In tumor samples, our analysis detected major conserved mitogenic and survival signaling pathways strongly associated with HNSCC, suggesting that some of the pathways identified by our algorithm, but not yet validated as HNSCC related, may be attractive targets for future research. While pathways activation landscape in the majority of leukoplakias was different from that seen in OSCC, a subset of pre-neoplastic lesions has demonstrated some degree of similarity to the signaling profile seen in tumors, including dysregulation of the cancer-driving pathways related to survival and apoptosis. These results suggest that dysregulation of these signaling networks may be the driving force behind the early stages of OSCC tumorigenesis. While future studies with larger leukoplakia data sets are warranted to further estimate the values of this approach for capturing signaling features that characterize relevant lesions that actually progress to cancers, our platform proposes a promising new approach for detecting cancer-promoting pathways and tailoring the right therapy to prevent tumorigenesis.A subset of patients with oral squamous cell carcinoma (OSCC), the most common subtype of head and neck squamous cell carcinoma (HNSCC), harbor dysplastic lesions  prior to cancer diagnosis. Although evidence suggest that leukoplakia represents an initial step in the progression to cancer, signaling networks driving this progression are poorly understood. Here, we applied  Despite improvements in molecular diagnosis, oral squamous cell carcinoma (OSCC), the most common subtype of HNSCC, has a poor prognosis with a 5-year overall survival of ~50%, and no targeted curative treatments for late-stage OSCC are currently available. As such, there is a significant unmet clinical need for development of novel targeted approaches against OSCC.Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, As some of these lesions evolve to malignant neoplasms, they represent intermediate steps in OSCC progression. It has been postulated, that this multistep process from normal epithelium to early pre-malignant change to fully invasive OSCC, involves the accumulation of molecular and cellular changes. Indeed, several signaling pathways have been shown to be dysregulated in OSCC through genetic and epigenetic alterations such as those involving TP53, PIK3CA, NOTCH1, SMAD4, CDKN2A, CCND1, FBXW7, HRAS, NRAS and FAT1. Although these signaling axes have been implicated in tumorigenesis, and are correlated with poor patients prognosis, relatively few molecular changes critical to the progression of oral leukoplakia to OSCC are currently recognized, and our understanding of the complex signaling networks that both promote OSCC pathogenesis and can be targeted therapeutically is still limited.Nearly 20% of patients with OSCC harbor multiple pre-malignant lesions showing signs of dysplasia, often visually identified as leukoplakia. analyses that rely solely on gene enrichment statistics fail to capture subtle differences between samples that arise from dynamic interactions between genes at the level of signaling networks. The major advantage of pathway-based methods is their capability to perform biologically relevant dimensionality reduction as a result of the analysis. However, despite the significant advancements in large-scale analytical methodologies that infer complex transcriptomic changes into the network of biologically relevant signaling axes, a systematic comprehensive analysis of the signaling pathways activation in OSCC and oral pre-neoplastic lesions has never been done.The Gene Expression Omnibus (GEO), the largest public repository for high-throughput gene expression data, provides unprecedented opportunities to reveal molecular mechanisms of cancer. Although multiple efforts taken to identify differentially expressed genes between OSCC and normal samples have led to the identification of prospective genetic biomarkers and expression signature patterns,in silico Pathway Activation Network Decomposition Analysis (iPANDA) as a scalable robust method for quantitative and qualitative large-scale transcriptomic data analysis. The iPANDA method combines pre-calculated gene co-expression data with gene importance factors based on the degree of differential gene expression and pathway topology decomposition for obtaining pathway activation scores. It has been demonstrated that iPANDA provides significant noise reduction in transcriptomic data and identifies highly robust sets of biologically relevant pathway signatures. In this study, we applied iPANDA on the transcriptomic data from hundreds of OSCC and leukoplakia samples to identify the differentially dysregulated signaling pathways between these neoplasms and normal oral mucosa tissues. Our work further contributes to the current understanding of the complex signaling networks underlying HNSCC, and may aid in the development of novel means of prevention, diagnosis and treatment.We have recently introduced the in silico pathway activation analysis of 359 OSCC samples obtained from the publicly available data sets deposited at NCBI GEO database   , and used for the computational algorithm as described previously. Using the normal samples cohort as a reference, we determined a quantitative measure of the signaling pathway activation scores  for each one of the signaling axes analyzed. The iPANDA values represent the signed scores showing the intensity and direction of the pathway activation . A total of 248 of 374 pathways analyzed (including the 64 main pathways) were significantly dysregulated (P<0.05) in OSCC tumors when these samples were compared with non-tumorous oral mucosa  . All theata set) . A collel mucosa . Focusinl mucosa . Upregulcontrols . Our patβ expression and spontaneous HNSCC formation. Whereas activation of PI3K/AKT via loss of PTEN or copy-number gain/activating mutations in PIK3CA also occurs in 40–60% of HNSCCs, leading to increased IL-6 production, STAT3 activation and tumor-promoting inflammation in HNSCC stroma. In concordance with this evidence, PTEN and SMAD signaling, as well as pathways associated with apoptosis were significantly downregulated in the cohort of 359 OSCC tumors analyzed  in leukoplakia samples compared to healthy controls (P<0.0005) in both OSCC (red bars) and leukoplakia (blue bars) samples  . Given tcontrols . The hea samples . Unlike l cohort . Since il cohort . Notably and potentially unravel the most critical branches associated with cancer progression. A list of pathway branches predicted to be significantly dysregulated (P<0.0005) in both OSCC and leukoplakia samples is shown in Many well-established cancer-driving genes simultaneously modulate activation or repression of multifunctional signaling networks that control cell growth, differentiation and migration. Since ‘main’ pathways aggregate branches that may be inversely activated, analysis of the pathway branches (which represent linearized fragments of the main pathway networks with multiple downstream targets) may help to scale down the complexity of common non-linear topology To adjust for the possible batch effect and other variations that may arise during the microarray processing, we have employed cross-platform normalization and filtering procedures as previously described . While most of the leukoplakia samples clustered together according to their pathway activation landscape, a subset of 20 pre-neoplastic lesions has clustered toward the center of the heatmap, demonstrating some degree of similarity to the pathway activation profile seen in OSCC , indicating that predisposition for leukoplakia progression may not have significant manifestation on the functional (pathway) level. One possible explanation is that the most differentially expressed genes in a given signature may not be part of the pathways that actually drive tumor behavior. Alternatively, expression of some genes within the cancer-driving pathways is not always predictive of the overall pathway activation. While iPANDA may be a useful tool when used as input for machine learning algorithms to make better prediction models, we were unable to use modern machine learning methods, since currently available data to system dimensionality ratio precludes the development of a strong classifier at the pathway level. As comprehensive analysis of the tumor pathway activation profile may provide broader clinical utility than raw gene expression evaluation, it would be of paramount importance to reanalyze the data upon accumulation of additional leukoplakia data sets, and further estimate the values of this approach for capturing signaling features that characterize relevant lesions that actually progress to cancers.Using the transcriptomic data from the same 86 leukoplakia samples and multiple independent OSCC data sets, Mao and colleagues proposed a 29-trancript prediction model of oral cancer progression (with 8% predicting error rate), indicating that gene expression levels can be effectively used for phenotype prediction. often fail to provide stable pathway signatures of a specific phenotype. iPANDA, a recently reported method for biologically relevant dimensionality reduction in transcriptomic data, demonstrates better performance for the noise reduction test in comparison to other pathway analysis approaches, and produces highly consistent sets of biologically relevant pathway perturbation signatures on multiple transcriptomic data sets. Here, we applied this novel bioinformatics prediction algorithm on transcriptomic data from 359 OSCC and 86 oral pre-neoplastic samples.An understanding of the protein signaling dynamics during the HNSCC progression is of critical importance for the development of new therapeutic approaches and identification of novel prognostic biomarkers. Signaling pathway activation analysis is a powerful tool for extracting biologically relevant features from large-scale transcriptomic data. While systematic application of such approach may contribute to better understanding of complex signaling networks in various types of cancer, many popular pathway-based methodsβ-catenin and TGFβ/SMAD signaling) in almost every OSCC tumor analyzed. Confirming the emerging view that while the specific molecules altered in each individual tumor may be distinct, they all participate in a handful of dysregulated molecular pathways that are likely shared among most HNSCC lesions. Although the association of the above signaling pathways with HNSCC is not novel, the ability of the gene aggregation algorithm to identify highly robust sets of pathway signatures relevant to the HNSCC tumorigenesis, suggests that our platform provides a rational biomathematical framework for studying signaling alterations driving the tumorigenic processes, and further supports the credibility of the pathway activation analysis as a promising analytical approach. It also suggests that some of the most dysregulated pathway branches identified by our algorithm but not yet wet-lab validated as HNSCC related, may provide an attractive target for future research.By utilizing our approach, we were able to detect dysregulation of the major molecular processes involved in HNSCC tumorigenesis  relies solely on gene enrichment statistics, treating pathways as unstructured sets of genes. Whereas our method estimates the topological coefficients for each gene module as a whole, rather than for individual genes inside the module, and therefore outperforms ssGSEA in respect to ranking of the putatively relevant pathways (described in details here).Interestingly, while gene set enrichment (GSEA) analysis of the same microarray data set with GSEA algorithm detected that gene sets related with proteasome machinery, MYC upregulation and ribosomes components were associated with a high risk of oral cancer development,Although this study focused on fundamental signaling processes involved in the development of OSCC, branched axes radiating from these main tumor-driving pathways may provide safer and more efficient targets for therapeutic intervention than a pan-pathway blockade. Since most of the existing pathways collections are being developed and cataloged within individual research groups, both in industry and in academia, inconsistency in pathway names annotations and number of pathway components (branches) poses a major challenge associated with prediction modeling of subnetworks within a large cancer driver superpathway. Therefore, systematic standardization and optimization of existing signaling pathways databases  will eventually contribute to better resolution of the signaling landscape, and enhance the development of novel prognostic biomarkers for risk assessment and treatment interventions at various stages of cancer progression.In conclusion, our work poses pathway-based expression data analysis as a promising hypothesis-generating approach for detecting cancer-promoting pathways at different stages of tumorigenesis. However, due to the limited number of currently available leukoplakia data sets, we could not dissect the molecular pathways predictive of progression from pre-neoplasia to carcinoma. As more data sets will become available, transcriptomic analysis of longitudinally collected leukoplakias and tumors that developed in the same patient over time may allow better detection of early drivers of OSCC carcinogenesis on the pathway level.For this study, we utilized microarray gene expression data obtained from NCBI GEO database. OSCC samples and tissue-specific normal controls used as a reference are listed in www.bioconductor.org). Microarray raw data were background-adjusted and quantile-normalized using the corresponding R packages . Obtained gene expression values were averaged across all replicates. Heatmap generation and hierarchical clustering were performed using R package gplots. Statistical tests and correlation analysis were done with the MS Excel software .OSCC and leukoplakia data with corresponding normal samples were processed using AFFY (version 1.46.1) and FRMA (version 1.20.0) algorithms from Bioconductor ) contains a set of 374 signaling pathways that cover a total of 2294 unique genes. Main pathways represent complex signaling networks with multiple downstream targets. Whereas branching axes represent dissected linear signal transduction units of a large multifunctional pathway. Each pathway contains an explicitly defined topology represented as a directed graph. Each node corresponds to a gene or a set of genes, while edges describe biochemical interactions between genes in nodes and/or their products. All interactions are classified as activation or inhibition of downstream nodes. The pathway size ranges from about 20 to over 600 genes in a single pathway. The algorithm accounts for the gene grouping into modules based on the precalculated gene co-expression data (using information from COEXPRESSdb database). Each gene module represents a set of genes that experience significant coordination in their expression levels and/or are regulated by the same expression factors. As described, it enables calculation of the iPANDA pathway activation scores, a value that serves as a quantitative measure of differential pathway activation between the two states. Pathway scoring is based on the expression level and the role of a particular gene in proprietary maps of 300 of signaling pathways. For estimation of pathway activation, we apply the following rule pathways with positive iPANDA values that are considered upregulated, while negative iPANDA values correspond to downregulated pathways.Pre-processed gene expression data were loaded into pathway analysis software, a proprietary suite developed by Insilico Medicine, Inc. that represents an implementation of the iPANDA algorithm,45 .To perform cross-platform normalization between Affymetrix U133 Plus 2.0 Array and Affymetrix 1.0 ST Array, we utilized XPN algorithm


