פרסומים

Profiling immunoglobulin (Ig) receptor repertoires with specialized assays can be cost-ineffective and time-consuming. Here we report ImReP, a computational method for rapid and accurate profiling of the Ig repertoire, including the complementary-determining region 3 (CDR3), using regular RNA sequencing data such as those from 8,555 samples across 53 tissues types from 544 individuals in the Genotype-Tissue Expression (GTEx v6) project. Using ImReP and GTEx v6 data, we generate a collection of 3.6 million Ig sequences, termed the atlas of immunoglobulin repertoires (TAIR), across a broad range of tissue types that often do not have reported Ig repertoires information. Moreover, the flow of Ig clonotypes and inter-tissue repertoire similarities across immune-related tissues are also evaluated. In summary, TAIR is one of the largest collections of CDR3 sequences and tissue types, and should serve as an important resource for studying immunological diseases.

Profiling immunoglobulin (Ig) receptor repertoires with specialized assays can be cost-ineffective and time-consuming. Here we report ImReP, a computational method for rapid and accurate profiling of the Ig repertoire, including the complementary-determining region 3 (CDR3), using regular RNA sequencing data such as those from 8,555 samples across 53 tissues types from 544 individuals in the Genotype-Tissue Expression (GTEx v6) project. Using ImReP and GTEx v6 data, we generate a collection of 3.6 million Ig sequences, termed the atlas of immunoglobulin repertoires (TAIR), across a broad range of tissue types that often do not have reported Ig repertoires information. Moreover, the flow of Ig clonotypes and inter-tissue repertoire similarities across immune-related tissues are also evaluated. In summary, TAIR is one of the largest collections of CDR3 sequences and tissue types, and should serve as an important resource for studying immunological diseases.

Progesterone plays a pivotal role during mammogenesis and serves as an inhibitor of the secretory activation of mammary cells in the last days of gestation. However, its role during lactogenesis, in particular its involvement in lipid metabolism, and milk fat content and composition, is unknown. Here, we provide new evidence of progesterone's involvement in the regulation of milk fat globule (MFG) synthesis and secretion. Findings from bothin vivoandin vitrostudies indicated that the concentration and the direction (increase vs. decrease) of progesterone concentration to which the mammary epithelial cells (MECs) are exposed affect MFG size. This was found to be very-low-density lipoprotein (VLDL) dependent: in the presence of VLDL, the proportion of MEC with small lipid droplets (<1 mu m) increased 2.4-fold, and the proportion of large lipid droplets (>1 mu m) increased 4-fold; in the absence of VLDL, no differences were found. The findings add to our understanding of the mechanism underlying the regulation of MFG size and provide new evidence for progesterone's role in lipid metabolism in the mammary gland during lactogenesis. The fact that the size, synthesis, and composition of MFG are affected by the cyclic pattern of progesterone concentration in the circulation might have physiologically relevant consequences, in particular on milk as a nutritional source.

Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID-19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27-30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2-deoxy-D-glucose, GAO-3-02, JNJ-40411813, NBI-921352, NTX-001, sec-butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with novel mechanisms of action, transplantation of interneurons into epileptogenic brain regions, and the targeting of rare, previously neglected syndromes.

The Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference from July 27 to July 30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 delegates from 63 countries attended lectures and interactive discussions, representing a broad range of disciplines from basic science, clinical research, and clinical care. This progress report provides summaries of recent findings on investigational compounds for which preclinical data as well as data from patient studies were presented. The report includes the following five compounds: anakinra, cenobamate, CVL-865, fenfluramine, and ganaxolone, all with novel modes of action compared to more established antiepileptic drugs. Some of these compounds demonstrated promising results in placebo-controlled phase 3 trials, and two have recently received approval from the US Food and Drug Administration (FDA). These include cenobamate, which was approved by the FDA on November 21, 2019 for the treatment of partial onset (focal) seizures in adults, and fenfluramine oral solution, which was approved by the FDA on June 25, 2020 for the treatment of seizures associated with Dravet syndrome in patients 2 years and older.

The Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference from July 27 to July 30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 delegates from 63 countries attended lectures and interactive discussions, representing a broad range of disciplines from basic science, clinical research, and clinical care. This progress report provides summaries of recent findings on investigational compounds for which preclinical data as well as data from patient studies were presented. The report includes the following five compounds: anakinra, cenobamate, CVL-865, fenfluramine, and ganaxolone, all with novel modes of action compared to more established antiepileptic drugs. Some of these compounds demonstrated promising results in placebo-controlled phase 3 trials, and two have recently received approval from the US Food and Drug Administration (FDA). These include cenobamate, which was approved by the FDA on November 21, 2019 for the treatment of partial onset (focal) seizures in adults, and fenfluramine oral solution, which was approved by the FDA on June 25, 2020 for the treatment of seizures associated with Dravet syndrome in patients 2 years and older.

Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID-19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27-30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2-deoxy-D-glucose, GAO-3-02, JNJ-40411813, NBI-921352, NTX-001, sec-butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with novel mechanisms of action, transplantation of interneurons into epileptogenic brain regions, and the targeting of rare, previously neglected syndromes.

