Despite the significance of efforts to understand the biological basis of autism, progress in this area has been hindered, in part, by the considerable heterogeneity in the disorder. Fragile X ...syndrome (FXS), a monogenic condition associated with high risk for autism, may pave the way for the dissection of biological heterogeneity within idiopathic autism. This article adopts a cross-syndrome biomarker approach to evaluate potentially overlapping profiles of cardiac arousal dysregulation (and broader autonomic dysfunction) in autism and FXS. Approaches such as this, aimed at delineating shared mechanisms across genetic syndromes, hold great potential for improving diagnostic precision, promoting earlier identification, and uncovering key systems that can be targeted in pharmaceutical/behavioral interventions. Biomarker approaches may be vital to deconstructing complex psychiatric disorders and are currently promoted as such by major research initiatives such as the NIMH Research Domain Criteria (RDoC). Evidence reviewed here supports physiological dysregulation in a subset of individuals with autism, as evidenced by patterns of hyperarousal and dampened parasympathetic vagal tone that overlap with the well-documented physiological profile of FXS. Moreover, there is growing support for a link between aberrant cardiac activity and core deficits associated with autism, such as communication and social impairment. The delineation of physiological mechanisms common to autism and FXS could lend insight into relationships between genetic etiology and behavioral endstates, highlighting FMR1 as a potential candidate gene. Research gaps and potential pitfalls are discussed to inform timely, well-controlled biomarker research that will ultimately promote better diagnosis and treatment of autism and associated conditions.
The molecular mechanisms by which tumor cells survive or die following therapeutic interventions are complex. There are three broadly defined categories of cell death processes: apoptosis (Type I), ...autophagic cell death (Type II), and necrosis (Type III). In hematopoietic tumor cells, the majority of toxic stimuli cause these cells to undergo a death process called apoptosis; apoptosis specifically involves the cleavage of DNA into large defined pieces and their subsequent localization in vesicles. Thus, ‘pure’ apoptosis largely lacks inflammatory potential. In carcinomas, however, the mechanisms by which tumor cells ultimately die are considerably more complex. Although the machinery of apoptosis is engaged by toxic stimuli, other processes such as autophagy (“self-eating”) and replicative cell death can lead to observations that do not simplistically correspond to any of the individual Type I-III formalized death categories. The ‘hybrid’ forms of cell death observed in carcinoma cells result in cellular materials being released into the extracellular space without packaging, which promotes inflammation, potentially leading to the accelerated re-growth of surviving tumor cells by macrophages. Drugs as single agents or in combinations can simultaneously initiate signaling via both apoptotic and autophagic pathways. Based on the tumor type and its oncogene drivers, as well as the drug(s) being used and the duration and intensity of the autophagosome signal, apoptosis and autophagy have the potential to act in concert to kill or alternatively that the actions of either pathway can act to suppress signaling by the other pathway. And, there also is evidence that autophagic flux, by causing lysosomal protease activation, with their subsequent release into the cytosol, can directly mediate killing. This review will discuss the interactive biology between apoptosis and autophagy in carcinoma cells. Finally, the molecular actions of the FDA-approved drugs neratinib and sorafenib, and how they enhance both apoptotic and toxic autophagic processes, alone or in combination with other agents, is discussed in a bench-to-bedside manner.
We focused on the ability of the pan-histone deacetylase (HDAC) inhibitors AR42 and sodium valproate to alter the immunogenicity of melanoma cells. Treatment of melanoma cells with HDAC inhibitors ...rapidly reduced the expression of multiple HDAC proteins as well as the levels of PD-L1, PD-L2 and ODC, and increased expression of MHCA. In a cell-specific fashion, melanoma isolates released the immunogenic protein HMGB1 into the extracellular environment. Very similar data were obtained in ovarian and H&NSCC PDX isolates, and in established tumor cell lines from the lung and kidney. Knock down of HDAC1, HDAC3, HDAC8 and HDAC10, but not HDAC6, recapitulated the effects of the HDAC inhibitors on the immunotherapy biomarkers. Using B16 mouse melanoma cells we discovered that pre-treatment with AR42 or sodium valproate enhanced the anti-tumor efficacy of an anti-PD-1 antibody and of an anti-CTLA4 antibody. In the B16 model, both AR42 and sodium valproate enhanced the anti-tumor efficacy of the multi-kinase inhibitor pazopanib. In plasma from animals exposed to HDAC inhibitor + anti-PD-1, but not HDAC inhibitor + anti-CTLA4, the levels of CCL2, CCL5, CXCL9 and CXCL2 were increased. The cytokine data from HDAC inhibitor plus anti-PD-1 exposed tumors correlated with increased activated T cell, M1 macrophage, neutrophil and NK cell infiltration. Collectively, our data support the use of pan-HDAC inhibitors in combination with kinase inhibitors or with checkpoint inhibitor antibodies as novel melanoma therapeutic strategies.