The “interhemispheric competition” model posits that the contralateral hemisphere suppresses activity of the ipsilateral hemisphere to reduce putative interference of ipsilateral descending pathways thought to degrade motor performance. Non-invasive brain stimulation paradigms are well positioned to test models of motor control. For instance, transcranial direct current stimulation (tDCS) applied to the human motor cortex (M1), can induce polarity-dependent changes in corticospinal excitability that outlast the period of stimulation. Therefore, facilitatory anodal tDCS of the contralateral hemisphere and/or inhibitory cathodal tDCS of the ipsilateral hemisphere should enhance motor learning. While the interhemispheric competition model has guided therapeutic application of tDCS in neurorehabilitation (Di Pino et al., Therapy to facilitate motor learning requires Recently, Waters et al.  investigWhile the conclusions of Waters et al.  were supNevertheless, both conventional and reverse-polarity bihemispheric tDCS induce similar improvements in motor learning. To explain this observation, Waters et al.  propose A and GABAB receptor mediated inhibition can be tested using paradigms known as short-latency intracortical inhibition and long-latency intracortical inhibition. Since GABA plays an important role in synaptic plasticity and motor learning (Stagg et al., To further examine the proposed interhemispheric cooperation model, we suggest additional TMS experimental approaches. First, paired-pulse TMS paradigms can be employed to investigate inhibitory synaptic activity Figure . Both GAThe recent study from Waters et al.  providesBH and MG all made substantial intellectual contributions to the manuscript and approved the final version for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Telomerase elongates telomeres and is crucial for maintaining genomic stability. While stem cells and cancer cells display high telomerase activity, normal somatic cells lack telomerase activity primarily due to transcriptional repression of telomerase reverse transcriptase (TERT), the catalytic component of telomerase. Transcription factor binding, chromatin status as well as epigenetic modifications at the TERT promoter regulates TERT transcription. Myc is an important transcriptional regulator of TERT that directly controls its expression by promoter binding and associating with other transcription factors. In this review, we discuss the current understanding of the molecular mechanisms behind regulation of TERT transcription by Myc. We also discuss future perspectives in investigating the regulation of Myc at TERT promoter during cancer development. Terc and accessory proteins   and associated histone acetyl transferases (HATs). It can also recruit P-TEFb, which is a kinase that phosphorylates the C-Terminus of RNA polymerase II, thereby helping in promoter clearance. However, the mechanism employed by Myc to activate the TERT promoter is not known  at positions −165 and +44 nucleotide position relative to the transcription start site (TSS)  mutations commonly occur in low-grade gliomas  domain  ligands inhibit TERT mRNA expression in colon cancer cells via modulation of the Myc/Max/Mad network (Toaldo et al., Alterations in Myc expression are commonly observed during cancer initiation and progression. They occur via chromosomal translocations, amplifications and gene mutations Dang, . TelomerMyc expression is usually measured at the protein level using immunohistochemistry. For measurement of TERT expression, some studies use mRNA expression, while others measure telomerase enzyme activity since TERT mRNA levels positively correlate with telomerase activity (Armstrong et al., Myc and TERT play crucial roles during normal development as well as in carcinogenesis. Therefore, understanding their interplay in both these processes is important. Myc can activate TERT transcription directly or by cooperating with other transcription factors like SP1, ER and ETS. The factors that discriminate Myc-dependent TERT regulation during normal development from cancer are not known and need further investigation. Mutations in the TERT promoter represent the most common non-coding somatic mutations in cancer and it would be interesting to investigate the role of Myc in regulating the mutant TERT promoter. The existing correlation studies between Myc and TERT are not very conclusive and need further analysis.EK conceived, designed and wrote the manuscript. EK and VT revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Echinococcus granulosus, development of jaundice in a patient with liver cyst is initially suspected to have hydatid cyst.Rupture into the biliary ducts is the most frequent complication of hydatid liver disease. In endemic areas of A 48 year-old woman with history of asymptomatic hydatid liver cysts was admitted to the emergency department with right upper quadrant abdominal pain, increased levels of liver enzymes, bilirubin and alkaline phosphatase and the initial clinical diagnosis was the hydatid cyst rupture into the bile ducts. Surgery was planned but radiological evaluation (MRI) revealed non-dilated intra-extra biliary ducts. High suspicion of hydatid rupture required diagnostic ERCP that was normal and surgery was cancelled then. A possible diagnosis of coexistent hepatitis was suspected. Liver function tests normalized gradually and no cyst rupture was determined during surgery. These findings suggest considering the possible development of cryptogenic hepatitis in patients with preexisting hydatid cyst. Echinococcus granulosus and it is still a serious health problem in endemic areas. Hydatid cysts can originate from all visceral organs but most often is located in the liver. Rupture of cysts into the biliary tract is the most frequent complication  1386 U/L, aspartate aminotransferase (AST) 1071 U/L, alkaline phosphatase (ALP) 307 U/l and gamma glutamyl transpeptidase (GGT) 156 U/L. Abdominal ultrasound showed a 68 mm in diameter exophytic and multivesicular hydatid cyst located at segment II and III of the liver.Gallbladder, biliary tract and pancreas were normal. Abdominal magnetic resonance imaging confirmed sonographic findings without dilation of intrahepatic and extrahepatic biliary ducts . Viral hepatitis and tumor markers were negative. She denied using any drugs or toxic products. The initial diagnosis of the patient was hydatid liver cyst ruptured into the biliary tract, hence an endoscopic retrograde cholangiopancreatography (ERCP) was performed with normal findings. The possibility of hepatitis with unknown origin (cryptogenic hepatitis) caused to postpone surgery until three weeks later when the levels of serum bilirubin, ALP and GGT decreased to normal values, but ALT and AST values remained high at 464 U/L and 372 U/L, respectively. The patient underwent an exploratory surgery which found no cyto-biliary rupture. A liver biopsy was performed and the patient was discharged on postoperative day 5. At this time, the ALT and AST values were 175 U/L and 58 U/L, respectively. Histopathology of the hydatid cyst was confirmed. The patient was well in the last follow-up performed 6 years after discharge with normal liver function tests and normal findings in computed tomography scanning .(i) an existing hydatid liver cyst, (ii) elevated bilirubin levels (direct bilirubin increase was dominant) and (iii) negative laboratory results for viral hepatitis and tumor markers. Retrospectively, we examined the diagnostic errors and found a clue against the presence of hydatid jaundice. The following findings may be helpful in ruling out hydatid jaundice; (i) normal color stool, (ii) greater increase in the serum levels of AST-ALT as compared to ALP-GGT and (iii) unremarkable dilatation in the bile ducts. Rupture into bile ducts is the most common and serious complication of hydatid liver disease. The predisposing factors for cysto-biliary communications are; preoperative increased levels of liver enzymes and large size cysts or multiple cysts . The symHepatocellular jaundice is the injury of hepatocytes without biliary obstruction. The most frequent causes of acute hepatocellular damage are viruses, natural and chemical toxic agents and drugs. Although performing laparotomy is necessary in patients with hydatid cyst rupture, anesthesia and trauma of surgery may cause hepatocellular jaundice to deteriorate, perhaps fatally . In the In the countries where hydatid disease is rare, the differential diagnosis of hydatid jaundice can be difficult as well . It may


