward processing, including learning and memory of approach/avoid responses. The PAC could potentially be involved in the multisensory integration of olfactory information with other sensory systems. These speculations can be used to form the basis of future studies aimed at clarifying the olfactory functions of these under-studied primary olfactory areas.
| S-EPMC8695617 | biostudies-literature
Project description:Primary dermal melanoma (PDM) is a rare variant of melanoma which simulates metastatic melanoma to the skin. Diagnosis of PDM cannot be established on histologic grounds alone but requires absence of evidence of melanoma elsewhere by clinical history and/or imaging studies. Despite this entity being clinically well documented, limited data on molecular characterization are available. We performed comprehensive mutation and copy number variation analysis in a series of PDMs in search for distinctive molecular features.Studies were approved by respective institutional review boards. Six cases fulfilling strict histologic criteria of PDM were identified in patients with absent history of melanoma elsewhere, negative sentinel lymph node biopsies and imaging studies. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue, and five cases passed quality control measures and were subjected to targeted exon sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets 410 panel. Two of five PDM carried NRAS hotspot mutations characteristic of cutaneous melanoma (CM) genomic subtypes. One case showed a probable low-activating NRAS mutation in combination with additional aberrations in other mitogen-activated protein kinase (MAPK) pathway effectors. Hotspot mutations were also identified in the TERT promoter region, and one tumor showed a mutation in the SWI/SNF remodeling complex. No oncogenic mutations were identified in one case. Furthermore, none of the tumors analyzed showed activating mutations in Gα subunits, including GNAQ and GNA11. Copy number alterations included deletions of Chr 9p, characteristic of CM.Despite PDM showing mutational heterogeneity, our findings suggest predominance of MAPK pathway aberrations in agreement with the mutational profile of CMs in general. Given the absence of genetic overlap with other distinct primary dermal melanocytic proliferations, mutational profiling will unlikely aid in the difficult differential diagnosis of PDM versus melanoma metastasis. Thorough metastatic workup remains crucial in establishing this rare diagnosis.
| S-EPMC8370683 | biostudies-literature
Project description:In melanoma, the presence of promoter related hypermethylation has previously been reported, however, no methylation-based distinction has been drawn among the diverse melanoma subtypes. Here, we investigated DNA methylation changes associated with melanoma progression and links between methylation patterns and other types of somatic alterations, including the most frequent mutations and DNA copy number changes. Our results revealed that the methylome, presenting in early stage samples and associated with the BRAF(V600E) mutation, gradually decreased in the medium and late stages of the disease. An inverse relationship among the other predefined groups and promoter methylation was also revealed except for histologic subtype, whereas the more aggressive, nodular subtype melanomas exhibited hypermethylation as well. The Breslow thickness, which is a continuous variable, allowed for the most precise insight into how promoter methylation decreases from stage to stage. Integrating our methylation results with a high-throughput copy number alteration dataset, local correlations were detected in the MYB and EYA4 genes. With regard to the effects of DNA hypermethylation on melanoma patients' survival, correcting for clinical cofounders, only the KIT gene was associated with a lower overall survival rate. In this study, we demonstrate the strong influence of promoter localized DNA methylation changes on melanoma initiation and show how hypermethylation decreases in melanomas associated with less favourable clinical outcomes. Furthermore, we establish the methylation pattern as part of an integrated apparatus of somatic DNA alterations.
