Efficacy Of Suppression Research Articles

Abstract 3894: Determination of the efficacious Entrectinib exposures required for pathway inhibition and anti-tumor activity in a subcutaneous and intracranialTPM3-NTRK1mutant tumor model

Abstract Entrectinib is a selective and brain penetrant inhibitor with potency against TRKA, TRKB, TRKC, ROS1 and ALK currently in clinical development for the treatment of tumors harboring NTRK or ROS1 gene fusions. In multiple non-clinical models harboring NTRK or ROS1 gene fusions, entrectinib demonstrates potent tumor growth inhibition leading to tumor regressions. Entrectinib achieves exposure in the brain across multiple species with brain-to-plasma concentration ratios of 0.4 in mice, 0.6-1.5 in rats, and 1.4-2.2 in dogs after multiple oral administration. Previously Cook, et al. demonstrated that entrectinib demonstrates anti-tumor efficacy in a BCAN-NTRK1 glioma model, however only testing higher doses. Here we sought to better understand the effective exposures of entrectinib required for pathway inhibition and anti-tumor efficacy through dose-ranging efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) studies using the TPM3-NTRK1 KM12-Luciferase (KM12-Luc) tumor model inoculated subcutaneously or intracranially. In the subcutaneous setting, entrectinib treatment results in significant dose-dependent inhibition of TRKA pathway signaling for up to 12 hours and anti-tumor activity with doses of 5 mg/kg (dosed orally (PO), every day (QD)) and above resulting in strong pathway suppression and tumor regressions. PK analysis demonstrated that an exposure of AUC24h of ≥20 µM.hr was associated with potent TRKA pathway inhibition and tumor growth inhibition. In the intracranial setting, entrectinib similarly demonstrated a dose-dependent effect on inhibition of tumor bioluminescence and enhanced animal survival. Pathway inhibition was observed at all doses of entrectinib with significant activity observed at doses of 5 mg/kg, PO, QD and above. In contrast to tumors inoculated subcutaneously, entrectinib doses of 15 mg/kg, PO, twice daily (BID) or 30 mg/kg, PO, QD were required to strongly inhibit anti-tumor efficacy with the highest dose of 60 mg/kg, PO, BID achieving full suppression of intracranial tumor growth. These data help to establish a model connecting entrectinib drug exposure in circulation and in the brain to pathway suppression and anti-tumor efficacy in an NTRK gene fusion tumor model, which support clinical use of entrectinib in patients with brain NTRK or ROS1 gene fusion tumors. Citation Format: Cecile C. de la Cruz, Thomas Hunsaker, Faye Vazvaei, Dragomir Draganov, Li Yu, Mark Merchant. Determination of the efficacious Entrectinib exposures required for pathway inhibition and anti-tumor activity in a subcutaneous and intracranialTPM3-NTRK1mutant tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3894.

Role of Dual-Specificity Phosphatase 1 in Glucocorticoid-Driven Anti-inflammatory Responses.

Glucocorticoids (GCs) potently inhibit pro-inflammatory responses and are widely used for the treatment of inflammatory diseases, such as allergies, autoimmune disorders, and asthma. Dual-specificity phosphatase 1 (DUSP1), also known as mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), exerts its effects by dephosphorylation of MAPKs, i.e., extracellular-signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). Endogenous DUSP1 expression is tightly regulated at multiple levels, involving both transcriptional and post-transcriptional mechanisms. DUSP1 has emerged as a central mediator in the resolution of inflammation, and upregulation of DUSP1 by GCs has been suggested to be a key mechanism of GC actions. In this review, we discuss the impact of DUSP1 on the efficacy of GC-mediated suppression of inflammation and address the underlying mechanisms.