Auditory mismatch negativity (MMN) and its magnetic counterpart (MMNm) are event-related potentials/fields elicited by violations of previously established auditory regularities . Reduced MMN amplitude is a robust finding in both medicated and unmedicated schizophrenia (ScZ) patients , potentially indicating impaired predictive processes . Furthermore, several studies have examined MMN responses in individuals at clinical high risk for psychosis (CHR) and have found MMN deficits to be present already in this population, indicating that MMN is compromised before psychosis onset and could represent a marker of risk for psychosis development. However, not all studies have reported significant differences in MMN amplitude between clinical high risk and healthy individuals and there is evidence to suggest that MMN deficits are primarily observed in CHR individuals who transition to psychosis .The purpose of the present study is to investigate MEG recorded MMNm amplitude responses to both duration deviants and sound omissions in n = 90 CHR-individuals who were screened with the Schizophrenia Proneness Instrument and the Comprehensive Assessment of At Risk Mental States. N = 50 healthy controls served as a comparison group. We employed an auditory oddball paradigm in which three different sequences of auditory stimuli were presented binaurally at ~ 70 dB . The standard sequence contained five identical tones (80 ms) and the deviant sequence contained four identical tones and one duration deviant tone (40 ms). In addition, an omission sequence which contained only four identical tones was included to examine auditory predictions. Participants were instructed to focus their attention away from the sounds and to perform a simple visual detection task. We analyzed MMNm responses to unpredictable deviant and omitted sounds in bsensor and source space. The linearly constrained minimum variance (LCMV) beamformer was used to identify the generators of the MMNm responses and to compute artefact-free source-level time-courses.Consistent with previous studies revealing MMN sources in auditory cortical areas, bilateral MMNm sources were localized in auditory cortices for both duration deviants and sound omissions. Our data show attenuated MMNm responses elicited by duration deviant sounds in CHR individuals compared to healthy controls.Taken together, the study findings suggest that reduced MMNm amplitude is present before psychosis onset and reflects aberrant predictive processing rather than deficient stimulus-specific adaptation. Clinical follow-up measurements will be obtained to determine whether MMNm amplitudes are a potential biomarker for predicting onset of psychosis.


Assessment of pyrazinamide susceptibility may be prudent before using it in regimens for drug-resistant tuberculosis.Although pyrazinamide is commonly used for tuberculosis treatment, drug-susceptibility testing is not routinely available. We found polymorphisms in the  We calculated the frequency of each pncA polymorphism and classified mutations as synonymous or nonsynonymous. We compared polymorphisms with those reported in the literature to identify any that are known to be associated with phenotypic susceptibility and to determine the proportion that are likely to confer phenotypic resistance  . CulturepncA mutations, we also compared IS6110-based restriction fragment-length polymorphism (RFLP) patterns with pncA mutations for the isolates from South Africa . The distribution of RFLP patterns among isolates with identical pncA mutations was examined to determine if the pncA mutation arose de novo or may have been transmitted.To determine the effect of clonal expansion of MDR and XDR TB on the diversity of pncA gene sequencing for 554 unique patient-isolates [1 isolate/patient], 167 MDR TB and 387 XDR TB; of these, 99 (59%) of MDR TB and 215 (56%) of XDR TB patients had previously received treatment for TB. A pncA polymorphism was found in 117 (70%) MDR TB and 370 (96%) XDR TB isolates .We completed targeted isolates , 2. The pncA polymorphisms were identified  have previously been associated with phenotypic pyrazinamide susceptibility  were present in >1 patient . We founmutation . MoreovepncA polymorphisms. Given the high likelihood of frameshift mutations resulting in resistance and the high specificity (94%–98%) of pncA SNPs for pyrazinamide resistance  (pncA sequence, but its diagnostic accuracy has not yet been adequately tested (A diversity of –A limitation of our study is that phenotypic pyrazinamide susceptibility testing was not performed on the sequenced isolates. Nonetheless, correlation with phenotypic testing has been previously reported in the literature for most polymorphisms, enabling us to estimate the proportion likely to be pyrazinamide resistant (pncA polymorphisms from geographically disparate countries suggests that guidelines to empirically use pyrazinamide in drug-resistant TB regimens, including shorter MDR TB regimens (The high prevalence of pncA gene mutations associated with pyrazinamide resistance in drug-resistant tuberculosis, South Africa and Georgia.Supplemental methods for study of


