Deep learning applications for predicting pharmacological properties of drugs and drug repurposing using transcriptomic data.

Mol Pharm. 2016 May 20;

Authors: Aliper A, Plis S, Artemov A, Ulloa A, Mamoshina P, Zhavoronkov A

Abstract
Deep learning is rapidly advancing many areas of science and technology with multiple success stories in image, text, voice and video recognition, robotics and autonomous driving. In this paper we demonstrate how deep neural networks (DNN) trained on large transcriptional response data sets can classify various drugs to therapeutic categories solely based on their transcriptional profiles. We used the perturbation samples of 678 drugs across A549, MCF-7 and PC-3 cell lines from the LINCS project and linked those to 12 therapeutic use categories derived from MeSH. To train the DNN, we utilized both gene level transcriptomic data and transcriptomic data processed using a pathway activation scoring algorithm, for a pooled dataset of samples perturbed with different concentrations of the drug for 6 and 24 hours. When applied to normalized gene expression data for "landmark genes," DNN showed cross-validation mean F1 scores of 0.397, 0.285 and 0.234 on 3-, 5- and 12-category classification problems, respectively. At the pathway level DNN performed best with cross-validation mean F1 scores of 0.701, 0.596 and 0.546 on the same tasks. In both gene and pathway level classification, DNN convincingly outperformed support vector machine (SVM) model on every multiclass classification problem. For the first time we demonstrate a deep learning neural net trained on transcriptomic data to recognize pharmacological properties of multiple drugs across different biological systems and conditions. We also propose using deep neural net confusion matrices for drug repositioning. This work is a proof of principle for applying deep learning to drug discovery and development.

PMID: 27200455 [PubMed - as supplied by publisher]

Web Ontologies to Categorialy Structure Reality: Representations of Human Emotional, Cognitive, and Motivational Processes.

Front Psychol. 2016;7:551

Authors: López-Gil JM, Gil R, García R

Abstract
This work presents a Web ontology for modeling and representation of the emotional, cognitive and motivational state of online learners, interacting with university systems for distance or blended education. The ontology is understood as a way to provide the required mechanisms to model reality and associate it to emotional responses, but without committing to a particular way of organizing these emotional responses. Knowledge representation for the contributed ontology is performed by using Web Ontology Language (OWL), a semantic web language designed to represent rich and complex knowledge about things, groups of things, and relations between things. OWL is a computational logic-based language such that computer programs can exploit knowledge expressed in OWL and also facilitates sharing and reusing knowledge using the global infrastructure of the Web. The proposed ontology has been tested in the field of Massive Open Online Courses (MOOCs) to check if it is capable of representing emotions and motivation of the students in this context of use.

PMID: 27199796 [PubMed]

Strategies for new and improved vaccines against ticks and tick-borne diseases.

Parasite Immunol. 2016 May 20;

Authors: de la Fuente J, Kopáček P, Lew-Tabor A, Maritz-Olivier C

Abstract
Ticks infest a variety of animal species and transmit pathogens causing disease in both humans and animals worldwide. Tick-host-pathogen interactions have evolved through dynamic processes that accommodated the genetic traits of the hosts, pathogens transmitted and the vector tick species that mediate their development and survival. New approaches for tick control are dependent on defining molecular interactions between hosts, ticks and pathogens to allow for discovery of key molecules that could be tested in vaccines or new generation therapeutics for intervention of tick-pathogen cycles. Currently, tick vaccines constitute an effective and environmentally sound approach for the control of ticks and the transmission of the associated tick-borne diseases. New candidate protective antigens will most likely be identified by focusing on proteins with relevant biological function in the feeding, reproduction, development, immune response, subversion of host immunity of the tick vector and/or molecules vital for pathogen infection and transmission. This review addresses different approaches and strategies used for the discovery of protective antigens, including focusing on relevant tick biological functions and proteins, reverse genetics, vaccinomics and tick protein evolution and interactomics. New and improved tick vaccines will most likely contain multiple antigens to control tick infestations and pathogen infection and transmission. This article is protected by copyright. All rights reserved.

