M. Celeste Simon

Globally, hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related death. We previously identified an immune evasion pathway whereby tumor cells produce retinoic acid (RA) to promote differentiation of intratumoral monocytes into protumor macrophages. Retinaldehyde dehydrogenase 1 (RALDH1), RALDH2, and RALDH3 are the three isozymes that catalyze RA biosynthesis. In this study, we have identified RALDH1 as the key driver of RA production in HCC and demonstrated the efficacy of RALDH1-selective inhibitors (Raldh1-INH) in suppressing RA production by HCC cells. Raldh1-INH restrained tumor growth in multiple mouse models of HCC by reducing the number and tumor-supporting functions of intratumoral macrophages as well as increasing T-cell infiltration and activation within tumors. Raldh1-INH also displayed favorable …

To identify drivers of sarcoma cancer stem-like cells (CSCs), we compared gene expression using RNA sequencing between HT1080 fibrosarcoma and SK-LMS-1 leiomyosarcoma spheroids (which are enriched for CSCs) compared with the parent populations. The most overexpressed survival signaling-related gene in spheroids was phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of PI3K, which functions in tumorigenesis and metastasis. In a human sarcoma microarray, PIK3R3 was also overexpressed by 4.1-fold compared with normal tissues. PIK3R3 inhibition using shRNA in the HT1080, SK-LMS-1, and DDLS8817 dedifferentiated liposarcoma in spheroids and in CD133+ cells (a CSC marker) reduced expression of CD133 and the stem cell factor Nanog and blocked spheroid formation by 61–71%. Mechanistic studies showed that in spheroid cells, PIK3R3 activated AKT and …

Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is …

Sensory deprivation, especially hearing loss (HL), offers a valuable model for studying neuroplasticity in the human brain and adaptive behaviours that support the daily lives of those with limited or absent sensory input. The study of olfactory function is particularly important as it is an understudied aspect of sensory deprivation. This study aimed to compare the effects of congenital HL on olfactory capacity by using psychophysical tasks. Methodological concerns from previous studies regarding the onset of HL and cognitive assessments were addressed. We recruited 11 individuals with severe‐to‐profound sensorineural HL (SNHL) since birth and 11 age‐ and sex‐matched typical hearing non‐signers. We used standardized neuropsychological tests to assess typical cognition among participants with SNHL. We evaluated olfactory functions by assessing olfactory detection threshold, odour discrimination and odour …

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting epithelial-mesenchymal transition (EMT) in PDAC primarily through a positive-feedback histone methylation-MAPK signaling axis. Transformed cells preferentially underwent EMT in hypoxic tumor regions in multiple model systems. Hypoxia drove a cell-autonomous EMT in PDAC cells which, unlike EMT in response to growth factors, could last for weeks. Furthermore, hypoxia reduced histone demethylase KDM2A activity, suppressed PP2 family phosphatase expression, and activated MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors played only a …

Retraction: Multimodal targeting of tumor vasculature and cancer stem-like cells in sarcomas with VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy - PMC Back to Top Skip to main content NIH NLM Logo Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search PMC Full-Text Archive Search in PMC Advanced Search User Guide Journal List Oncotarget v.15; 2024 PMC10852056 Other Formats PDF (217K) Actions Cite Collections Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Journal List Oncotarget v.15; 2024 PMC10852056 As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Logo of oncotarget Oncotarget. …

Molecular oxygen (O2) is essential for cellular bioenergetics and numerous biochemical reactions necessary for life. Solid tumors outgrow the native blood supply and diffusion limits of O2, and therefore must engage hypoxia response pathways that evolved to withstand acute periods of low O2. Hypoxia activates coordinated gene expression programs, primarily through hypoxia inducible factors (HIFs), to support survival. Many of these changes involve metabolic rewiring such as increasing glycolysis to support ATP generation while suppressing mitochondrial metabolism. Since low O2 is often coupled with nutrient stress in the tumor microenvironment, other responses to hypoxia include activation of nutrient uptake pathways, metabolite scavenging, and regulation of stress and growth signaling cascades. Continued development of models that better recapitulate tumors and their microenvironments will lead to …

● In Fig. 2a, the HT1080 spheroid images appear to have been published in a previous article with common authors [1], where they are described differently.● In Fig. 2b, sh. PIK3R3 panels appear to be the same for both HT1080 Spheroids and SK-LMS-1 Spheroids.● In Supplementary Fig. S2, the panel for invasion monolayer SK-LMS1 in S2a appears to be the same as the panel for invasion+ HT1080 Spheroids in S2d. Further, the panel for Migration Spheroids DDLS8817 in S2a appears to have been previously published in a paper with common authors [2], in which it is described differently.● In Supplementary Fig. S3b, the panel for HT1080 CD133+; LY294002 appears to have been previously published in a paper with common authors [3], where it is described differently.● In Supplementary Fig. S4, HT1080 and SK-LMS-1 panels appear to have been previously published in a paper with common authors …