The initiation and progression of malignant tumors is driven by distinct subsets of tumor-initiating or cancer stem-like cells (CSCs) which develop therapy/apoptosis resistance and self-renewal capacity. In order to be able to eradicate these CSCs with novel classes of anti-cancer therapeutics, a better understanding of their biology and clinically-relevant traits is mandatory.Several requirements and functions of a CSC niche physiology are combined with current concepts for CSC generation such as development in a hierarchical tumor model, by stochastic processes, or via a retrodifferentiation program. Moreover, progressive adaptation of endothelial cells and recruited immune and stromal cells to the tumor site substantially contribute to generate a tumor growth-permissive environment resembling a CSC niche. Particular emphasis is put on the pivotal role of multipotent mesenchymal stroma/stem cells (MSCs) in supporting CSC development by various kinds of interaction and cell fusion to form hybrid tumor cells.A better knowledge of CSC niche physiology may increase the chances that cancer stemness-depleting interventions ultimately result in arrest of tumor growth and metastasis. Various models are available for the generation of tumor initiating cells which subsequently give rise to neoplasias and malignant cancers including a hierarchical , 2 and aTumor initiation of the hierarchical model starts within a normal stem cell niche (SCN) which regulates proliferation, apoptosis resistance and maintains stemness whereby a normal stem cell evades regulation resulting in an aberrant/tumorigenic stem-like cell, also known as cancer stem-like cell (CSC) , 12. BesExamples of the hierarchical model have been shown in solid tumors such as breast cancer and in non-solid tumors such as acute myeloid leukemia , 2. For The stochastic model represents a second feasibility to circumstantiate tumor initiation. In comparison to the hierarchical model, every tumor cell within the stochastic model is biologically homogenous with an equal probability to initiate, maintain and promote tumor growth whereby functionalities depend on both, extrinsic factors originating from the tumor microenvironment and intrinsic factors such as signaling pathways and levels of transcription factors , 27. TumExamples of the stochastic model can also be found in solid and non-solid tumors such as colorectal cancer, lung adenocarcinoma and lymphoblastic leukemias –32.Whereas the stochastic model primarily addresses genetic heterogeneity without consideration of potential phenotypic variations within the genetically homogenous tumor cell population , the hieConsequently, both models of tumor initiation result in aberrant/tumorigenic stem-like cells which further promote tumor development and progression. However, little is known about the mechanism and the existence of a cancer stem cell niche (CSCN) for CSC generation and maintenance of tumor growth.Whereas tumor tissue harbors a variety of different cell populations including tumor cells in different states of development, one possibility of CSC development includes the hypothesis to be derived from neoplastic transformation during development or self-renewal of normal tissue-specific stem cells and to be primarily associated with solid tumors . AlternaMoreover, in a human myeloid leukemia model, phorbol ester-induced differentiation of U937 leukemia cells resulted in acquired adherence of cell cycle-arrested and differentiated monocyte/macrophage-like cells for several weeks. A decreasing threshold of phorbol ester or interference with the downstream signaling cascade of phorbol ester-activated protein kinase C interrupted transactivating processes via AP-1 (predominantly Jun/Fos) and NFκB and induced retrodifferentiation , 42. ThiTogether, these findings suggest that certain stimuli which may include damage products and DAMPs within a tumor cell population can establish a CSCN and contribute to a retrodifferentiation process to rejuvenate tumor cells to a more stem-like phenotype with enhanced self-renewal capacity Fig. . MoreoveA sensitive balance of timely available internal and external stimuli within a CSCN may also enable other modes of CSC development such as MSC-tumor cell fusion or entosis. Both types of interaction involve MSC as a potential cellular partner resulting in distinct functional hybrids. Although generally considered rare events, formation of hybrid cells via entosis or via fusion follow completely different mechanisms . EntosisThe normal SCN harbors stem cells and is responsible for regulating stem cell maintenance, in particular the balance between self-renewal and differentiation. Moreover, the normal SCN represents a dynamic and complex compartment whereby additional components including endothelial, immune and stromal cells, extracellular matrix, cell adhesion molecules, soluble factors and microvesicles/exosomes contribute to an environment necessary for enabling both, self-renewal and the capability to differentiate . Based oPrevious work described that stem cells reside in fixed compartments together with other cells determining stem cell behavior and regulating stem cell maintenance . Thus, tOne major prerequisite for tumor growth is the supply with nutrients and oxygen via blood vessels indicating the necessity of a CSCN localizing in the vicinity of vascular structures. Indeed, brain tumor stem cells have been reported to reside at perivascular regions . In variBesides neo-vascularization within the tumor microenvironment, the extracellular matrix (ECM) provides an important structural scaffold comprising fibrous proteins such as collagens, elastin, laminins, and fibronectin, globular proteins including the IgG superfamily integrins and cellular proteases, for instance MMPs, cathepsins and kallikreins for ECM remodeling . During When viewing a CSCN as a coordinated network of locally interacting cells  cells, adipocytes, immune cells  cells, dendritic cells (DC), macrophages) and mesenchymal cells ) together with dynamic thresholds and gradients of soluble factors  in a specific ECM environment , then interference with this balanced homeostasis is predicted to alter CSC development Fig. . Thus, EHuman tissue kallikreins also belong to the family of serine proteinases that are involved in degradation of ECM components such as fibronectin, laminin and collagen , 80. In Apart from distinct ECM components and appropriate restructure by distinct proteases that are required for a CSCN to promote CSC development, self-renewal and migration, adjacent cell types are also associated with a CSCN establishment via direct and indirect communication processes with tumor-derived cells to enable CSC development.An important cell population during tumorigenesis is represented by MSC. These multipotent stromal cells are located predominantly at perivascular niches of nearly all human tissues and organs and display a plethora of functions including tissue repair, immunomodulation and stem cell homeostasis –89. SubpRegulation of CSC generation also involves a diverse range of soluble factors including cytokines, chemokines, growth factors, hormones, metabolites and further trophic molecules. Breast cancer stem-like cells which are characterized by low levels of CD24, high levels of CD44, and aldehyde dehydrogenase expression , 103 havProduction and release of CCL5 by MSC has been suggested to activate corresponding receptors such as CCR5 on adjacent breast cancer cells thereby promoting altered breast cancer development and metastasis . MoreoveAccording to their recruitment to tumor sites associated with direct interactions of MSC with tumor cells, multipotent MSC may represent a major cellular component of a CSCN since various studies reported mutual acquisition of properties between both interaction partners which alter the original cell fate , 52.2+, small molecules such as microRNAs or second messenger are transported and exchanged via gap junctions allowing regulation of cell proliferation, differentiation and homeostasis maintenance [Gap junctions enable the direct interaction between two neighboring cells, also known as gap junctional intercellular communication (GJIC). Thereby, each cell contributes equally to gap junction formation. Gap junction channels consist of hemichannels/connexons which in turn are composed of six connexin protein subunits that form a pore through the plasma membrane , 112. Inntenance , 113. Duntenance . Furtherntenance . Moreoventenance . Dormancntenance  Whereas GJIC proceeds between two tightly adjacent cells, nanotubes are characterized by thin, F-actin rich structures which link interacting cells over longer distances. These dynamic cytoplasmic protrusions facilitate communication via exchange of various biological cargo including small molecules and organelles . NotablyThe Notch signaling pathway plays a crucial role in cellular processes including tissue repair, stem cell maintenance and regulation of immune cell functions . There iTrogocytosis has been initially observed between immune cells as an active mechanism whereby lymphocytes extract surface molecules from antigen-presenting cells . More reDirect interaction and communication between MSC and tumor cells including GIJC, nanotube formation, Notch signaling, and trogocytosis may contribute to the generation of CSCs together with mutual exchange of distinct factors which alter properties of the involved cell populations. For example, cancer cell–derived interleukin1 can stimulate prostaglandin E2 secretion by MSC operating in an autocrine manner to further induce expression of cytokines by the MSC which in turn activate β-catenin signaling in the cancer cells in a paracrine fashion and formation of CSCs .Together, these different types of direct interactions emphasize the importance and requirements of tumor-associated cells such as MSC within a CSCN to relay cellular properties that alter the original phenotype of tumor cells towards CSCs.In addition to direct interactions altering CSC phenotype and function, indirect communication plays a pivotal role within CSCN. It involves both the release of soluble molecules such as metabolites and hormones and the exchange of microvesicles and exosomes .In CSCN, metabolites including lactate, glutamine and keton bodies mutually reprogram metabolism of stromal stem cells and cancer cells favoring adaption of tumor cells to dynamic fluctuation of CSCN. Activation of CSCN homing CAFs by tumor cells leads to metabolic reprogramming of CAFs to a glycolytic phenotype meaning elevation of glucose uptake and elevation of lactate secretion serving as nutrient for adjacent cancer cells , 130. OnFurthermore, hormones as soluble agents have been demonstrated to influence CSCs. For instance, progesterone induced the expansion of breast cancer stem-like cells .Exosomes are characterized as homogeneous, 40 to 100 nm small endocytosed membrane particles which can be mutually exchanged by tumor cells and adjacent cell populations in the tumor microenvironment, particularly macrophages and MSC. These small particles contain a variety of proteins, lipids, functional RNAs and regulatory miRs , 136. AlAlthough knowledge about CSCs originating from a CSCN is limited, the tumor microenvironment in which CSCs reside, provides a structural scaffold with various resident cancer-associated aberrant cell types which contribute to tumor growth and exchange soluble factors by mutual intercellular communications. Due to progressively increasing tumor cell growth and impaired vascularization, some tumor cells within the center of a solid tumor have limited access to nutrients. An impaired nutrient availability during expansion of the tumor size leads to hypoxic and more acidic conditions with starvation of the inner tumor cells eventually resulting in autophagy and necrosis/necroptosis  , a process required for metastasis, through activation of EMT transcription factors resulting in e.g. loss of E-cadherin , 157. InFollowing hypoxia and EMT, cancer cells can escape the primary tumor niche and migrate and disseminate to distant organs , 165.Besides the contribution of hypoxic conditions to metastasis, low pH/acidic conditions as a result of lactate release from increased anaerobic glycolysis of tumor cells may favor metastasis as well. Acidic conditions are proposed to activate proteases such as cathepsins which in turn degrade ECM for tumor invasion –168. Alslow/CD44high breast cancer stem-like cells [Hypoxic and more acidic conditions in the inner part of a tumor are often accompanied by starvation and reduced tumor cell viability, Enhanced cell death of centrally located tumor cells by progressive nutrient deficiency, starvation and low oxygen levels can involve three main mechanisms: apoptosis, autophagy and necrosis/necroptosis. Apoptosis is a highly regulated cell death program that can be triggered by both extrinsic and intrinsic stimuli after induction in consequence of inevitable cell stress , 171. Hoke cells . Converske cells  further Necrosis depicts another process of cell death characterized as random, accidental and unregulated . NonetheThe release of DAMPs initiates an innate and adaptive immune response attracting immune cells such as DC, NK cells, macrophages and regulatory T cells (Tregs)  Fig. 1)1). AlthoReduced immune response to tumor cells can also be mediated by MSC which are recruited to tumor sites due to the inflammatory microenvironment Fig. . OverallMacrophages (M1) contribute to tumor destruction via IFNγ activation followed by production of type 1 cytokines and chemokines. Conversely, activation of M2 macrophages via MSC promotes tumorigenesis by production of type 2 cytokines and chemokines strengthening the dual role of macrophages depending on the phenotype and activation status. During progressive adaption to the tumor microenvironment, TAMs represent a further macrophage phenotype that triggers tumor development through support of angiogenesis and ECM remodeling . ConsequTogether, the cascade of hypoxic conditions and low nutrient supply accompanied by limited apoptosis, autophagy and necrosis/necroptosis followed by release of DAMPs evokes an inflammatory microenvironment which is modulated by interacting MSC. These mechanisms which are also influenced by protease activities and subsequent ECM modulation interfere with the dynamic and sensitive equilibrium of the CSCN which can critically alter the amount of CSCs affecting clinical outcomes and patient prognoses .The presence of a CSC population as part of a heterogeneous tumor entity  is suggeAccording to metabolic alterations and functional interference with the requirements of a carefully balanced factor homeostasis for CSC generation, the sensitive maintenance of a CSCN is likely subject to changes. Such CSCN structures can be disabled at certain sites of the tumor and newly established at more favorable places within the tumor suggesting multiple and simultaneous possibilities for CSCNs with appropriate turnover. A potential CSCN turnover may depend on the stability of the environment. For example, CSCNs of tumor metastases in the bone marrow are more protected and stabilized in the spongy bone cavities as compared to CSCNs in more metabolically-exposed tissues such as primary organ-associated tumor tissues or lymph node metastases. Nevertheless, the dynamic generation and changes of CSCs within the plasticity of tumor tissues and the continuously functional alterations/adaptations of developing and metastasizing tumor cells by loss of distinct functions and/or acquisition of new properties represent the real challenge of a successful tumor therapy.


Our study aimed to present the distinctive correlates of formal thought disorder in patients with schizophrenia, using the Clinical Language Disorder Rating Scale (CLANG).We compared the formal thought disorder and other clinical characteristics between schizophrenia patients with (n = 82) and without (n = 80) formal thought disorder. Psychometric scales including the CLANG, Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Calgery Depression Scale for Schizophrenia (CDSS) and Word Fluency Test (WFT) were used.After adjusting the effects of age, sex and total scores on the BPRS, YMRS and WFT, the subjects with disorganized speech presented significantly higher score on the poverty of contents of abnormal syntax , lack of semantic association , disclosure failure , pragmatics disorder , dysarthria , and paraphasic error  items than those without formal thought disorder. With defining the mentioned item scores as covariates, binary logistic regression model predicted that disclosure failure  and pragmatics disorder  were distinctive correlates of formal thought disorder in patients with schizophrenia.Disclosure failure and pragmatics disorder might be used as the distinctive indexes for formal thought disorder in patients with schizophrenia.


Deficits in social cognition and on social perception tasks are well studied and widely found in populations with schizophrenia. In addition, our work consistently replicates findings that individuals with schizophrenia report severe loneliness, significantly higher than healthy matches. Loneliness is a chronic, gnawing condition that induces distress and impedes life satisfaction and function across the spectrum of mental health. We also find social isolation impedes interpretation of social information and may lead to socio-perceptual deficits.The present study examines the effectiveness of a novel, adaptive virtual reality simulated social exposure training intervention  in both decreasing feelings of loneliness and improving social cognitive function in individuals with schizophrenia. We investigate baseline relationships between social isolation, loneliness and social cognition abilities, as well as pre to post intervention changes in function and subjective social well-being.Fifteen medicated SZ outpatients completed 10 virtual reality social skills training sessions over the course of 5 weeks. Training sessions depicted three naturalistic social scenarios in which participants were instructed to complete 12 total social “missions” to obtain information from VR avatar characters. Prior to training and following the final training session, participants were assessed using the CogState Brief Schizophrenia Battery Social Emotional cognition task and rated loneliness using the UCLA Loneliness Scale. Independent raters conducted pre- and post-training clinical interviews to assess changes in participants’ levels of positive, negative, and overall psychiatric symptomsGreater overall psychiatric symptoms were significantly correlated with higher levels of experienced loneliness, consistent with previous findings. There was a significant improvement in social emotional cognition accuracy, and a trend-level reduction in loneliness from pre-training to post-testing following social VR training.Previous research indicates that individuals higher on the psychosis spectrum perform worse at social cognition and social perception tasks. Our own research indicates that individuals higher on the psychosis spectrum also endorse higher levels of social distress via social isolation and loneliness. The present study attempts to enhance social cognitive and interpersonal abilities of individuals with schizophrenia while decreasing loneliness by strengthening social bonds and skills using a virtual reality training game. We find that following 10 sessions of VR social training, accuracy on measures of social cognition is improved significantly, however loneliness is reduced non-significantly. These initial results demonstrate potential feasibility of a novel VR social skills training game for improving social experience for patients with schizophrenia.