Efficacy and safety of adjuvant ovarian suppression with Buserelin-depo in premenopausal women with hormone-positive breast cancer

Breast cancer (BC) ranks first in the morbidity pattern among women in Russia. Adjuvant endocrinotherapy is an important step in the complex treatment of premenopausal patients with hormone-positive early breast cancer. The drug ovarian suppression with GnRH-agonists have supplanted surgical castration and radiation-based treatment of the ovaries in patients with hormone-positive early breast cancer. Today, several drugs authorised for the treatment of breast cancer are used in clinical practice: goserelin, buserelin and triptorelin. Buserelin-depo is an effective method for achieving ovarian suppression. The results obtained do not differ from similar indicators obtained in using imported LHRH analogues.

Paris Polyphylla Inhibits Colorectal Cancer Cells via Inducing Autophagy and Enhancing the Efficacy of Chemotherapeutic Drug Doxorubicin.

Colorectal cancer is one of the most common cancers worldwide and chemotherapy is the main approach for the treatment of advanced and recurrent cases. Developing an effective complementary therapy could help to improve tumor suppression efficiency and control adverse effects from chemotherapy. Paris polyphylla is a folk medicine for treating various forms of cancer, but its effect on colorectal cancer is largely unexplored. The aim of the present study is to investigate the tumor suppression efficacy and the mechanism of action of the ethanolic extract from P. polyphylla (EEPP) in DLD-1 human colorectal carcinoma cells and to evaluate its combined effect with chemotherapeutic drug doxorubicin. The data indicated that EEPP induced DLD-1 cell death via the upregulation of the autophagy markers, without triggering p53- and caspase-3-dependent apoptosis. Moreover, EEPP treatment in combination with doxorubicin enhanced cytotoxicity in these tumor cells. Pennogenin 3-O-beta-chacotrioside and polyphyllin VI were isolated from EEPP and identified as the main candidate active components. Our results suggest that EEPP deserves further evaluation for development as complementary chemotherapy for colorectal cancer.

Global patterns in the biocontrol efficacy of spiders: A meta‐analysis

AbstractAimTo investigate the overall effect of spiders on pest suppression and crop performance, and to explore the extent to which the biocontrol efficacy of spiders depends on the characteristics of spiders, pests, agroecosystems, climate and geography.LocationGlobal.Time period1970–2017.Major taxa studiedSpiders.MethodsWe performed a meta‐analysis of 58 published studies where we investigated (a) the overall effect of spiders on pest density and crop performance; (b) the extent to which the biocontrol efficacy of spiders depends on the taxonomy of pests (aphids, leafhoppers, beetles, and lepidopteran larvae), the hunting strategy of spiders (hunters, web‐weavers), crop type (vine, cabbage, wheat, rice), climate, and geography.ResultsSpiders suppressed agricultural pest insects in 79% of cases. The mean effect size of increased spider density on pest suppression was large (Hedge's d = 0.89; 95% confidence interval (CI95 )= 0.66–1.12). Spider pest suppression efficacy slightly increased also with taxonomic diversity (d = 0.33; CI95 = 0.05–0.61). The effects of spiders cascaded down and improved crop performance (d = 2.3, CI95 = 0.70–3.84). The effects of spiders seemed to escalate rather than attenuate down through the agricultural food‐chains (regression slopes > 1). The biocontrol efficacy of spiders was highest in rice followed by grape, cabbage and wheat. The pest suppression efficacy of spiders and the positive effect of spiders on crop yield slightly increased towards the tropics and with mean annual temperature. Spiders suppressed the four pest groups with similar efficacy.Main conclusionsThe meta‐analysis provides strong evidence that spiders are effective in natural pest control and improve crop performance. However, the efficacy of spiders differed among crops. Our study substantiates the few earlier findings that predation pressure and the intensity of trophic cascades in terrestrial ecosystems intensify towards the tropics.

