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Long-lasting cognitive impairment is one of the most central negative consequences related to the exposure to cannabis during adolescence, and particularly of delta-9-tetrahydrocannabinol (THC). The aim of this study was to compare the protracted effects of adolescent versus late-adolescent chronic exposure to THC on short-term memory and plasticity, and to examine whether rapamycin, a blocker of the mammalian target of rapamycin (mTOR) pathway, can restore THC-induced deficits in memory and plasticity. Male rats were injected with ascending doses of THC [2.5, 5, 10 mg/kg; intraperitoneally (i.p.)] during adolescence and late-adolescence (post-natal days 30-41 and 45-56, respectively), followed by daily injections of rapamycin (1mg/kg, i.p.) during the first ten days of cessation from THC. Thirty days after the last injection, rats were tested for short-term and working memory, anxiety-like behavior, and plasticity in the pathways projecting from the ventral subiculum (vSub) of the hippocampus to the prefrontal cortex (PFC) and nucleus accumbens (NAc). THC exposure in adolescence, but not late-adolescence, was found to induce long-term deficits in object recognition short-term memory and synaptic plasticity in the hippocampal-accumbens pathway. Importantly, rapamycin rescued these persistent effects of THC administered during adolescence. Our findings show that some forms of memory and plasticity are sensitive to chronic THC administration during adolescence, and that rapamycin administered during THC cessation may restore cognitive function and plasticity, thus potentially protecting against the possible long-term harmful effects of THC.

In advanced nonsmall cell lung cancer (aNSCLC), stopping nivolumab after 12 months negatively affects outcomes. We performed a world data-based analysis assessing the value of nivolumab continuation and optimal dosing beyond 24 months. Out of 697 consecutive patients with aNSCLC in whom nivolumab was initiated between 2015 and 2018, 45 patients receiving nivolumab for ≥24 months were selected. These were divided into Groups A: nivolumab administered at a dose 3 mg/kg q2 weeks/240 mg q2 weeks/480 mg q4 weeks, n = 25; B: nivolumab re-scheduled to a nonstandard dose 3 mg/kg q3 weeks-q8 weeks, n = 13; C: nivolumab stopped after 24 months, n = 7; (in Groups B and C-for reasons other than progressive disease or intolerable toxicity). Progression-free survival (PFS) (Revised Response Evaluation Criteria in Solid Tumors, version 1.1) and safety (Common Terminology Criteria for Adverse Events, version 4.03) were assessed. With median follow-up of 35.6 months (interquartile range 28.4-41.8), 4%, 31%, 29% and 30% of patients progressed in Groups A, B, C and B+C, respectively. PFS at 36 months since nivolumab initiation comprised 100%, 67%, 67% and 67%, in Groups A, B, C and B+C, respectively. PFS at 40 months since nivolumab initiation comprised 83%, 67%, 67% and 67%, in Groups A, B, C and B+C, respectively. Allocation to Group A vs Group B, C and B+C was associated with hazard ratio for PFS-0.20 (95% confidence interval [CI], 0.02-1.77, P-.15), 0.20 (95% CI, 0.02-2.25, P-.19) and 0.20 (95% CI, 0.02-1.66, P-.14), respectively. No differences in newly occurring or worsening adverse events between the groups were observed. A trend for worse PFS was observed with alternative nivolumab scheduling or quitting 24 months after initiation. Continuing nivolumab at a standard dose until disease progression or intolerable toxicity remains the standard treatment option.

Our lab has developed a new series of self-immolative MR agents for the rapid detection of enzyme activity in mouse models expressing β-galactosidase (β-gal). We investigated two molecular architectures to create agents that detect β-gal activity by modulating the coordination of water to Gd(III). The first is an intermolecular approach, wherein we designed several structural isomers to maximize coordination of endogenous carbonate ions. The second involves an intramolecular mechanism for q modulation. We incorporated a pendant coordinating carboxylate ligand with a 2, 4, 6, or 8 carbon linker to saturate ligand coordination to the Gd(III) ion. This renders the agent ineffective. We show that one agent in particular (6-C pendant carboxylate) is an extremely effective MR reporter for the detection of enzyme activity in a mouse model expressing β-gal.