Chromatin is a very long DNA–protein complex that controls the expression and inheritance of the genetic information. Chromatin is stored within the nucleus in interphase and further compacted into chromosomes during mitosis. This process, known as chromosome condensation, is essential for faithful segregation of genomic DNA into daughter cells. Condensin and cohesin, members of the structural maintenance of chromosomes (SMC) family, are fundamental for chromosome architecture, both for establishment of chromatin structure in the interphase nucleus and for the formation of condensed chromosomes in mitosis. These ring-shaped SMC complexes are thought to regulate the interactions between DNA strands by topologically entrapping DNA. How this activity shapes chromosomes is not yet understood. Recent high throughput chromosome conformation capture studies revealed how chromatin is reorganized during the cell cycle and have started to explore the role of SMC complexes in mitotic chromatin architecture. Here, we summarize these findings and discuss the conserved nature of chromosome condensation in eukaryotes. We highlight the unexpected finding that condensin-dependent intra-chromosomal interactions in mitosis increase within a distinctive distance range that is characteristic for an organism, while longer and shorter-range interactions are suppressed. This reveals important molecular insight into chromosome architecture. How chromatin is spatially organized within the cell nucleus and within chromosomes is a fundamental question in cell biology. Centimeter-long DNA molecules change their spatial chromatin organization within micrometer-sized cells during cell cycle progression. In interphase, chromatin is distributed throughout the nucleus to express the genetic information. When cells enter mitosis, chromatin becomes compacted to form mitotic chromosomes. Chromosome condensation, the gross morphological change of spatial chromatin organization in mitosis, is indispensable for the faithful inheritance of genetic information. Structural maintenance of chromosomes (SMC) complexes are large proteinaceous rings that control spatial chromatin organization at various stages during cell growth and differentiation. By topologically entrapping more than one DNA strand within its ring, SMC complexes are thought to mediate interactions between DNA strands for the establishment of chromatin architecture Uhlmann . Two memChromosome conformation capture is a powerful technique to investigate spatial chromatin organization (Dekker et al. Recent Hi-C results have illustrated the dramatic alteration of chromatin organization during cell cycle progression in several species (Gibcus et al. A notable feature of mitotic chromosomes is a steep drop of contact probabilities at very large genomic distances, over 10 Mb in human cells (Naumova et al. The mitotic reduction of local chromatin contacts comes as a surprise, as one would expect that all DNA sequences come closer together in a condensed chromosome. However, new interactions at longer distances will restrict the freedom of movement of the chromatin chain, thereby reducing the probability of local interactions. Consistently, local chromatin motility becomes constrained in mitosis (Kakui et al. All the above described changes of chromatin contacts in fission yeast mitosis are dependent on condensin Fig.  Kakui e. FurtherThe recent Hi-C experiments unveiled that SMC complexes drive a dramatic reorganization of chromatin contacts as cells enter mitosis. They did not elucidate the mechanism of how SMC complexes mediate chromatin interactions. Two proposed models how SMC rings modulate chromatin contacts are the stabilization of stochastic pairwise interactions and loop extrusion, two models that need not be mutually exclusive (Cheng et al.


Motivational deficits are prevalent feature of schizophrenia, which have been tightly linked to real-world outcomes. Abnormalities in effort cost computations have been proposed as a candidate mechanism underlying these deficits. In the present study, we sought to employ behavioural economic analyses to further understand cost-benefit decision making abnormalities in schizophrenia.58 young adults with schizophrenia and 58 matched controls participated in this study. Participants completed an effort-based decision-making task in which they made decisions to expend physical effort in exchange for monetary rewards. From participants choice behaviour, we computed indifference values  for each individual participant. Other computational parameters were also computed such as choice consistency and subjective reward valuation.Patents and controls did not differ in their subjective valuation of reward. On the decision-making task, patients made more inconsistent choices relative to controls. In both univariate and multivariate analyses controlling for potential confounders, patients had higher indifference values meaning that patients required more money in the exchange of their effort. Among patients, higher indifference values were associated with more severe clinical motivational deficits.Patients had multiple abnormalities related to their decisions to expend effort for reward. Choices were more chaotic and reward value was discounted by effort at a steeper rate in patients. These results point toward an abnormality in the computation of effort costs or in the integration of these costs with value signals.


Intra-aortic balloon pump (IABP) counterpulsation is a catheter-based treatment for coronary artery disease and decompensated heart failure to increase coronary blood flow and improve cardiac output. IABP is generally well tolerated, and complications are usually related to peripheral vasculature or red blood cell and platelet consumption. The usual insertion site via femoral artery renders the patient bedbound. Recently, axillary artery has been used in patients with atherosclerotic peripheral vascular disease and documented small arteries or in those awaiting transplant to ensure ambulation and prevent deconditioning. We present a patient with ischemic cardiomyopathy and severe left ventricular dysfunction, awaiting Orthotropic Heart Transplant. His worsening intractable angina and dyspnea necessitated IABP placement via left axillary artery, significantly improving his condition. He subsequently experienced migraine-type persistent unilateral headache refractory to standard pain management. Multiple strategies were utilized to treat his pain, but the patient insisted that his pain commenced after IABP placement. Ultimately, the removal of the pump led to complete resolution with no recurrence. The authors hypothesize that the unilaterally directed blood flow and direct increase in cerebral perfusion from the intra-aortic balloon pump may have caused vasodilation of the extracranial arteries, leading to a persistent and debilitating headache in this susceptible patient. Intra-aortic balloon pump (IABP) is a cylindrical polyethylene device inserted into the descending thoracic aorta, which increases myocardial oxygen delivery and cardiac output . Its “coA 63-year-old male with ischemic cardiomyopathy and severe left ventricular dysfunction was admitted with chest pain and dyspnea at rest. He was on maximal medical therapy and had received multiple prior percutaneous coronary interventions and two previous coronary artery bypass surgeries. Recent coronary angiography revealed no possibility of further revascularization. He was evaluated for Orthotropic Heart Transplant (OHT) and listed as Status 1A-e (urgent need). His worsening intractable angina and dyspnea necessitated IABP placement via left axillary artery, which significantly improved his condition. Axillary artery was the chosen site of insertion  in order to enable ambulation and prevent deconditioning, as the patient was awaiting transplant . The IABExamination revealed tender and bulging left temporal artery suspicious of temporal arteritis (TA); however, his normal erythrocyte sedimentation rate minimized TA as a likely diagnosis. Nonetheless, he was offered prophylactic prednisone, which he refused. Pain management service was consulted and multimodal treatment including acetaminophen, oxycodone, citalopram, and tizanidine was initiated, while nitrates were withheld . The patIn accordance with patient's wishes, the IABP was weaned and removed, and nitrates were initiated for angina prophylaxis. On postremoval assessment, the patient's headache had completely resolved with no future recurrence. He subsequently received OHT and was discharged with normal EF and no further headaches.Intra-aortic balloon pump (IABP) is a widely used circulatory assist device to improve coronary perfusion in acute coronary syndromes and improve cardiac output in acute decompensated heart failure. Coronary perfusion has often been compared to cerebral perfusion, drawing similarities in the pathophysiology and pharmacology of myocardial infarction and acute stroke , 8. AugmOne study showed that IABP augmentation causes a significantly higher increase in transcranial Doppler CBF velocity change in the middle cerebral artery with enhanced CBF especially in patients with preexisting left ventricular dysfunction . Data inFurther case reports suggest that IABP placement can increase proximal pressures and carotid blood flow above the IABP and decrease distal pressures and perfusion below it, leading to distal perfusion injuries (ischemia) , 18. The


Swift and adequate fluid loading is a cornerstone of septic shock therapy. Yet, careful assessment of volume responsiveness and volume amount during the resuscitation process is a prerequisite. Both overzealous initial fluid administration and late fluid overload are harmful and may be associated with increased mortality.Static  pressure readings are erroneous for monitoring fluid resuscitation and should be abandoned. Dynamic measurements  better predict fluid responsiveness than static filling pressures but the conditions necessary for these parameters to correctly evaluate preload dependency are frequently not met. The passive leg raising maneuver as a means to alter biventricular preload in combination with real-time measurement of cardiac output changes is an easy-to-use, fast, relatively unbiased, and accurate bedside test to guide fluid management and to avoid fluid overload during early septic shock treatment. Moreover, PLR may also be particularly useful to assist various treatments that trigger fluid removal during the “de-resuscitation” phase of septic shock.The passive leg raising maneuver in combination with real-time measurement of cardiac output changes is an easy-to-use, fast, relatively unbiased, and accurate bedside test to guide fluid management during septic shock. The recently published Surviving Sepsis Campaign guidelines strongly recommend ample volume resuscitation during the first day of septic shock treatment . Such agJournal of Intensive Care, Krige et al. prospectively investigated the use of a novel generation Vigileo FloTrac™ system during a PLR maneuver in medico-surgical patients with vasopressor-dependent circulatory shock [At the beginning of this millennium, several authors proposed to use physiologic heart-lung interactions during positive pressure ventilation as more reliable predictors of fluid responsiveness in septic shock . Variatiry shock . The stuThrough the years, awareness has risen that after initial aggressive fluid resuscitation the focus should shift towards obtaining a net and even negative fluid balance . Late liIn conclusion, PLR testing in combination with more sophisticated real-time hemodynamic monitoring actually seems to be the most appropriate method to guide a bedside “do not harm” volume resuscitation strategy in septic shock. Future studies should assess the PLR maneuver using calibrated intermittent  or continuous  monitoring and evaluate whether this test could become pivotal in managing fluid removal during the “de-resuscitation” phase of septic shock.


