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•Only 18 out of 44 medulloblastoma cell-lines have been subtyped.•11/18 are Group 3 and all Group 3 cell-lines have MYC-amplification.•The most cited cell line is DAOY, followed by ...D283, UW228, D341, D425 and D458.•In vitro models of the future: 3D, with the right ECM and including the normal brain.•To progress we need an online database for in vitro tools with a linked cell bank.
The recently-defined four molecular subgroups of medulloblastoma have required updating of our understanding of in vitro models to include molecular classification and risk stratification features from clinical practice. This review seeks to build a more comprehensive picture of the in vitro systems available for modelling medulloblastoma.
The subtype classification and molecular characterisation for over 40 medulloblastoma cell-lines has been compiled, making it possible to identify the strengths and weaknesses in current model systems. Less than half (18/44) of established medulloblastoma cell-lines have been subgrouped. The majority of the subgrouped cell-lines (11/18) are Group 3 with MYC-amplification. SHH cell-lines are the next most common (4/18), half of which exhibit TP53 mutation. WNT and Group 4 subgroups, accounting for 50% of patients, remain underrepresented with 1 and 2 cell-lines respectively.
In vitro modelling relies not only on incorporating appropriate tumour cells, but also on using systems with the relevant tissue architecture and phenotype as well as normal tissues. Novel ways of improving the clinical relevance of in vitro models are reviewed, focusing on 3D cell culture, extracellular matrix, co-cultures with normal cells and organotypic slices. This paper champions the establishment of a collaborative online-database and linked cell-bank to catalyse preclinical medulloblastoma research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The TFCP2/Grainyhead family of transcription factors is divided into two distinct subfamilies, one of which includes the Grainyhead-like 1-3 (GRHL1-3) proteins and the other consists of TFCP2 ...(synonyms: CP2, LSF, LBP-1c), TFCP2L1 (synonyms: CRTR-1, LBP-9) and UBP1 (synonyms: LBP-1a, NF2d9). Transcription factors from the TFCP2/TFCP2L1/UBP1 subfamily are involved in various aspects of cancer development. TFCP2 is a pro-oncogenic factor in hepatocellular carcinoma, pancreatic cancer and breast cancer, may be important in cervical carcinogenesis and in colorectal cancer. TFCP2 can also act as a tumor suppressor, for example, it inhibits melanoma growth. Furthermore, TFCP2 is involved in epithelial-mesenchymal transition and enhances angiogenesis. TFCP2L1 maintains pluripotency and self-renewal of embryonic stem cells and was implicated in a wide variety of cancers, including clear cell renal cell carcinoma, breast cancer and thyroid cancer. Here we present a systematic review of current knowledge of this protein subfamily in the context of cancer. We also discuss potential challenges in investigating this family of transcription factors. These challenges include redundancies between these factors as well as their interactions with each other and their ability to modulate each other's activity.