Aim Immune checkpoint inhibitors (ICIs) have revolutionized the treatment for advanced non-small-cell lung cancer (NSCLC), yet many patients do not benefit from Programmed cell death protein 1 (PD-1) axis inhibitors, emphasizing the need for additional markers for better patient selection. Our aim was to evaluate the association between tumor volume and response to ICI. Methods This retrospective ethically-approved study included all consecutive patients with advanced NSCLC who were evaluated with a fluorodeoxyglucose-positron emission tomography scan, prior to the first administration of a single-agent ICI between 1/2016 and 6/2017. Tumor burden was calculated based on total body metabolic tumor volume and sum of all measurable lesions (SOML). Results Median SOML was 88 mm, and was inversely and significantly associated with progression-free survival (PFS) (hazard ratio [HR] 2, CI 1.28-3.37, P = .003) and overall survival (OS) (HR 2.36, CI 1.13-4.94, P = .02). SOML≤80 mm had a significantly longer PFS compared to patients with a SOML≥80 mm (median PFS 9.7 vs 3.7 months, respectively, HR for progression 2.26, CI 1.1-4.5, P = .02). Patients with a SOML≤80 also had longer median OS compared to patients with SOML≥80 (median OS 12 vs 9.8 months, respectively, HR for death 3.1, CI 1.2-8, P = .018). Conclusions Low tumor burden was associated with higher response rates (RR), and better PFS and OS in advanced NSCLC patients treated with ICI. These results may improve the selection of patients for treatment with single-agent ICI, as opposed to the combination with chemotherapy, which might be more appropriate for patients with high tumor burden. Prospective analysis is warranted.

INTRODUCTION Breast and chest wall desmoid tumours can cause debilitating symptoms and deformity. The mutilating effects of surgical treatment have prompted a shift to medical treatments and even to a wait-and-see approach. This study sought to highlight specific characteristics of breast and chest wall desmoid tumours on long-term follow-up by sequential MRI scans. METHODS Thirty-two breast MRI scans from six patients with chest wall or breast desmoid tumours followed up for up to 6 years were retrospectively reviewed. RESULTS All patients underwent breast surgery prior to the development of the desmoid tumour. Five of the patients had reconstruction or augmentation using silicone implants. Two desmoids were treated primarily with surgery, three with medical means and one is under wait-and-see approach. On MRI, tumours appeared either oval and lobulated (chest wall) or spiculated with architectural distortion (breast). Chest wall desmoids demonstrated both an enhancing high-T2-signal component and a non-enhancing low-T2- signal component. The histologically defined phases during the course of desmoid tumours (progression, regression, residual disease) could be demonstrated by corresponding MRI changes in each of the components. CONCLUSIONS Magnetic resonance imaging delineates the complex infiltrative features of chest wall and breast desmoid tumours. In tumours with a bright cellular enhancing and dark collagenous non-enhancing component, treatment response may be predicted by changes on serial T2-weighted sequences, beyond the tumour-dimension-based RECIST assessment alone.

Background Malignant pleural mesothelioma (MPM) is a rare disease and management of localized disease is controversial. Radiotherapy has been shown to be useful after extrapleural pneumonectomy (EPP), as well as with less aggressive surgery. As no reports of the treatment of this disease have ever been published from Israel, we report our experience with MPM and intensity-modulated radiotherapy (IMRT). Methods The complete medical records of patients treated for MPM at the Rabin Medical Center from 1 August 2007 to 31 March 2016 were reviewed. Twenty-seven patients were treated with IMRT, either post-EPP or without EPP. Patients received 54 Gy in 2 Gy fractions using the restricted field IMRT technique. Chemotherapy was administered sequentially in 26% of patients. Patients were followed up from the date of diagnosis to death or treatment failure. Results Seventy-eight percent of patients had the epithelioid subtype. Nearly all patients were male (85%) and 90% of non-surgical patients were administered chemotherapy compared to 56% of post-EPP patients. All patients completed therapy and only 16% had grade 1-2 radiation pneumonitis, with no incidence of grade 3 or higher. The median follow-up was 22 months and the mean overall survival was 34.9 months. The mean time to progression following radiation therapy was 26.7 months. The mean time to local and distant failure was 19 and 16 months, respectively. Conclusions IMRT for localized pleural mesothelioma is a tolerable and effective therapy both post-EPP or without surgery. These results suggest that future investigation in this area is required.

