Clinical and genetic characterization of leukoencephalopathies in adults.

Brain. 2017 Mar 02;:

Authors: Lynch DS, Rodrigues Brandão de Paiva A, Zhang WJ, Bugiardini E, Freua F, Tavares Lucato L, Macedo-Souza LI, Lakshmanan R, Kinsella JA, Merwick A, Rossor AM, Bajaj N, Herron B, McMonagle P, Morrison PJ, Hughes D, Pittman A, Laurà M, Reilly MM, Warren JD, Mummery CJ, Schott JM, Adams M, Fox NC, Murphy E, Davagnanam I, Kok F, Chataway J, Houlden H

Abstract
Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults.

PMID: 28334938 [PubMed - as supplied by publisher]

SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome.

Brain. 2017 Feb 09;:

Authors: Perez Y, Shorer Z, Liani-Leibson K, Chabosseau P, Kadir R, Volodarsky M, Halperin D, Barber-Zucker S, Shalev H, Schreiber R, Gradstein L, Gurevich E, Zarivach R, Rutter GA, Landau D, Birk OS

Abstract
A novel autosomal recessive cerebro-renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration was evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI was normal. Four of the six affected individuals also had early-onset nephropathy with features of tubulo-interstitial nephritis, hypertension and tendency for hyperkalemia, though none had rapid deterioration of renal function. Genome wide linkage analysis identified an ∼18 Mb disease-associated locus on chromosome 4 (maximal logarithm of odds score 4.4 at D4S2971; θ = 0). Whole exome sequencing identified a single mutation in SLC30A9 within this locus, segregating as expected within the kindred and not found in a homozygous state in 300 Bedouin controls. We showed that SLC30A9 (solute carrier family 30 member 9; also known as ZnT-9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH-SY5Y cells overexpressing SLC30A9 fused to enhanced green fluorescent protein demonstrated vesicular cytosolic localization associated with the endoplasmic reticulum, not co-localizing with endosomal or Golgi markers. SLC30A9 encodes a putative zinc transporter (by similarity) previously associated with Wnt signalling. However, using dual-luciferase reporter assay in SH-SY5Y cells we showed that Wnt signalling was not affected by the mutation. Based on protein modelling, the identified mutation is expected to affect SLC30A9's highly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn2+ measurements in HEK293 cells overexpressing wild-type and mutant SLC30A9 showed lower zinc concentration within mutant rather than wild-type SLC30A9 cells. This suggests that SLC30A9 has zinc transport properties affecting intracellular zinc homeostasis, and that the molecular mechanism of the disease is through defective function of this novel activity of SLC30A9 rather than by a defect in its previously described role in transcriptional activation of Wnt signalling.

PMID: 28334855 [PubMed - as supplied by publisher]

Hereditary spastic paraplegia caused by compound heterozygous mutations outside the motor domain of the KIF1A gene.

Eur J Neurol. 2017 Mar 22;:

Authors: Krenn M, Zulehner G, Hotzy C, Rath J, Stogmann E, Wagner M, Haack TB, Strom TM, Zimprich A, Zimprich F

Abstract
BACKGROUND AND PURPOSE: Hereditary spastic paraplegia is a clinically and genetically heterogeneous group of rare, inherited disorders causing an upper motor neuron syndrome with (complex) or without (pure) additional neurological symptoms. Mutations in the KIF1A gene have already been associated with recessive and dominant forms of hereditary spastic paraplegia (SPG30) in a few cases.
METHODS: All family members included in the study were examined neurologically. Whole-exome sequencing was used in affected individuals to identify the responsible candidate gene. Conventional Sanger sequencing was conducted to validate familial segregation.
RESULTS: A family of Macedonian origin with two affected siblings, one with slowly progressive and the other one with a more complex and rapidly progressing hereditary spastic paraplegia is reported. In both affected individuals, two novel pathogenic mutations outside the motor domain of the KIF1A gene were found (NM_001244008.1:c.2909G>A, p.Arg970His and c.1214dup, p.Asn405Lysfs*40) that segregate with the disease within the family establishing the diagnosis of autosomal recessive SPG30.
CONCLUSIONS: This report provides the first evidence that mutations outside the motor domain of the gene can cause (recessive) SPG30 and extends the genotype-phenotype association for KIF1A-related diseases.