Simulation tools for assessment of tick suppression treatments of Rhipicephalus (Boophilus) microplus on non-lactating dairy cattle in Puerto Rico

BackgroundThe southern cattle fever tick (SCFT), Rhipicephalus (Boophilus) microplus, remains endemic in Puerto Rico. Systematic treatment programmes greatly reduced and even eradicated temporarily this tick from the island. However, a systemic treatment programme that includes integrated management practices for livestock against SCFT remains to be established in the island. We describe a spatially-explicit, individual-based model that simulates climate–livestock–SCFT–landscape interactions. This model was developed as an investigative tool to aid in a research project on integrated management of the SCFT that took place in Puerto Rico between 2014 and 2017. We used the model to assess the efficacy of tick suppression and probability of tick elimination when applying safer acaricides at 3-week intervals to different proportions of a herd of non-lactating dairy cattle.ResultsProbabilities of eliminating host-seeking larvae from the simulated system decreased from ≈ 1 to ≈ 0 as the percentage of cattle treated decreased from 65 to 45, with elimination probabilities ≈ 1 at higher treatment percentages and ≈ 0 at lower treatment percentages. For treatment percentages between 65% and 45%, a more rapid decline in elimination probabilities was predicted by the version of the model that produced higher densities of host-seeking larvae. Number of weeks after the first acaricide application to elimination of host-seeking larvae was variable among replicate simulations within treatment percentages, with within-treatment variation increasing markedly at treatment percentages ≤ 65. Number of weeks after first application to elimination generally varied between 30 and 40 weeks for those treatment percentages with elimination probabilities ≈ 1.ConclusionsExplicit simulation of the spatial and temporal dynamics of off-host (host-seeking) larvae in response to control methods should be an essential element of research that involves the evaluation of integrated SCFT management programmes. This approach could provide the basis to evaluate novel control technologies and to develop protocols for their cost-effective use with other treatment methods.

Endogenous Reactive Oxygen Species-Triggered Morphology Transformation for Enhanced Cooperative Interaction with Mitochondria.

The morphology controlled molecular assemblies play vital roles in biological systems. Here we present endogenous reactive oxygen species (ROS)-triggered morphology transformation of polymer-peptide conjugates (PPCs) for cooperative interaction with mitochondria, exhibiting high tumor therapeutic efficacy. The PPCs are composed of (i) a β-sheet-forming peptide KLVFF conjugated with poly(ethylene glycol) through ROS-cleavable thioketal, (ii) a mitochondria-targeting cytotoxic peptide KLAK, and (iii) a poly(vinyl alcohol) backbone. The self-assembled PPCs nanoparticles can enter cells and target mitochondria. Because of overgenerated ROS around mitochondria in most cancer cells, the thioketal linker can be cleaved, leading to transformation from nanoparticles to fibrous nanostructures. As a result, the locational nanofibers with exposure of KLAK exhibit enhanced multivalent cooperative interactions with mitochondria, which causes selective cytotoxicity against cancer cells and powerful tumor suppression efficacy in vivo. As the first example of ROS-triggered intracellular transformation, the locational assembly strategy in vivo may provide a new insight for disease diagnosis and therapy through enhanced interaction with targeting site.

Intercropping cereals with faba bean reduces plant disease incidence regardless of fertilizer input; a meta-analysis

Ecological intensification of agriculture calls for ecological mechanisms to replace anthropogenic inputs. Cereal/legume intercropping increases yields due to species complementarities, it produces high protein food and feed, and it reduces the need for artificial N fertilizer because legumes fix N biologically. In addition, intercropping has the potential to suppress plant diseases, but its efficacy for disease suppression in cereal/legume mixtures has not been well characterized quantitatively. Here we conducted meta-analysis to quantify the disease suppressive effect of intercropping cereals with legumes at different levels of N fertilizer. Intercropping reduced disease incidence (measured by the odds ratio of disease occurrence) by 45% on average. This reduction was significant (P < 0.01) for four out of six studied pathogens: yellow rust (Puccinia striiformis f.sp. tritici) and mildew (Blumeria graminis) in wheat (Triticum aestivum), and chocolate spot (Botrytis fabae) and Fusarium wilt (Fusarium oxysporum) in faba bean (Vicia faba). Disease reduction was marginally significant for yellow rust in barley (Puccinia striiformis f.sp. hordei) (P < 0.10) and not significant for bean rust (Uromyces fabae). The reduction in disease incidence was greatest during the early stages of epidemics. N fertilizer strongly increased the incidence of powdery mildew of wheat, but it did not affect the incidence of the other diseases and it did not affect the effectiveness of intercropping as a management strategy for disease control. While nitrogen input increased powdery mildew incidence in both sole and intercropped wheat, the incidence was lower in the intercropped than sole wheat at all levels of N input. The disease suppressive effect of intercropping on wheat powdery mildew or any other disease was not affected by the amount of nitrogen fertilizer. The results show that intercropping has a substantial and consistent effect on disease incidence in cereal/faba bean mixtures across studies, but is not sufficient to provide complete disease control. Intercropping is therefore best used as a component in an integrated approach for managing plant diseases.