PMID: 27203187 [PubMed - as supplied by publisher]

The Obama Administration's Cancer Moonshot: A Call for Proteomics.

Clin Cancer Res. 2016 May 19;

Authors: Conrads TP, Petricoin EF

Abstract
The Cancer Moonshot Program has been launched and represents a potentially paradigm-shifting initiative with the goal to implement a focused national effort to double the rate of progress against cancer. The placement of precision medicine, immunotherapy, genomics, and combination therapies was placed at the central nexus of this initiative. While we are extremely enthusiastic about the goals of the program, it is time we meet this revolutionary project with equally bold and cutting-edge ideas: its time we move firmly into the post-genome era and provide the necessary resources to propel and seize on innovative recent gains in the field of proteomics required for it to stand on equal footing in this narrative as a combined, synergistic engine for molecular profiling. After all, while the genome is the information archive, it is the proteins that actually do the work of the cell and represent the structural cellular machinery. It is the proteins that comprise most of the biomarkers that are measured to detect cancers, constitute the antigens that drive immune response and inter and itntracellular communications, and it is the proteins that are the drug targets for nearly every targeted therapy that is being evaluated in cancer trials today. We believe that a combined systems biology view of the tumor microenvironment that orients cancer studies back to the functional proteome, phosphoproteome and biochemistry of the cell will be essential to deliver on the promise of the Cancer Moonshot program.

PMID: 27199492 [PubMed - as supplied by publisher]

Reconstruction of gene regulatory networks reveals chromatin remodelers and key transcription factors in tumorigenesis.

Genome Med. 2016;8(1):57

Authors: Malysheva V, Mendoza-Parra MA, Saleem MA, Gronemeyer H

Abstract
BACKGROUND: Alterations in genetic and epigenetic landscapes are known to contribute to the development of different types of cancer. However, the mechanistic links between transcription factors and the epigenome which coordinate the deregulation of gene networks during cell transformation are largely unknown.
METHODS: We used an isogenic model of stepwise tumorigenic transformation of human primary cells to monitor the progressive deregulation of gene networks upon immortalization and oncogene-induced transformation. We applied a systems biology approach by combining transcriptome and epigenome data for each step during transformation and integrated transcription factor-target gene associations in order to reconstruct the gene regulatory networks that are at the basis of the transformation process.
RESULTS: We identified 142 transcription factors and 24 chromatin remodelers/modifiers (CRMs) which are preferentially associated with specific co-expression pathways that originate from deregulated gene programming during tumorigenesis. These transcription factors are involved in the regulation of divers processes, including cell differentiation, the immune response, and the establishment/modification of the epigenome. Unexpectedly, the analysis of chromatin state dynamics revealed patterns that distinguish groups of genes which are not only co-regulated but also functionally related. Decortication of transcription factor targets enabled us to define potential key regulators of cell transformation which are engaged in RNA metabolism and chromatin remodeling.
CONCLUSIONS: We reconstructed gene regulatory networks that reveal the alterations occurring during human cellular tumorigenesis. Using these networks we predicted and validated several transcription factors as key players for the establishment of tumorigenic traits of transformed cells. Our study suggests a direct implication of CRMs in oncogene-induced tumorigenesis and identifies new CRMs involved in this process. This is the first comprehensive view of the gene regulatory network that is altered during the process of stepwise human cellular tumorigenesis in a virtually isogenic system.

PMID: 27198694 [PubMed - in process]

Simple biophysics underpins collective conformations of the intrinsically disordered proteins of the Nuclear Pore Complex.

Elife. 2016;5

Authors: Vovk A, Gu C, Opferman MG, Kapinos LE, Lim RY, Coalson RD, Jasnow D, Zilman A

Abstract
Nuclear Pore Complexes (NPCs) are key cellular transporter that control nucleocytoplasmic transport in eukaryotic cells, but its transport mechanism is still not understood. The centerpiece of NPC transport is the assembly of intrinsically disordered polypeptides, known as FG nucleoporins, lining its passageway. Their conformations and collective dynamics during transport are difficult to assess in vivo. In vitro investigations provide partially conflicting results, lending support to different models of transport, which invoke various conformational transitions of the FG nucleoporins induced by the cargo-carrying transport proteins. We show that the spatial organization of FG nucleoporin assemblies with the transport proteins can be understood within a first principles biophysical model with a minimal number of key physical variables, such as the average protein interaction strengths and spatial densities. These results address some of the outstanding controversies and suggest how molecularly divergent NPCs in different species can perform essentially the same function.