Une femme de 67 ans s’ est présentée aux urgences pour une urticaire et une sensation de malaise suite à deux piqûres de guêpe survenues 30 minutes auparavant: la première localisée sur l’avant-bras gauche, faisant l’objet d’un œdème localisé important, et la seconde sur la face antérieure du cou avec présence d’un érythème local sans détresse respiratoire associée. À son arrivée aux urgences, cette patiente présentait une pâleur importante, des sueurs, ainsi qu’une hypotension artérielle à 64/43 mmHg, avec une tachycardie à 113 bpm. Elle ne rapportait aucune allergie connue et avait pour seul antécédent une hypertension artérielle traitée par énalapril. Dans l’hypothèse d’un choc anaphylactique lié à une piqûre d’hyménoptère, elle a bénéficié de l’injection de 0, 5 mg d’adrénaline intramusculaire, permettant une normalisation de la pression artérielle trois minutes plus tard, avec une tachycardie …

Kidney cancer is the seventh leading cause of cancer in the world, and its incidence is on the rise. Renal cell carcinoma (RCC) is the most common form and is a heterogeneous disease comprising three major subtypes that vary in their histology, clinical course and driver mutations. These subtypes include clear cell RCC, papillary RCC and chromophobe RCC. Molecular analyses of hereditary and sporadic forms of RCC have revealed that this complex and deadly disease is characterized by metabolic pathway alterations in cancer cells that lead to deregulated oxygen and nutrient sensing, as well as impaired tricarboxylic acid cycle activity. These metabolic changes facilitate tumour growth and survival. Specifically, studies of the metabolic features of RCC have led to the discovery of oncometabolites — fumarate and succinate — that can promote tumorigenesis, moonlighting functions of enzymes, and substrate …

Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. Elevated lipid uptake and storage is required for ccRCC cell viability. As stored cholesterol is the most abundant component in ccRCC intracellular lipid droplets, it may also play an important role in ccRCC cellular homeostasis. In support of this hypothesis, ccRCC cells acquire exogenous cholesterol through the HDL receptor SCARB1, inhibition or suppression of which induces apoptosis. Here, we showed that elevated expression of 3 beta-hydroxy steroid dehydrogenase type 7 (HSD3B7), which metabolizes cholesterol-derived oxysterols in the bile acid biosynthetic pathway, is also essential for ccRCC cell survival. Development of an HSD3B7 enzymatic assay and screening for small molecule inhibitors uncovered the compound celastrol as a potent HSD3B7 inhibitor with low micromolar activity. Repressing HSD3B7 …

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death with a five-year survival rate of 10%. Dense desmoplasia results in poor intratumoral perfusion and elevated interstitial fluid pressure, creating regions with severe oxygen and nutrient deprivation. One result is a deficiency in unsaturated fatty acids (uFAs), as the de novo synthesis of uFAs requires oxygen. Our results indicate that PDAC cells experience endoplasmic reticulum (ER) stress and trigger subsequent ER stress responses under uFA limited conditions in vitro. ER stress responses are governed by three major stress sensors: Inositol-requiring enzyme 1???? (IRE1????), PKR-like ER kinase (PERK) and activating transcription factor 6 (ATF6). ER stress responses are also activated in PDAC murine and patient samples. Interestingly, the expression of ER stress markers is much higher in malignant lesions than benign …

Intratumoral hypoxia correlates with metastasis and poor survival in sarcoma patients. Using an impedance sensing assay and a zebrafish intravital microinjection model, we demonstrated here that the hypoxia-inducible collagen-modifying enzyme lysyl hydroxylase PLOD2 and its substrate collagen type VI (COLVI) weaken the lung endothelial barrier and promote transendothelial migration. Mechanistically, hypoxia-induced PLOD2 in sarcoma cells modified COLVI, which was then secreted into the vasculature. Upon reaching the apical surface of lung endothelial cells, modified COLVI from tumor cells activated integrin β1 (ITGβ1). Furthermore, activated ITGβ1 co-localized with Kindlin2, initiating their interaction with F-actin and prompting its polymerization. Polymerized F-actin disrupted endothelial adherens junctions (AJ) and induced barrier dysfunction. Consistently, modified and secreted COLVI was …

Localized tissue hypoxia is a consequence of vascular compromise or rapid cellular proliferation and is a potent inducer of compensatory angiogenesis. The oxygen-responsive transcriptional regulator hypoxia-inducible factor 2α (HIF-2α) is highly expressed in vascular ECs and, along with HIF-1α, activates expression of target genes whose products modulate vascular functions and angiogenesis. However, the mechanisms by which HIF-2α regulates EC function and tissue perfusion under physiological and pathological conditions are poorly understood. Using mice in which Hif2a was specifically deleted in ECs, we demonstrate here that HIF-2α expression is required for angiogenic responses during hindlimb ischemia and for the growth of autochthonous skin tumors. EC-specific Hif2a deletion resulted in increased vessel formation in both models; however, these vessels failed to undergo proper arteriogenesis …

Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor …

Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is unclear. Fructose-1,6-bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis, and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin dependent. Independently of its catalytic activity, FBP1 prevents insulin hyperresponsiveness by forming a stable complex with AKT, PP2A-C, and aldolase B (ALDOB), which …

Nuclear speckles are membrane-less bodies within the cell nucleus enriched in RNA biogenesis, processing, and export factors. In this study we investigated speckle phenotype variation in human cancer, finding a reproducible speckle signature, based on RNA expression of speckle-resident proteins, across> 20 cancer types. Of these, clear cell renal cell carcinoma (ccRCC) exhibited a clear correlation between the presence of this speckle expression signature, imaging-based speckle phenotype, and clinical outcomes. ccRCC is typified by hyperactivation of the HIF-2α transcription factor, and we demonstrate here that HIF-2α drives physical association of a select subset of its target genes with nuclear speckles. Disruption of HIF-2α-driven speckle association via deletion of its s peckle targeting m otifs (STMs)—defined in this study—led to defective induction of speckle-associating HIF-2α target genes without …