Numerical investigation of the effects of polydisperse water sprays on extinction conditions of counterflow methane non-premixed flames

Water, sprayed in the form of tiny droplets, has emerged as a potential fire suppressant after the halon compounds such as trifluorobromomethane (CF3Br, Halon 1301) were banned by the Montreal protocol. The size distribution of the water droplet plays a crucial role in the effectiveness of the water spray in fire suppression. A numerical investigation of the influence of size distribution of a polydisperse water spray on extinction of counterflow diffusion flames is presented in this paper. This study uses laminar finite rate model with reduced CHEMKIN chemistry for numerical simulations. The discrete phase, namely the water spray, is simulated using Lagrangian Discrete Phase Modelling approach. In this work, the polydispersity of water spray is taken into account in the numerical simulation by a suitable Rosin–Rammler distribution. Results obtained from numerical simulation are validated with the experimental results reported in the literature. This study demonstrates that the representation of the polydisperse spray by a monodisperse spray (with droplet diameter same as the SMD of the polydisperse spray) in numerical simulations is not always justified and it leads to deviation from the experimental results. The effects of number mean diameter and spread parameter on the efficacy of flame suppression are investigated for polydisperse sprays. A comprehensive comparison is done between the effectiveness of monodisperse and polydisperse water sprays. An optimum droplet diameter is obtained for monodisperse sprays for which the effectiveness of the spray is maximum. The effects of evaporation Damköhler number and Stokes number of water droplets on flame suppression have also been explained.

ASSESSMENT OF CANCER TARGETING POTENTIAL OF DOXORUBICIN CONJUGATED WITH SURFACE FUNCTIONALIZED MULTI-WALLED CARBON NANOTUBES

Our main aim in the present investigation was to assess the cancer targeting potential of doxorubicin conjugated with folic acid (FA), ethylene di-amine (EDA) and surface F- MWCNTs (FA-EDA-MWCNTs- DOX) conjugate employing on MCF-7 (breast cancer cell line) for efficient tumor targeting. We developed a highly effective novel targeted drug delivery based on DOX-conjugated with the surface of F-MWCNTs by using nucleophilic substitution reaction mechanism and evaluated in facile strategy for cancer treatment. The in vitro drug release study shows that the percentage of drug release under an acidic condition pH-5.4 is higher than that under normal physiological conditions. The FA-EDAMWCNTs- DOX nano-conjugate affords higher efficacy in tumor growth suppression due to its stealth nature and most preferentially taken up by cultured MCF-7 cells through receptor-mediated endocytosis mechanism. Fourier Transform Infrared Spectroscopy (FTIR), UV-Visible Spectroscopy, Nuclear Magnetic Resonance Spectroscopy (NMR) and Scanning Electron Microscopy (SEM) measurements clearly confirmed the functionalization &amp; conjugation steps. The results concluded that developed watersoluble nano-conjugate might emerge as “safe and effective” nano-medicine in cancer treatment by minimizing the side effects with generally regarded as a safe prominence.

Targeted inactivation of Salmonella Agona metabolic genes by group II introns and in vivo assessment of pathogenicity and anti-tumour activity in mouse model.