PMID: 27198189 [PubMed - in process]

Metabolomics in cardiovascular diseases.

J Pharm Biomed Anal. 2015 Sep 10;113:121-36

Authors: Kordalewska M, Markuszewski MJ

Abstract
Cardiovascular diseases (CVDs) are the main cause of death globally. There is a need for the development of specific diagnostic methods, more effective therapeutic procedures as well as drugs, which can decrease the risk of deaths in the course of CVDs. For this reason, better understanding and explanation of molecular pathomechanisms of CVDs are essential. Metabolomics is focused on analysis of metabolites, small molecules which reflect the state of an organism in a certain point of time. Application of metabolomics approach in the investigation of molecular processes responsible for CVDs development may provide valuable information. In this article we overviewed recent reports employing application of untargeted and targeted metabolomic analyses in particular CVDs. Moreover, we focused on applications of various analytical platforms and metabolomics approaches which may contribute to the explanation of the pathomechanisms of different cardiovascular diseases.

PMID: 25958299 [PubMed - indexed for MEDLINE]

Metabolomics for laboratory diagnostics.

J Pharm Biomed Anal. 2015 Sep 10;113:108-20

Authors: Bujak R, Struck-Lewicka W, Markuszewski MJ, Kaliszan R

Abstract
Metabolomics is an emerging approach in a systems biology field. Due to continuous development in advanced analytical techniques and in bioinformatics, metabolomics has been extensively applied as a novel, holistic diagnostic tool in clinical and biomedical studies. Metabolome's measurement, as a chemical reflection of a current phenotype of a particular biological system, is nowadays frequently implemented to understand pathophysiological processes involved in disease progression as well as to search for new diagnostic or prognostic biomarkers of various organism's disorders. In this review, we discussed the research strategies and analytical platforms commonly applied in the metabolomics studies. The applications of the metabolomics in laboratory diagnostics in the last 5 years were also reviewed according to the type of biological sample used in the metabolome's analysis. We also discussed some limitations and further improvements which should be considered taking in mind potential applications of metabolomic research and practice.

PMID: 25577715 [PubMed - indexed for MEDLINE]

Text Mining of Journal Articles for Sleep Disorder Terminologies.

PLoS One. 2016;11(5):e0156031

Authors: Lam C, Lai FC, Wang CH, Lai MH, Hsu N, Chung MH

Abstract
OBJECTIVE: Research on publication trends in journal articles on sleep disorders (SDs) and the associated methodologies by using text mining has been limited. The present study involved text mining for terms to determine the publication trends in sleep-related journal articles published during 2000-2013 and to identify associations between SD and methodology terms as well as conducting statistical analyses of the text mining findings.
METHODS: SD and methodology terms were extracted from 3,720 sleep-related journal articles in the PubMed database by using MetaMap. The extracted data set was analyzed using hierarchical cluster analyses and adjusted logistic regression models to investigate publication trends and associations between SD and methodology terms.
RESULTS: MetaMap had a text mining precision, recall, and false positive rate of 0.70, 0.77, and 11.51%, respectively. The most common SD term was breathing-related sleep disorder, whereas narcolepsy was the least common. Cluster analyses showed similar methodology clusters for each SD term, except narcolepsy. The logistic regression models showed an increasing prevalence of insomnia, parasomnia, and other sleep disorders but a decreasing prevalence of breathing-related sleep disorder during 2000-2013. Different SD terms were positively associated with different methodology terms regarding research design terms, measure terms, and analysis terms.
CONCLUSION: Insomnia-, parasomnia-, and other sleep disorder-related articles showed an increasing publication trend, whereas those related to breathing-related sleep disorder showed a decreasing trend. Furthermore, experimental studies more commonly focused on hypersomnia and other SDs and less commonly on insomnia, breathing-related sleep disorder, narcolepsy, and parasomnia. Thus, text mining may facilitate the exploration of the publication trends in SDs and the associated methodologies.

