Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic ...derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each agent, we evaluate the preclinical studies demonstrating antitumor and TME effects and review ongoing clinical trials. The goal of this Review is to provide an overview of the landscape of metabolic inhibitors in clinical development for oncology.
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bstract
Current Higgs data at the Large Hadron Collider is compatible with a SM signal at the 2σ level, but the central value of the signal strength in the diphoton channel is enhanced with respect ...to the SM expectation. If the enhancement resides in the diphoton partial decay width, the data could be accommodated in the Minimally Super-symmetric Standard Model (MSSM) with highly mixed light staus. We revisit the issue of vacuum instability induced by large mixing in the stau sector, including effects of a radiatively-corrected tau Yukawa coupling. Further, we emphasize the importance of taking into account the tan β dependence in the stability bound. While the metastability of the Universe constrains the possible enhancement in the Higgs to diphoton decay width in the light stau scenario, an increase of the order of 50% can be achieved in the region of large tan β. Larger enhancements may be obtained, but would require values of tan β associated with non-perturbative values of the tau Yukawa coupling at scales below the GUT scale, thereby implying the presence of new physics beyond the MSSM.
The focus of spatial attention can be not only oriented to a particular location, but also adjusted in its size to select visual information from a narrow (zoom-in) or broad (zoom-out) region of the ...visual field. Attentional orienting, saccades programming, and visual search have been linked to the frontal eye fields (FEF) activity. However, the FEF causal role in the frontoparietal network for the attentional focus size modulation remains unclear. Here, we delivered single-pulse transcranial magnetic stimulation (TMS) on FEF while participants performed an attentional zooming task. They were asked to detect a visual target appearing at 3 eccentricities from the fixation. Two cue types modulated the size of the attended region: a small cue was employed to narrow the attentional focus, whereas a large cue induced participants to broaden the attended region. Results showed that TMS delivered on the right FEF, but not on the left FEF, was able to interfere with both zoom-in and zoom-out attentional mechanisms. Our results provide the first evidence of the right FEF casual role in the attentional zooming control and give new insights into the neural mechanisms of dysfunctional spatial attention deployment shown in neurodevelopmental disorders, such as autism and dyslexia.
The 2016–2017 seismic sequence, in central Italy, was caused by the Mt. Vettore‐Mt. Bove active fault system, which generated three mainshocks, the largest one of Mw 6.6, on 30 October 2016. On 18 ...January 2017, four Mw 5–5.5 seismic events nucleated on the Campotosto active fault. The fault is considered as potentially responsible for M ~6.6 seismic events and a seismic gap. The structure also nucleated a Mw 5.4 aftershock during the 2009 L'Aquila seismic sequence. We here combined new geological/geomorphological field data, 1945 aerial photographs interpretation, geodetic (Differential Interferometric Synthetic Aperture Radar and Global Positioning System) data, and local historical seismicity analysis to determine how much of the Campotosto seismogenic source ruptured during the 2009 and 2016–2017 seismic sequences. The obtained residual seismic moment of the Campotosto seismic gap is in the range Mw 6.4–6.6 earthquake. Moreover, the review of the regional tectonic setting and evolution allowed us a brand new and comprehensive reading of the seismotectonics for the region, in terms of both seismic potential and segmentation of the seismogenic sources, which results strictly connected to the long‐term activity of inherited lithospheric discontinuities, among which the major Ancona‐Anzio fault. We here first highlight that such regional structures strongly influenced the structural setting and evolution of the surrounding regions, in a progressive and continuous process of tectonic inversions, which implies that structural heritage must be understood and considered when dealing with seismotectonics of a given tectonically active region.