During an immune response, naïve T lymphocytes undergo rapid clonal expansion and must reprogram their metabolism to meet high energetic and biosynthetic demands. The sudden increase in metabolic activity associated with a proliferative burst generates reactive oxygen species (ROS) increasing intracellular oxidative stress, which can disrupt homeostasis or trigger cell death, unless properly regulated. Our studies show that a constitutively active isoform of gluconeogenic enzyme, fructose 1, 6-bisphosphatase 1 (FBP1), facilitates re-entry of glucose carbons into the pentose phosphate pathway to ensure the sustained production of NADPH for redox homeostasis and lipid synthesis in stimulated T cells as they transition to a phase of rapid growth, and is essential for their unperturbed clonal expansion and for an effective immune response. Wildtype (wt) FBP1, which catalyzes hydrolysis of fructose-1, 6 …

Over the last two decades, the rapidly expanding field of tumor metabolism has enhanced our knowledge of the impact of nutrient availability on metabolic reprogramming in cancer. Apart from established roles in cancer cells themselves, various nutrients, metabolic enzymes, and stress responses are key to the activities of tumor microenvironmental immune, fibroblastic, endothelial, and other cell types that support malignant transformation. In this article, we review our current understanding of how nutrient availability affects metabolic pathways and responses in both cancer and "stromal" cells, by dissecting major examples and their regulation of cellular activity. Understanding the relationship of nutrient availability to cellular behaviors in the tumor ecosystem will broaden the horizon of exploiting novel therapeutic vulnerabilities in cancer.

A role for hypoxia‐inducible factors (HIFs) in hypoxia‐dependent regulation of tumor cell metabolism has been thoroughly investigated and covered in reviews. However, there is limited information available regarding HIF‐dependent regulation of nutrient fates in tumor and stromal cells. Tumor and stromal cells may generate nutrients necessary for function (metabolic symbiosis) or deplete nutrients resulting in possible competition between tumor cells and immune cells, a result of altered nutrient fates. HIF and nutrients in the tumor microenvironment (TME) affect stromal and immune cell metabolism in addition to intrinsic tumor cell metabolism. HIF‐dependent metabolic regulation will inevitably result in the accumulation or depletion of essential metabolites in the TME. In response, various cell types in the TME will respond to these hypoxia‐dependent alterations by activating HIF‐dependent transcription to alter …

Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets (LDs) comprised primarily of free and esterified cholesterol molecules; however, the functional significance of cholesterol accumulation in ccRCC cells was unknown. We demonstrated that, surprisingly, genes encoding cholesterol biosynthetic pathway enzymes are strongly repressed in ccRCC cells, making them auxotrophic for exogenous cholesterol. Intriguingly, Mendelian randomization analyses of over 31,000 human genomes indicate a causal link between elevated serum levels of high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and ccRCC tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. We showed that Scavenger Receptor B1 (SCARB1) is uniquely required for …

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated …

Nuclear speckles are dynamic substructures within the nucleus that contain a myriad of factors involved in gene activation. While nuclear speckles were discovered over 100 years ago, how they vary in human health and disease and the consequences of such variation remain enigmatic. Using RNA-seq data to estimate nuclear speckle content, we found that nuclear speckle phenotypes vary reproducibly in >20 cancer types. Of these cancers, nuclear speckle variation predicted patient outcomes specifically in clear cell renal cell carcinoma (ccRCC). This ccRCC speckle sensitivity was confirmed in a separate cohort using immunofluorescence to independently assess speckle phenotypes, and was specific to ccRCC with VHL mutation or copy number loss, suggesting involvement of the VHL-degraded HIF stress-responsive transcription factors. Given our previous findings linking nuclear speckles to another stress …

Gene expression states persist for varying lengths of time at the single-cell level, a phenomenon known as gene expression memory. When cells switch states, losing memory of their prior state, this transition can occur in the absence of genetic changes. However, we lack robust methods to find regulators of memory or track state switching. Here, we develop a lineage tracing-based technique to quantify memory and identify cells that switch states. Applied to melanoma cells without therapy, we quantify long-lived fluctuations in gene expression that are predictive of later resistance to targeted therapy. We also identify the PI3K and TGF-β pathways as state switching modulators. We propose a pretreatment model, first applying a PI3K inhibitor to modulate gene expression states, then applying targeted therapy, which leads to less resistance than targeted therapy alone. Together, we present a method for finding …

Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is not clear. Fructose-1,6 bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia in affected individuals. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin-dependent. FBP1 prevents insulin hyperresponsiveness, independently of its catalytic activity, by interacting with AKT, PP2A-C and Aldolase-B (ALDOB) to specifically accelerate AKT dephosphorylation. Enhanced by fasting and weakened by elevated insulin, FBP1:AKT:PP2A-C:ALDOB complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, a complex disrupting peptide reverses diet-induced insulin resistance.