PMID: 27203858 [PubMed - as supplied by publisher]

An Integrated Data Driven Approach to Drug Repositioning Using Gene-Disease Associations.

PLoS One. 2016;11(5):e0155811

Authors: Mullen J, Cockell SJ, Woollard P, Wipat A

Abstract
Drug development is both increasing in cost whilst decreasing in productivity. There is a general acceptance that the current paradigm of R&D needs to change. One alternative approach is drug repositioning. With target-based approaches utilised heavily in the field of drug discovery, it becomes increasingly necessary to have a systematic method to rank gene-disease associations. Although methods already exist to collect, integrate and score these associations, they are often not a reliable reflection of expert knowledge. Furthermore, the amount of data available in all areas covered by bioinformatics is increasing dramatically year on year. It thus makes sense to move away from more generalised hypothesis driven approaches to research to one that allows data to generate their own hypothesis. We introduce an integrated, data driven approach to drug repositioning. We first apply a Bayesian statistics approach to rank 309,885 gene-disease associations using existing knowledge. Ranked associations are then integrated with other biological data to produce a semantically-rich drug discovery network. Using this network, we show how our approach identifies diseases of the central nervous system (CNS) to be an area of interest. CNS disorders are identified due to the low numbers of such disorders that currently have marketed treatments, in comparison to other therapeutic areas. We then systematically mine our network for semantic subgraphs that allow us to infer drug-disease relations that are not captured in the network. We identify and rank 275,934 drug-disease has_indication associations after filtering those that are more likely to be side effects, whilst commenting on the top ranked associations in more detail. The dataset has been created in Neo4j and is available for download at https://bitbucket.org/ncl-intbio/genediseaserepositioning along with a Java implementation of the searching algorithm.

PMID: 27196054 [PubMed - as supplied by publisher]

Whole Exome Sequencing in a Rare Disease: A Patient with Anomalous Left Coronary Artery from the Pulmonary Artery (Bland-White-Garland Syndrome).

OMICS. 2016 May;20(5):325-327

Authors: Hekim N, Batyraliev T, Trujillano D, Wang W, Dandara C, Karben Z, Saygılı Eİ, Çetin Z, Mıhcıoğlu D, Türkmen S, İkidağ MA, Cüce MA, Rolfs A

PMID: 27195969 [PubMed - as supplied by publisher]

A Novel ECM1 Splice Site Mutation in Lipoid Proteinosis: Case Report plus Review of the Literature.

Mol Syndromol. 2016 Apr;7(1):26-31

Authors: Rey LK, Kohlhase J, Möllenhoff K, Dekomien G, Epplen JT, Hoffjan S

Abstract
Lipoid proteinosis (LP) is an autosomal recessive genodermatosis known to be caused by mutations in ECM1. Nonsense and missense mutations are the most common variations in LP. Up to date, only 6 splice site mutations have been observed. We report on a 26-year-old female LP patient from a Turkish consanguineous family carrying a novel homozygous splice site mutation in intron 8 of the ECM1 gene and summarize the current knowledge on ECM1 mutations and possible genotype-phenotype correlations.

PMID: 27194970 [PubMed]

First reported association of chronic lymphocytic leukaemia and interstitial granulomatous dermatitis.

BMJ Case Rep. 2016;2016

Authors: Riaz IB, Kamal MU, Segal RJ, Anwer F

Abstract
Interstitial granulomatous dermatitis (IGD), a rare disease, is well known to be associated with connective tissue disorders, malignancies and several drugs. We describe this first case of IGD in association with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). A 66-year-old woman with a 6-year history of untreated CLL/SLL, presented with a 2-month history of progressively worsening eruption of the left thigh, along with fatigue, lymphadenopathy and night sweats. Skin biopsy showed findings consistent with IGD and infiltration of CLL. The eruption was non-responsive to treatment with antibiotics and local steroids. There was a significant improvement in the rash after an initial cycle of chemotherapy (combination therapy with bendamustine and rituximab) and complete resolution by the third cycle, for the treatment of her CLL. We suggest that the possibility of an underlying haematological malignancy should be investigated in patients with a skin rash non-responsive to conventional therapy.