Key Points
Geological/geomorphological information is coupled with seismological and geodetic data related to the 2009 and 2016–2017 central Italy seismic sequences
Coseismic dislocation model, based on GPS and InSAR data related to the 18 January 2017 earthquakes on the Campotosto fault, is presented
The residual seismogenic potential of the Campotosto fault is on the order of 6.4–6.5 moment magnitude earthquake
The term liquid biopsy (LB) refers to the use of various biological fluids as a surrogate for neoplastic tissue to achieve information for diagnostic, prognostic and predictive purposes. In the ...current clinical practice, LB is used for the identification of driver mutations in circulating tumor DNA derived from both tumor tissue and circulating neoplastic cells. As suggested by a growing body of evidence, however, there are several clinical settings where biological samples other than tissue could be used in the routine practice to identify potentially predictive biomarkers of either response or resistance to targeted treatments. New applications are emerging as useful clinical tools, and other blood derivatives, such as circulating tumor cells, circulating tumor RNA, microRNAs, platelets, extracellular vesicles, as well as other biofluids such as urine and cerebrospinal fluid, may be adopted in the near future. Despite the evident advantages compared with tissue biopsy, LB still presents some limitations due to both biological and technological issues. In this context, the absence of harmonized procedures corresponds to an unmet clinical need, ultimately affecting the rapid implementation of LB in clinical practice. In this position paper, based on experts’ opinions, the AIOM–SIAPEC-IAP–SIBIOC–SIF Italian Scientific Societies critically discuss the most relevant technical issues of LB, the current and emerging evidences, with the aim to optimizing the applications of LB in the clinical setting.
•In the current clinical practice LB is used for the identification of driver mutations in circulating tumor DNA (ctDNA).•New applications in tumors other than non-small-cell lung cancer (NSCLC) are emerging as useful clinical tools.•Other blood derivatives, together with other biofluids, are an active field of research and may be adopted in the near future.•Despite the evident advantages, liquid biopsy still presents limitations due to both biological and technological issues.•Standardization of the procedures needs to be addressed to ensure widespread implementation in clinical practice.
Developmental dyslexia (DD) is a heritable neurodevelopmental reading disorder that could arise from auditory, visual, and cross-modal integration deficits. A deletion in intron 2 of the DCDC2 gene ...(hereafter DCDC2d) increases the risk for DD and related phenotypes. In this study, first we report that illusory visual motion perception-specifically processed by the magnocellular-dorsal (M-D) stream-is impaired in children with DD compared with age-matched and reading-level controls. Second, we test for the specificity of the DCDC2d effects on the M-D stream. Children with DD and DCDC2d need significantly more contrast to process illusory motion relative to their counterpart without DCDC2d and to age-matched and reading-level controls. Irrespective of the genetic variant, children with DD perform normally in the parvocellular-ventral task. Finally, we find that DCDC2d is associated with the illusory motion perception also in adult normal readers, showing that the M-D deficit is a potential neurobiological risk factor of DD rather than a simple effect of reading disorder. Our findings demonstrate, for the first time, that a specific neurocognitive dysfunction tapping the M-D stream is linked with a well-defined genetic susceptibility.
•Dyslexia is characterized not only by phonological but also orthographic deficits.•Orthographic processing assigns letter identities to different spatial locations.•Spatial location encoding is ...driven by the “where” dorsal-attentional stream.•Adults with dyslexia show impaired IOR during orthographic processing.•Adults with dyslexia show a “where” dorsal-attentional dysfunction.
Dyslexia (D) is a neurodevelopmental reading disorder characterized by phonological and orthographic deficits. Before phonological decoding, reading requires a specialized orthographic system for parallel letter processing that assigns letter identities to different spatial locations. The magnocellular-dorsal (MD) stream rapidly process the spatial location of visual stimuli controlling visuo-spatial attention. To investigate the visuo-spatial attention efficiency during orthographic processing, inhibition of return (IOR) was measured in adults with and without D in a lexical decision task. IOR is the delay in responding to stimuli displayed in a cued location after a long cue-target interval. Only adults with D did not showed IOR effect during letter-string recognition, despite the typical left-hemisphere specialization for word identification. A specific deficit in coherent-dot-motion perception confirmed an MD-stream disorder in adults with D. Our results suggest that adults with D might develop an efficient visual word form area, but a dorsal-attentional dysfunction impairs their reading fluency.