Our understanding of the neurobiology of psychiatric disorders remains limited, and biomarker-based clinical management is yet to be developed. Induced pluripotent stem cell (iPSC) technology has revolutionized our capacity to generate patient-derived neurons to model psychiatric disorders. Here, we highlight advantages and caveats of iPSC disease modeling and outline strategies for addressing current challenges. Even as neuropsychiatric research has boomed, psychiatric disorders have remained a leading cause of global morbidity and disease burden . CurrentAs a result, definitive diagnoses and treatment strategies based on objective biomarkers continue to evade us. The development of human iPSC technology offers one approach to allow researchers to address the genetic complexity issue in psychiatric disorder research. Somatic cells such as skin fibroblasts from adult patients can be dedifferentiated to a pluripotent state by transient overexpression of the reprogramming transcription factors. Theoretically, iPSC clones can then be differentiated to any other cell type by exposure to an appropriate combination of patterning molecules. Parallel in vitro disease modeling efforts for studying the neural correlates of disease-associated genotypes may provide novel insights into the neurological underpinnings of psychiatric disorders . iPSCs aDISC1) gene altered synaptic activity and downstream signaling in iPSC-derived neurons, establishing a causal relationship between patient genetics and cellular phenotypes [A central goal of biological psychiatry is to understand how healthy and aberrant brain function may arise from the interaction of neural circuits. Crucial to this effort is generating relevant neural cell types from iPSCs, because studying the basic units of neural circuits in isolation enables the construction of in vitro model systems. Given the diversity of cell types in the mammalian brain, the field continues to develop protocols for generating relatively homogeneous populations of neuronal and glial subtypes, as well as genetic reporters to help label and identify specific cell types in mixed populations . This apenotypes . Furtherenotypes .While recent studies provide evidence for mechanisms that may contribute to disease pathology, excitement must be tempered by experimental knowledge addressing the caveats of in vitro disease modeling Fig. . A downsAnother issue is that of variability between cell lines and across experimental batches, possibly due to somatic mosaicism in donor cells prior to reprogramming, accumulation of de novo mutations with selective advantages, stochastic events during differentiation, and heterogeneous patient genetics . HoweverOne such approach is the stratification of large patient cohorts based on factors such as genetic risk, pharmacological response profiles, distinctive and quantitative endophenotypes, or comorbidities with other diseases. Modeling genetic risk includes rare variants conferring large genetic risk, such as copy number variation, or higher frequency common variants, such as single nucleotide polymorphisms, conferring relatively lower risk . CellulaAnother strategy is to study iPSC-derived neurons from a subset of well-characterized patients from a larger cohort. Here, in vitro phenotypes can be correlated with multiple continuous variables such as clinical severity, behavioral/biological measures, brain activity, and blood metabolites. Obtaining such multidimensional data from even small patient cohorts could inform the predictive value of individual variables and lead to the discovery of biomarkers. The explosion of rich neuropsychiatric disease sequence databases coincides with the emergence of powerful and accessible predictive machine learning tools. In conjunction with large-scale genetic data, deep-learning models may enjoy improved performance by using intermediate cellular phenotypes from patient-derived cells to bridge the gap between molecular and circuit or clinical features .In addition to careful study design, picking appropriate in vitro models will be critical for discovering clinically relevant in vitro phenotypes. Three-dimensional iPSC-derived organoids may be able to recapitulate maturation-related signatures in developing circuits, as has been successfully done with autism spectrum disorder . SimilarIt is increasingly clear that gaining fresh insights into the biology of psychiatric disorders demands a multipronged approach, including but not limited to patient iPSC-based diseased modeling. Furthermore, concerted efforts across laboratories for tackling the inherent variability of in vitro systems may pave the way for establishing standardized in vitro parameters, which would be immensely helpful for moving toward high-throughput profiling and screening in the future . Despite


Despite numerous medical advances in the care of at-risk preterm neonates, oral feeding still represents one of the first and most advanced neurological challenges facing this delicate population. Objective, quantitative, and noninvasive assessment tools, as well as neurotherapeutic strategies, are greatly needed in order to improve feeding and developmental outcomes. Pulsed pneumatic orocutaneous stimulation has been shown to improve nonnutritive sucking (NNS) skills in preterm infants who exhibit delayed or disordered nipple feeding behaviors. Separately, the study of the salivary transcriptome in neonates has helped identify biomarkers directly linked to successful neonatal oral feeding behavior. The combination of noninvasive treatment strategies and transcriptomic analysis represents an integrative approach to oral feeding in which rapid technological advances and personalized transcriptomics can safely and noninvasively be brought to the bedside to inform medical care decisions and improve care and outcomes.The study aimed to conduct a multicenter randomized control trial (RCT) to combine molecular and behavioral methods in an experimental conceptualization approach to map the effects of PULSED somatosensory stimulation on salivary gene expression in the context of the acquisition of oral feeding habits in high-risk human neonates. The aims of this study represent the first attempt to combine noninvasive treatment strategies and transcriptomic assessments of high-risk extremely preterm infants (EPI) to (1) improve oral feeding behavior and skills, (2) further our understanding of the gene ontology of biologically diverse pathways related to oral feeding, (3) use gene expression data to personalize neonatal care and individualize treatment strategies and timing interventions, and (4) improve long-term developmental outcomes.A total of 180 extremely preterm infants from three neonatal intensive care units (NICUs) will be randomized to receive either PULSED or SHAM (non-pulsing) orocutaneous intervention simultaneous with tube feedings 3 times per day for 4 weeks, beginning at 30 weeks postconceptional age. Infants will also be assessed 3 times per week for NNS performance, and multiple saliva samples will be obtained each week for transcriptomic analysis, until infants have achieved full oral feeding status. At 18 months corrected age (CA), infants will undergo neurodevelopmental follow-up testing, the results of which will be correlated with feeding outcomes in the neo-and post-natal period and with gene expression data and intervention status.The ongoing National Institutes of Health funded randomized controlled trial R01HD086088 is actively recruiting participants. The expected completion date of the study is 2021.Differential salivary gene expression profiles in response to orosensory entrainment intervention are expected to lead to the development of individualized interventions for the diagnosis and management of oral feeding in preterm infants.ClinicalTrials.gov NCT02696343; https://clinicaltrials.gov/ct2/show/NCT02696343 (Archived by WebCite at http://www.webcitation.org/6r5NbJ9Ym) The biological complexities of oral feeding have made it the most advanced neurological milestone of the newborn and a predictor of both short- and long-term developmental outcomes in the at-risk premature neonatal population ,2. SucceThere is currently no objective and quantitative tool to assess oral feeding maturity in premature infants. The current standard of care to determine oral feeding readiness in the EPI population is to use largely subjective, qualitative, and unvalidated cue-based assessment tools -22. CareA new translational application, approved by the FDA in 2008, has been shown to promote ororhythmic motor patterning (nonnutritive suck) in preterm infants who exhibit delayed or disordered nipple feeding behaviors. This approach is based on mechanosensory entrainment of the suck central pattern generator using servo-controlled pulsed pneumatic stimuli to drive peri- and intra-oral afferents, which in turn modulate local reflex activity and produce nonnutritive suck rhythms -31. Sincμ L of saliva , and (3) Santa Clara Valley Medical Center . The research protocol has been approved by each site’s Institutional Review Board (IRB). Participant recruitment began in July 2016, and NTrainer intervention is expected to be completed by 2020. Neurodevelopmental follow-up testing will begin in 2018.The primary outcome variables include salivary gene expression of a panel of genes previously identified as playing a role in oral feeding of preterm infants, time to transition to full oral feeding, and oromotor NNS pattern formation. Secondary outcome variables include: NICHD NRN 18-month Feeding-Growth-Nutrition Questionnaire, and Bayley III scores of cognitive, motor, and language skills at 18 months’ corrected age (CA).Oral feeding is a complex neurological milestone that can pose a significant challenge for many preterm infants, particularly for those born extremely prematurely , as well as those with a compromised respiratory status. Persistent feeding difficulties can result in numerous short- and long-term medical complications, as well as place infants at risk for developmental disabilities. Currently, there is no objective method for treating delayed or disordered feeding skills, or for assessing oral feeding maturity. Therefore, there is a strong need for objective assessment tools and novel therapeutic interventions to identify the underlying mechanisms that delay and disrupt oral feeding success and provide evidence-based intervention strategies to help ameliorate outcomes. The current study aims to combine safe, noninvasive treatment strategies and salivary diagnostics in EPIs to improve oral feeding skills as well as long-term neurodevelopmental outcomes and to further our understanding of the gene ontology of biological pathways related to oral feeding, which may ultimately individualize the type and timing of interventions and personalize neonatal care.