Monday morning on-call had included the cataclysmic event of a patient calling to report finding her husband had taken his own life. She was having a panic attack and reception had put through the ...call as urgent. The story ached with poignancy and pain and the grief being expressed was visceral. And there was other stuff lurking in the back of Roberts mind; a patient complaint, a coroner's report to write. Her shoulders and lower back were getting ever more tense and her brain tired; the day was long. There is no mistaking the pressure our profession is under. Even before the emergence of COVID-19 we were sinking. The 2019 GMC report, Caring for Doctors, Caring for Patients, shows GPs reporting the lowest levels of job satisfaction and the highest levels of stress since 1998. Like many before she who have written on this highly topical subject, individual doctors are not the cause of nor the answer to occupational burnout.
Cortical areas in the ventral visual pathway become selectively tuned towards the processing of faces compared to non-face stimuli beginning around 3 months of age and continuing over the first year. ...Studies using event-related potentials in the EEG (ERPs) have found an ERP component, the N290, that displays specificity for human faces. Other components, such as the P1, P400, and Nc have been studied to a lesser degree in their responsiveness to human faces. However, little is known about the systematic changes in the neural responses to faces during the first year of life, and the localization of these responses in infants’ brain. We examined ERP responses to pictures of faces and objects in infants from 4.5 months through 12 months in a cross-sectional study. We investigated the activity of all the components reported to be involved in infant face processing, with particular interest to their amplitude variation and cortical localization. We identified neural regions responsible for the component through the application of cortical source localization methods. We found larger P1 and N290 responses to faces than objects, and these components were localized in the lingual and middle/posterior fusiform gyri, respectively. The amplitude of the P400 was not differentially sensitive to faces over objects. The Nc component was different for faces and objects, was influenced by the infant’s attentional state, and localized in medial-anterior brain areas. The implications of these results are discussed in the identification of developmental ERP precursors to face processing.
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•Face-sensitive N290 responses are localized in the middle and posterior fusiform gyri.•The amplitude of the P400 component is not sensitive to faces.•The Nc sensitivity to faces is modulated by infant’s attentional state.•Posterior generators reflect the activity of the P1, while the Nc sources are localized in more anterior areas.
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AR12 is a derivative of celecoxib which no-longer acts against COX2 but instead inhibits the ATPase activity of multiple chaperone proteins, in particular GRP78. GRP78 acts as a ...sensor of endoplasmic reticulum stress and is an essential chaperone required for the life cycle of all mammalian viruses. We and others previously demonstrated in vitro and in vivo that AR12 increases autophagosome formation and autophagic flux, enhances virus protein degradation, preventing virus reproduction, and prolonging the survival of infected animals. In this report, we determined whether AR12 could act against SARS-CoV-2. In a dose-dependent fashion AR12 inhibited SARS-CoV-2 spike protein expression in transfected or infected cells. AR12 suppressed the production of infectious virions via autophagosome formation, which was also associated with degradation of GRP78. After AR12 exposure, the colocalization of GRP78 with spike protein was reduced. Knock down of eIF2α prevented AR12-induced spike degradation and knock down of Beclin1 or ATG5 caused the spike protein to localize in LAMP2+ vesicles without apparent degradation. HCT116 cells expressing ATG16L1 T300, found in the majority of persons of non-European descent, particularly from Africa, expressed greater amounts of GRP78 and SARS-CoV-2 receptor angiotensin converting enzyme 2 compared to ATG16L1 A300, predominantly found in Europeans, suggestive that ATG16L1 T300 expression may be associated with a greater ability to be infected and to reproduce SARS-CoV-2. In conclusion, our findings demonstrate that AR12 represents a clinically relevant anti-viral drug for the treatment of SARS-CoV-2.
Prior studies from our group have combined the multi-kinase inhibitor sorafenib with HDAC inhibitors in GI tumor cells that resulted in the trials NCT02349867 and NCT01075113. The multi-kinase ...inhibitor lenvatinib, for the treatment of liver cancer, has fewer negative sequelae than sorafenib. We determined the mechanisms by which lenvatinib interacted with the HDAC inhibitor entinostat to kill hepatoma cells. Lenvatinib and entinostat interacted in an additive to greater-than-additive fashion to kill liver cancer cells. The drugs inactivated mTORC1 and mTORC2 and interacted to further increase the phosphorylation of ATM, ATG13 and eIF2α. Elevated eIF2α phosphorylation was responsible for reduced MCL-1 and BCL-XL expression and for increased Beclin1 and ATG5 expression. Over-expression of BCL-XL or knock down of Beclin1 or ATG5, significantly reduced killing. The drugs synergized to elevate ROS production; activation of ATM was ROS-dependent. ATM activation was required for enhanced phosphorylation of γH2AX, eIF2α and ATG13 S318. The drug combination reduced histone deacetylase protein expression which required autophagy. Knock down of HDACs1/2/3 prevented the lenvatinib and entinostat combination from regulating PD-L1 and MHCA expression. Collectively, our data demonstrate that lenvatinib and entinostat interact to kill liver cancer cells via ROS-dependent activation of ATM and inactivation of eIF2α, resulting in greater levels of toxic autophagosome formation and reduced expression of protective mitochondrial proteins.