The peroxidation of unsaturated fatty acids is a widely recognized metabolic process that creates a complex mixture of volatile organic compounds including aldehydes. Elevated levels of reactive ...oxygen species in cancer cells promote random lipid peroxidation, which leads to a variety of aldehydes. In the case of lung cancer, many of these volatile aldehydes are exhaled and are of interest as potential markers of the disease. Relevant studies reporting aldehydes in the exhaled breath of lung cancer patients were collected for this review by searching the PubMed and SciFindern databases until 25 May 2022. Information on breath test results, including the biomarker collection, preconcentration, and quantification methods, was extracted and tabulated. Overall, 44 studies were included spanning a period of 34 years. The data show that, as a class, aldehydes are significantly elevated in the breath of lung cancer patients at all stages of the disease relative to healthy control subjects. The type of aldehyde detected and/or deemed to be a biomarker is highly dependent on the method of exhaled breath sampling and analysis. Unsaturated aldehydes, detected primarily when derivatized during preconcentration, are underrepresented as biomarkers given that they are also likely products of lipid peroxidation. Pentanal, hexanal, and heptanal were the most reported aldehydes in studies of exhaled breath from lung cancer patients.
Neutrophils suppress γδ T‐cell function Sabbione, Florencia; Gabelloni, María L.; Ernst, Glenda ...
European Journal of Immunology,
March 2014, Letnik:
44, Številka:
3
Journal Article
Recenzirano
Odprti dostop
γδ T cells have been shown to stimulate the recruitment and activation of neutrophils through the release of a range of cytokines and chemokines. Here, we investigated the reverse relationship, ...showing that human neutrophils suppress the function of human blood γδ T cells. We show that the upregulation of CD25 and CD69 expression, the production of IFN‐γ, and the proliferation of γδ T cells induced by (E)‐1‐hydroxy‐2‐methylbut‐2‐enyl 4‐diphosphate are inhibited by neutrophils. Spontaneous activation of γδ T cells in culture is also suppressed by neutrophils. We show that inhibitors of prostaglandin E2 and arginase I do not exert any effect, although, in contrast, catalase prevents the suppression of γδ T cells induced by neutrophils, suggesting the participation of neutrophil‐derived ROS. We also show that the ROS‐generating system xanthine/xanthine oxidase suppresses γδ T cells in a similar fashion to neutrophils, while neutrophils from chronic granulomatous disease patients only weakly inhibit γδ T cells. Our results reveal a bi‐directional cross‐talk between γδ T cells and neutrophils: while γδ T cells promote the recruitment and the activation of neutrophils to fight invading pathogens, neutrophils in turn suppress the activation of γδ T cells to contribute to the resolution of inflammation.
Although a genetic component is known to have an important role in the etiology of developmental dyslexia (DD), we are far from understanding the molecular etiopathogenetic pathways. Reduced measures ...of neurobiological functioning related to reading (dis)ability, i.e. endophenotypes (EPs), are promising targets for gene finding and the elucidation of the underlying mechanisms. In a sample of 100 nuclear families with DD (229 offspring) and 83 unrelated typical readers, we tested whether a set of well‐established, cognitive phenotypes related to DD i.e. rapid auditory processing (RAP), rapid automatized naming (RAN), multisensory nonspatial attention and visual motion processing fulfilled the criteria of the EP construct. Visual motion and RAP satisfied all testable criteria (i.e. they are heritable, associate with the disorder, co‐segregate with the disorder within a family and represent reproducible measures) and are therefore solid EPs of DD. Multisensory nonspatial attention satisfied three of four criteria (i.e. it associates with the disorder, co‐segregates with the disorder within a family and represents a reproducible measure) and is therefore a potential EP for DD. Rapid automatized naming is heritable but does not meet other criteria of the EP construct. We provide the first evidence of a methodologically and statistically sound approach for identifying EPs for DD to be exploited as a solid alternative basis to clinical phenotypes in neuroscience.
Criterion 4 results. The 50% threshold mean for the rotating‐tilted‐lines illusion (RTLI) task (a). The slope mean of the fitted function for the RTLI (b). Mean accuracy among the five inter‐stimulus intervals of the rapid auditory processing task (c). Warning effect (d). Age and socio‐economic status are included as covariates. Aff, subjects with DD; UnAffSibs, unaffected siblings; TR, typical readers. *Two‐tailed significant P‐value < 0.05; ** two‐tailed significant P‐value < 0.001.
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