Arming AAV9 with a Single-Chain Fragment Variable Antibody Against PD-1 for Systemic Glioblastoma Therapy.

Glioblastoma (GBM) is a highly aggressive brain cancer with a low survival rate, prompting the exploration of novel therapeutic strategies. Immune checkpoint inhibitors have shown promise in cancer treatment but are associated with immune-related toxicities and brain penetration. Here, we present a targeted approach using an adeno-associated virus serotype 9 (AAV9) to systemically deliver a single-chain fragment variable antibody against PD-1 (scFv-PD-1) into the tumor microenvironment (TME).

The natural compound obtusaquinone targets pediatric high-grade gliomas through ROS-mediated ER stress.

Background: Pediatric high-grade gliomas (pHGGs) are aggressive primary brain tumors with local invasive growth and poor clinical prognosis. Treatment of pHGGs is particularly challenging given the intrinsic resistance to chemotherapy, an absence of novel therapeutics, and the difficulty of drugs to reach the tumor beds. Accumulating evidence suggests that production of reactive oxygen species (ROS) and misfolded proteins, which typically leads to endoplasmic reticulum (ER) stress, is an essential mechanism in cancer cell survival.

A multiplexed bioluminescent reporter for sensitive and non-invasive tracking of DNA double strand break repair dynamics in vitro and in vivo.

Tracking DNA double strand break (DSB) repair is paramount for the understanding and therapeutic development of various diseases including cancers. Herein, we describe a multiplexed bioluminescent repair reporter (BLRR) for non-invasive monitoring of DSB repair pathways in living cells and animals. The BLRR approach employs secreted Gaussia and Vargula luciferases to simultaneously detect homology-directed repair (HDR) and non-homologous end joining (NHEJ), respectively.

Extracellular Vesicles Induce Mesenchymal Transition and Therapeutic Resistance in Glioblastomas through NF-κB/STAT3 Signaling.

Glioblastoma (GBM) is the most common primary malignant brain tumor and despite optimal treatment, long-term survival remains uncommon. GBM can be roughly divided into three different molecular subtypes, each varying in aggressiveness and treatment resistance. Recent evidence shows plasticity between these subtypes in which the proneural (PN) glioma stem-like cells (GSCs) undergo transition into the more aggressive mesenchymal (MES) subtype, leading to therapeutic resistance.

Obtusaquinone: A Cysteine-Modifying Compound That Targets Keap1 for Degradation.

We have previously identified the natural product obtusaquinone (OBT) as a potent antineoplastic agent with promising activity in glioblastoma and breast cancer through the activation of oxidative stress; however, the molecular properties of this compound remained elusive. We used a multidisciplinary approach comprising medicinal chemistry, quantitative mass spectrometry-based proteomics, functional studies in cancer cells, and pharmacokinetic analysis, as well as mouse xenograft models to develop and validate novel OBT analogs and characterize the molecular mechanism of action of OBT. We show here that OBT binds to cysteine residues with a particular affinity to cysteine-rich Keap1, a member of the CUL3 ubiquitin ligase complex.

Chemical composition, antitumor and antioxidant effects of four lebanese plants extracts on human pulmonary adenocarcinoma.

Lung cancer leading cause of humans' cancer-related death remains incurable with current drug therapies having many side-effects. Finding new natural cancer remedies would help design better therapies. This study aims to investigate the anticancer and antioxidant effects of the Levant endemic plants , , and on human pulmonary adenocarcinoma.

Opioid-induced hypoadrenalism resulting in fasting hypoglycaemia.

An 18-year-old woman with a history of hollow visceral myopathy presented with a small-bowel obstruction. High-dose opioid analgesia was required subsequently during hospital admission. She suffered two episodes of documented fasting hypoglycaemia, despite adjustment of parenteral carbohydrate administration.

Genetic and Phenotypic Characterisation of a Population of 'Merwah' White Wine.

The study of yeast biodiversity represents an important step in the preservation of the local heritage, and this work in particular has an innovative character since no further studies have investigated 'Merwah', one of the main grape varieties used in winemaking in Lebanon. To gain deeper knowledge of the genetic diversity and population structure of native wine strains, 202 isolates were collected during spontaneous alcoholic fermentation of eight must/wine samples of cultivar 'Merwah', over two consecutive years (2016, 2017) in a traditional winery in Mount Lebanon (1400 m a.s.

Erratum: Author Correction: Sustained NF-κB-STAT3 signaling promotes resistance to Smac mimetics in Glioma stem-like cells but creates a vulnerability to EZH2 inhibition.

[This corrects the article DOI: 10.1038/s41420-019-0155-9.].

Sustained NF-κB-STAT3 signaling promotes resistance to Smac mimetics in Glioma stem-like cells but creates a vulnerability to EZH2 inhibition.

Glioblastoma is an incurable and highly aggressive brain tumor. Understanding therapeutic resistance and survival mechanisms driving this tumor type is key to finding effective therapies. Smac mimetics (SM) emerged as attractive cancer therapeutics particularly for tumor populations that are highly resistant to conventional apoptosis-inducing therapies.

Chlordecone potentiates auto-immune hepatitis and promotes brain entry of MHV3 during viral hepatitis in mouse models.

Chlordecone is an organochlorine used in the 1970's as a pesticide in banana plantations. It has a long half-life in the soil and can potentially contaminate humans and animals through food. Chlordecone targets, and mainly accumulates in, the liver, leading to hepatomegaly and neurological signs in mammals.