PMID: 28332297 [PubMed - as supplied by publisher]

Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in a Shwachman-Diamond like syndrome.

J Med Genet. 2017 Mar 22;:

Authors: Stepensky P, Chacón-Flores M, Kim KH, Abuzaitoun O, Bautista-Santos A, Simanovsky N, Siliqi D, Altamura D, Méndez-Godoy A, Gijsbers A, Naser Eddin A, Dor T, Charrow J, Sánchez-Puig N, Elpeleg O

Abstract
BACKGROUND: For the final step of the maturation of the ribosome, the nascent 40S and 60S subunits are exported from the nucleus to the cell cytoplasm. To prevent premature association of these ribosomal subunits, eukaryotic initiation factor 6 (eIF6) binds the 60S subunit within the nucleus. Its release in the cytoplasm requires the interaction of EFL1 and SDBS proteins. In Shwachman-Diamond syndrome (SDS), a defective SDBS protein prevents eIF6 eviction, inhibiting its recycle to the nucleus and subsequent formation of the active 80S ribosome.
OBJECTIVE: This study aims to identify the molecular basis of an SDS-like disease, manifested by pancytopenia, exocrine pancreatic insufficiency and skeletal abnormalities in six patients from three unrelated families.
METHODS: Whole exome analysis was used for mutation identification. Fluorescence microscopy studies assessed the localisation of Tif6-GFP, the yeast eIF6 homologue, in yeast WT and mutant cells. Human and yeast EFL1 proteins, WT and mutants, were expressed in Saccharomyces cerevisiae BCY123 strain, and circular dichroism and small-angle X-ray scattering were used to assess the folding and flexibility of these proteins. Green malachite colorimetric assay was performed to determine the GTPase activity of WT and Efl1 mutants.
RESULTS: Four patients were homozygous for p.R1095Q variant and two patients were homozygous for p.M882K variant in EFL1. Residue R1095 and M882 are conserved across species. Neither the GTPase activity of the mutant proteins nor its activation by the SDBD protein or the 60S ribosomal subunit were affected. Complementation of efl1Δ yeast cells with the EFL1 mutants rescued the slow growth phenotype. Nonetheless, Tif6-GFP was relocalised to the cytoplasm in mutant yeast cells in contrast to its nuclear localisation in WT cells.
CONCLUSIONS: Mutations in EFL1 clinically manifest as SDS-like phenotype. Similar to the molecular pathology of SDS, mutant EFL1 proteins do not promote the release of cytoplasmic Tif6 from the 60S subunit, likely preventing the formation of mature ribosomes.

PMID: 28331068 [PubMed - as supplied by publisher]

Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine.

Cancer Discov. 2017 Mar 22;:

Authors: Pauli C, Hopkins BD, Prandi D, Shaw R, Fedrizzi T, Sboner A, Sailer V, Augello M, Puca L, Rosati R, McNary TJ, Churakova Y, Cheung C, Triscott J, Pisapia D, Rao R, Mosquera JM, Robinson B, Faltas BM, Emerling BE, Gadi VK, Bernard B, Elemento O, Beltran H, Demichelis F, Kemp CJ, Grandori C, Cantley LC, Rubin MA

Abstract
Precision medicine is an approach that takes into account the influence of individuals' genes, environment, and lifestyle exposures to tailor interventions. Here, we describe the development of a robust precision cancer care platform that integrates whole-exome sequencing with a living biobank that enables high-throughput drug screens on patient-derived tumor organoids. To date, 56 tumor-derived organoid cultures and 19 patient-derived xenograft (PDX) models have been established from the 769 patients enrolled in an Institutional Review Board-approved clinical trial. Because genomics alone was insufficient to identify therapeutic options for the majority of patients with advanced disease, we used high-throughput drug screening to discover effective treatment strategies. Analysis of tumor-derived cells from four cases, two uterine malignancies and two colon cancers, identified effective drugs and drug combinations that were subsequently validated using 3-D cultures and PDX models. This platform thereby promotes the discovery of novel therapeutic approaches that can be assessed in clinical trials and provides personalized therapeutic options for individual patients where standard clinical options have been exhausted.SIGNIFICANCE: Integration of genomic data with drug screening from personalized in vitro and in vivo cancer models guides precision cancer care and fuels next-generation research. Cancer Discov; 7(5); 1-16. ©2017 AACR.