The fight against cancer has been a never-ending battle. Limitations of conventional therapies include lack of selectivity, poor penetration and highly toxic to the host. Using genetically modified bacteria as a tumour therapy agent has gained the interest of scientist from the past few decades. Low virulence and highly tolerability of Salmonella spp. in animals and humans make it as the most studied pathogen with regards to anti-tumour therapy. The present study aims to construct a genetically modified S. Agona auxotroph as an anti-tumour agent. LeuB and ArgD metabolic genes in ΔSopBΔSopD double knockout S. Agona were successfully knocked out using a Targetron gene knockout system. The knockout was confirmed by colony PCR and the strains were characterized in vitro and in vivo. The knockout of metabolic genes causes significant growth defect in M9 minimal media. Quadruple knockout ΔSopBΔSopDΔLeuBΔArgD (BDLA) exhibited lowest virulence among all of the strains in all parameters including bacterial load, immunity profile and histopathology studies. In vivo anti-tumour study on colorectal tumour bearing-BALB/c mice revealed that all strains of S. Agona were able to suppress the growth of the large solid tumour as compared with negative control and ΔLeuBΔArgD (LA) and BDLA auxotroph showed better efficacy. Interestingly, higher level of tumour growth suppression was noticed in large tumour. However, multiple administration of bacteria dosage did not increase the tumour suppression efficacy. In this study, the virulence of BDLA knockout strain was slightly reduced and tumour growth suppression efficacy was successfully enhanced, which provide a valuable starting point for the development of S. Agona as anti-tumour agent.

The effects of casing soil treatment with bacillus subtilis Ch-13 biofungicide on green mould control and mushroom yield

The impact of a biofungicide based on Bacillus subtilis Ch-13 on mushroom yield and efficacy in suppression of Trichoderma aggressivum f. europaeum T77 from Serbia was estimated in comparision with a similar microbial fungicide, Bacillus velezensis QST713, and the chemical fungicide prochloraz manganese. The biofungicide B. velezensis QST713 is registered for treatments of mushrooms and other crops in many countries but it is not currently available on the Serbian market. The tested B. subtilis Ch-13 fungicide enhanced mushroom yield 12%, compared with an uninoculated control, and notably more than B. velezensis QST713 applied at its higher test concentrations. Regarding the efficacy of the biofungicides in control of the compost pathogen T. aggressivum f. europaeum, B. subtilis Ch-13 applied in concentration of 3 ? 108 CFU per m2 showed higher efficacy than the higher concentrations (5 ? 109 and 1 ? 1010 CFU per m2) of B. velezensis QST713. The biofungicide based on B. subtilis Ch-13 should be further investigated regarding its different modes of application to ensure better efficacy in disease control as it showed beneficial features in both promoting A. bisporus production and suppressing the growth of the aggressive compost pathogen T. aggressivum, the causal agent of devastating green mould disease.

Role of Acid Suppression in Acid-related Diseases: Proton Pump Inhibitor and Potassium-competitive Acid Blocker.

Proton pump inhibitors are commonly utilized for the treatment of gastric acid-related diseases, such as gastroesophageal reflux disease, peptic ulcer disease, and Helicobacter pylori infection, and for the prevention of low-dose aspirin or nonsteroidal anti-inflammatory drug-induced peptic ulcers. Vonoprazan is a first-in-class potassium-competitive acid blocker, which has distinct advantages compared to other conventional proton pump inhibitors in terms of the efficacy for acid suppression. Due to its strong gastric acid suppression capabilities, vonoprazan serves as an effective drug for the treatment of gastroesophageal reflux disease and H. pylori infection.