North America has the highest incidence of renal cancer in the world with the most common subtype being clear cell renal cell carcinoma (ccRCC). Metabolic dysfunction is a hallmark of ccRCC based on molecular analysis and its clear cell histologic appearance due to significant cytoplasmic accumulation of lipid droplets and glycogen. Using publicly available RNA-Seq and proteomic datasets, we identified reduced expression of branched-chain amino acid (BCAA) enzymes BCAA transaminase 2 (BCAT2) and the branched-chain ketoacid dehydrogenase complex (BCKDH) in ccRCC compared to healthy kidney tissue. We validated these results by confirming that BCAT2 and the BCKDH complex are decreased at the mRNA and protein level in ccRCC tumors and cell lines compared to pair-matched normal adjacent kidney tissue. The reduced expression of the BCKDH complex was reinforced at the genome …

Circadian rhythms are endogenous periodic biological processes that occur on a daily timescale. These rhythms are generated by a transcriptional/translational feedback loop that consists of the CLOCK-BMAL1 heterodimeric transcriptional activator complex and the PER1/2-CRY1/2-CK1δ/ε repressive complex. The output pathways of this molecular feedback loop generate circadian rhythmicity in various biological processes. Among these, metabolism is a primary regulatory target of the circadian clock which can also feedback to modulate clock function. This intertwined relationship between circadian rhythms and metabolism makes circadian clock components promising therapeutic targets. Despite this, pharmacological therapeutics that target the circadian clock are relatively rare. In this review, we hope to stimulate interest in chemical chronobiology by providing a comprehensive background on the molecular …

NAD+ is a key electron acceptor in proliferating cells, needed to increase biomass. Computational and experimental approaches demonstrate that NAD+ regeneration is critical for de novo lipid synthesis when exogenous sources are limited, underlying cancer cell dependence on lipids when mitochondrial respiration is reduced.

The present invention describes methods for quantifying and analyzing cell migration and drug screening. Such methods include a gel (or a hydrogel) comprising a polymer, and cells that forms an oxygen gradient within the gel by controlling the balance of the diffusion of oxygen through the top of the gel and by the consumption of oxygen uptake by the cells. The migration of the cells is determined while the cells are grown in the gel of the present invention.

MethodsWe completed RNA-seq of four Formalin-Fixed Paraffin-Embedded (FFPE) gonadal tissue samples from this mosaic individual to identify differentially regulated genes (DRGs). After quality control, two lines representing with and without the duplication were analyzed.ResultsIn gonadal tissue containing the duplication, increased dosage of ZFPM2 in a SRY-negative-46-XX individual appears to upregulate transcriptional activity of gonadal specific promoters such as SOX9 and AMH via its protein interaction with known regulator of early testis development GATA4. ZFPM2 is essential to the GATA4/ZFPM2 transcription complex; our results show that increased ZFPM2 dosage enhances ZFPM2’s interaction with GATA4 and results in upregulation of SOX9 that is sufficient to initiate testis differentiation independent of SRY. SOX9 (FC= 39.2, p= 1.1 x10-121) and SF-1 (FC= 1.4, p= 4.8 x10-4) interact to produce …

Around birth, globin expression in human red blood cells (RBCs) shifts from γ-globin to β-globin, which results in fetal haemoglobin (HbF, α2γ2) being gradually replaced by adult haemoglobin (HbA, α2β2). This process has motivated the development of innovative approaches to treat sickle cell disease and β-thalassaemia by increasing HbF levels in postnatal RBCs. Here we provide therapeutically relevant insights into globin gene switching obtained through a CRISPR–Cas9 screen for ubiquitin–proteasome components that regulate HbF expression. In RBC precursors, depletion of the von Hippel–Lindau (VHL) E3 ubiquitin ligase stabilized its ubiquitination target, hypoxia-inducible factor 1α (HIF1α),, to induce γ-globin gene transcription. Mechanistically, HIF1α–HIF1β heterodimers bound cognate DNA elements in BGLT3, a long noncoding RNA gene located 2.7 kb downstream of the tandem γ-globin genes …

BackgroundDeregulated glucose metabolism is a critical component of cancer growth and survival, clinically evident via FDG-PET imaging of enhanced glucose uptake in tumor nodules. Tumor cells utilize glucose in a variety of interconnected biochemical pathways to generate energy, anabolic precursors, and other metabolites necessary for growth. Glucagon-stimulated gluconeogenesis opposes glycolysis, potentially representing a pathway-specific strategy for targeting glucose metabolism in tumor cells. Here, we test the hypothesis of whether glucagon signaling can activate gluconeogenesis to reduce tumor proliferation in models of liver cancer.MethodsThe glucagon receptor, GCGR, was overexpressed in liver cancer cell lines consisting of a range of etiologies and genetic backgrounds. Glucagon signaling transduction was measured by cAMP ELISAs, western blots of phosphorylated PKA substrates, and …

Molecular oxygen (O2) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased oxygen concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. On a cellular level, ATP- consuming reactions are suppressed, and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense oxygen levels to coordinate diverse biological outputs during hypoxia. The best- studied …

Low oxygen concentrations (hypoxia) are detrimental to most species on Earth; thus, cells have evolved with adaptations allowing them to withstand transient hypoxia. As with other survival pathways, cancer cells have co-opted these mechanisms to keep up with the metabolic demands of rapid growth and proliferation in harsh tumor microenvironments. The most well-studied oxygen response pathway involves hypoxia-inducible factors (HIF) and their regulation by the von Hippel–Lindau protein (pVHL) and the prolyl hydroxylases (PHD1-3). This study from Zhong and colleagues, published in Cancer Research in 1999, was the first to show increased HIF1α expression in several cancer types and in metastases, suggesting a role for HIFs in disease progression. Since publication, significant progress has been made in the understanding of tumor hypoxia responses and efforts to target this pathway as a …

