scholarly journals Antiviral Activity of N-ω-Chloroacetyl-L-Ornithine on In Vitro Replication of the Chikungunya Virus

2020 ◽  
Author(s):  
Lucero Luna-Rojas ◽  
Amanda Marineth Avila-Trejo ◽  
Veronica Alcantara-Farfán ◽  
Lorena I Rodriguez-Paez ◽  
Marvin Omar Pastor-Alonso ◽  
...  
Keyword(s):  
Cytotoxic Effect ◽  
Chikungunya Virus ◽  
Vero Cells ◽  
Competitive Inhibitor ◽  
Morbidity Rate ◽  
High Morbidity ◽  
Dependent Manner ◽  
Post Exposure ◽  
High Morbidity Rate

The infections caused by Chikungunya virus (CHIKV), genus Alphavirus, have become a health problem around the world, due to this virus’s widespread occurrence and high morbidity rate and the absence of vaccines or antiviral drugs. In this study, we analyzed a competitive inhibitor of ornithine decarboxylase—an enzyme that is key in the biosynthesis of polyamines (PAs), N-ω-chloroacetyl-L-ornithine (NCAO), which is a possible inhibitor of CHIKV replication because intracellular polyamines participate in the in vitro transcription and translation of CHIKV. NCAO does not have any cytotoxic effect on C6/36 cells even at 1000 μM at 72 h post-exposure. However, in Vero cells, a cytotoxic effect was present above 380 μM at 48 h post-exposure, which was considered when determining the inhibitory effect on viral replication. In this work, we demonstrate that NCAO inhibits the replication of CHIKV in Vero and C6/36 cells in a dose-dependent manner, causing a decrease in the PFU/mL of at least 4 logarithms (p <0.01) in both cell lines. Viral yields were restored by the addition of exogenous polyamines, mainly putrescine. The HPLC analyses showed that NCAO decreases the content of intracellular PAs, even though mainly spermidines and spermines are present in infected cells. NCAO inhibits CHIKV replication by depleting the intracellular polyamines in Vero and C6/36 cells, suggesting that this compound is a possible antiviral for CHIKV infections.

scholarly journals Antiviral activity of N-ω-Chloroacetyl-L-Ornithine on in vitro replication of Chikungunya virus

2019 ◽  
Author(s):  
Lucero Luna-Rojas ◽  
Amanda M. Avila-Trejo ◽  
Verónica Alcántara-Farfán ◽  
Lorena I. Rodríguez-Páez ◽  
Marvin Omar Pastor-Alonso ◽  
...  
Keyword(s):  
Viral Replication ◽  
Ornithine Decarboxylase ◽  
Health Problem ◽  
Cytotoxic Effect ◽  
Chikungunya Virus ◽  
Competitive Inhibitor ◽  
Morbidity Rate ◽  
High Morbidity ◽  
High Morbidity Rate

AbstractThe infections causes by Chikungunya virus (CHIKV), family Togaviridae, genus Alfavirus, have become a health problem around the world, due to its widespread occurrence, the high morbidity rate and the absence of vaccines or antiviral treatments. We analyzed a competitive inhibitor of ornithine decarboxylase, enzyme key in the biosynthesis of Polyamines (PAs), N-ω-chloroacetyl-L-ornithine (NCAO), as a possible inhibitor of CHIKV replication because intracellular polyamines participate in the transcription and in vitro translation of CHIKV. NCAO does not have any cytotoxic effect on C6/36 cells even at a concentration of 1000μM at 72h after post-exposure but in Vero cells the cytotoxic effect was presented above 380μM at 48h post-exposure, which was considered when determining the inhibitory effect on viral replication. We demonstrate that NCAO inhibits the replication of CHIKV in Vero and C6/36 cells in a dose-dependent manner causing a decrease in the PFU/mL of at least 4-logarithm (p <0.01) in both cell lines. Viral yields were restored by the addition of exogenous polyamines, mainly putrescine. HPLC analyses it shown that NCAO decrease content of intracellular PAs even though in infected cells mainly decreased spermidine and spermine, so NCAO inhibits CHIKV replication, by depleting the intracellular polyamines in Vero and C6/36 cells, suggesting that this compound is a possible antiviral in CHIKV infections.ImportanceThe infections caused by Chikungunya virus (CHIKV), genus Alfavirus, have become a worldwide health problem, due to its high morbidity rate and the absence of vaccines or antiviral treatments. It is known that CHIKV use intracellular poliamines during transcription and traduction process, so the depletion of intracellular putrescine, spermidine and spermine reduce the viral replication. N-ω-chloroacetyl-L-ornithine (NCAO) is known as a competitive inhibitor of ornithine decarboxylase, key enzyme in Polyamines biosynthesis, but no studies have proven its activity on the inhibition of polyamine-dependent viral replication. Here we demonstrate NCAO inhibits in vitro CHIKV replication, so we propose NCAO as an antiviral candidate.

