tbuckley/cabot-search huggingface dataset:
Insights into Ciliary Genes and Evolution from Multi-Level Phylogenetic Profiling
Authors: Yannis Nevers, Megana K. Prasad, Laetitia Poidevin, Kirsley Chennen, Alexis Allot, Arnaud Kress, Raymond Ripp, Julie D. Thompson, Hélène Dollfus, Olivier Poch, Odile Lecompte
Journal: Molecular Biology and Evolution (2017)

Cilia (flagella) are important eukaryotic organelles, present in the Last Eukaryotic Common Ancestor, and are involved in cell motility and integration of extracellular signals. Ciliary dysfunction causes a class of genetic diseases, known as ciliopathies, however current knowledge of the underlying mechanisms is still limited and a better characterization of genes is needed. As cilia have been lost independently several times during evolution and they are subject to important functional variation between species, ciliary genes can be investigated through comparative genomics. We performed phylogenetic profiling by predicting orthologs of human protein-coding genes in 100 eukaryotic species. The analysis integrated three independent methods to predict a consensus set of 274 ciliary genes, including 87 new promising candidates. A fine-grained analysis of the phylogenetic profiles allowed a partitioning of ciliary genes into modules with distinct evolutionary histories and ciliary functions (assembly, movement, centriole, etc.) and thus propagation of potential annotations to previously undocumented genes. The cilia/basal body localization was experimentally confirmed for five of these previously unannotated proteins (LRRC23, LRRC34, TEX9, WDR27, and BIVM), validating the relevance of our approach. Furthermore, our multi-level analysis sheds light on the core gene sets retained in gamete-only flagellates or Ecdysozoa for instance. By combining gene-centric and species-oriented analyses, this work reveals new ciliary and ciliopathy gene candidates and provides clues about the evolution of ciliary processes in the eukaryotic domain. Additionally, the positive and negative reference gene sets and the phylogenetic profile of human genes constructed during this study can be exploited in future work.
Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome
Authors: Najim Lahrouchi, Hariharan Raju, Elisabeth M. Lodder, Efstathios Papatheodorou, James S. Ware, Michael Papadakis, Rafik Tadros, Della Cole, Jonathan R. Skinner, Jackie Crawford, Donald R. Love, Chee J. Pua, Bee Y. Soh, Jaydutt D. Bhalshankar, Risha Govind, Jacob Tfelt-Hansen, Bo G. Winkel, Christian van der Werf, Yanushi D. Wijeyeratne, Greg Mellor, Jan Till, Marta C. Cohen, Maria Tome-Esteban, Sanjay Sharma, Arthur A.M. Wilde, Stuart A. Cook, Connie R. Bezzina, Mary N. Sheppard, Elijah R. Behr
Journal: Journal of the American College of Cardiology (2017)

Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.
German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients
Authors: V. Möbus, G. von Minckwitz, C. Jackisch, H.-J. Lück, A. Schneeweiss, H. Tesch, D. Elling, N. Harbeck, B. Conrad, T. Fehm, J. Huober, V. Müller, I. Bauerfeind, A. du Bois, S. Loibl, V. Nekljudova, M. Untch, C. Thomssen
Journal: Annals of Oncology (2017)
TMOD-27. A NOVEL SET OF PATIENT-DERIVED ORTHOTOPIC XENOGRAFT (PDOX) MODELS OF PRIMARY AND RECURRENT INTRACRANIAL MENINGIOMA
Authors: Huiyuan Zhang, Lin Qi, Yuchen Du, Frank Braun, Mari Kogiso, Sibo Zhao, Holly Lindsay, Sarah Injac, Patricia Baxter, Jack Su, Akash Patel, Xiao-Nan Li
Journal: Neuro-Oncology (2017)

Meningioma is the most common brain tumors in adults. Cranial-base meningioma are difficult to achieve complete resection while others exhibit progression and aggressive profiles characterized by high recurrence rates and resistance to standard treatment. The lack of clinically relevant animal models is blocking the development of novel therapies. Here, we report our establishment of orthotopic xenograft mouse models and in vitro culture systems from surgical specimens of primary and recurrent meningiomas. 6 primary surgical samples and 4 recurrent samples were obtained from meningioma patients. Tumor tissues were dissociated into single cells and directly implanted into right cranial base of NOD/SCID mice (1x105 cells/mouse). Primary cultures were initiated in serum-free and traditional FBS-based media. Tumor growth was monitored by small animal MRI. Pathologic features of the PDOX models and the matched patient tumors were compared with standard H&E and immunohistochemical staining. Three of the 10 tumors were not tumorigenic, and xenograft tumor formation from 5 additional samples is pending. Growth of intracranial (cranial base) xenograft was confirmed in two samples derived from the same patient diagnosed as atypical meningioma (K029MEN) and progressed as anaplastic meningioma at recurrence (K037MEN). These PDOX have since been serially subtransplanted in mouse brains for generation 2. The xenograft tumors replicated histopathological features (invasion, high proliferation and increased microvessel density) of their parental tumors. In vitro growth of K029MEN and K037MEN as neurospheres and monolayer were maintained for passaging for 10 times. Additionally, cells from K030MEN (WHO grade I meningioma) has been passaged as monolayer for more than 30 times. A novel set of meningioma PDOX models derived from matching primary and recurrent tumor was established. The xenograft tumors replicated the histopathological of the original patient tumors, providing the opportunities to understand the biology of meningiomas and to conduct preclinical drug testing.
ED-SAFE—Can Suicide Risk Screening and Brief Intervention Initiated in the Emergency Department Save Lives?
Authors: Jeffrey A. Bridge, Lisa M. Horowitz, John V. Campo
Journal: JAMA Psychiatry (2017)