Hepatocellular carcinoma (HCC) is a typically fatal malignancy exhibiting genetic heterogeneity and limited therapy responses. We demonstrate here that HCCs consistently repress urea cycle gene expression and thereby become auxotrophic for exogenous arginine. Surprisingly, arginine import is uniquely dependent on the cationic amino acid transporter SLC7A1, whose inhibition slows HCC cell growth in vitro and in vivo. Moreover, arginine deprivation engages an integrated stress response that promotes HCC cell-cycle arrest and quiescence, dependent on the general control nonderepressible 2 (GCN2) kinase. Inhibiting GCN2 in arginine-deprived HCC cells promotes a senescent phenotype instead, rendering these cells vulnerable to senolytic compounds. Preclinical models confirm that combined dietary arginine deprivation, GCN2 inhibition, and senotherapy promote HCC cell apoptosis and tumor …

Sensory deprivation, particularly hearing loss, is an excellent model to study neuroplasticity in the human brain and the adaptive behaviors that support the daily lives of deprived individuals. In adaptation to their hearing loss, deaf individuals rely on their other intact senses. Visual and tactile abilities are enhanced in deafness, but few studies have evaluated the olfactory function. This study aimed to compare the impact of congenital deafness on olfactory capacities using psychophysical tasks. Methodological issues raised in previous studies, such as homogeneous onset of deafness and cognitive function assessment, were considered. Eleven individuals with bilateral severe-to-profound deafness since birth were compared to 11 hearing non-signers similar in age (age range = 20-51 years old) and sex (7 women). The deaf subjects were assessed using various standardized neuropsychological tests to ascertain typical cognition. Olfactory functions were evaluated using the Sniffin’ Sticks battery test, which measures olfactory detection threshold, odor discrimination, and odor identification. Further, accuracy and response time were examined for the identification and localization of two odors to disentangle olfactory sensitivity from sensitivity in the trigeminal system. The Sniffin’ Sticks test demonstrated superior performances in the deaf participants to discriminate and identify odors. In line with this, they also showed higher sensitivity when both identifying and localizing odors. These findings suggest that congenital deafness is associated with superior performance in higher-level olfactory processing and increased sensitivity in the trigeminal system.

Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex that catalyses messenger RNA N6-methyladenosine (m6A) modification. Despite the expanding list of m6A-dependent functions of the methyltransferase complex, the m6A-independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 transcriptionally drives the senescence-associated secretory phenotype (SASP) in an m6A-independent manner. METTL14 is redistributed to the enhancers, whereas METTL3 is localized to the pre-existing NF-κB sites within the promoters of SASP genes during senescence. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m6A mRNA modification. METTL3 and METTL14 are required for both the tumour-promoting and immune-surveillance …

Defining the mechanisms that control the perinatal switch from γ-globin (HBG1 and HBG2) to β-globin (HBB) gene expression in human red blood cells (RBCs) has informed novel approaches to reactivate fetal hemoglobin (HbF, α2γ2) therapeutically for sickle cell disease and β-thalassemia. However, one longstanding unsolved problem is to explain how HbF becomes elevated in conditions such as blood loss, hypoxia and hemolysis. These conditions are associated with accelerated RBC production, also referred to as stress erythropoiesis, driven by activation of hypoxia-inducible factor (HIF) via a canonical O 2 sensing pathway. At high O 2 levels (“normoxia”), O 2-dependent prolyl hydroxylase domain (PHD) enzymes hydroxylate HIFα, thereby targeting it for ubiquitination by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex, followed by proteasomal degradation. At low O 2 tension (hypoxia), PHD activity …

The role of PPAR gamma (PPARγ) has been well characterized in the developmental process of adipogenesis, yet its aberrant expression patterns and functions in cancer subtypes are less understood. Although PPARγ has been recently demonstrated to play non–cell-autonomous roles in promoting bladder urothelial carcinoma (UC) progression, underlying mechanisms of the cell-intrinsic oncogenic activity remain unknown. Here, we report robust expression and nuclear accumulation of PPARγ in 47% of samples of patients with UC, exceeding mRNA expression patterns published by The Cancer Genome Atlas. In vitro assays revealed for the first time that treatment of UC cells with PPARγ inverse agonist or PPARG knockout by CRISPR-Cas9 reduces proliferation, migration, and invasion of multiple established UC cell lines, most strongly in those characterized by PPARG genomic amplification …

The growing field of tumor metabolism has greatly expanded our knowledge of metabolic reprogramming in cancer. Apart from their established roles, various metabolic enzymes and metabolites harbor non-canonical ("moonlighting") functions to support malignant transformation. In this article, we intend to review the current understanding of moonlighting functions of metabolic enzymes and related metabolites broadly existing in cancer cells by dissecting each major metabolic pathway and its regulation of cellular behaviors. Understanding these non-canonical functions may broaden the horizon of the cancer metabolism field and uncover novel therapeutic vulnerabilities in cancer.