•TFCP2 acts as a pro-oncogenic factor in several different cancers.•It is involved in cell stemness, epithelial-mesenchymal transition and angiogenesis.•Small molecule inhibitors of TFCP2 may potentially serve as anti-cancer medicines.•TFCP2L1 is also relevant to carcinogenesis.•There are redundancies and interactions between the TFCP2, TFCP2L1 and UBP1 factors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Selecting appropriate stimuli to induce emotional states is essential in affective research. Only a few standardized affective stimulus databases have been created for auditory, language, and visual ...materials. Numerous studies have extensively employed these databases using both behavioral and neuroimaging methods. However, some limitations of the existing databases have recently been reported, including limited numbers of stimuli in specific categories or poor picture quality of the visual stimuli. In the present article, we introduce the Nencki Affective Picture System (NAPS), which consists of 1,356 realistic, high-quality photographs that are divided into five categories (people, faces, animals, objects, and landscapes). Affective ratings were collected from 204 mostly European participants. The pictures were rated according to the valence, arousal, and approach–avoidance dimensions using computerized bipolar semantic slider scales. Normative ratings for the categories are presented for each dimension. Validation of the ratings was obtained by comparing them to ratings generated using the Self-Assessment Manikin and the International Affective Picture System. In addition, the physical properties of the photographs are reported, including luminance, contrast, and entropy. The new database, with accompanying ratings and image parameters, allows researchers to select a variety of visual stimulus materials specific to their experimental questions of interest. The NAPS system is freely accessible to the scientific community for noncommercial use by request at
http://naps.nencki.gov.pl
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We describe and share a device, methodology and image analysis algorithms, which allow up to 66 spheroids to be arranged into a gel-based array directly from a culture plate for downstream processing ...and analysis. Compared to processing individual samples, the technique uses 11-fold less reagents, saves time and enables automated imaging. To illustrate the power of the technology, we showcase applications of the methodology for investigating 3D spheroid morphology and marker expression and for in vitro safety and efficacy screens. First, spheroid arrays of 11 cell-lines were rapidly assessed for differences in spheroid morphology. Second, highly-positive (SOX-2), moderately-positive (Ki-67) and weakly-positive (βIII-tubulin) protein targets were detected and quantified. Third, the arrays enabled screening of ten media compositions for inducing differentiation in human neurospheres. Last, the application of spheroid microarrays for spheroid-based drug screens was demonstrated by quantifying the dose-dependent drop in proliferation and increase in differentiation in etoposide-treated neurospheres.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Diabetes mellitus (DM) is the most common metabolic disease in humans, and its prevalence is increasing worldwide in parallel with the obesity pandemic. A lack of insulin or insulin resistance, and ...consequently hyperglycemia, leads to many systemic disorders, among which diabetic encephalopathy (DE) is a long-term complication of the central nervous system (CNS), characterized by cognitive impairment and motor dysfunctions. The role of oxidative stress and neuroinflammation in the pathomechanism of DE has been proven. Fractalkine (CX3CL1) has unique properties as an adhesion molecule and chemoattractant, and by acting on its only receptor, CX3CR1, it regulates the activity of microglia in physiological states and neuroinflammation. Depending on the clinical context, CX3CL1-CX3CR1 signaling may have neuroprotective effects by inhibiting the inflammatory process in microglia or, conversely, maintaining/intensifying inflammation and neurotoxicity. This review discusses the evidence supporting that the CX3CL1-CX3CR1 pair is neuroprotective and other evidence that it is neurotoxic. Therefore, interrupting the vicious cycle within neuron–microglia interactions by promoting neuroprotective effects or inhibiting the neurotoxic effects of the CX3CL1-CX3CR1 signaling axis may be a therapeutic goal in DE by limiting the inflammatory response. However, the optimal approach to prevent DE is simply tight glycemic control, because the elimination of dysglycemic states in the CNS abolishes the fundamental mechanisms that induce this vicious cycle.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Treatment of prostate cancer (PC) is a rapidly evolving field of pharmacology research. In recent years, numerous novel therapeutics that improve survival and ameliorate disease control have been ...approved. Currently, the systemic treatment for prostate neoplasm consists of hormonal therapy, chemotherapy, immunotherapy, radiopharmaceuticals, targeted therapy, and supportive agents (e.g., related to bone health). Unfortunately, many of them carry a risk of cardiovascular complications, which occasionally pose a higher mortality threat than cancer itself. This article provides a unique and comprehensive overview of the prevalence and possible mechanisms of cardiovascular toxicities of all PC therapies, including state-of-the-art antineoplastic agents. Additionally, this article summarizes available recommendations regarding screening and prevention of the most common cardiac complications among patients with advanced cancer disease.
Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. ...Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood-brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.