Suppression efficacy of lignosulfonate/mercerized cotton fiber composite against cancer cell’s activities

Lignosulfonate (LS)/mercerized cotton composite was prepared to study the LS suppressive possibility to control malignant cell activities to facilitate chemotherapy treatment. The composite was characterized by cross-polarized/magic angle spinning 13C nuclear magnetic resonance (NMR) spectrometry and scanning electron microscope (SEM). 13C NMR spectra and SEM indicated that the presence of LS increased crystallinity and porosity of mercerized cellulose, respectively. Furthermore, the composite efficacy against cancer cell activity was evaluated by cytotoxicity for malignant cell line HCT116, HepG2, and MCF-7. The cancer cells thrive in an acidic environment and they do not survive in normal or alkaline media. The release of LS was intended at acidic pH, in which, the acidity increased due to the activity of the cancer cells that activate the LS released from the mercerized cotton into the media. Therefore, this release process reduced the activity of cancer cells. The released LS kept cancer cells in a low activity via decreasing acidity. Hence, the composite may not eliminate the cancer cells, but it reduces the activity of cancer cells.

The impact of mating competitiveness and incomplete cytoplasmic incompatibility on Wolbachia-driven mosquito population suppressio.

To control mosquito-borne diseases such as dengue, malaria, and Zika, {\it Wolbachia}-infected male mosquitoes have been released in open areas to suppress wild mosquito population driven by cytoplasmic incompatibility (CI). In this work, we initiate a preliminary assessment on how the CI intensity $\xi$, and the mating competitiveness $\mu$ of released males relative to wild males, impact the suppression efficacy by a delay differential equation model. Our analysis identifies a threshold CI intensity $\xi_0\in (0, 1)$ as an increasing function of the natural reproduction rate of the wild mosquitoes, and a threshold value $r^*$ for the ratio $r(t)$ between the numbers of released males and wild males. The population suppression fails when $\xi\le \xi_0$, and succeeds when $\xi>\xi_0$ and $r(t)\ge r^*$. Our analyses indicate that $\xi$ plays a more important role than $\mu$ in the population suppression. For instance, a slight decrease of $\xi$ from 1 to 0.92 is more devastating than halving $\mu$ from 1 to 0.5. In our estimation of the optimal starting date for infected male release to target a more than $95\%$ wild population reduction during the peak season of dengue in Guangzhou, we find that the optimal date is almost independent of $\mu$ but is sensitive to $\xi$. If CI is complete, then starting about two months ahead can be an optimal option for less financial and labor costs. A slight reduction in the CI intensity requires a considerably earlier starting date.

Experimental and Modeling Studies of the Hysteresis Behavior and Dendrite Suppression Efficacy of an Electrolyte Additive in Zinc Electrodeposition

During Zn-air battery charging, the electrodeposited Zn metal is known to evolve undesirable dendritic morphology. Here, we report on a novel electrolyte additive benzyltrimethylammonium hydroxide (BTMAH), which effectively suppresses Zn dendrites. In cyclic voltammetry studies of Zn electrodeposition, BTMAH presents a unique hysteresis effect suggesting that the Zn surface is rendered either polarized or depolarized depending on the relative rates of BTMAH transport, adsorption and its deactivation at the Zn surface, as well as the potential scan direction. Mass spectroscopy indicates that BTMAH deactivation is likely not due to its inclusion into the Zn deposit. A mathematical model, which incorporates a dimensionless parameter ξ representative of the relative rates of BTMAH transport and surface deactivation, is presented to explain conditions under which BTMAH can suppresses accelerated growth at micro-scale dendrite tips. At high BTMAH concentrations and small dendrite tip radii, BTMAH transport rates exceed surface deactivation rates (ξ is large) thereby favoring surface saturation by BTMAH and thus suppressed Zn growth. Experimental data supports model predictions of the concentration-dependent efficacy of BTMAH in suppressing dendrites. BTMAH opens the possibility for ‘localized’ suppression of dendrites during charging of energy-efficient Zn-metal batteries.