•Lenvatinib and entinostat interact to kill liver cancer cells.•The drugs inactivated mTOR and caused autophagosome formation; autophagy mediated tumor cell killing.•Increased eIF2a phosphorylation reduced MCL-1 and BCL-XL expression and increased Beclin1 and ATG5 expression.•Knock down of ATG5 or Beclin1 or over-expression of BCL-XL suppressed tumor cell killing.•The drugs synergized to elevate ROS production and ROS was essential in the toxic autophagy and ER stress responses.
Prospective longitudinal studies of idiopathic autism spectrum disorder (ASD) have provided insights into early symptoms and predictors of ASD during infancy, well before ASD can be diagnosed at age ...2-3 years. However, research on the emergence of ASD in disorders with a known genetic etiology, contextualized in a developmental framework, is currently lacking. Using a biobehavioral multimethod approach, we (a) determined the rate of ASD in N = 51 preschoolers with fragile X syndrome (FXS) using a clinical best estimate (CBE) procedure with differential diagnoses of comorbid psychiatric disorders and (b) investigated trajectories of ASD symptoms and physiological arousal across infancy as predictors of ASD in preschoolers with FXS. ASD was not diagnosed if intellectual ability or psychiatric disorders better accounted for the symptoms. Our results determined that 60.7% of preschoolers with FXS met the Diagnostic and Statistical Manual of Mental Disorders (fifth edition) (DSM-5) criteria for ASD using the CBE procedure. In addition, 92% of these preschoolers presented with developmental delay and 45.4% also met criteria for psychiatric disorders, either anxiety, ADHD, or both. ASD diagnoses in preschoolers with FXS were predicted by elevated scores on traditional ASD screeners in addition to elevated autonomic arousal and avoidant eye contact from infancy.
Herein we discuss multiple pre-clinical projects developed by our group that have been translated into patients at Massey Cancer Center. Our work has used multi-kinase inhibitors, for example, ...sorafenib, regorafenib and neratinib, and combined with additional agents, for example, histone deacetylase inhibitors, the thymidylate synthase inhibitor pemetrexed, and PDE5 inhibitors. In broad-brush terms, our experience has been that these drug combinations enhance signaling by ATM-AMPK-ULK-1 and decrease signaling from growth factor receptors and RAS proteins, thereby lowering the activities of the intracellular signaling kinase ERK1/2, AKT, mTOR and p70 S6K . This collectively results in reduced protein synthesis and the induction of an endoplasmic reticulum stress response alongside autophagosome formation and autophagic flux. The rupture of autolysosomes, releasing proteases such as cathepsin B into the cytosol results in the cleavage and activation of the toxic BH3 domain protein BID which cooperates with BAX, BAK and BIM to cause mitochondrial dysfunction, leading to the release of cytochrome c and AIF, which then execute the tumor cell. For each of our two-drug combinations, we then performed additional laboratory-based studies to define the development of evolutionary resistance mechanisms, with the long-term concept of performing new three-drug clinical trials to prolong therapeutic efficacy and disease control.
Inflammatory bowel diseases (IBDs) are chronic relapsing and remitting conditions associated with long-term gut dysfunction resulting from alterations to the enteric nervous system and a loss of ...enteric neurons. The mechanisms underlying inflammation-induced enteric neuron death are unknown. Here using in vivo models of experimental colitis we report that inflammation causes enteric neuron death by activating a neuronal signaling complex composed of P2X7 receptors (P2X7Rs), pannexin-1 (Panx1) channels, the Asc adaptor protein and caspases. Inhibition of P2X7R, Panx1, Asc or caspase activity prevented inflammation-induced neuron cell death. Preservation of enteric neurons by inhibiting Panx1 in vivo prevented the onset of inflammation-induced colonic motor dysfunction. Panx1 expression was reduced in Crohn's disease but not ulcerative colitis. We conclude that activation of neuronal Panx1 underlies neuron death and the subsequent development of abnormal gut motility in IBD. Targeting Panx1 represents a new neuroprotective strategy to ameliorate the progression of IBD-associated dysmotility.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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