scholarly journals About Minimization of Expenses on Allergy Diagnosis in Children: Analysis of Consistency of in Vitro- and in Vivo-Allergic Examinations Results

2015 ◽  
Vol 70 (6) ◽  
pp. 748-755
Author(s):  
Marina Andreevna Snovskaya ◽  
Anna Sergeevna Batyrova ◽  
Leyla Seymurovna Namazova-Baranova ◽  
Anna Aleksandrovna Alekseeva ◽  
Elena Aleksandrovna Vishneva ◽  
...  
Keyword(s):  
Atopic Disease ◽  
Skin Tests ◽  
Morbidity Rate ◽  
In Vitro Tests ◽  
High Morbidity ◽  
Meadow Fescue ◽  
Ige Antibodies ◽  
High Morbidity Rate

High morbidity rate of atopic diseases among children, including high importance of grass pollen as a sensitizing agent, determine the relevance of studies on diagnostic examination systems for appointment of adequate therapy. The research of the most relevant allergens for patients to exclude of duplicating and uninformative tests became urgent after development of a new type of diagnostic tests that does not require expensive equipment. The objective of this research was to evaluate the results of in vitro- and in vivo-diagnostic examinations of children with various forms of atopic disease caused by pollen of meadow grasses, and to choose the most significant prognostic parameters for the diagnosis. Methods: 277 children aged 4–16 years with various forms of atopic disease were included in the study. There were performed skin prick tests and determination of IgE-antibodies levels to allergen extracts of cocksfoot (g3), meadow fescue (g4), timothy grass (g6). Results: In the studied group of patients 32–50% of children have antibodies to grass allergens. There was a close correlation of antibody response on the investigated allergens, quantitative coincidence of IgE-antibodies to g3 and g4 allergens levels. IgE (g6) concentration was close to the IgE(g3) and IgE(g4) levels (85,0±21,6%). Analysis of the skin tests results showed that 44% of patients have a positive response to grass allergens, and in vivo-tests results coincide with serological tests results, mostly in a qualitative sense. The most significant relationship was noted between in vivo and in vitro-tests in the results of testing the response to meadow fescue pollen.Conclusion: Based on these data IgE concentration index to meadow fescue allergens can be used as a prognostic marker to determine the sensitization of patients with different nosology forms of allergy and can help to improve allergic diagnostics.

In Silico Insights on GD2 : A Potential Target for Pediatric Neuroblastoma

2020 ◽  
Vol 19 (30) ◽  
pp. 2766-2781 ◽  
Author(s):  
Akanksha Limaye ◽  
Jajoriya Sweta ◽  
Maddala Madhavi ◽  
Urvy Mudgal ◽  
Sourav Mukherjee ◽  
...  
Keyword(s):  
In Silico ◽  
Electrostatic Interactions ◽  
3D Structure ◽  
Biological Marker ◽  
Morbidity Rate ◽  
Local Alignment ◽  
Pharmacokinetic Studies ◽  
High Morbidity ◽  
High Morbidity Rate