Endometrial or uterine glands secrete substances essential for uterine receptivity to the embryo, implantation, conceptus survival, and growth. Adenogenesis is the process of gland formation within the stroma of the uterus. In the mouse, uterine gland formation initiates at postnatal day (P) 5. Uterine gland morphology is poorly understood because it is primarily based on two-dimensional (2D) histology. To more fully describe uterine gland morphogenesis, we generated three-dimensional (3D) models of postnatal uterine glands from P0 to P21, based on volumetric imaging using light sheet microscopy. At birth (P0), there were no glands. At P8, we found bud- and teardrop-shaped epithelial invaginations. By P11, the forming glands were elongated epithelial tubes. By P21, the elongated tubes had a sinuous morphology. These morphologies are homogeneously distributed along the anterior–posterior axis of the uterus. To facilitate uterine gland analyses, we propose a novel 3D staging system of uterine gland morphology during development in the prepubertal mouse. We define five uterine gland stages: Stage 1: bud; Stage 2: teardrop; Stage 3: elongated; Stage 4: sinuous; and Stage 5: primary branches. This staging system provides a standardized key to assess and quantify prepubertal uterine gland morphology that can be used for studies of uterine gland development and pathology. In addition, our studies suggest that gland formation initiation occurs during P8 and P11. However, between P11 and P21 gland formation initiation stops and all glands elongate and become sinuous. We also found that the mesometrial epithelium develops a unique morphology we term the uterine rail.

Photosynthetic microorganisms encounter an erratic nutrient environment characterized by periods of iron limitation and sufficiency. Surviving in such an environment requires mechanisms for handling these transitions. Our study identified a regulatory system involved in the process of recovery from iron limitation in cyanobacteria. We set out to study the role of bacterioferritin co-migratory proteins during transitions in iron bioavailability in the cyanobacterium Synechocystis sp. PCC 6803 using knockout strains coupled with physiological and biochemical measurements. One of the mutants displayed slow recovery from iron limitation. However, we discovered that the cause of the phenotype was not the intended knockout but rather the serendipitous selection of a mutation in an unrelated locus, slr1658. Bioinformatics analysis suggested similarities to two-component systems and a possible regulatory role. Transcriptomic analysis of the recovery from iron limitation showed that the slr1658 mutation had an extensive effect on the expression of genes encoding regulatory proteins, proteins involved in the remodeling and degradation of the photosynthetic apparatus and proteins modulating electron transport. Most significantly, expression of the cyanobacterial homologue of the cyclic electron transport protein PGR5 was upregulated 1000-fold in slr1658 disruption mutants. pgr5 transcripts in the Δslr1658 mutant retained these high levels under a range of stress and recovery conditions. The results suggest that slr1658 is part of a regulatory operon that, among other aspects, affects the regulation of alternative electron flow. Disruption of its function has deleterious results under oxidative stress promoting conditions.

Cold water extract of P. citrinopileatus (CWEPC) was fractioned into 4 fractions, PC-I ( 10 kDa), by ultrafiltration. The antioxidant activities, the inhibition of pancreatic α-amylase, intestinal α-glucosidase, and hypertension-linked angiotensin converting enzyme (ACE), as well as the contents of polysaccharides, protein, and phenolic compounds of 4 fractions were determined. The results showed that lower MW fractions exerted a higher antioxidant activity, which was correlated to phenolic contents. The high molecular fraction (PC-IV) exhibited significantly higher inhibitory activity on α-amylase, α-glucosidase, and ACE compared to CWEPC and the other 3 lower MW fractions (

Reduced Prostatic acid Phosphatase (PAcP) secretion is associated with inhibition of the proliferation rate of prostate cancer cells. Signal peptidase 1 (SPase 1) is the main protease that cleaves the signal peptide of secretory proteins and allows their secretion. Thus, we hypothesised that inhibition of SPase 1 might lead to an antiproliferative effect in prostate cancer cells. Using homology computer modelling, we created a human SPase 1 model. With this model we designed and synthesised four novel (S)-3-(4-aminobutyl)piperazin-2-one-based peptidomimetics. The in vitro cytotoxic activity of these compounds was evaluated in the Lymph Node Carcinoma of the Prostate (LNCaP) cancer cell line. Indeed, (S)-(3-(2-(4-(((benzyloxy)carbonyl)amino)butyl)-4-(3-methoxy-3-oxopropyl)-3-oxopiperazin-1-yl)propyl)boronic acid, compound 8) reduced PAcP secretion, as well as exhibited significant cytotoxic effect in LNAcP cells. As reported in this study, an antiprostate cancer drug development approach, which is based on inhibiting PAcP secretion, is innovative and it might serve as source for developing novel antiprostate cancer drugs.

A new emission mechanism was proposed to enhance the OLED operation lifetime by using exciplex emission to sensitize the triplet-triplet annihilation blue emission. 3-times improvement in operation lifetime was achieved due to the alleviation of electron accumulation at the interface of the hole-transporting layer and the emitting layer.

Operation lifetime of a blue OLED exhibiting triplet-triplet annihilation increased by 89.3% with the incorporation of 10% assistant host in the emitting layer, which increased diffusion length of singlet exciton, reduced the quenching of triplet exciton, and blocked the triplet pair diffusion.