This chapter investigates the relationship between prolonged exposure to political violence (EPV) and post-traumatic stress symptoms (PTSS) among Palestinian adolescents. It also examines the moderating effect of participants’ age, gender, and parental socialization styles on the relationship between EPV and PTSS. A systematic cluster random sample of 2, 934 Palestinian adolescents aged 14 to 19 years living in the West Bank and East Jerusalem responded to self-administered questionnaires. Multiple regression analysis showed a positive relationship between levels of EPV and of PTSS. Girls showed higher levels of PTSS than boys. Hostile and rejecting parenting styles, strict discipline, and negative evaluation from parents correlated positively with high PTSS, whereas intimate and loving parenting correlated with low levels of PTSS, supporting the hypotheses presented here. The chapter discusses the importance of intimate and loving parenting styles as a possible protective factor for mitigating the effects of political violence on children.

Delivery of drugs through oral mucosa enables bypass of the gastrointestinal tract and “first pass“ metabolism in the liver and the gut. Thus, a higher and less variable bioavailability can be obtained. Mechanisms of this administration route for cannabidiol were investigated in the current research in pigs. Results show that cannabidiol has substantially low permeability rate over 8 h through oral mucosa and accumulates significantly within it. Furthermore, following the removal of the delivery device, residual prolongation of release from the oral mucosa into systemic blood circulation continues for several hours. This method of delivery enabled acquisition of clinically relevant plasma levels of cannabidiol. The absorption profile indicates that cannabidiol, as well as other lipophilic molecules, should be delivered through oral mucosa for systemic absorption from a device that conceals the drug and prevents its washout by the saliva flow and subsequent ingestion into gastrointestinal tract. © 2020 Elsevier B.V.

Delivery of drugs through oral mucosa enables bypass of the gastrointestinal tract and "first pass" metabolism in the liver and the gut. Thus, a higher and less variable bioavailability can be obtained. Mechanisms of this administration route for cannabidiol were investigated in the current research in pigs. Results show that cannabidiol has substantially low permeability rate over 8 h through oral mucosa and accumulates significantly within it. Furthermore, following the removal of the delivery device, residual prolongation of release from the oral mucosa into systemic blood circulation continues for several hours. This method of delivery enabled acquisition of clinically relevant plasma levels of cannabidiol. The absorption profile indicates that cannabidiol, as well as other lipophilic molecules, should be delivered through oral mucosa for systemic absorption from a device that conceals the drug and prevents its washout by the saliva flow and subsequent ingestion into gastrointestinal tract.

Delivery of drugs through oral mucosa enables bypass of the gastrointestinal tract and "first pass" metabolism in the liver and the gut. Thus, a higher and less variable bioavailability can be obtained. Mechanisms of this administration route for cannabidiol were investigated in the current research in pigs. Results show that cannabidiol has substantially low permeability rate over 8 h through oral mucosa and accumulates significantly within it. Furthermore, following the removal of the delivery device, residual prolongation of release from the oral mucosa into systemic blood circulation continues for several hours. This method of delivery enabled acquisition of clinically relevant plasma levels of cannabidiol. The absorption profile indicates that cannabidiol, as well as other lipophilic molecules, should be delivered through oral mucosa for systemic absorption from a device that conceals the drug and prevents its washout by the saliva flow and subsequent ingestion into gastrointestinal tract.

Delivery of drugs through oral mucosa enables bypass of the gastrointestinal tract and "first pass" metabolism in the liver and the gut. Thus, a higher and less variable bioavailability can be obtained. Mechanisms of this administration route for cannabidiol were investigated in the current research in pigs. Results show that cannabidiol has substantially low permeability rate over 8 h through oral mucosa and accumulates significantly within it. Furthermore, following the removal of the delivery device, residual prolongation of release from the oral mucosa into systemic blood circulation continues for several hours. This method of delivery enabled acquisition of clinically relevant plasma levels of cannabidiol. The absorption profile indicates that cannabidiol, as well as other lipophilic molecules, should be delivered through oral mucosa for systemic absorption from a device that conceals the drug and prevents its washout by the saliva flow and subsequent ingestion into gastrointestinal tract.

Both pancreatic intraepithelial neoplasia (PanIN), a frequent precursor of pancreatic cancer, and intraductal papillary mucinous neoplasm (IPMN), a less common precursor, undergo several phases of molecular conversions and finally develop into highly malignant solid tumors with negative effects on the quality of life. We approached this long-standing issue by examining the following PanIN/IPMN cell lines derived from mouse models of pancreatic cancer: Ptf1a-Cre; KrasG12D; p53f/+ and Ptf1a-Cre; KrasG12D; and Brg1f/f pancreatic ductal adenocarcinomas (PDAs). The mRNA from these cells was subjected to a cap analysis of gene expression (CAGE) to map the transcription starting sites and quantify the expression of promoters across the genome. Two RNA samples extracted from three individual subcutaneous tumors generated by the transplantation of PanIN or IPMN cancer cell lines were used to generate libraries and Illumina Seq, with four RNA samples in total, to depict discrete transcriptional network between IPMN and PanIN. Moreover, in IPMN cells, the transcriptome tended to be enriched for suppressive and inhibitory biological processes. In contrast, the transcriptome of PanIN cells exhibited properties of stemness. Notably, the proliferation capacity of the latter cells in culture was only minimally constrained by well-known chemotherapy drugs such as GSK690693 and gemcitabine. The various transcriptional factor network systems detected in PanIN and IPMN cells reflect the distinct molecular profiles of these cell types. Further, we hope that these findings will enhance our mechanistic understanding of the characteristic molecular alterations underlying pancreatic cancer precursors. These data may provide a promising direction for therapeutic research.