Background: Originating from the abnormal growth of neuroblasts, pediatric neuroblastoma affects the age group below 15 years. It is an aggressive heterogenous cancer with a high morbidity rate. Biological marker GD2 synthesised by the GD2 gene acts as a powerful predictor of neuroblastoma cells. GD2 gangliosides are sialic acid-containing glycosphingolipids. Differential expression during brain development governs the function of the GD2. The present study explains the interaction of the GD2 with its established inhibitors and discovers the compound having a high binding affinity against the target protein. Technically, during the development of new compounds through docking studies, the best drug among all pre-exist inhibitors was filtered. Hence in reference to the best docked compound, the study proceeded further. Methodology: The In silico approach provides a platform to determine and establish potential inhibitor against GD2 in Pediatric neuroblastoma. The 3D structure of GD2 protein was modelled by homology base fold methods using Smith-Watermans’ Local alignment. A total of 18 established potent compounds were subjected to molecular docking and Etoposide (CID: 36462) manifested the highest affinity. The similarity search presented 336 compounds similar to Etoposide. Results: Through virtual screening, the compound having PubChem ID 10254934 showed a better affinity towards GD2 than the established inhibitor. The comparative profiling of the two compounds based on various interactions such as H-bond interaction, aromatic interactions, electrostatic interactions and ADMET profiling and toxicity studies were performed using various computational tools. Conclusion: The docking separated the virtual screened drug (PubChemID: 10254934) from the established inhibitor with a better re-rank score of -136.33. The toxicity profile of the virtual screened drug was also lesser (less lethal) than the established drug. The virtual screened drug was observed to be bioavailable as it does not cross the blood-brain barrier. Conclusively, the virtual screened compound obtained in the present investigation is better than the established inhibitor and can be further augmented by In vitro analysis, pharmacodynamics and pharmacokinetic studies.

scholarly journals Surveillance of influenza A H1N1 2009 among school children during 2009 and 2010 in São Paulo, Brazil

2012 ◽  
Vol 45 (5) ◽  
pp. 563-566 ◽  
Author(s):  
Sandra Baltazar Guatura ◽  
Aripuana Sakurada Aranha Watanabe ◽  
Clarice Neves Camargo ◽  
Ana Maria Passos ◽  
Sheila Negrini Parmezan ◽  
...  
Keyword(s):  
School Children ◽  
Influenza A ◽  
Respiratory Infections ◽  
Vaccination Campaign ◽  
Sao Paulo ◽  
Morbidity Rate ◽  
High Morbidity ◽  
São Paulo ◽  
High Morbidity Rate ◽  
Influenza A H1n1

INTRODUCTION: Influenza A H1N1 2009 is associated with a high morbidity rate among children around the world, including Brazil. This survey was conducted on samples of symptomatic children (< 12 years) to investigate the influenza virus as the etiological agent of respiratory infections in a day care school in a health facility during the first and second pandemic wave of H1N1 (2009-2010) in São Paulo, Brazil. METHODS: Influenza infections were determined by real-time PCR in 34% (47/137) of children with a median age of 5 years (8 months - 12 years), from June to October 2009 and in 16% (14/85) of those with median age of 6 years (1-12 years), from March to November 2010. RESULTS: In general, most positive cases (64%) occurred in children aged 5-12 years, this age group was significantly the most affected (39.8%, p = 0.001, OR = 8.3, CI 95% 1.9-36.9). Wheezing was reported by 31% (19/61) and dyspnea by 23% (14/61) of the studied patients. An outbreak of influenza H1N1 with an attack rate of 35.7% among children (median age 6 years) was documented in April 2010, before the vaccination campaign against the pandemic virus was extended for children up to 5 years in Brazil. CONCLUSIONS: Therefore, the study reinforces the recommendation to immunize school children to reduce the incidence of the disease.

scholarly journals In vitro cytotoxic study for partially purified resveratrol extracted from grape skin fruit Vitis vinifera

2009 ◽  
Vol 3 (2) ◽  
pp. 40-47
Author(s):  
Zainab Y. Mohammed ◽  
Essam F. Al-Jumaily ◽  
Nahi Y. Yaseen
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Cytotoxic Effect ◽  
Inhibitory Effect ◽  
Mammary Adenocarcinoma ◽  
Dependent Manner ◽  
Grape Skin ◽  
Grape Fruit ◽  
Glass Column