Glycogen accumulation is a highly consistent, distinguishable characteristic of clear cell renal cell carcinoma (ccRCC). While elevated glycogen pools might be advantageous for ccRCC cells in nutrient-deprived microenvironments to sustain tumour viability, data supporting a biological role for glycogen in ccRCC are lacking. Here, we demonstrate that glycogen metabolism is not required for ccRCC proliferation in vitro nor xenograft tumour growth in vivo. Disruption of glycogen synthesis by CRISPR-mediated knockout of glycogen synthase 1 (GYS1) has no effect on proliferation in multiple cell lines, regardless of glucose concentrations or oxygen levels. Similarly, prevention of glycogen breakdown by deletion or pharmacological inhibition of glycogen phosphorylase B (PYGB) and L (PYGL) has no impact on cell viability under any condition tested. Lastly, in vivo xenograft experiments using the ccRCC cell line …

High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here, we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in patients with neuroblastoma. DLST is an E2 component of the α-ketoglutarate (αKG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, αKG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified …

Erratum zu: InFo Neurologie + Psychiatrie 2020;22(12):30-39In der Online-Fassung des Beitrags war die Reihenfolge der Autoren nicht korrekt angegeben. Die richtige Reihenfolge der Autoren lautet: Barbara B. Barton, Maria S. Simon, Catherine Glocker, Richard Musil - München.Wir bitten, diesen Fehler zu entschuldigen. Der Originala...

Vascular remodeling is a phenomenon seen in the cutaneous lesions formed during infection with Leishmania parasites. Within the lesion, Leishmania major infection leads to the infiltration of inflammatory cells, including macrophages, and is associated with hypoxic conditions and lymphangiogenesis in the local site. This low-oxygen environment is concomitant with the expression of hypoxic inducible factors (HIFs), which initiate the expression of vascular endothelial growth factor-A (VEGF-A) in macrophages during the infection. Here, we found that macrophage hypoxia is elevated in the skin, and the HIF target Vegfa is preferentially expressed at the site of infection. Further, transcripts indicative of both HIF-1α and HIF-2α activation were increased at the site of infection. Given that HIF mediates VEGF-A and that VEGF-A/VEGFR-2 signaling induces lymphangiogenesis, we wanted to investigate the link between …

Background Kidney cancer is a common adult malignancy in the USA. Clear cell renal cell carcinoma (ccRCC), the predominant subtype of kidney cancer, is characterized by widespread metabolic changes. Urea metabolism is one such altered pathway in ccRCC. The aim of this study was to elucidate the contributions of urea cycle enzymes, argininosuccinate synthase 1 (ASS1), and argininosuccinate lyase (ASL) towards ccRCC progression. Methods We employed a combination of computational, genetic, and metabolomic tools along with in vivo animal models to establish a tumor-suppressive role for ASS1 and ASL in ccRCC. Results We show that the mRNA and protein expression of urea cycle enzymes ASS1 and ASL are reduced in ccRCC tumors when compared to the normal kidney. Furthermore, the loss of ASL …

The self-renewal transcription factor Nanog and the phosphoinositide 3-kinase (PI3K)–Akt pathway are known to be essential for maintenance of mesenchymal stem cells. We evaluated their contribution to the maintenance of CD133(+) cancer stem-like cells (CSCs) and spheroid-forming cells in patient-derived cell lines from three human sarcoma subtypes: HT1080 fibrosarcoma, SK-LMS-1 leiomyosarcoma, and DDLS8817 dedifferentiated liposarcoma. Levels of Nanog and activated Akt were significantly higher in sarcoma cells grown as spheroids or sorted for CD133 expression to enrich for CSCs. shRNA knockdown of Nanog decreased spheroid formation 10- to 14-fold, and reversed resistance to both doxorubicin and radiation in vitro and in H1080 flank xenografts. In the HT1080 xenograft model, doxorubicin and Nanog knockdown reduced tumor growth by 34% and 45%, respectively, and the combination …

Johnston et al. developed an intra-operative U13C-glucose infusion protocol that is well tolerated by patients with pediatric cancers and shows cancer-type-specific metabolic alterations with therapeutical consequences. The development of this procedure and their findings will strongly benefit metabolic analysis of pediatric cancers and design of new therapeutic strategies.

Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses based on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell-cycle arrest …

The primary objective of this chapter is to describe the consequences of central deficiencies on the neurodevelopment of children. We approach this topic from the standpoint of congenital deafness. Thus we first present the current state of knowledge on cortical reorganization following congenital deafness. The allocation of auditory cortices to other sensory systems can enhance sensory processing and therefore the cognitive functions related to them. Second, we explore the linguistic development of deaf children. Given that the English written system is speech-based, its acquisition is complex and atypical for deaf children, usually leading to poorer achievements. Next, we explore the impact of a neural prosthesis named the cochlear implant on the neurocognitive and linguistic development of deaf children. In some cases, it allows the individuals to, at least partially, regain access to the lost sense. We also …

Solid tumors reside in harsh tumor microenvironments (TMEs) together with various stromal cell types. During tumor progression and metastasis, both tumor and stromal cells undergo rapid metabolic adaptations. Tumor cells metabolically coordinate or compete with their "neighbors" to maintain biosynthetic and bioenergetic demands while escaping immunosurveillance or therapeutic interventions. Here, we provide an update on metabolic communication between tumor cells and heterogeneous stromal components in primary and metastatic TMEs and discuss emerging strategies to target metabolic communications for improved cancer treatments.

