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Pediatric high-grade gliomas (pHGGs) are common malignant brain tumors without effective treatment and poor patient survival. Abnormal posttranslational modification at the histone H3 tail plays critical roles in tumor cell malignancy. We have previously shown that the trimethylation of lysine 4 at histone H3 (H3K4me3) plays a significant role in pediatric ependymoma malignancy and is associated with tumor therapeutic sensitivity. Here, we show that H3K4me3 and its methyltransferase WDR82 are elevated in pHGGs. A reduction in H3K4me3 by downregulating WDR82 decreases H3K4me3 promoter occupancy and the expression of genes associated with stem cell features, cell proliferation, the cell cycle, and DNA damage repair. A reduction in WDR82-mediated H3K4me3 increases the response of pediatric glioma cells to chemotherapy. These findings suggest that WDR82-mediated H3K4me3 is an important determinant of pediatric glioma malignancy and therapeutic response. This highlights the need for a more thorough understanding of the potential of WDR82 as an epigenetic target to increase therapeutic efficacy and improve the prognosis for children with malignant gliomas.

BACKGROUND Organophosphate compounds (OPC) are important cause of poisoning in developing countries. They are irreversible cholinesterase inhibitors and produce signs and symptoms pertaining to various organ systems via their muscarinic and nicotinic effects. The cardiac manifestations include hemodynamic instability and various arrhythmias. Here, in this study, we described various electrocardiographic (ECG) changes in patients of OPC poisoning in our population. METHODS This is a descriptive, cross-sectional study conducted at tertiary academic centre. All patients (>14 years and < 75 years) with history of OPC poisoning were included. Diagnosis was made on the basis of history and clinical features. ECG analysis of each patient was done for rate, rhythm, ST segment and T wave changes, PR and QTc interval, conduction defects and atrial and ventricular premature complexes before and after administration of atropine. RESULTS A total of 54 patients with OPC poisoning were included. The mean age was 28 ± 14.5 years. The predominant age group was < 30 years. There was female predominance with male : female ratio of 1 : 1.45. The most common ECG finding was sinus arrhythmia (tachycardia 25.9 % and bradycardia 20.4 %), followed by prolonged QTc (14.8 %), ST - T changes (11.1 %), premature ventricular complexes (PVCs) (7.4 %), prolonged PR interval (3.7 %) and atrial fibrillation (1.9 %). There was no mortality. The mean ICU and Hospital stay was three and six days respectively. CONCLUSIONS Sinus arrhythmia was the most common ECG changes followed by prolonged QTc, ST - T segment changes and PVCs in our setup. Careful observation of these ECG changes and timely intervention can prevent from sudden cardiac death in these patients. KEY WORDS Cardiac, Complications, Electrocardiogram, Organophosphates, Poisoning

Pediatric high-grade gliomas (pHGGs) are common malignant brain tumors without effective treatment and poor patient survival. Abnormal posttranslational modification at the histone H3 tail plays critical roles in tumor cell malignancy. We have previously shown that trimethylation of lysine 4 at histone H3 (H3K4me3) plays a significant role in pediatric ependymoma malignancy and is associated with tumor therapeutic sensitivity. Here, we show that H3K4me3 and its methyltransferase WDR82 are elevated in pHGGs. Reduction of H3K4me3 by downregulating WDR82 decreases H3K4me3 promoter occupancy and expression of genes associated with stem cell features, cell proliferation, the cell cycle and DNA damage repair. Reduction of WDR82 mediated H3K4me3 increases the response of pediatric glioma cells to chemotherapy. These findings suggest that WDR82 mediated H3K4me3 is an important determinant of pediatric glioma malignancy and therapeutic response. This highlights the need for a more thorough understanding of the potential of WDR82 as an epigenetic target to increase therapeutic efficacy and improve prognosis for children with malignant gliomas.

Episodes of rage and anger with violent outbursts are common manifestations of various psychiatric and behavioral disorders. Though rare, it can be a manifestation of fronto-temporal lobe epilepsy which is often misdiagnosed. Here we present a case of 20 years male having intermittent episodes of anger and violent outburst for three years who was later diagnosed as a case of fronto-temporal lobe epilepsy.