Olfactory Ensheathing Cells: A Trojan Horse for Glioma Gene Therapy.

Background: The olfactory ensheathing cells (OECs) migrate from the peripheral nervous system to the central nervous system (CNS), a critical process for the development of the olfactory system and axonal extension after injury in neural regeneration. Because of their ability to migrate to the injury site and anti-inflammatory properties, OECs were tested against different neurological pathologies, but were never studied in the context of cancer. Here, we evaluated OEC tropism to gliomas and their potential as a "Trojan horse" to deliver therapeutic transgenes through the nasal pathway, their natural route to CNS.

The occurrence of maedi-visna virus in Lebanon.

Maedi-visna (MV) is a chronic viral disease prevalent in adult sheep that is caused by a virus belonging to the small ruminant lentivirus group (SRLV). This disease is considered to affect the international trade of sheep and is classified in the World Organisation for Animal Health (OIE) list of notifiable animal diseases. Although maedi-visna virus (MVV) has been detected in many countries, no study on its occurrence has been carried out in Lebanon.

Activity-Independent Effects of CREB on Neuronal Survival and Differentiation during Mouse Cerebral Cortex Development.

Neuronal survival and morphological maturation depends on the action of the transcription factor calcium responsive element binding protein (CREB), which regulates expression of several target genes in an activity-dependent manner. However, it remains largely unknown whether CREB-mediated transcription could play a role at early stages of neuronal differentiation, prior to the establishment of functional synaptic contacts. Here, we show that CREB is phosphorylated at very early stages of neuronal differentiation in vivo and in vitro, even in the absence of depolarizing agents.

Imaging Tumor Vascularity and Response to Anti-Angiogenic Therapy Using Gaussia Luciferase.

We developed a novel approach to assess tumor vascularity using recombinant Gaussia luciferase (rGluc) protein and bioluminescence imaging. Upon intravenous injection of rGluc followed by its substrate coelenterazine, non-invasive visualization of tumor vascularity by bioluminescence imaging was possible. We applied this method for longitudinal monitoring of tumor vascularity in response to the anti-angiogenic drug tivozanib.

Caprine arthritis encephalitis virus: prevalence and risk factors in Lebanon.

An epidemiological survey, accompanied by a serological analysis,was conducted on samples taken from Lebanese goat herds in order to determine the prevalence of infection with the caprine arthritis encephalitis virus (CAEV) in Lebanon. The results of the survey provided information on various livestock production, animal health and herd management factors. Serum samplesfrom 952 goats, including the local breeds (Baladi and Damascene) and imported breeds (Alpine and Saneen), were taken from 60 farms distributed throughout Lebanon and tested for the presence of anti-CAEV antibodies.

Chlordecone potentiates hepatic fibrosis in chronic liver injury induced by carbon tetrachloride in mice.

Chronic liver damage due to viral or chemical agents leads to a repair process resulting in hepatic fibrosis. Fibrosis may lead to cirrhosis, which may progress to liver cancer or a loss of liver function, with an associated risk of liver failure and death. Chlordecone is a chlorinated pesticide used in the 1990s.

Therapeutic play: preparing the child for the vaccine.

Objective: To identify and compare behaviors of children during vaccination, who were prepared or not for the procedure using an instructional therapeutic play.

Methods: A quasi experimental study, with quantitative approach of 60 children aged 3 to 6 years. The child's reactions were recorded in a checklist.

The introduction of insulin in type 2 diabetes mellitus.

Background: Conservatively, over 1 million people have been diagnosed with diabetes mellitus in Australia, the majority with type 2 diabetes mellitus (T2DM). Until the progressive decline in pancreatic beta cell function, which characterises T2DM, can be meaningfully halted, most of these patients will require insulin therapy to maintain optimal glycaemic control over time.

Objective: The aim of this article is to provide a pragmatic overview of when and how to initiate insulin therapy for T2DM in a primary care setting.

Management of obesity and cardiometabolic risk - role of phentermine/extended release topiramate.

The US Food and Drug Administration (FDA) recently approved lorcaserin and the combination of phentermine and extended release topiramate (phentermine/topiramate ER) for the treatment of obesity in conjunction with a lifestyle intervention, expanding the therapeutic options for long-term obesity pharmacotherapy, which was previously limited to orlistat. Combination phentermine/topiramate ER is associated with greater weight loss compared to its constituent monotherapy, with a more favorable adverse effect profile. Phentermine/topiramate ER also appears to have beneficial effects on cardiometabolic risk, although longer-term cardiovascular safety data are required.

A flexible tool for calculating the consequences of a hypothetical nuclear accident.

The paper presents a parametric model, implemented on a personal computer, for calculating contamination and doses following a hypothetical nuclear accident. The model is embedded in the high level environment of Mathematica and uses the Gaussian solution for the plume structure at short and medium distances and a wedge-like behaviour for long distances calculation. Along with the usual effects, like the influence of a local wet ground deposition or the corrections due to build-up, the model deals also with other aspects, such as the long distance behaviour of the plume, by taking into account random wind direction variations.

An enyne cycloisomerization approach to the triple reuptake inhibitor GSK1360707F.

The triple reuptake inhibitor GSK1360707F was synthesized via an efficient and scalable route that features an enyne cycloisomerization reaction catalyzed by either Pt(II) or Au(I). Key aspects of this work such as the choice of the nitrogen protecting group and initial enantioselectivity studies are discussed.