| S-EPMC4022506 | biostudies-literature
Project description:Physical properties of primary cilia membranes in living cells were examined using two independent, high-spatiotemporal-resolution approaches: fast tracking of single quantum dot-labeled G protein-coupled receptors and a novel two-photon super-resolution fluorescence recovery after photobleaching of protein ensemble. Both approaches demonstrated the cilium membrane to be partitioned into corralled domains spanning 274 ± 20 nm, within which the receptors are transiently confined for 0.71 ± 0.09 s. The mean membrane diffusion coefficient within the corrals, Dm1 = 2.9 ± 0.41 µm2/s, showed that the ciliary membranes were among the most fluid encountered. At longer times, the apparent membrane diffusion coefficient, Dm2 = 0.23 ± 0.05 µm2/s, showed that corral boundaries impeded receptor diffusion 13-fold. Mathematical simulations predict the probability of G protein-coupled receptors crossing corral boundaries to be 1 in 472. Remarkably, latrunculin A, cytochalasin D, and jasplakinolide treatments altered the corral permeability. Ciliary membranes are thus partitioned into highly fluid membrane nanodomains that are delimited by filamentous actin.
| S-EPMC6080922 | biostudies-literature
Project description:Cytoskeletal actin dynamics are crucial for the activation of T-cells. Immortalised Jurkat T-cells have been the model system of choice to examine and correlate the dynamics of the actin cytoskeleton and the immunological synapse leading to T-cell activation. However, it has remained unclear whether immortalised cellular systems, such as Jurkat T-cells can recapitulate the cytoskeletal behaviour of primary T-cells. Studies delineating the cytoskeletal behaviour of Jurkat T-cells in comparison to primary T-cells are lacking. Here, we employ live-cell super-resolution microscopy to investigate the cytoskeletal actin organisation and dynamics of living primary and immortalised Jurkat T-cells at the appropriate spatiotemporal resolution. Under comparable activation conditions, we found differences in the architectural organisation and dynamics of Jurkat and primary mouse and human T-cells. Although the three main actin network architectures in Jurkat T-cells were reminiscent of primary T-cells, there were differences in the organisation and molecular mechanisms underlying these networks. Our results highlight mechanistic distinctions in the T-cell model system most utilised to study cytoskeletal actin dynamics.
| S-EPMC6898998 | biostudies-literature
Project description:In the rodent auditory system, the primary cortex is subdivided into two regions, both receiving direct inputs from the auditory thalamus: the primary auditory cortex (A1) and the anterior auditory field (AAF). Although neurons in the two regions display different response properties, like response latency, firing threshold or tuning bandwidth, it is still not clear whether they process sound in a distinct way. Using in vivo electrophysiological recordings in the mouse auditory cortex, we found that AAF neurons have significantly stronger responses to tone offset than A1 neurons. AAF neurons also display faster and more transient responses than A1 neurons. Additionally, offset responses in AAF - unlike in A1, increase with sound duration. Local field potential (LFP) and laminar analyses suggest that the differences in sound responses between these two primary cortices are both of subcortical and intracortical origin. These results emphasize the potentially critical role of AAF for temporal processing. Our study reveals a distinct role of two primary auditory cortices in tone processing and highlights the complexity of sound encoding at the cortical level.
| S-EPMC6610078 | biostudies-literature
Project description:Aspergillus nidulans contains two functionally distinct fatty acid synthases (FASs): one required for primary fatty acid metabolism (FAS) and the other required for secondary metabolism (sFAS). FAS mutants require long-chain fatty acids for growth, whereas sFAS mutants grow normally but cannot synthesize sterigmatocystin (ST), a carcinogenic secondary metabolite structurally and biosynthetically related to aflatoxin. sFAS mutants regain the ability to synthesize ST when provided with hexanoic acid, supporting the model that the ST polyketide synthase uses this short-chain fatty acid as a starter unit. The characterization of both the polyketide synthase and FAS may provide novel means for modifying secondary metabolites.
| S-EPMC26229 | biostudies-literature
Project description:Synchronous Hodgkin Lymphoma and Primary Mediastinal B-cell Lymphoma is possible, with molecular analyses proving the absence of clonal filiation between both entities. This suggests a common etiology but the existence of two divergent clones.