ANTIFUNGAL ACTIVITY OF DIFFERENT SYSTEMIC FUNGICIDES AGAINST FUSARIUM OXYSPORUM F. SP. LYCOPERSICI ASSOCIATED WITH TOMATO WILT AND EMERGENCE OF RESISTANCE IN THE PATHOGEN

Fusarium wilt in tomato (Lycopersicon esculentum L.) caused by Fusarium oxysporum f. sp. lycopersici. Pathogen is notorious because of its adverse effect on plant growth with causing significant yields losses. Further complication is developing by raising issue of resistance in F. oxysporum f. sp. lycopersici particularly in developing countries due to injudicious fungicides applications in the field of tomato plant infected by this pathogen. F. oxysporum f. sp. lycopersici was isolated from collected infected samples from tomato field in Multan, southern Punjab on Potato dextrose medium by adopting poisoned food technique. Antifungal activity of different systemic fungicides viz. Pyrimethanil, Fludioxonil, Benlate, Bromuconazole, Fosetyl-Al, Flumorph, Prochloraz, Myclobutanil, Epoxiconazole, Strobilurin, carbendazim, Fentin hydroxide, Streptomycin, Tebuconazole, Iprobenfos and azoxystrobin were tested against F. oxysporum f. sp. lycopersici in vitro by using poisoned food technique. All tested fungicides suppressed fungal mycelial growth with significantly high or low percent inhibition ranging from 1.48 to 85.92%. Among 16 tested fungicides, different concentrations of Bloom, Prochloraz and Bromuconazole significantly inhibited fungal growth ranging from 75 to 85.92 %. Carbendazim and epic reside in the bottom with reference to their efficacy in suppression of F. oxysporum f. sp. lycopersici. The results of present research expressed that isolates of Fusarium oxysporum f. sp. lycopersici develops resistance with time which causes reduced efficacy of fungicides as compared to previously published data. The results provided information about fungicides application and selection for the management of holistic disease in tomato crop in Pakistan.

Intrapallidal injection of botulinum toxin A recovers gait deficits in a parkinsonian rodent model.

Modulation of electrical activity in the subthalamic nucleus has been therapeutically effective in Parkinson's disease. Pharmacological manipulation of glutamate release from subthalamic neurons could also favourably alter basal ganglia activity to improve motor symptoms. This study investigates the efficacy of selective suppression of hyperactive glutamatergic input from the subthalamic nucleus to the globus pallidus internal segment by botulinum toxin A (BoNT-A) in a parkinsonian model. Unilateral 6-hydroxydopamine lesioned parkinsonian rodents and controls received microinfusions of BoNT-A or vehicle into the ipsilateral internal globus pallidus (n=8 per group). Changes in gait were measured by the CatWalk apparatus, along with assessment of apomorphine-induced rotational behaviour prior to and following BoNT-A injection. Immunofluorescent staining for markers of glutamatergic, GABAergic and total terminals was performed at the internal globus pallidus. Administration of a single dose of BoNT-A (0.5ng) significantly improved the rotational asymmetry and gait abnormalities. Ameliorations in speed, body speed variation, cadence and walking pattern were comparable to pre-lesioned animals, and persisted up to 1month following BoNT-A injection. These changes are associated to BoNT-A's ability to selectively target glutamatergic terminals. Blockade of subthalamic hyperactivity by BoNT-A leads to sufficient reorganization in the basal ganglia needed to generate a consistent rhythmic pattern of walking. This suggests the potential use of intracerebral BoNT-A to produce effective neuromodulation in the parkinsonian brain, as well as expansion into other neurodegenerative disorders linked to excitotoxity.

Safety and Efficacy of Long Term Suppression of PI3Kinase Pathway By Small Molecule PI3K-Delta Inhibitor, Leniolisib in Apds (Activated PI3Kδ Syndrome)