The partial purified resveratrol was obtained from the skin of black grape fruit cultivated in Iraq using 80% ethanolic solution, then an acid hydrolysis with 10% HCl solution for (10–30) min at 60Cº was carried out. The aglycone moiety was taken with an organic solvent (chloroform), then using an open glass column packed with silica gelG 60 as a stationary phase and a mobile phase of; benzene: methanol: actic acid (20:4:1). The study utilized an in vitro evaluation for the cytotoxic effect of the partially purified resveratrol on some cell lines including, the murine mammary adenocarcinoma (Ahmed –Mohammed –Nahi–2003 -AMN -3) cell line; the human laryngeal carcinoma (Hep -2) cell line and the Rat Embryo Fibroblast (REF) cell line at different concentrations and different exposure time of treatment. The partial purified resveratrol extract concentrations ranging (7.8–4000) µg/ml in a two fold serial dilutions were used to treat the three types of cell lines for 48 and 72 hours intervals. AMN-3 cell lines showed highest sensitivity toward the cytotoxic effect of the paritial purified resveratrol than other cell lines after 48 hours in a dose dependent manner. While Hep-2 cell line showed novel behavior, the lowest concentration of cell treatment gave the most significant (P< 0.01) inhibitory effect. Only the highest concentration gave significant inhibitory effect (P< 0.01) with the transformed Ref cell line.

scholarly journals Unsafe abortion among secondary school girls in a local authority in South-South Nigeria

2020 ◽  
Vol 9 (9) ◽  
pp. 3547
Author(s):  
Matthias G. Abah ◽  
Emem E. Bassey ◽  
Emmanuel B. Edu ◽  
Okupa D. Ovie
Keyword(s):  
Secondary School ◽  
Sex Education ◽  
Unwanted Pregnancy ◽  
Morbidity Rate ◽  
High Morbidity ◽  
School Students ◽  
Cross Sectional ◽  
Level Of Education ◽  
Dilation And Curettage ◽  
High Morbidity Rate

Background: Voluntary abortion for social reasons is illegal in Nigeria; however, the practice remains mostly clandestine and unsafe with varying consequences and determinants yet to be studied in all settings.Methods: A descriptive cross-sectional study design was used to assess the prevalence, practice and determinants of termination of pregnancy amongst 119 female Secondary School students in South-South Nigeria.Results: The prevalence of abortion was 57.1%. Most of the students were above 18years (58.8%), Christian (95.8%) and of rural residence (66.4%). While 58.8% had experienced an unwanted pregnancy, 61.4% had used some form of contraceptive with condom being the commonest (39.5%). Most (89.1%) have heard of abortions while 67.6% and 16.2% have had abortions once and twice respectively with the top reasons for abortion being that they were still in school (33.8%), too young (25.9%) and to avoid shame or stigma associated with the pregnancy (11.7%). Dilation and curettage was the predominant method employed (40.2%) mainly by medical doctors (34.1% and pharmacists (35.6%) while 51 (75%) had post-abortal complaints such as pain (41.2%) and bleeding (21.6%). There was a significant association between having an abortion and place of residence (rural more than urban), (p=0.04), being pregnant more than once (p<0.001), mothers` level of education (p=0.03), fathers` level of education (p=0.02) and mothers occupation (p=0.04).Conclusions: The prevalence of abortion is high and complicated by high morbidity rate despite a higher contraceptive prevalence rate whose major determinants were the socio-demographic characteristics of the parents. There is a need for early sex education from parents as this can influence abortion perception and practice in later years.

scholarly journals Monoclonal Antibodies in Multiple Sclerosis: Present and Future

Biomedicines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 20 ◽  
Author(s):  
Natalia Voge ◽  
Enrique Alvarez
Keyword(s):  
Multiple Sclerosis ◽  
Monoclonal Antibodies ◽  
Morbidity Rate ◽  
High Morbidity ◽  
Disease Modifying Therapies ◽  
High Morbidity Rate ◽  
New Treatments ◽  
Near Future ◽  
Risk Ratios

The global incidence of multiple sclerosis (MS) appears to be increasing. Although it may not be associated with a high mortality rate, this disease has a high morbidity rate which affects the quality of life of patients and reduces their ability to do their activities of daily living. Thankfully, the development of novel disease modifying therapies continues to increase. Monoclonal antibodies (MABs) have become a mainstay of MS treatment and they are likely to continue to be developed for the treatment of this disease. Specifically, MABs have proven to be some of the most efficacious treatments at reducing relapses and the inflammation in MS patients, including the first treatment for primary progressive MS and are being explored as reparative/remyelinating agents as well. These relatively new treatments will be reviewed here to help evaluate their efficacy, adverse events, immunogenicity, and benefit-risk ratios in the treatment of the diverse spectrum of MS. The focus will be on MABs that are currently approved or may be approved in the near future.