PMID: 27194675 [PubMed - in process]

The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network.

Orphanet J Rare Dis. 2016;11(1):66

Authors: Merkel PA, Manion M, Gopal-Srivastava R, Groft S, Jinnah HA, Robertson D, Krischer JP, Rare Diseases Clinical Research Network

Abstract
BACKGROUND: Among the unique features of the Rare Diseases Clinical Research Network (RDCRN) Program is the requirement for each Consortium to include patient advocacy groups (PAGs) as research partners. This development has transformed the work of the RDCRN and is a model for collaborative research. This article outlines the roles patients and PAGs play in the RDCRN and reports on the PAGs' impact on the Network's success.
METHODS: Principal Investigators from the 17 RDCRN Consortia and 28 representatives from 76 PAGs affiliated with these Consortia were contacted by email to provide feedback via an online RDCRN survey. Impact was measured in the key areas of 1) Research logistics; 2) Outreach and communication; and 3) Funding and in-kind support. Rating choices were: 1-very negative, 2-somewhat negative, 3-no impact, 4-somewhat positive, and 5-very positive.
RESULTS: Twenty-seven of the PAGs (96 %) disseminate information about the RDCRN within the patient community. The Consortium Principal Investigators also reported high levels of PAG involvement. Sixteen (94 %) Consortium Principal Investigators and 25 PAGs (89 %) reported PAGs participation in protocol review, study design, Consortium conference calls, attending Consortium meetings, or helping with patient recruitment.
CONCLUSIONS: PAGs are actively involved in shaping Consortia's research agendas, help ensure the feasibility and success of research protocols by assisting with study design and patient recruitment, and support training programs. This extensive PAG-Investigator partnership in the RDCRN has had a strongly positive impact on the success of the Network.

PMID: 27194034 [PubMed - as supplied by publisher]

Portosystemic Shunt Surgery in Patients with Idiopathic Noncirrhotic Portal Hypertension.

Ann Transplant. 2016;21:317-20

Authors: Karagul S, Yagci MA, Tardu A, Ertugrul I, Kirmizi S, Sumer F, Isik B, Kayaalp C, Yilmaz S

Abstract
BACKGROUND Idiopathic noncirrhotic portal hypertension (INCPH) is a rare disease characterized by increased portal venous pressure in the absence of cirrhosis and other causes of liver diseases. The aim of the present study was to present our results in using portosystemic shunt surgery in patients with INCPH. MATERIAL AND METHODS Patients who had been referred to our Liver Transplantation Institute for liver transplantation and who had undergone surgery from January 2010 to December 2015 were retrospectively analyzed. Patients with INCPH who had undergone portosystemic shunt procedure were included in the study. Age, sex, symptoms and findings, type of portosystemic shunt, and postoperative complications were assessed. RESULTS A total of 1307 patients underwent liver transplantation from January 2010 to December 2015. Eleven patients with INCPH who did not require liver transplantation were successfully operated on with a portosystemic shunt procedure. The mean follow-up was 30.1±19 months (range 7-69 months). There was no mortality in the perioperative period or during the follow-up. Two patients underwent surgery again due to intra-abdominal hemorrhage; one had bleeding from the surgical site except the portacaval anastomosis and the other had bleeding from the h-graft anastomosis. No patient developed encephalopathy and no patient presented with esophageal variceal bleeding after portosystemic shunt surgery. Shunt thrombosis occurred in 1 patient (9.9%). Only 1 patient developed ascites, which was controlled medically. CONCLUSIONS Portosystemic shunt surgery is a safe and effective procedure for the treatment of patients with INCPH.

PMID: 27194018 [PubMed - in process]

Altered localization and functionality of TAR DNA Binding Protein 43 (TDP-43) in niemann- pick disease type C.