Pediatric high-grade glioma (pHGG) is among the most formidable cancers occurring in childhood. Bone morphogenetic protein 4 (BMP4) reduces the number of glioma stem-like cells and induces apoptosis. Treating tumors with exogenous BMP4 could prove effective in treating gliomas. However, a short half-life limits its clinical application. Glycosylated peptide amphiphile (GlycoPA), with a design inspired by heparin’s natural ability to bind growth factors including BMP4 through non-covalent interactions, was previously characterized and found to form high-aspect ratio supramolecular nanofibers that present growth-factor binding sulfated monosaccharides on their surface. These supramolecular nanofibers could carry excessive amounts of growth factor and markedly enhance their biological function. In this study, we verified that GlycoPA is able to bind BMP4 and dramatically increase its half-life with an ELISA assay. We also show that GlycoPA-BMP4, in comparison to free BMP4, significantly decreases pHGG cells’ proliferation in vitro. Initial in vivo intracranial distribution experimental results showed that GlycoPA has a superior normal brain distribution in comparison to a control PA (E2 PA) that has the same base structure as GlycoPA except with no glycosylated group. Preliminary results show that GlycoPA-BMP4 markedly decreases pediatric glioma tumor growth in comparison to free BMP4. Our combined in vitro and in vivo results demonstrate PA supramolecular nanofibers as an innovative and promising BMP4 delivery platform for clinical application in the treatment of brain tumors. Our future directions will investigate the therapeutic efficacy of GlycoPA-BMP4 in pediatric HGG through testing large numbers of animals and introducing first-line clinical chemotherapy drugs in combination and in various consequence.

Malignant gliomas are heterogeneous neoplasms. Glioma stem-like cells (GSCs) are undifferentiated and self-renewing cells that develop and maintain these tumors. These cells are the main population that resist current therapies. Genomic and epigenomic analyses has identified various molecular subtypes. Bone morphogenetic protein 4 (BMP4) reduces the number of GSCs through differentiation and induction of apoptosis, thus increasing therapeutic sensitivity. However, the short half-life of BMP4 impedes its clinical application. We have previously reviewed BMP4 signaling in central nervous system development and glioma tumorigenesis and its’ potential as a treatment target in human gliomas. Recent advances in understanding both adult and pediatric malignant gliomas highlight critical roles of BMP4 signaling pathways in the regulation of tumor biology, and indicate its’ potential as a therapeutic molecule. Furthermore, significant progress has been made on synthesizing BMP4 biocompatible delivery materials, which can bind to and markedly extend BMP4 half-life. Here, we review current research associated with BMP4 in brain tumors, especially in pediatric malignant gliomas. We also summarize BMP4 delivery strategies, with a focus on biocompatible BMP4 binding peptide amphiphile nanostructures as promising novel delivery platforms for treatment of these devastating tumors.

Posttranslational modifications (PTMs) on histone tails spatiotemporally dictate mammalian neural stem cell (NSC) fate. Bone morphogenetic protein 4 (BMP4), a member of the transforming growth factor β (TGF-β) superfamily, suppresses NSC proliferation and fosters differentiation into astroglial cells. Whether PTMs mediate these effects of BMP4 is unknown. Here we demonstrate that BMP4 signaling causes a net reduction in cellular histone H3 lysine 4 trimethylation (H3K4me3), an active histone mark at promoters of genes associated with human NSC proliferation. We also show that H3K4me3 reduction by BMP4 is mediated by decreased expression of SETD1A and WDR82, two methyltransferase components of SETD1A-COMPASS. Down-regulation of these components decreases expression of key genes expressed in hNSCs, while ectopic expression via transfection dedifferentiates human astrocytes (HAs). These observations suggest that BMP4 influences NSC fate by regulating PTMs and altering chromatin structure.SIGNIFICANCE STATEMENTBMP4 is critical in determining hNSC fate. Whether histone posttranslational modifications (PTM) mediate the effects of BMP4 is unknown. Here we report that H3K4me3, brought about by its methyltransferases SETD1A and WDR82, at promoters of stem cell genes OCT4 and NESTIN is involved in human neural stem cell (hNSC) maintenance. BMP4 promotes hNSC astroglial differentiation in part through reduction of SETD1A and WDR82 and thus decreased frequency of H3K4me3 at the promoters of these genes. These results provide evidence that BMP4 promotes hNSC differentiation through a potential epigenetic mechanism and extend our understanding of the role of histone PTM in central nervous system development.