scholarly journals The Population Pharmacokinetics of Rifampicin in Japanese Pulmonary Tuberculosis Patients

Drug Research ◽  
2020 ◽  
Vol 70 (05) ◽  
pp. 199-205
Author(s):  
Takahiro Nishimura ◽  
Haruichi Kohno ◽  
Hideaki Nagai ◽  
Daisuke Maruoka ◽  
Yuichi Koike ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Japanese Patients ◽  
Morbidity Rate ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
High Morbidity ◽  
Power Model ◽  
Time Data ◽  
Nonlinear Mixed Effects Model ◽  
High Morbidity Rate

AbstractIn Japan, tuberculosis has been recognized as one of the major infections requiring urgent measures because of its high morbidity rate even now especially in elderly people suffering from tuberculosis during the past epidemic and its reactivation. Hence, many Japanese clinicians have made efforts to suppress the onset of tuberculosis and treat it effectively. The objectives of this study are to (1) identify covariate(s) that may explain the variation of rifampicin, which is the key antitubercular agent, under the steady-state by evaluating its population pharmacokinetics and (2) to propose an appropriate dosing method of rifampicin to Japanese patients. For this purpose, serum concentration–time data were obtained from 138 patients receiving rifampicin (300–450 mg) and isoniazid (300–400 mg) every day over 14 days, and analyzed using nonlinear mixed effects model. Thereby, population pharmacokinetic parameters were estimated followed by elucidating relations between the parameters and statistical factors. The analysis adopted one-compartment model including Lag-time by assuming that the absorption process is 0+1st order. The analyses demonstrate that meal affected the bioavailability, primary absorption rate constant, and zero order absorption time in the constructed model. A body weight calculated from the power model was selected as the covariate by the Stepwise Covariate Model method and found to highly affect the clearance in the range from −31.6% to 47.4%. We conclude that the dose in Japanese tuberculous patients can be well estimated by the power model formula and should be taken into consideration when rifampicin is administered.

scholarly journals The Pseudomonas aeruginosa product pyochelin interferes with Trypanosoma cruzi infection and multiplication in vitro

2020 ◽  
Vol 114 (7) ◽  
pp. 492-498 ◽  
Author(s):  
Gabriele Sass ◽  
Laura C Miller Conrad ◽  
Terrence-Thang H Nguyen ◽  
David A Stevens
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Trypanosoma Cruzi ◽  
Mammalian Cells ◽  
Iron Acquisition ◽  
Vero Cells ◽  
Dependent Manner ◽  
Wild Type ◽  
Current Standard ◽  
Cruzi Infection

Abstract Background Bacteria are sources of numerous molecules used in treatment of infectious diseases. We investigated effects of molecules produced by 26 Pseudomonas aeruginosa strains against infection of mammalian cell cultures with Trypanosoma cruzi, the aetiological agent of Chagas disease. Methods Vero cells were infected with T. cruzi in the presence of wild-type P. aeruginosa supernatants or supernatants of mutants with defects in the production of various virulence, quorum sensing and iron acquisition factors. Quantification of T. cruzi infection (percentage of infected cells) and multiplication (number of amastigotes per infected cell) was performed and cell viability was determined. Results Wild-type P. aeruginosa products negatively affected T. cruzi infection and multiplication in a dose-dependent manner, without evident toxicity for mammalian cells. PvdD/pchE mutation (loss of the P. aeruginosa siderophores pyoverdine and pyochelin) had the greatest impact on anti–T. cruzi activity. Negative effects on T. cruzi infection by pure pyochelin, but not pyoverdine, or other P. aeruginosa exoproducts studied, were quantitatively similar to the effects of benznidazole, the current standard therapy against T. cruzi. Conclusions The P. aeruginosa product pyochelin showed promising activity against T. cruzi and might become a new lead molecule for therapy development.