Acta Neuropathol Commun. 2016;4(1):52

Authors: Dardis A, Zampieri S, Canterini S, Newell KL, Stuani C, Murrell JR, Ghetti B, Fiorenza MT, Bembi B, Buratti E

Abstract
Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by the occurrence of visceral and neurological symptoms. At present, the molecular mechanisms causing neurodegeneration in this disease are unknown. Here we report the altered expression and/or mislocalization of the TAR-DNA binding protein 43 (TDP-43) in both NPC mouse and in a human neuronal model of the disease. We also report the neuropathologic study of a NPC patient's brain, showing that while TDP-43 is below immunohistochemical detection in nuclei of cerebellar Purkinje cells, it has a predominant localization in the cytoplasm of these cells. From a functional point of view, the TDP-43 mislocalization, that occurs in a human experimental neuronal model system, is associated with specific alterations in TDP-43 controlled genes. Most interestingly, treatment with N-Acetyl-cysteine (NAC) or beta-cyclodextrin (CD) can partially restore TDP-43 nuclear localization. Taken together, the results of these studies extend the role of TDP-43 beyond the Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)/Alzheimer disease (AD) spectrum. These findings may open novel research/therapeutic avenues for a better understanding of both NPC disease and the TDP-43 proteinopathy disease mechanism.

PMID: 27193329 [PubMed - in process]

Novel European SLC1A4 variant: infantile spasms and population ancestry analysis.

J Hum Genet. 2016 May 19;

Authors: Conroy J, M Allen N, Gorman K, O'Halloran E, Shahwan A, Lynch B, Lynch SA, Ennis S, King MD

Abstract
SLC1A4 deficiency is a recently described neurodevelopmental disorder associated with microcephaly, global developmental delay, abnormal myelination, thin corpus callosum and seizures. It has been mainly reported in the Ashkenazi-Jewish population with affected individuals homozygous for the p.Glu256Lys variant. Exome sequencing performed in an Irish proband identified a novel homozygous nonsense SLC1A4 variant [p.Trp453*], confirming a second case of SLC1A4-associated infantile spasms. As this is the first European identified, population ancestry analysis of the Exome Aggregation Consortium database was performed to determine the wider ethnic background of SLC1A4 deficiency carriers. p.Glu256Lys was found in Hispanic and South Asian populations. Other potential disease-causing variants were also identified. Investigation for SLC1A4 deficiency should be performed regardless of ethnicity and extend to include unexplained early-onset epileptic encephalopathy.Journal of Human Genetics advance online publication, 19 May 2016; doi:10.1038/jhg.2016.44.

PMID: 27193218 [PubMed - as supplied by publisher]

A partial trace amine-associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment.

Addict Biol. 2016 May 19;

Authors: Pei Y, Asif-Malik A, Hoener M, Canales JJ

Abstract
Recent evidence suggests that the trace amine-associated receptor 1 (TAAR1) plays a pivotal role in the regulation of dopamine (DA) transmission and psychostimulant action. Several selective TAAR1 agonists have previously shown efficacy in models of cocaine addiction. However, the effects of TAAR1 activation on methamphetamine (METH)-induced behaviours are less well understood, as indeed are the underlying neurochemical mechanisms mediating potential interactions between TAAR1 and METH. Here, in a progressive ratio schedule of reinforcement the partial TAAR1 agonist, RO5263397, reduced the break-point for METH self-administration, while significantly increasing responding maintained by food reward. Following self-administration and extinction training, RO5263397 completely blocked METH-primed reinstatement of METH seeking. Moreover, when used as a substitute, unlike a low dose of METH, which sustained vigorous responding when substituting for the training dose of METH, RO5263397 was not self-administered at any dose, thus exhibiting no apparent abuse liability. Fast-scan cyclic voltammetry experiments showed that RO5263397 prevented METH-induced DA overflow in slices of the nucleus accumbens, while having no effect on DA transmission in its own right. Collectively, the present observations demonstrate that partial TAAR1 activation decreases the motivation to self-administer METH, blocks METH-primed reinstatement of METH seeking and prevents METH-induced DA elevations in the nucleus accumbens, and strongly support the candidacy of TAAR1-based medications as potential substitute treatment in METH addiction.