To date, the oral cavity has yielded a diverse menagerie of adult stem cells that includes dental pulp stem cells (DPSCs), dental follicle stem cells (DFSCs), stem cells from apical papilla (SCAP), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), and gingival mesenchymal stem cells (GMSCs). These stem cells have various useful applications in clinical dentistry that is dental pulp regeneration after root canal treatment, osseous integration of titanium implants, and maxillofacial and periodontal regeneration. Stem cells-based approaches in clinical dentistry are reviewed by D. Hughes and B. Song, as well as S. Miran et al. within this special issue. in vitro culture, these dental and oral-derived adult stem cell populations exhibit much divergent characteristics  and express variable cell surface markers and transcription factors. In this special issue, C.-M. Kang et al. compared the transcriptional profile of human DPSCs and umbilical cord stem cells (UCSCs) with microarray and qRT-PCR techniques and found similar expression levels of the various canonical mesenchymal stem cell markers. However, gene ontology analyses revealed significant differences in the expression of genes related to cell proliferation, angiogenesis, immune responses, growth factor activities, and signal transduction, between DPSCs and UCSCs, which could indicate divergent propensity to differentiate into various lineages.Despite their common embryonic origin from the cranial neural crest and their similar fibroblastic morphology within in vitro culture. Subsequently, L. Liu et al. demonstrated that transgenic expression of the human xeroderma pigmentosum group C (XPC) gene through a lentiviral vector could mitigate this age-related decline in pluripotency markers expression by DPSCs.Dental and oral-derived stem cells have a number of advantages over other more commonly utilized sources of adult stem cells. Compared to the invasive surgical procedure required for obtaining mesenchymal stem cells from bone marrow, these adult stem cells are readily isolated from biological waste produced during routine dental treatment . Several studies have reported that dental and oral stem cells such as SHED possess much more extensive multidifferentiation potential and proliferative capacity compared to other adult stem cells. This is extensively discussed in a review on SHED by V. Rosa et al. within this special issue. Even more surprising are reports of the expression of pluripotency markers such as OCT4, MYC, and SOX2 by some dental and oral-derived stem cells, which are not usually expressed in most other adult stem cell types. Expression of these markers might be indicative of the more extensive plasticity and multilineage differentiation potential of dental and oral-derived stem cells when compared to other sources of stem cells. In this special issue, the study of L. Liu et al. reported that these pluripotency markers were strongly expressed in DPSCs at early passage numbers but were gradually downregulated with extendedIt is possible that the relatively high baseline expression of pluripotency markers by dental and oral-derived stem cells such as DPSCs could render these adult stem cells more amenable to reprogramming into induced pluripotent stem cells (iPSCs). This is critically examined and discussed in a review by J.-H. Lee and S.-J. Seo within this special issue. The study of H. Okawa et al. utilized iPSCs derived from GMSCs to fabricate scaffold-free osteoinductive cellular constructs. Besides the derivation of iPSCs from dental and oral-derived stem cells, it may also be worthwhile to explore the reverse approach, which is the derivation of dental and oral adult stem cell-like lineages from pluripotent stem cells. This may allow us to recapitulate the developmental pathway of the various differentiated somatic lineages of the oral cavity, thus providing us with an extremely useful tool for studying the underlying genetic and developmental basis of various oral and maxillofacial disorders. In this special issue, Q. Zhu et al. reviewed the potential applications of pluripotent stem cell-derived neural crest stem cells, which resemble the various adult stem cell niches of the oral cavity. The study of G. Sriram et al. demonstrated that human embryonic stem cell-derived fibroblasts could be utilized as an alternative to GMSCs for studying the innate immune response to pathogens related to periodontitis (periodontopathogens).In view of the various promising biomedical applications of dental and oral-derived stem cells, we have organized this special issue as a platform to highlight some of the recent developments and cutting-edge research in this field. It is hoped that the comprehensive reviews and research articles presented in this special issue would stimulate greater interest amongst the scientific community to pursue this field of research, as well as facilitating the translation of research data into clinical therapy.Boon Chin HengBoon Chin HengChengfei ZhangChengfei ZhangXuliang DengXuliang DengYin XiaoYin XiaoAlessandra PisciottaAlessandra PisciottaFahad KidwaiFahad KidwaiThimios A. MitsiadisThimios A. Mitsiadis


We describe a patient with right hemisphere damage affected by mild left visuo-spatial neglect and constructional apraxia. During the rehabilitation, he failed to draw a draught-board using horizontal and vertical trajectories, but he performed it successfully using oblique trajectories. These observations suggested an impairment of vertical/horizontal spatial coordinates system. In copying tasks including figure elements in different orientations he drew more accurately components in oblique orientation, whereas failed to reproduce components in horizontal orientation. The patient performed visuospatial perceptual and perceptual-imaginative tasks successfully. From these findings, it is possible to suggest that the oblique coordinate system of reference operates independently of vertical and horizontal coordinate systems in building a complex figure and that, therefore, cardinal orientation do not constitute a reference norm to define oblique orientation, as previously suggested.


To accurately predict atherosclerotic plaque progression, a detailed phenotype of the lesion at the molecular level is required. Here, we assess the respective merits and limitations of molecular imaging tools. Clinical imaging includes contrast-enhanced ultrasound, an inexpensive and non-toxic technique but with poor sensitivity. CT benefits from high spatial resolution but poor sensitivity coupled with an increasing radiation burden that limits multiplexing. Despite high sensitivity, positron emission tomography and single-photon emission tomography have disadvantages when applied to multiplex molecular imaging due to poor spatial resolution, signal cross talk and increasing radiation dose. In contrast, MRI is non-toxic, displays good spatial resolution but poor sensitivity. Preclinical techniques include near-infrared fluorescence (NIRF), which provides good spatial resolution and sensitivity; however, multiplexing with NIRF is limited, due to photobleaching and spectral overlap. Fourier transform infrared spectroscopy and Raman spectroscopy are label-free techniques that detect molecules based on the vibrations of chemical bonds. Both techniques offer fast acquisition times with Raman showing superior spatial resolution. Raman signals are inherently weak; however, leading to the development of surface-enhanced Raman spectroscopy (SERS) that offers greatly increased sensitivity due to using metallic nanoparticles that can be functionalised with biomolecules targeted against plaque ligands while offering high multiplexing potential. This asset combined with high spatial resolution makes SERS an exciting prospect as a diagnostic tool. The ongoing refinements of SERS technologies such as deep tissue imaging and portable systems making SERS a realistic prospect for translation to the clinic. Atherosclerosis is a complex multifactorial pathology that progresses over many decades. Immune-inflammatory responses play key roles in all phases of the pathology and inflammation contributes to plaque rupture resulting in clinical manifestations such as myocardial infarction (MI) and stroke.Multiple imaging techniques are available for both invasive and non-invasive imaging of the vasculature. These include contrast-enhanced ultrasound (CEUS), CT, MRI, positron emission tomography (PET), single-photon emission tomography (SPECT), near-infrared fluorescence (NIRF) microscopy and vibrational spectroscopy. MRI, CT and PET/SPECT are already in clinical use for diagnosing and monitoring atherosclerosis and can provide structural information such as quantifying stenosis and plaque size/location. In some instances, invasive imaging using intra-arterial probes employing one of the above modalities can reveal basic morphological information on plaque composition, yet there remains an urgent unmet requirement for non-invasive imaging tools that can provide information beyond the anatomic and functional level that are able to interrogate the cellular and molecular pathways driving local inflammatory responses that promote plaque vulnerability.Molecular imaging moves beyond anatomic and morphological detail to the level of cellular and molecular events. Activated endothelium offers a number of potential imaging targets, including adhesion molecules promoting leucocyte binding and transmigration into subendothelial locations. The complex inflammatory environment of a developing atherosclerotic plaque offers additional targets such as scavenger receptors present on macrophages/foam cells, and plaque destabilising proteases and peroxidases. True molecular imaging requires a targeting ligand , peptides, aptamers) to specific molecules/cells which are conjugated to a detection agent compatible with the imaging tool of choice, eg, microbubbles (CEUS), iodinated compounds (CT), radionucleotides (PET/SPECT), magnetic/superparamagnetic compounds (MRI) or fluorochromes (fluorescence imaging). Vibrational spectroscopy, such as Raman spectroscopy, offers the advantage of not requiring external imaging tracers owing to direct detection of endogenous biological molecules; however, Raman spectroscopy employing exogenous targeted nanoparticles (NPs) (surface-enhanced Raman spectroscopy (SERS)) results in an imaging capability with remarkably increased sensitivity and ability to simultaneously detect multiple analytes (multiplexing), which may improve diagnostic specificity. Advantages and limitations of the described techniques are summarised in In this review, we will highlight recent advances in molecular imaging and their application in identifying vascular inflammation, with a particular focus on the potentialities of Raman and SERS.et alUltrasound-based molecular imaging relies on CEUS, which employs the use of microbubbles as a vascular wall targeting agent. Signals are generated through vibration/oscillation or release of free gas when the microbubbles are exposed to sonic energy. Kaufmann CT possesses relatively good temporal and spatial resolution which can further be improved on by multidetector spiral computed tomography and the concomitant use of iodinated contrast agents. This approach allowed the non-invasive identification of plaque location and sizeAs the current technology stands, clinical use of CT for cellular and molecular imaging of atherosclerosis may be restricted to the narrow use of identifying plaque mineral composition and cellular density. As with anatomic CT imaging, use in this area will be subject to careful review of the radioactive burden associated with CT X-ray exposure, especially in the context of repeated scans. To date, the low sensitivity of CT contrast agents combined with spatial resolution inadequate to detect vulnerable plaque componentsPET and SPECT are widespread imaging tools that rely on the administration of radionucleotides and subsequent detection of γ-rays to construct three-dimensional images of biological tissue forming the cornerstone of nuclear imaging. PET/SPECT are attractive options for molecular imaging owing to their non-invasive nature and high sensitivity. Furthermore, the high sensitivity of nuclear imaging is frequently combined with CT or MRI, tools with superior spatial resolution to form hybrid imaging systems such as PET/CT, SPECT/CT and PET/MRI.18F]-Fluorodeoxyglucose (FDG) is a glucose analogue radiotracer commonly used in PET and uptake by tissues correlates with metabolic activity. Combined PET/CT imaging has shown that FDG accumulates more in symptomatic lesions than asymptomatic sites of stenosis, particularly in macrophage-rich regions.F-FluorodMRI is perhaps the most studied tool to date for molecular imaging in atherosclerosis, owing to excellent spatial and temporal resolution without requiring the administration of ionising radioactive nucleotides.-/- mice offering the potential for early intervention and monitoring.To overcome the major weakness of MRI (poor sensitivity), the use of paramagnetic agents such as gadolinium (Gd) chelates and superparamagnetic (iron oxide microparticles and nanoparticles) contrast agents have been employed to non-invasively image arterial diseases. MRI molecular imaging of atherosclerosis primarily employs ultrasmall paramagnetic iron oxide particles . The properties of USPIOs allow extravasation into vascular tissues enabling potential analysis of atherosclerotic lesions. This approach has been used as a tool for measuring plaque macrophage burden through MRI signal loss following phagocytic uptake of USPIOs in rabbits-/- mice.The use of microparticles of iron oxide (MPIO) offers several advantages over USPIOs. Their larger size (0.9–8 µm) confines their location to endothelial surfaces, preventing cellular uptake and potential consequences of cellular toxicity and loss of molecular specificity. Furthermore, the greater iron payload carried by MIOPs improves signal detection. These attributes coupled with rapid clearance from the circulation can allow early imaging of vascular inflammation with a high degree of specificity.-/- mice.Fluorescence imaging is an optical imaging technique that detects the emission spectra from fluorescent probes excited by a light source. As with other imaging modalities, probes are either passively or actively targeted to a biological molecule or tissue of interest or can act as ‘smart probes’ that are activated at the target site, for example, enzymatic conversion from a non-fluorescent substrate to a fluorescent product allowing functional read outs of local enzyme activity.The wide optical imaging window available for NIRF imaging allows the use of multiple probes to be assessed in a single system owing to fluorochromes emitting in distinct spectral regions; however, the difficulty in resolving such spectra often requires multiple excitation wavelengths for optimal signal discrimination.Vibrational spectroscopy mainly encompasses two techniques: infrared (IR) and Raman spectroscopies, which create molecularly specific spectra based on the vibrational energies of chemical bonds.FTIR, the most refined modern form of IR spectroscopy gains information from the vibration of molecular bonds caused by absorbance of light; requiring no external labelling method. The ability to detect chemically specific IR spectra over a wide wavelength window allows FTIR to detect multiple classes of biological molecules. FTIR is especially useful for differentiating lipids and proteins and these have been the main focus of FTIR research in cardiovascular studies to date.FTIR has been employed to map the distribution of collagen I, collagen III and elastin in the fibrous cap region of human atheroma samples postmortemLike FTIR, Raman spectroscopy has been used to map the detailed composition of atherosclerotic plaques but improves on FTIR in terms of both spatial and spectral resolution.Raman spectroscopy is a particularly attractive molecular imaging tool for interrogation of atherosclerotic plaques and potential diagnostic agent due to its ability to non-destructively acquire biochemical data on the processes that drive plaque development. Although the non-invasive nature of Raman is an important advantage of the technique, the main disadvantage pertains to its low sensitivity due to the weakness of the Raman scattering effect leading to long imaging times and an inability to discriminate low-level target molecules from background ‘noise’. Furthermore, many biological molecules are spectrally similar requiring complex chemometric analysis to separate signals of interest.The shortcomings associated with Raman spectroscopy have led to the development of SERS, a highly sensitive advancement of conventional Raman spectroscopy. The enhancement of Raman signal is achieved when a molecule is adsorbed onto or in close proximity to a metal surface and is dependent on the nature of metal surface, the excitation frequency used, the attachment of the molecule to the surface and also the nature of the molecule itself.-/- mice with a superior signal-to-noise ratio compared with immunofluorescence.We have previously shown that intercellular adhesion molecule 1 (ICAM-1)-targeted NPs could detect ICAM-1 expression on aortic sinus tissue sections derived from apoEThe use of metallic NPs offers potential therapeutic applications to atherosclerosis, specifically through photothermal therapy in addition to acting as enhancers of Raman scattering. The photothermal effect arises when the plasmonic resonance wavelength of the NP matches the excitation wavelength of the laser and light is absorbed and converted to heat. If NPs are attached to or internalised by cells, the energy produced can be dissipated to the surrounding biological medium causing thermal destruction of the cell. Gold nanorods and single-walled carbon nanotubes are internalised by carotid artery resident macrophages in vivo following carotid ligation in mice and subsequent exposure of excised ligated vessels to NIR excitation-induced photothermal apoptosis of the macrophage population.https://clinicaltrials.gov/ct2/show/NCT01270139). This multicentre trial involved 180 patients aged 45–65 years diagnosed as having coronary artery disease with flow-limiting lesions. The two treatment groups received either a surgical implanted ‘on-artery’ patch capable of transferring silica-gold NPs to the plaque (Nano group) or an intracoronary infusion of silica-gold iron-bearing NPs with CD68 targeted microbubbles and stem cells via a magnetic navigation system (Ferro group). A control group received a stent implantation void of any NP. Following ‘detonation’ of the NPs via intravascular or transcutaneous NIR laser excitation, no adverse events related to the procedure such as site-related thrombosis were recorded throughout the 1-year follow-up. Both treatments were associated with a reduction in total atheroma volume and the nano group displayed increased survival relative to control during follow-up.The first human trial using plasmonic phototherapy, as a technique for regressing atherosclerosis, was the Plasmonic Nanophotothermal Therapy of Atherosclerosis (NANOM-FIM: Despite risks associated with induced apoptosis in the atheroma, this approach highlights the range of options coupled with SERS/NP usage. Gold NPs are also amenable as carriers for drug delivery to the vessel wall owing to their low toxicity, versatile surface chemistry conjugation and efficient uptake by vascular endothelial cells.Looking forward, this review has summarised activities in the common molecular imaging approaches in atherosclerosis, focusing on Raman and SERS. Images showing typical findings with each modality are shown in