PMID: 28331002 [PubMed - as supplied by publisher]

Outcomes of Diagnostic Exome Sequencing in Patients With Diagnosed or Suspected Autism Spectrum Disorders.

Pediatr Neurol. 2017 Feb 08;:

Authors: Rossi M, El-Khechen D, Black MH, Farwell Hagman KD, Tang S, Powis Z

Abstract
BACKGROUND: Exome sequencing has recently been proved to be a successful diagnostic method for complex neurodevelopmental disorders. However, the diagnostic yield of exome sequencing for autism spectrum disorders has not been extensively evaluated in large cohorts to date.
MATERIALS AND METHODS: We performed diagnostic exome sequencing in a cohort of 163 individuals with autism spectrum disorder (66.3%) or autistic features (33.7%).
RESULTS: The diagnostic yield observed in patients in our cohort was 25.8% (42 of 163) for positive or likely positive findings in characterized disease genes, while a candidate genetic etiology was reported for an additional 3.3% (4 of 120) of patients. Among the positive findings in the patients with autism spectrum disorder or autistic features, 61.9% were the result of de novo mutations. Patients presenting with psychiatric conditions or ataxia or paraplegia in addition to autism spectrum disorder or autistic features were significantly more likely to receive positive results compared with patients without these clinical features (95.6% vs 27.1%, P < 0.0001; 83.3% vs 21.2%, P < 0.0001, respectively). The majority of the positive findings were in recently identified autism spectrum disorder genes, supporting the importance of diagnostic exome sequencing for patients with autism spectrum disorder or autistic features as the causative genes might evade traditional sequential or panel testing.
CONCLUSIONS: These results suggest that diagnostic exome sequencing would be an efficient primary diagnostic method for patients with autism spectrum disorders or autistic features. Moreover, our data may aid clinicians to better determine which subset of patients with autism spectrum disorder with additional clinical features would benefit the most from diagnostic exome sequencing.

PMID: 28330790 [PubMed - as supplied by publisher]

First-in-human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors.

Clin Cancer Res. 2017 Mar 22;:

Authors: Stein MN, Bertino JR, Kaufman HL, Mayer T, Moss R, Silk A, Chan N, Malhotra J, Rodriguez-Rodriguez L, Aisner J, Aiken RD, Haffty BG, DiPaola RS, Saunders T, Zloza A, Damare S, Beckett Y, Yu B, Najmi S, Gabel C, Dickerson S, Zheng L, El-Deiry WS, Allen J, Stogniew M, Oster W, Mehnert JM

Abstract
Purpose ONC201 is a small molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design This open-label study treated 10 patients during dose escalation with histologically-confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic (PK), and pharmacodynamic (PD) information. Results No Grade >1 drug-related adverse events occurred and the RP2D was defined as 625 mg. PK analysis revealed a Cmax of 1.5 - 7.5µg/mL (~3.9-19.4µM), mean half-life of 11.3 hours, and mean AUC of 37.7 h.ug/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved, however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (> 9 cycles) in prostate and endometrial cancer patients. Conclusion ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks.

PMID: 28331050 [PubMed - as supplied by publisher]

Dementia with Lewy bodies presenting marked tongue protrusion and bite due to lingual dystonia: A case report.