| S-EPMC8365538 | biostudies-literature
Project description:Multiparameter flow cytometry is a robust and reliable method for determining tumour DNA content applicable to formalin-fixed paraffin-embedded (FFPE) tissue. This study examined the clinical and pathological associations of DNA content in primary breast cancer using an improved multiparametric technique.The FFPE tissue from 201 primary breast cancers was examined and the cancers categorised according to their DNA content using multiparametric flow cytometry incorporating differential labelling of stromal and tumour cell populations. Mathematical modelling software (ModFit 3.2.1) was used to calculate the DNA index (DI) and percentage S-phase fraction (SPF%) for each tumour. Independent associations with clinical and pathological parameters were sought using backward stepwise Binary Logistic Regression (BLR) and Cox's Regression (CR) analysis.Tumours were grouped into four categories based on the DI of the tumour cell population. Low DI tumours (DI=0.76-1.14) associated with progesterone receptor-positive status (P=0.012, BLR), intermediate DI (DI=1.18-1.79) associated with p53 mutant tumours (P=0.001, BLR), high DI (DI1.80) tumours with human epidermal growth factor receptor 2 (HER2)-positive status (P=0.004, BLR) and 'multiploid tumours' (two or more tumour DNA peaks) did not show any significant associations. Tumours with high SPF% (10%) independently associated with poor overall survival (P=0.027, CR).Multiparametric flow analysis of FFPE tissue can accurately assess tumour DNA content. Tumour sub-populations associated with biomarkers of prognosis or likely response to therapy. The alterations in DNA content present the potential for greater understanding of the mechanisms underlying clinically significant biomarker changes in primary breast cancer.
| S-EPMC3590677 | biostudies-other
Project description:Primary progressive aphasia is a syndrome characterized by progressive loss of language abilities with three main phenotypic clinical presentations, including logopenic, non-fluent/agrammatic, and semantic variants. Previous imaging studies have shown unique anatomic impacts within language networks in each variant. However, direct measures of spontaneous neuronal activity and functional integrity of these impacted neural networks in primary progressive aphasia are lacking. The aim of this study was to characterize the spatial and temporal patterns of resting state neuronal synchronizations in primary progressive aphasia syndromes. We hypothesized that resting state brain oscillations will show unique deficits within language network in each variant of primary progressive aphasia. We examined 39 patients with primary progressive aphasia including logopenic variant (n = 14, age = 61 ± 9 years), non-fluent/agrammatic variant (n = 12, age = 71 ± 8 years) and semantic variant (n = 13, age = 65 ± 7 years) using magnetoencephalographic imaging, compared to a control group that was matched in age and gender to each primary progressive aphasia subgroup (n = 20, age = 65 ± 5 years). Each patient underwent a complete clinical evaluation including a comprehensive battery of language tests. We examined the whole-brain resting state functional connectivity as measured by imaginary coherence in each patient group compared to the control cohort, in three frequency oscillation bands-delta-theta (2-8 Hz); alpha (8-12 Hz); beta (12-30 Hz). Each variant showed a distinct spatiotemporal pattern of altered functional connectivity compared to age-matched controls. Specifically, we found significant hyposynchrony of alpha and beta frequency within the left posterior temporal and occipital cortices in patients with the logopenic variant, within the left inferior frontal cortex in patients with the non-fluent/agrammatic variant, and within the left temporo-parietal junction in patients with the semantic variant. Patients with logopenic variant primary progressive aphasia also showed significant hypersynchrony of delta-theta frequency within bilateral medial frontal and posterior parietal cortices. Furthermore, region of interest-based analyses comparing the spatiotemporal patterns of variant-specific regions of interest identified in comparison to age-matched controls showed significant differences between primary progressive aphasia variants themselves. We also found distinct patterns of regional spectral power changes in each primary progressive aphasia variant, compared to age-matched controls. Our results demonstrate neurophysiological signatures of network-specific neuronal dysfunction in primary progressive aphasia variants. The unique spatiotemporal patterns of neuronal synchrony signify diverse neurophysiological disruptions and pathological underpinnings of the language network in each variant.
| S-EPMC5841154 | biostudies-literature