Ectopic cardiac fatty images are not rarely detected incidentally by computed tomography and cardiac magnetic resonance, or by exams focused on the heart as in general thoracic imaging evaluations. A correct interpretation of these findings is essential in order to recognize their normal or pathological meaning, focusing on the eventually associated clinical implications. The development of techniques such as computed tomography and cardiac magnetic resonance allowed a detailed detection and evaluation of adipose tissue within the heart. This pictorial review illustrates the most common characteristics of cardiac fatty images by computed tomography and cardiac magnetic resonance, in a spectrum of normal and pathological conditions ranging from physiological adipose images to diseases presenting with cardiac fatty foci. Physiologic intramyocardial adipose tissue may normally be present in healthy adults, being not related to cardiac affections and without any clinical consequence. However cardiac fatty images may also be the expression of various diseases, comprehending arrhythmogenic right ventricular dysplasia, postmyocardial infarction lipomatous metaplasia, dilated cardiomyopathy, and lipomatous hypertrophy of the interatrial septum. Fatty neoplasms of the heart as lipoma and liposarcoma are also described. Ectopic intracardiac fatty images are not uncommon findings in thoracic imaging in both healthy and diseased patients. Development of diagnostic techniques with high spatial and contrast resolution as computed tomography (CT) and cardiac magnetic resonance (CMR) enabled detailed fat visualization within the heart. An incidental frequency of cardiac adipose images in about 11% of the patients performing cardiovascular CT examinations has been estimated .Physiologic ectopic cardiac adipose tissue may normally be present in healthy adults not affected by any cardiac disease, without clinical consequences . In factArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by structural and functional abnormalities that may lead to arrhythmias and sudden cardiac death . PatholoPostmyocardial infarction lipomatous metaplasia (PILM) is a tissue transformation process that may take place within the scar region after a healed myocardial infarction (MI). The prevalence of PILM at histology in the LV reached values of 68–84% of excised heart transplanted for ischemic heart disease . In imagIdiopathic or “primary” dilated cardiomyopathy (DCM) is characterized by left or biventricular dilatation and impaired systolic function without significant coronary artery lesions, excluding other possible etiologic causes . PrimaryRegarding the differential diagnoses of this disease, left-dominant ARVC with fibrofatty replacement of the LV represents an affection hardly distinguishable from idiopathic DCM at CMR imaging: in this case a careful evaluation of the adipose tissue and of the LGE location is crucial, being both in ARVC predominantly represented in the subepicardium and not in the middle layer of the myocardium as in primary DCM.Besides the evidence of fatty intramyocardial tissue at imaging sparing the subendocardial layer and having no relationship with a coronary artery perfusion territory allows excluding a DCM secondary to a PILM.Finally fatty myocardial metaplasia phenomena in secondary DCM have also been described after an inflammatory process as chronic myocarditis  28]. In. In28]. Lipomatous hypertrophy of the interatrial septum (LHIAS) is an uncommon benign disorder with fatty accumulation into the interatrial septum that usually measures a transverse diameter > 2 cm in this condition . LHIAS iTuberous sclerosis complex (TSC) represents a genetic multisystemic disorder with cardiac tumor-like manifestations such as rhabdomyomas that regress during childhood and intramyocardial fat-containing lesions in adults [n adults . Fatty in adults . A previn adults . Althougn adults . A possin adults . Notwithn adults . Howevern adults .Muscular dystrophies (MD) are X-linked recessive diseases characterized by cardiac involvement with replacement of the myocardium by connective and adipose tissue [e tissue . Particue tissue . Typicale tissue .Hypertrophic cardiomyopathy (HCM) has also been described to be related to the presence of intramyocardial fatty foci, with adipose tissue placed within the thickened myocardial segments involved by this disease [ disease . The rea disease .Although the presence of ectopic adipose tissue within the myocardium is often detectable in CT and CMR images, the “cardiac steatosis” defined as cardiomyocytes accumulation of lipids is not easily appreciable with these imaging techniques. Cardiomyopathies secondary to lipid metabolism disorders may have a heterogeneous clinical expression, mimic dilated or hypertrophic cardiomyopathy, and led to progressive heart failure.Fabry disease is a rare X-linked genetic lysosomal storage disease, resulting from dysfunctional metabolism of sphingolipids [golipids .Intramyocardial triglyceride deposition is linked to various pathological hereditary and acquired conditions .Triglyceride deposit cardiomyovasculopathy is a genetic disorder with accumulation of triglyceride in cardiomyocytes and smooth muscle cells due to abnormal intracellular deposit of triglyceride and its substrates [bstrates , 44.Usually in these conditions myocardial signal is not altered in the conventional T1- and T2-weighed sequences, whereas T1 mapping technique has emerged as a sensitive and specific CMR biomarker of tissue lipid accumulation irrespective of ventricular morphology and function .Moreover a case has been reported where the excessive production of fatty acids in subjects with high alcohol consumption caused an alcohol-related cardiomyopathy associated with left ventricular fatty infiltration .LP represent the second most common benign cardiac tumor after myxomas, accounting for about 10% of primary cardiac neoplasms . They arPrimary cardiac liposarcomas (LS) are extremely rare neoplasms, mostly originating from the right chambers of the heart, particularly from the right atrium . CardiacCardiac metastases from a primary LS located in other anatomical districts have also been reported, although rare . In factTypical features in CT imaging of cardiac primary LS or its metastatic lesions consist of large unencapsulated hypoattenuating inhomogeneous masses, mostly rounded shaped with thick septa and mild contrast enhancement, infiltrating the surrounding cardiac structures and the pericardium . Notably