Rinsho Shinkeigaku. 2016 Jun 22;56(6):418-23

Authors: Shiga Y, Kanaya Y, Kono R, Takeshima S, Shimoe Y, Kuriyama M

Abstract
We report the patient of a 53-year-old woman who developed subacute-onset marked tonge protrusion and bite. She was diagnosed as dementia with Lewy bodies (DLB) from the clinical features including progressive cognitive decline, visual hallucinations, parkinsonism, and severe insomnia and depression, and the radiological finding of low dopamine transported uptake in basal ganglia by Dat SCAN and low blood circulation in occipital lobe of cerebrum. The patient received 600 mg doses of levodopa for over a year, followed by rotigotine and ropinirole with a rapid increase of dosage. It is believed that these treatments stimulated and sensitized dopamine D1 receptors, thereby inducing lingual dystonia. Furthermore, the patient demonstrated dyspnea and attacks of apnea caused by the closure of bilateral vocal cords due to laryngeal dyskinesia. After initiation of the neuroleptic, olanzapine, for a short duration, the high dose of levodopa overlapped with neuroleptic sensitivity, suggesting DOPA-induced dystonia and dyskinesia. This interaction can sometimes lead to lethal adverse events, and must be considered very important when treating patients with DLB.

PMID: 27212676 [PubMed - indexed for MEDLINE]

A combined in vitro approach to improve the prediction of mitochondrial toxicants.

Toxicol In Vitro. 2016 Aug;34:161-70

Authors: Eakins J, Bauch C, Woodhouse H, Park B, Bevan S, Dilworth C, Walker P

Abstract
Drug induced mitochondrial dysfunction has been implicated in organ toxicity and the withdrawal of drugs or black box warnings limiting their use. The development of highly specific and sensitive in vitro assays in early drug development would assist in detecting compounds which affect mitochondrial function. Here we report the combination of two in vitro assays for the detection of drug induced mitochondrial toxicity. The first assay measures cytotoxicity after 24h incubation of test compound in either glucose or galactose conditioned media (Glu/Gal assay). Compounds with a greater than 3-fold toxicity in galactose media compared to glucose media imply mitochondrial toxicity. The second assay measures mitochondrial respiration, glycolysis and a reserve capacity with mechanistic responses observed within one hour following exposure to test compound. In order to assess these assays a total of 72 known drugs and chemicals were used. Dose-response data was normalised to 100× Cmax giving a specificity, sensitivity and accuracy of 100%, 81% and 92% respectively for this combined approach.

PMID: 27083147 [PubMed - indexed for MEDLINE]

Adverse Effects of Plant Food Supplements and Plants Consumed as Food: Results from the Poisons Centres-Based PlantLIBRA Study.

Phytother Res. 2016 Jun;30(6):988-96

Authors: Lüde S, Vecchio S, Sinno-Tellier S, Dopter A, Mustonen H, Vucinic S, Jonsson B, Müller D, Veras Gimenez Fruchtengarten L, Hruby K, De Souza Nascimento E, Di Lorenzo C, Restani P, Kupferschmidt H, Ceschi A

Abstract
Plant food supplements (PFS) are products of increasing popularity and wide-spread distribution. Nevertheless, information about their risks is limited. To fill this gap, a poisons centres-based study was performed as part of the EU project PlantLIBRA. Multicentre retrospective review of data from selected European and Brazilian poisons centres, involving human cases of adverse effects due to plants consumed as food or as ingredients of food supplements recorded between 2006 and 2010. Ten poisons centres provided a total of 75 cases. In 57 cases (76%) a PFS was involved; in 18 (24%) a plant was ingested as food. The 10 most frequently reported plants were Valeriana officinalis, Camellia sinensis, Paullinia cupana, Melissa officinalis, Passiflora incarnata, Mentha piperita, Glycyrrhiza glabra, Ilex paraguariensis, Panax ginseng, and Citrus aurantium. The most frequently observed clinical effects were neurotoxicity and gastro-intestinal symptoms. Most cases showed a benign clinical course; however, five cases were severe. PFS-related adverse effects seem to be relatively infrequent issues for poisons centres. Most cases showed mild symptoms. Nevertheless, the occurrence of some severe adverse effects and the increasing popularity of PFS require continuous active surveillance, and further research is warranted. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 26948409 [PubMed - indexed for MEDLINE]

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"Rare Diseases"[Mesh] OR "orphan disease"

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pharmacogenomics

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"systems biology"

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("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

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Foxh1 Occupies cis-Regulatory Modules Prior to Dynamic Transcription Factor Interactions Controlling the Mesendoderm Gene Program.