Deep neural networks (DNNs) have been recently found popular for image captioning problems in remote sensing (RS). Existing DNN based approaches rely on the availability of a training set made up of a high number of RS images with their captions. However, captions of training images may contain redundant information (they can be repetitive or semantically similar to each other), resulting in information deficiency while learning a mapping from the image domain to the language domain. To overcome this limitation, in this paper, we present a novel Summarization Driven Remote Sensing Image Captioning (SD-RSIC) approach. The proposed approach consists of three main steps. The first step obtains the standard image captions by jointly exploiting convolutional neural networks (CNNs) with long short-term memory (LSTM) networks. The second step, unlike the existing RS image captioning methods, summarizes the ground-truth captions of each training image into a single caption by exploiting sequence to sequence neural networks and eliminates the redundancy present in the training set. The third step automatically defines the adaptive weights associated to each RS image to combine the standard captions with the summarized captions based on the semantic content of the image. This is achieved by a novel adaptive weighting strategy defined in the context of LSTM networks. Experimental results obtained on the RSCID, UCM-Captions and Sydney-Captions datasets show the effectiveness of the proposed approach compared to the state-of-the-art RS image captioning approaches. The code of the proposed approach is publicly available at https://gitlab.tubit.tu-berlin.de/rsim/SD-RSIC., Comment: Accepted in the IEEE Transactions on Geoscience and Remote Sensing. For code visit: https://gitlab.tubit.tu-berlin.de/rsim/SD-RSIC

Glioma stem cells (GSCs), with neural stem cell (NSC) like properties are key factors behind therapeutic resistance in pediatric high-grade gliomas (HGG), the second most formidable childhood cancers. Targeting GSCs is a promising pathway for enhancing therapeutic effect and improving patient outcomes. Histone post-translational modifications (PTMs) regulate gene expression patterns dictate stem cell fate and regulate drug resistance. Tri-methylation on histone 3 lysine 4 (H3K4me3) has been associated with human NSCs and GSCs, with its reduction results in cell differentiation and increases chemotherapeutic efficacy in pediatric HGGs. Human SETD1A facilitates H3K4me3 on active gene promoters. Levels of SETD1A and H3K4me3 are high in NSCs and malignant gliomas, highlighting potentially novel treatment targets. BMP4 increases cell sensitivity to cytotoxic therapies. However, BMP4 effects on H3K4me3 in human NSCs and pediatric HGGs are unknown. In this study, cellular phenotype, levels of H3K4me3 and SETD1A following BMP4 treatment in human NSC and pediatric HGGs are investigated. The results indicate BMP4 promotes differentiation and decreases H3K4me3 and SETD1A levels, as well as H3K4me3 occupancy on stemness and drug resistant genes’ promoters decreased in NSC and pediatric HGGs, respectively. BMP4 also increases chemosensitivity in pediatric HGGs. The results demonstrate that BMP4 differentiates human NSCs and increases chemotherapy sensitivity through regulation of SETD1A by altering H3K4me3 levels at key stemness and drug resistance genes’ promoter. Subsequently, targeting SETD1A concomitantly with conventional chemotherapy may provide novel therapeutic strategies to improve prognosis for children with HGGs.

Pediatric gliomas, particularly high-grade gliomas, which include diffuse intrinsic pontine gliomas (DIPGs), are among the most formidable and devastating cancers in children. These tumors remain incurable, despite many treatment approaches. We recently identified a small population of glioma cells with stem-like features in pediatric gliomas (glioma stem cells: GSCs), that may be responsible, for therapeutic resistance. Bone morphogenetic protein 4 (BMP4), essential for CNS development, increases GSC therapeutic sensitivity and is a promising adjuvant for glioma treatment. Mechanisms through which BMP4 increases therapeutic sensitivity need to be elucidated, as this can lead to identification of additional treatment targets and delivery systems for BMP4 administration in a clinical setting. Additionally, extension of BMP4 short half-life would enhance its’ clinical application. Here we show that BMP4 increases chemosensitivity by decreasing H3K4me3 at the promoter of multidrug resistant gene 1 (MDR1), resulting in decreased MDR1 expression. BMP4 appears to bring about this effect by decreasing hSETD1A, an H3K4me3 methyltransferase. Our work also demonstrates the first use of a novel sulfated glycopeptide (glyco-PA) nanostructure as a vector for BMP4 delivery. Glyco-PA markedly extended and enhanced BMP4 function, and increased chemotherapeutic anti-tumor activity against pediatric malignant glioma cells in culture. Overall, this work illuminates BMP4 effects on pediatric glioma therapeutic sensitivity through epigenetic mechanisms, and demonstrates the potential of bioactive glyco-PA nanostructures as a delivery mechanism for treating pediatric malignant gliomas and other tumors.