Background Hypoxia is pervasive in cancer and other diseases. Cells sense and adapt to hypoxia by activating hypoxia-inducible transcription factors (HIFs), but it is still an outstanding question why cell types differ in their transcriptional response to hypoxia. Results We report that HIFs fail to bind CpG dinucleotides that are methylated in their consensus binding sequence, both in in vitro biochemical binding assays and in vivo studies of differentially methylated isogenic cell lines. Based on in silico structural modeling, we show that 5-methylcytosine indeed causes steric hindrance in the HIF binding pocket. A model wherein cell-type-specific methylation landscapes, as laid down by the differential expression and binding of other transcription factors under normoxia, control cell-type-specific hypoxia responses is observed. We also discover ectopic HIF binding sites in repeat regions which are normally methylated …

The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor-associated macrophages (TAMs) rather than immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we find that the TME induces tumor cells to produce retinoic acid (RA), which polarizes intratumoral monocyte differentiation toward TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production in tumor cells or pharmacologic inhibition of RA signaling within TME increases stimulatory monocyte-derived cells, enhances T cell-dependent anti-tumor immunity, and synergizes with immune checkpoint blockade. Furthermore, an RA-responsive gene signature in human monocytes correlates with an immunosuppressive TME in multiple …

In 2017, French institutions reformed their data access policy regarding the national insurance and administrative databases systems (French abbreviation: SNDS), including claims data from hospitalization discharge summaries for the entire population follow-up encompassing over 10 years. Our study aimed to quantitatively and qualitatively describe such authorization before and after the reform. We extracted data access demands for French National Health Data Institute (INDS) data before and after the reforms. We included only studies that needed data extracted from the SNDS database and authorization of the regulator. We inferred the number of projects accepted pre-and post-reform, and we describe the types of studies, their topics, and the types of data used. We included 802 data access demands between January 1st 2008 and September 21st 2019. The median of data access demands by year …

Introduction: We extensively reported on a higher expression of inflammatory gene clusters in monocytes of Major Depressive Disorder (MDD) patients, particularly those with a history of childhood adversity (CA). In our studies there were also signs that not only inflammatory, but also apoptosis/growth and cholesterol metabolism genes were abnormally expressed. Objectives: To study the expression of growth/apoptosis and cholesterol metabolism genes in circulating monocytes of MDD patients collected at three EU-MOODINFLAME sites. Methods: Adult patients with DSM-IV diagnosed MDD with (N= 77) or without (N= 58) CA (measured by Childhood Trauma Questionnaire) and healthy controls (HC) with (N= 37) and without CA (N= 81; reference group) were recruited. Monocyte gene expressions were determined using qPCR. Results: 1. MDD monocytes showed an abnormal expression of two inter-correlating …

Although the consequences of the General Data Protection Regulation (GDPR) have been widely discussed, the violations have not been described in medical literature. In this study, we focus our analyses on the data breach notifications, in France, defined in the article 4 of GDPR as “a breach of security resulting, accidentally or unlawfully, in the destruction, loss, alteration, unauthorized disclosure of personal data transmitted, stored or otherwise processed, or unauthorized access to such data.” Among 3,824 data breach notifications reported between May 2018 and February 2020, 244 (6.4%) is related to the health sector. Loss of confidentiality is the most important breach (80.7%) in this sector, followed by the loss of availability (27.5%). Malicious cause occurred in 58.2% of them. We hypothesized a phenomenon of underreported data breach incidents in health due to a mismatch between cybersecurity and data privacy issues.

Understanding the cellular adaptation to oxygen deficiency -hypoxia- has a profound impact on our knowledge of the pathogenesis of several diseases. The elucidation of the molecular machinery that regulates response to hypoxia has been awarded the Nobel Prize in Physiology or Medicine.

On estime que 5 % de la population dans le monde souffre d’une perte auditive handicapante, dont 34 millions d’enfants. Ce déficit perceptif, lorsqu’il survient dès la naissance ou lors des premières années de vie, a de multiples répercussions sur le développement cérébral et neurocognitif. La réorganisation cérébrale ayant cours dans le cerveau des individus privés de l’audition précocement constitue un sujet d’étude très prisé par la communauté scientifique, mais pour laquelle de nombreuses questions restent en suspens. Ainsi, les articles qui composent cette thèse ont pour objectif principal d’améliorer nos connaissances portant sur les mécanismes de réorganisation cérébrale, tant au niveau fonctionnel que structurel afin de mieux comprendre leur implication comportementale chez les individus sourds. Pour ce faire, nous avons souhaité investiguer, par le biais de l’imagerie par résonance magnétique fonctionnelle, quel était le lien entre les activations cérébrales et les performances comportementales lors d’une tâche portant sur les mouvements biologiques chez des adultes sourds congénitaux, en comparaison à des pairs neurotypiques. L’article 1 révèle que les individus sourds présentent une sensibilité accrue à la reconnaissance du mouvement biologique, et notamment des emblèmes, en comparaison à des individus neurotypique. De plus, cette spécificité comportementale observée uniquement chez les individus sourds, s’accompagne d’un recrutement extensif des régions comprises dans le gyrus temporal supérieur, et tout particulièrement le cortex auditif primaire ainsi que le planum temporale. Nos résultats supportent la …