Dev Cell. 2017 Mar 17;:

Authors: Charney RM, Forouzmand E, Cho JS, Cheung J, Paraiso KD, Yasuoka Y, Takahashi S, Taira M, Blitz IL, Xie X, Cho KW

Abstract
The interplay between transcription factors and chromatin dictates gene regulatory network activity. Germ layer specification is tightly coupled with zygotic gene activation and, in most metazoans, is dependent upon maternal factors. We explore the dynamic genome-wide interactions of Foxh1, a maternal transcription factor that mediates Nodal/TGF-β signaling, with cis-regulatory modules (CRMs) during mesendodermal specification. Foxh1 marks CRMs during cleavage stages and recruits the co-repressor Tle/Groucho in the early blastula. We highlight a population of CRMs that are continuously occupied by Foxh1 and show that they are marked by H3K4me1, Ep300, and Fox/Sox/Smad motifs, suggesting interplay between these factors in gene regulation. We also propose a molecular "hand-off" between maternal Foxh1 and zygotic Foxa at these CRMs to maintain enhancer activation. Our findings suggest that Foxh1 functions at the top of a hierarchy of interactions by marking developmental genes for activation, beginning with the onset of zygotic gene expression.

PMID: 28325473 [PubMed - as supplied by publisher]

A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase.

Sci Rep. 2017 Mar 21;7:44912

Authors: Segura-Cabrera A, Tripathi R, Zhang X, Gui L, Chou TF, Komurov K

Abstract
Valosin-containing protein (VCP/p97) ATPase (a.k.a. Cdc48) is a key member of the ER-associated protein degradation (ERAD) pathway. ERAD and VCP/p97 have been implicated in a multitude of human diseases, such as neurodegenerative diseases and cancer. Inhibition of VCP/p97 induces proteotoxic ER stress and cell death in cancer cells, making it an attractive target for cancer treatment. However, no drugs exist against this protein in the market. Repositioning of drugs towards new indications is an attractive alternative to the de novo drug development due to the potential for significantly shorter time to clinical translation. Here, we employed an integrative strategy for the repositioning of drugs as novel inhibitors of the VCP/p97 ATPase. We integrated structure-based virtual screening with the chemical genomics analysis of drug molecular signatures, and identified several candidate inhibitors of VCP/p97 ATPase. Importantly, experimental validation with cell-based and in vitro ATPase assays confirmed three (ebastine, astemizole and clotrimazole) out of seven tested candidates (~40% true hit rate) as direct inhibitors of VCP/p97 and ERAD. This study introduces an effective integrative strategy for drug repositioning, and identified new drugs against the VCP/p97/ERAD pathway in human diseases.

PMID: 28322292 [PubMed - in process]

Cystic fibrosis pulmonary exacerbations attributable to respiratory syncytial virus and influenza: a population-based study.

Clin Infect Dis. 2017 Mar 09;:

Authors: Somayaji R, Goss CH, Khan U, Neradilek M, Neuzil KM, Ortiz JR

Abstract
Background: Characterization of the role of respiratory viral pathogens on cystic fibrosis (CF) pulmonary disease is needed. We aimed to determine the association of influenza and respiratory syncytial virus (RSV) activity with risk of pulmonary exacerbation (PEx) in persons with CF in the United States.
Methods: We conducted a cohort study from January 2003 - March 2009 using the CF Foundation Patient Registry merged with CDC respiratory virus surveillance data. The primary goal was to determine the association between regional influenza or RSV detections with risk of PEx requiring intravenous antibiotics or hospitalization. We analyzed outcomes by geographic region and week of event using multivariable regression models adjusted for demographic and clinical predictors of PEx stratified for children (<18 years) and adults (18 years) to calculate relative risks (RR) of PEx.
Results: There were 21,022 individuals (52% male) in the CF patient cohort in 2003 comprised of 12,702 children and 8,320 adults. The overall incidence rate of PEx was 521.9 per 10,000 person-months. In children, a 10% increase in the proportion of surveillance tests positive for influenza or RSV were significantly associated with increased PEx risk (RR 1.02 [95% CI 1.01-1.03] ) and (RR 1.05 [95% CI 1.02-1.07],) respectively. In adults, surveillance tests positive for influenza (RR 1.02 [95% CI 1.01-1.02]) but not RSV (RR 0.99 [0.98-1.01]), had a significant association with PEx risk.
Conclusions: Our large CF population based cohort demonstrated a significant association between PEx risk and influenza activity in children and adults and with RSV activity in children.

PMID: 28329304 [PubMed - as supplied by publisher]

Lack of small colony variants of Staphylococcus aureus from lower respiratory tract specimens.

Pediatr Pulmonol. 2017 Mar 22;:

Authors: Carzino R, Hart E, Sutton P, King L, Ranganathan S, AREST CF

Abstract
BACKGROUND: Small-colony variants (SCVs) of Staphylococcus aureus are associated with worse lung disease in children with Cystic Fibrosis (CF), exhibit a higher resistance to antibiotics and co-colonize more commonly with Pseudomonas aeruginosa compared to the normal phenotype. The prevalence of SCVs in lower airway specimens from children with CF is largely unknown.
METHODS: Each visible morphotype of S. aureus was subcultured onto horse blood agar (HBA) to enable identification of SCVs.
RESULTS: Sixty-one samples from 41 children (mean age 11.7 (SD 5.3) years) were identified with a positive S. aureus culture from lower respiratory tract specimens collected in 2014-2015. None of the differing morphotypes isolated were identified as S. aureus SCVs.
CONCLUSION: In a center where anti staphylococcal prophylaxis is adopted, S. aureus SCVs were not isolated from the lower airways specimens in young children with CF indicating that acquisition of small colony variant S. aureus may not be a significant clinical problem in young children with CF.

PMID: 28328157 [PubMed - as supplied by publisher]

The Smac Mimetic BV6 Improves NK Cell-Mediated Killing of Rhabdomyosarcoma Cells by Simultaneously Targeting Tumor and Effector Cells.

Front Immunol. 2017;8:202

Authors: Fischer K, Tognarelli S, Roesler S, Boedicker C, Schubert R, Steinle A, Klingebiel T, Bader P, Fulda S, Ullrich E

Abstract
Rhabdomyosarcoma (RMS), the most common cancer of connective tissues in pediatrics, is often resistant to conventional therapies. One underlying mechanism of this resistance is the overexpression of Inhibitor of Apoptosis (IAP) proteins, leading to a dysfunctional cell death program within tumor cells. Smac mimetics (SM) are small molecules that can reactivate the cell death program by antagonizing IAP proteins and thereby compensating their overexpression. Here, we report that SM sensitize two RMS cell lines (RD and RH30) toward natural killer (NK) cell-mediated killing on the one hand, and increase the cytotoxic potential of NK cells on the other. The SM-induced sensitization of RH30 cells toward NK cell-mediated killing is significantly reduced through blocking tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on NK cells prior to coculture. In addition, the presence of zVAD.fmk, a pancaspase inhibitor, rescues tumor cells from the increase in killing, indicating an apoptosis-dependent cell death. On the NK cell side, the presence of SM in addition to IL-2 during the ex vivo expansion leads to an increase in their cytotoxic activity against RH30 cells. This effect is mainly TNFα-dependent and partially mediated by NK cell activation, which is associated with transcriptional upregulation of NF-κB target genes such as IκBα and RelB. Taken together, our findings implicate that SM represent a novel double-hit strategy, sensitizing tumor and activating NK cells with one single drug.

PMID: 28326081 [PubMed - in process]