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Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including ...Mycobacterium tuberculosis. The toxin, MbcT, is bactericidal unless neutralized by its antitoxin MbcA. To investigate the mechanism, we solved the 1.8 Å-resolution crystal structure of the MbcTA complex. We found that MbcT resembles secreted NAD+-dependent bacterial exotoxins, such as diphtheria toxin. Indeed, MbcT catalyzes NAD+ degradation in vitro and in vivo. Unexpectedly, the reaction is stimulated by inorganic phosphate, and our data reveal that MbcT is a NAD+ phosphorylase. In the absence of MbcA, MbcT triggers rapid M. tuberculosis cell death, which reduces mycobacterial survival in macrophages and prolongs the survival of infected mice. Our study expands the molecular activities employed by bacterial TA modules and uncovers a new class of enzymes that could be exploited to treat tuberculosis and other infectious diseases.
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•MbcTA is a RES-Xre toxin-antitoxin system in M. tuberculosis (Mtb)•MbcT is a NAD+ phosphorylase•MbcT-catalyzed NAD+ depletion leads to Mtb cell death•MbcT activity synergizes with antibiotics to reduce Mtb burden in infected mice
Toxin-antitoxin systems regulate bacterial growth in response to stress through modification of macromolecules, including proteins, RNA, and DNA. Freire et al. show that MbcT, a toxin produced by the tubercle bacillus, induces bacterial cell death through NAD+ phosphorolysis, an unprecedented enzymatic activity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Regions of low oxygen (hypoxia) are found in >50% of breast tumours, most frequently in the more aggressive triple negative breast cancer subtype (TNBC). Metastasis is the cause of 90% of breast ...cancer patient deaths. Regions of tumour hypoxia tend to be more acidic and both hypoxia and acidosis increase tumour metastasis. In line with this the metastatic process is dependent on pH regulatory mechanisms. We and others have previously identified increased hypoxic expression of Na+ driven bicarbonate transporters (NDBTs) as a major mechanism of tumour pH regulation. Hypoxia induced the expression of NDBTs in TNBC, most frequently SLC4A4 and SLC4A5. NDBT inhibition (S0859) and shRNA knockdown suppressed migration (40% reduction) and invasion (70% reduction) in vitro. Tumour xenograft metastasis in vivo was significantly reduced by NDBT knockdown. To investigate the mechanism by which NDBTs support metastasis, we investigated their role in regulation of phospho-signalling, epithelial-to-mesenchymal transition (EMT) and metabolism. NDBT knockdown resulted in an attenuation in hypoxic phospho-signalling activation; most notably LYN (Y397) reduced by 75%, and LCK (Y394) by 72%. The metastatic process is associated with EMT. We showed that NDBT knockdown inhibited EMT, modulating the expression of key EMT transcription factors and ablating the expression of vimentin whilst increasing the expression of E-cadherin. NDBT knockdown also altered metabolic activity reducing overall ATP and extracellular lactate levels. These results demonstrate that targeting hypoxia-induced NDBT can be used as an approach to modulate phospho-signalling, EMT, and metabolic activity and reduce tumour migration, invasion, and metastasis in vivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recent studies suggest that depression and anxiety are associated with unique aspects of EEG responses to reward and punishment, respectively; also, abnormal responses to punishment in depressed ...individuals are related to anxiety, the symptoms of which are comorbid with depression. In a non-clinical sample, we aimed to investigate the relationships between reward processing and anxiety, between punishment processing and anxiety, between reward processing and depression, and between punishment processing and depression. Towards this aim, we separated feedback-related brain activity into delta and theta bands to isolate activity that indexes functionally distinct processes. Based on the delta/theta frequency and feedback valence, we then used machine learning (ML) to classify individuals with high severity of depressive symptoms and individuals with high severity of anxiety symptoms versus controls. The significant difference between the depression and control groups was driven mainly by delta activity; there were no differences between reward- and punishment-theta activities. The high severity of anxiety symptoms was marginally more strongly associated with the punishment- than the reward-theta feedback processing. The findings provide new insights into the differences in the impacts of anxiety and depression on reward and punishment processing; our study shows the utility of ML in testing brain-behavior hypotheses and emphasizes the joint effect of theta-RewP/FRN and delta frequency on feedback-related brain activity.
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