▪Inherited gain-of-function mutations in PIK3CD encoding PI3Kδ (phosphoinositide 3-kinase delta) lead to accumulation of senescent T cells, lymphadenopathy, splenomegaly and immune-deficiency (Activated PI3Kδ Syndrome, APDS). Clinical manifestations include multilineage cytopenias and susceptibility to B cell Non-Hodgkins Lymphoma.We recently reported use of leniolisib (CDZ173), a novel, potent and selective oral PI3Kd inhibitor in six APDS patients in a 12-week, open-label, multi-center, within-subject dose-escalation study (Rao et al, Blood 23 November 2017). Leniolisib was safe and well tolerated and led to a dose-dependent reduction in PI3K/AKT pathway activity and improved the immune dysregulation with normalization of circulating transitional and naïve B cells and reduction in PD-1+CD4+ and senescent CD57+CD8+ T cells. Elevated serum IgM and other biomarkers including IFNg, TNF, CXCL13 and CXCL10 normalized or decreased with leniolisib. Cytopenias and lymphoproliferation improved in all patients with index lymph node sizes and spleen volumes reduced by 39% and 40%, respectively.Here we report the long term follow up safety and efficacy data in all six patients (Table 1) who have continued treatment with leniolisib in an extension study at 70 mg b.i.d (ClinicalTrials.gov number NCT02859727). These patients have been treated for up to 949 days (as of July 20th 2018). Three of them were lymphoma survivors. Three patients were treated with rapamycin prior to starting leniolisib. No patient in the 12-week clinical trial or in the long term extension study has experienced any significant adverse events. Notably, side effects prevalent with mTOR or other PI3K inhibitors such as diarrhea/colitis, skin rashes, susceptibility to infections or liver enzyme elevation were absent. Three patients have stopped immunoglobulin supplementation as a reflection of the normalization of their B cell function. Cytopenias, including anemia, thrombocyopenia, neutropenia and lymphopenia have continued to improve. (Figure 1: Showing representative improvement of laboratory data including normalization of IgM for patient 002, following 18 months of treatment with leniolisib; Figure2: Showing improvement of lymphoproliferation in CT scans from 2016 and 2018 for Patient 003. This patient stopped leniolisib for 15 months from October 2016 until January 2018 leading to worsening lymphoproliferation that improved promptly on resumption of therapy). Available data on longterm safety, effects on lymphoproliferation and immune dysregulation in the ongoing leniolisib extension study will be shared during the meeting.The results support safe and efficacious long term inhibition of PI3Kδ protein as a new targeted therapeutic approach in APDS and other disorders of nonmalignant lymphopoliferation associated with hyperactive PI3Kinase pathway. [Display omitted] DisclosuresRao:novartis: Research Funding. Dalm:Novartis: Research Funding. Sediva:Novartis: Research Funding. van Hagen:Novartis: Research Funding. Cabanski:Novartis: Employment. Valentin:Novartis: Employment. de Buck:Novartis: Employment. Kalis:Novartis: Employment. Hasselberg:Novartis: Employment. Burkhart:Novartis: Employment. Kucher:Novartis: Employment. Sloth:Novartis: Employment. Uzel:Novartis: Research Funding.

559. Efficacy and Tolerability of Integrase Inhibitors: Experiences From a Nationwide Real-Life Cohort

BackgroundThe integrase strand transfer inhibitors (INSTIs) are widely used in first-line and alternative antiretroviral therapy. Observational studies have documented a 2–12% incidence of adverse drug reactions sometimes leading to INSTI discontinuation.MethodsProspectively collected cohort data of INSTI use were analyzed between January 2008 and March 2017, in Hungary, a Central-European country with centralized HIV care. Efficacy of viral suppression and reasons for discontinuation were evaluated for available INSTIs (raltegravir (RAL) and dolutegravir (DTG)).ResultsThere were 2,232 patients registered in the national HIV Center in 2017 March 31. Six hundred seventeen patients received during the study period RAL (259 patients—41.9%) or DTG (358—58.1%). There were 55 cases (9%) of switch within class (39 patients for simplification, 13 due to toxicity, two virological failures, and one other reason). Sixteen cases (3%) changed INSTI to another class (eight virological failures, four due to toxicity, and four other reasons). Ten cases of virological failure occurred in patients taking RAL, whereas none of those taking DTG, but in patients on DTG higher rates of side effects were observed compared with patients on RAL (11—3.1% vs. 6—2.3%, respectively).ConclusionLarge and homogenous, nationwide cohort of patients taking INSTIs confirm good tolerability and excellent efficacy of the class with slight differences between RAL and DTG.Disclosures All authors: No reported disclosures.