Review Article in Nature Chemical Biology exploring pharmacological targeting of the UPR for disease intervention 1 in which they discussed the efficacy of the IRE1 inhibitor B-I09 to induce leukemic regression without causing systemic toxicity in mouse models. They also pointed out a caveat that high concentrations of B-I09 were administered frequently using 100% DMSO as a carrier and suggested that this reduces the translational potential of B-I09. Representing the team leading to the development and optimization of B-109 for clinical use, we believe that some of the features of the compound and the characterization of its translational potential require clarification.B-I09 was developed as a prodrug to target the RNase activity of IRE1, leading to the suppressed expression of XBP1s 2. We have used chemical synthesis to tune prodrug stability within a series of B-I09 analogs and achieve spatiotemporal control …

The crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, as well as the consequent effects on liver tumorigenesis, are not completely understood. We show here that hepatocyte-specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours. Hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype. Depleting senescent HSCs by ‘senolytic’ treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits …

Tumour cells frequently utilize glutamine to meet bioenergetic and biosynthetic demands of rapid cell growth. However, glutamine dependence can be highly variable between in vitro and in vivo settings, based on surrounding microenvironments and complex adaptive responses to glutamine deprivation. Soft tissue sarcomas (STSs) are mesenchymal tumours where cytotoxic chemotherapy remains the primary approach for metastatic or unresectable disease. Therefore, it is critical to identify alternate therapies to improve patient outcomes. Using autochthonous STS murine models and unbiased metabolomics, we demonstrate that glutamine metabolism supports sarcomagenesis. STS subtypes expressing elevated glutaminase (GLS) levels are highly sensitive to glutamine starvation. In contrast to previous studies, treatment of autochthonous tumour-bearing animals with Telaglenastat (CB-839), an orally …

The microenvironment of cancerous tissue consists of inflammatory cells, immune cells, blood vessels, neuroendocrine cells, myofibroblasts, proliferating tumour cells, adipose cells, and various other cells. Tumorigenesis connection can be traced by looking into stromal cells, the extracellular matrix, and the tumor microenvironment of the developing tumour. Progression of the tumor depends mainly on interactions with the host system. For instance, the presence of inflammatory cells aids in the development and progression of the tumor. The various immune cells are dendritic cells, B-cells, T-lymphocytes, macrophages, rare natural killer cells, and polymorphonuclear leucocytes. The tumour microenvironment plays a role in the development of resistance against cytotoxic drugs. Knowledge of the tumour microenvironment can lead to new anti-cancer moieties and targeted drug delivery systems. For instance, the …

Molecular oxygen (O2) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased oxygen concentration (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth and circulating red blood cell numbers. On a cellular level, ATP-consuming reactions are suppressed, and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense oxygen levels to coordinate diverse biological outputs during hypoxia. The best-studied mechanism …

The remarkable cellular and genetic heterogeneity of soft tissue sarcomas (STSs) limits the clinical benefit of targeted therapies. Here, we show that expression of the gluconeogenic isozyme fructose-1,6-bisphosphatase 2 (FBP2) is silenced in a broad spectrum of sarcoma subtypes, revealing an apparent common metabolic feature shared by diverse STSs. Enforced FBP2 expression inhibits sarcoma cell and tumor growth through two distinct mechanisms. First, cytosolic FBP2 antagonizes elevated glycolysis associated with the "Warburg effect," thereby inhibiting sarcoma cell proliferation. Second, nuclear-localized FBP2 restrains mitochondrial biogenesis and respiration in a catalytic-activity-independent manner by inhibiting the expression of nuclear respiratory factor and mitochondrial transcription factor A (TFAM). Specifically, nuclear FBP2 colocalizes with the c-Myc transcription factor at the TFAM locus and …

Deafness leads to brain modifications that are generally associated with a cross-modal activity of the auditory cortex, particularly for visual stimulations. In the present study, we explore the cortical processing of biological motion that conveyed either non-communicative (pantomimes) or communicative (emblems) information, in early-deaf and hearing individuals, using fMRI analyses. Behaviorally, deaf individuals showed an advantage in detecting communicative gestures relative to hearing individuals. Deaf individuals also showed significantly greater activation in the superior temporal cortex (including the planum temporale and primary auditory cortex) than hearing individuals. The activation levels in this region were correlated with deaf individuals’ response times. This study provides neural and behavioral evidence that cross-modal plasticity leads to functional advantages in the processing of biological motion following lifelong auditory deprivation.

Background: Auditory deprivation alters cortical and subcortical brain regions, primarily linked to auditory and language processing, resulting in behavioral consequences. Neuroimaging studies have reported various degrees of structural changes, yet multiple variables in deafness profiles need to be considered for proper interpretation of results. To date, many inconsistencies are reported in the gray and white matter alterations following early profound deafness. The purpose of this study was to provide the first systematic review synthesizing gray and white matter changes in deaf individuals.Methods: We conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement in 27 studies comprising 626 deaf individuals.Results: Evidence shows that auditory deprivation significantly alters the white matter across the primary and secondary auditory cortices. The most consistent alteration across studies was in the bilateral superior temporal gyri. Furthermore, reductions in the fractional anisotropy of white matter fibers comprising in inferior fronto-occipital fasciculus, the superior longitudinal fasciculus, and the subcortical auditory pathway are reported. The reviewed studies also suggest that gray and white matter integrity is sensitive to early sign language acquisition, attenuating the effect of auditory deprivation on neurocognitive development.Conclusions: These findings suggest that understanding cortical reorganization through gray and white matter changes in auditory and non-auditory areas is an important factor in the development of auditory rehabilitation strategies in the …