Pediatric gliomas, particularly high-grade gliomas, are among the most formidable and devastating cancers in children. These tumors have remained incurable, regardless of the many treatment approaches attempted. We recently identified a small population of glioma cells with stem-like features in pediatric gliomas (glioma stem cells: GSCs), that may be responsible, for therapeutic resistance in pediatric gliomas. Signaling by bone morphogenetic protein 4 (BMP4), an essential molecule for central nervous system (CNS) development, increases GSC therapeutic sensitivity, and whose activation is a promising adjuvant for glioma treatment. Mechanisms through which BMP4 increases therapeutic sensitivity need to be elucidated as this can lead to the identification of additional targets for treating malignant gliomas in children. Delivery systems for administering BMP4 in a clinical setting also need to be developed. Here, we show that BMP4 increases chemosensitivity by decreasing H3 lysine 4 trimethylation (H3K4me3) at the promoter of multidrug resistant gene 1 (MDR1) that, in turn, results in increased BMP4 expression. This appears to be the result of BMP4 decreasing levels of hSETD1A, a critical methyltransferase for H3K4me3. Our work also demonstrates the first use of a novel sulfated glycopeptide (glycol-PA) nanostructure as a vector for delivery of BMP4. Glycol-PA markedly extended and enhanced BMP4 function, and increased chemotherapeutic anti-tumor activity against pediatric malignant glioma cells in culture. Overall, our results expand understanding of how BMP4 brings about glioma therapeutic sensitization through epigenetic mechanisms, and show that highly bioactive glyco-PA nanostructures have potential as a novel delivery mechanism for treating pediatric malignant glioma, as well as other tumors. Citation Format: Guifa Xi, Benjamin Best, Sonali Nayak, Mark McClendon, Barbara Mania-Farnell, John Kessler, Charles David James, Samuel Stupp, Tadanori Tomita. Sulfated glycopeptide nanostructures activate and extend bone morphogenetic protein 4 ability to increase pediatric malignant glioma chemotherapeutic efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3175.

Exendin-4, originally isolated from saliva of the lizard Heloderma suspectum, shares 53% sequence homology and several potentially antidiabetic actions with the mammalian hormone glucagon-like peptide-1(7-36)amide (GLP-1). It shows a higher potency and longer duration of effect in vivo, which may be partly attributed to pharmacokinetic properties. The present study compares the pharmacokinetics of GLP-1 and exendin-4 in rats after intravenous (iv), subcutaneous (sc), or intraperitoneal (ip) administration. Samples were assayed for active GLP-1 (7-36) amide using an enzyme-linked immunosorbent assay that does not detect GLP-1 (1-36-amide), (1-37), (9-36-amide) or (9-37). In parallel experiments, samples were assayed for exendin-4 using a two-site immunoradiometric assay that reacts specifically with full-length exendin-4. The estimated half-life for GLP-1 and exendin-4 were 0.8–4.7 min and 18–41 min for iv bolus, and 4.6–7.1 min and 90–216 min for SC administration, respectively. Half-lives after ip injection were 0.6–13.5 min for GLP-1 and 125–174 min for exendin-4. Bioavailability for GLP-1 and exendin-4 was 44–71% and 65–75%, respectively, for sc injection. For ip injection, bioavailability for GLP-1 and exendin-4 was 36–67% and 74–76%, respectively. Plasma clearance, as determined from iv infusion data, was 35–38 ml/min for GLP-1 and 4-8 ml/min for exendin-4. Both Co/Cmax and AUC values were proportional to dose with each route of administration. Plasma clearance of exendin-4 was reduced by 4.4-fold in nephrectomized animals. In conclusion, exendin-4 exhibited a much longer plasma half-life than GLP-1 in rats after iv, sc, or ip injection, which may contribute in some part to reported differences in duration of biological action of the two peptides. Drug Dev. Res. 53:260–267, 2001. © 2001 Wiley-Liss, Inc.