CRM1/XPO1 Represents a Promising Therapeutic Target for Treatment of Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 232-232
Author(s):  
Rosa Lapalombella ◽  
Caroline Berglund ◽  
Emilia Mahoney ◽  
Katie Williams ◽  
Shruti Jha ◽  
...  
Keyword(s):  
Small Molecule ◽  
Cytotoxic Effect ◽  
Stromal Cell ◽  
Time Dependent ◽  
Dependent Manner ◽  
Spontaneous Apoptosis ◽  
Stromal Cell Line ◽  
Equity Ownership

Abstract Abstract 232 Exportin 1 (CRM1, XPO1) is a nuclear exporter that promotes the transit of tumor suppressor proteins (TSPs) including p53, I-κB, and FOXO3A out of the nucleus, thereby preventing their activity and contributing to disrupted apoptosis and enhanced proliferation. Recently, whole-genome sequencing in patients with CLL allowed the identification of recurrent mutations in a highly conserved region of CRM1 that can potentially affects its gene function, suggesting a direct role for CRM1 in the pathogenesis of CLL (Puente XS, et al: Nature 75:101, 2011). However the role of CRM1 and the consequences of its mutation in the development of CLL have yet to be explored. CRM1 has been shown to be up-regulated in hematologic and various solid tumors, making it a highly attractive molecular target impacting multiple pro apoptotic pathways. KPT-SINEs are new, potent and irreversible small molecule selective inhibitors of nuclear export developed by Karyopharm that specifically and irreversibly bind to CRM1 and block the function of this protein. CLL is characterized by disrupted apoptosis caused both by co-dependent stromal elements and aberrant activation of several survival-promoting signaling/transcriptional pathways including PI3K/Akt, NF-kB, and p53. Because of the distinct subtypes of CLL and multiple signaling pathways dysregulated, a therapeutic agent targeting a single biological pathway is unlikely to be effective. Thus, pursuit of CRM1 inhibition as a novel strategy aimed to restore multiple death pathways is crucial and has broad implications for many types of patients. Our preliminary work demonstrated CRM1 is over-expressed in CLL cells compared to normal B cells at a protein (3 fold, p<0.005) and mRNA level (2.6 fold p=0.014). Inhibition of CRM1 by KPT-185 induced apoptosis in primary patient CLL cells in a dose and time dependent manner (EC50<500nM) while limited cytotoxicity against normal PBMC and isolated B, NK and T cells was observed (EC50 values >20 μM). Additionally, KPT-185 treatment of NK cells had no effect on their function as measured by ability of NK cells to mediate antibody dependent (ADCC) as wekk as direct cytotoxicity. The effect of KPT-185 on T function is currently under evaluation. Nuclear accumulation of FOXO3, p53 and IkB was also observed in primary CLL cells in a time dependent manner as shown by western blot and confocal microscopy. The evaluation of activated target genes is currently ongoing. Given the importance of microenvironmental stimuli on survival of CLL cells and response to therapy, we evaluated the ability of KPT-185 to induce cytotoxicity of CLL cells in the presence or absence of soluble factors such as CPG, CD40L, BAFF, TNF-α, IL-6, or IL-4, which are known to reduce the spontaneous apoptosis associated with CLL cells. KPT-185 treatment abrogated the protection induced by each of these factors suggesting that KPT-SINEs can disrupt signaling from the microenvironment that lead to in vivo CLL cell survival and potentially drug resistance. Interestingly the cytotoxic effect elicited by KPT-185 was enhanced in CPG activated cells (p=0.02). We also tested the ability of KPT-185 to kill CLL cells under coculture conditions with Hs5 stromal cell line. Coculture of CLL cells alone for 48 hours on the Hs5 stromal cell line resulted in a marked reduction of spontaneous apoptosis suggesting a strong protective effect elicited (P<0.001) by the stromal cells. Interestingly the cytotoxic effect mediated by KPT-185 was enhanced under coculture conditions (p=0.013). KPT-185 was also proven to be effective on murine TCL1+ cells (EC50<500nM) in vitro. The in vivo efficacy of this compound and other structurally related analogs is currently being assessed in an ongoing study in theTCL1 mouse model of CLL. In conclusion CRM1 represents a novel target that has not been adequately explored in CLL. KPT-SINEs are a class of promising therapeutic agents with proven selective in vitro activity in CLL cells providing the rationale for developing small molecule, drug-like CRM1 inhibitors for the treatment of this disease. Disclosures: Sandanayaka: Karyopharm Therapeutics: Employment. Shechter:Karyopharm Therapeutics: Employment. McCauley:Karyopharm Therapeutics: Employment. Shacham:Karyopharm: Equity Ownership. Kauffman:Karyopharm: Equity Ownership.

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