PMID: 27193165 [PubMed - as supplied by publisher]

Clinical and pathologic features of patients with non-epithelial ovarian cancer: retrospective analysis of a single institution 15-year experience.

Clin Transl Oncol. 2016 May 18;

Authors: Kempf E, Desamericq G, Vieites B, Diaz-Padilla I, Calvo E, Estevez P, Garcia-Arreza A, Martinez-Maestre MA, Duran I

Abstract
PURPOSE: Non-epithelial ovarian cancers (NEOCs) are rare diseases. Despite their overall good prognosis, the best management and current prognostic factors remain unclear. The objective of our study was to assess the clinical and pathological features of NEOC patients treated in our institution in the last 15 years and to explore risk factors for relapse and survival.
METHODS/PATIENTS: All patients with a pathological diagnosis of NEOC referred to the medical oncology department at Hospital Universitario Virgen del Rocio between 1999 and 2014 were included. Demographics, tumor characteristics, treatment procedures, and clinical follow-up were retrospectively collected. Risk factors for disease-free survival (DFS) and overall survival (OS) were assessed.
RESULTS: Fifty-seven patients were included, 33 (58 %) had a sex cord-stromal tumor (SCST) and 24 (42 %) had a germ-cell tumor (GCT). Median age, non-conservative surgery rates and DFS were lower in the GCT cohort; however, salvage chemotherapy led to a high proportion of complete responses in this group translating into a 90 % 3-year OS rate in both NEOC subtypes. The only identified risk factors statistically significant were stage and tumour relapse that associated, respectively, with DFS (HR = 8.84; 95 % CI 1.85-42) and OS (HR = 11.02; 95 % CI 1.76-68.7).
CONCLUSIONS: Despite their rarity, NEOCs remain a highly curable group of neoplasm. In our series, a more conservative treatment approach in ovarian GCTs revealed comparable OS outcomes to SCST. No new risk factors that would help in patient stratification were identified.

PMID: 27193130 [PubMed - as supplied by publisher]

A de novo 0.63 Mb 6q25.1 deletion associated with growth failure, congenital heart defect, underdeveloped cerebellar vermis, abnormal cutaneous elasticity and joint laxity.

Am J Med Genet A. 2015 Sep;167A(9):2042-51

Authors: Salpietro V, Ruggieri M, Mankad K, Di Rosa G, Granata F, Loddo I, Moschella E, Calabro MP, Capalbo A, Bernardini L, Novelli A, Polizzi A, Seidler DG, Arrigo T, Briuglia S

Abstract
Deletions of the long arm of chromosome 6 are rare and are characterized by great clinical variability according to the deletion breakpoint. We report a on 6-year-old girl with a de novo 0.63 Mb deletion on chromosome 6q25.1 who demonstrated multiple congenital anomalies including a ventricular septal defect and an underdeveloped cerebellar vermis. She presented with severe pre- and post-natal growth failure, hyperextensible small joints (Beighton scores = 8/9; with normal parental scores), and an abnormally elastic, redundant skin. Abnormally high upper/lower segment ratio (i.e., 1.34 = > 3SD), mild dysmorphic facial features and developmental delay were also present. The girl's phenotype was compared with: (i) two girls, each previously reported by Bisgaard et al. and Caselli et al. with similar albeit larger (2.6-7.21 Mb) deletions; (ii) seven additional individuals (6 M; 1 F) harboring deletions within the 6q25.1 region reported in the literature; and (iii) ten further patients (5 M; 4 F; 1 unrecorded sex) recorded in the DECIPHER 6.0 database. We reported on the present girl as her findings could contribute to advance the phenotype of 6q deletions. In addition, the present deletion is the smallest so far recorded in the 6q25 region encompassing eight known genes [vs. 41 of Bisgaard et al., and 23 of Caselli et al.,], including the TAB2 (likely responsible for the girl's congenital heart defect), LATS1 gene, and the UST gene (a regulator of the homeostasis of proteoglycans, which could have played a role in the abnormal dermal and cartilage elasticity).

PMID: 25940952 [PubMed - indexed for MEDLINE]