By applying a newly developed ELISA technique for determining biologically active intact glucagon-like peptide [GLP-1, GLP-1-(7–36)amide] in mouse, plasma baseline GLP-1 in normal NMRI mice was found to be normally distributed (4.5 ± 0.3 pmol/l; n = 72). In anesthetized mice, gastric glucose (50 or 150 mg) increased plasma GLP-1 levels two- to threefold ( P < 0.01). The simultaneous increase in plasma insulin correlated to the 10-min GLP-1 levels ( r = 0.36, P < 0.001; n = 12). C57BL/6J mice deleted of the gastrin-releasing peptide (GRP) receptor by genetic targeting had impaired glucose tolerance ( P = 0.030) and reduced early (10 min) insulin response ( P = 0.044) to gastric glucose compared with wild-type controls. Also, the GLP-1 response to gastric glucose was significantly lower in the GRP receptor-deleted mice than in the controls ( P = 0.045). In conclusion, this study has shown that 1) plasma levels of intact GLP-1 increase dose dependently on gastric glucose challenge in correlation with increased insulin levels in mice, and 2) intact GRP receptors are required for normal GLP-1 and insulin responses and glucose tolerance after gastric glucose in mice.

The role of host immunity in the development of virus-induced cancers has been difficult to elucidate, in part because of our inability to effectively measure multiple immune parameters using available amounts of biological material. The objective of the present study was to validate the use of a newly developed multiplex assay, the LINCOplex assay, for the simultaneous measurement of multiple cytokines [interleukin/(IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, and tumor necrosis factor-alpha]. Supernatants obtained from peripheral blood mononuclear cell cultures stimulated with various different mitogens and antigens (including phytohemagglutinin, influenza, tetanus, HPV16 E6 and E7 peptides, and media alone) were selected for study. In total, 750 specimens obtained from 26 participants were tested in replicate using the 8-plex LINCOplex assay (25 micro l of specimen required per well). Every specimen was included in duplicate in a blinded fashion. For some specimens, multiple 2-fold dilutions of the same specimen were included to evaluate the linearity of results. The availability of independently obtained IL-2 and IFN-gamma results from standard single cytokine (simplex) assays allowed for a direct comparison between the LINCOplex results and those obtained from the simplex assays. Spearman correlation coefficients for continuous results, and exact agreement rates and weighted kappa statistics for quartiled variables, were computed to evaluate intra- and interassay agreement. IL-4 levels were consistently below the detectable level of the assay (3 pg/ml) whereas IL-6 and IL-8 levels were consistently above the highest detectable level of the assay (10,000 pg/ml), and these three cytokines were, therefore, not evaluated further. For the remaining five cytokines, excellent intra-assay reproducibility was observed, with Spearman correlation coefficients consistently above 0.90 for all five cytokines. Exact agreement rates ranging from 77.6-90.3% and weighted kappas ranging from 0.81-0.92 were observed. Similar results were observed when analysis was restricted to supernatants obtained from cultures that had been stimulated with HPV16 peptides and when analysis was restricted to supernatants obtained from cultures containing no antigen or mitogen, suggesting that the LINCOplex assay is applicable under conditions where moderate or weak cytokine responses/levels are expected. Linearity of results was observed when dilutions of a single specimen were blindly tested, with the exception of IL-2 and IL-10, where deviations from linearity were sometimes observed. For IL-2 and IFN-gamma, where results from simplex assays were available for comparison, the LINCOplex assay and the simplex assay results agreed well. Spearman correlation coefficients were 0.86 and 0.93 for IL-2 and IFN-gamma, respectively. Exact agreement and weighted kappa values were 68.5% and 0.72 (95% confidence interval, 0.65-0.79), respectively, for IL-2 and 67.3% and 0.73 (95% confidence interval, 0.67-0.80), respectively, for IFN-gamma. These results indicate the applicability of the LINCOplex assay for the simultaneous measurement of multiple cytokines using small amounts of biological material.

A set of benzophenone derivatives was evaluated for the antimalarial activity against Plasmodium berghei in mice and the mean survival time of mice for all the compounds was determined. The QSAR analysis was carried out for the fourteen benzophenone derivatives using different physicochemical descriptors. The multiple linear regression analysis was used to correlate the physicochemical descriptors with the antimalarial activity of the benzophenone derivatives from the training set and the best QSAR model was developed, which was further used to predict the antimalarial activity of other compounds from the class of benzophenones. To confirm the predictivity of the best QSAR model, a new set (test set) of six compounds was designed, synthesized and evaluated for the antimalarial activity. A good correlation between the experimental and predicted antimalarial activities was obtained for the test set compounds in the validation procedure, indicating the high predictivity of the developed QSAR model. Five benzophenone derivatives, which showed good antimalarial activity, were further studied for their drug-likeliness characteristic and per cent oral absorption using software “QikProp”. It was observed that all the five benzophenone derivatives were found to be good drug candidates and showed good oral absorption.