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The aryl hydrocarbon receptor is over-expressed and constitutively activated in advanced breast carcinoma
Authors: Sakina E. Eltom, Azza A. Gasmelseed, Dajla Saoudi-Guentri
Journal: Cancer Research (2006)

1730  The aryl hydrocarbon receptor (AhR), a ligand-activated helix loop helix transcription factor, binds environmental poly aromatic hydrocarbons (PAH) such as dioxin, and mediates their toxicity, including carcinogenesis. This study was designed to investigate the functional significance of AhR in breast carcinogenesis. The AhR expression and its transcriptional activity was analyzed in a battery of human breast carcinoma (HBC) cell lines with varying degrees of malignancy in comparison to immortalized normal and primary human mammary epithelial cells (HMEC). Western immuno-blotting revealed dramatic elevated levels of AhR proteins in tumorigenic HBC of advanced malignancy (MD231, MDA468, ZR-75, MDA435, MCF-7), while less levels were expressed in HBC typically categorized as early stages of maliganacy (T-47D, HBL100, BT-549), normal immortalized (H16N2 and MCF10A) and primary HMEC. RT-PCR analysis of mRNA revealed a similar trend although not as dramatic high levels, suggesting a role for protein stabilization in these elevated levels. These results were further confirmed in Sager’s 21T series, which are closely matched pairs of HBC derived from a single patient and are characterized by exhibiting a gradient order of malignancy (21MT2>21NT>21PT). The 21MT-2 lines showed the highest expression of protein and mRNA and 21NT was medium between 21MT-2 and 21PT lines. This high expression of AhR is independent of estrogen receptor (ER) status, as verified in MDA 231 (ER negative) and its variant S30 (ER positive), as well as T47D-A18 (ER positive) and its variant T47D-C4:2W (ER negative), as well as in 21T series which are all ER negative. The AhR is usually localized in the cytoplasm of most normal cells including HMEC and is translocated to the nucleus upon ligand (dioxin) activation. However, both sub-cellular fractionation experiments and fluorescence immuno-cytochemical staining has shown that the AhR in the HBC are predominantly localized to the nuclear compartments in absence of ligand treatment. Similarly, immuno-histochemical analysis of human breast tumors has shown an increase in AhR expression in the invasive carcinomas, where the AhR staining was predominantly or exclusively nuclear. Notably, this nuclear accumulation of AhR in untreated HBC was transcriptionally active as evidenced by the substantial expression of CYP1A1 mRNA, which is exclusively regulated transcriptionally by the activated AhR. In conclusion, this study reports a novel finding of elevated levels of AhR in human breast carcinomas in direct proportion to their degree of malignancy. These data identify the AhR as a possible regulator of breast cancer progression and its possible consideration as a candidate prognostic factor for survival as well as its potential as a target for breast cancer therapeutic intervention.
Analysis of Clinical Features, Laboratory Characteristics and Therapeutic Outcome in Patients with Thrombotic Thrombocytopenic Purpura Treated at King Fahad Medical City, Riyadh, Saudi Arabia
Authors: Shahid Iqbal, Syed Ziauddin A. Zaidi, Ibraheem H. Motabi, Nawal Faiez Alshehry, Mubarak S. AlGhamdi, Samer Mudaibigh, Atta Munawar Gill, Karrar ElHussein, May Al-Moshary, Imran Pukhta, Abdul Rehman Zia Zaidi, Imran K Tailor, Muhammad Nabulsiah, Belal Albtoosh
Journal: Blood (2016)
P14.04 Characteristics of cerebrospinal fluid in hematologic malignancy
Authors: Y. Diansari, T. Aninditha, R. Andriani
Journal: Neuro-Oncology (2017)

Hematologic malignancies such as leukemia and lymphoma demonstrate leptomeningeal cell infiltration more frequently than solid tumors. Special approach in diagnosis and management is necessary, including analysis of cerebrospinal fluid (CSF) obtained from lumbar puncture (LP). The procedure of LP is more warranted among hematologic malignancy patients suspected of suffering from central nervous system (CNS) involvement. It can be performed during sessions of intrathecal chemotherapy, or as prophylactic procedure. The obtained CSF may have properties similar to CNS inflammation. There has been no specific research describing the CSF characteristics of hematologic malignancy in Indonesia; nonetheless, it is essential because, if found, the subsequent management of the patient will be quite different. Aim: To identify the characteristics of CSF in hematologic ­malignancy. Method: This study was retrospective study on medical records of patients with hematologic malignancy admitted to Dharmais Cancer Hospital in 2014-2015 and the Neurology wards of Cipto Mangunkusumo Hospital from 2014-2016. Inclusion criteria are subjects ≥18 years old who had pretreatment CSF analysis. Patients suspected of intracranial infection are excluded. Data collected include routine CSF analysis (cell count, glucose and protein level), cytology (presence of cancer cells), MRI (cranial or spinal), and neurologic examination. Results: 26 subjects were identified, 14 were female. Most were diagnosed with leukemia (19), Mean age was 37,4 ± 13,8 years. Of 21 subjects who had cytology analysis, only five had positive results. MRI was performed on only 10 subjects, with leptomeningeal enhancement and intracranial mass lesions found in 7 subjects. Median CSF cell count was 3 (1-356)/mm3, protein level 36 (16-129)mg/dl, and glucose 63 (8-181)mg/dl. Increased cell count (>5/mm3) and protein level >45mg/dl were found in 7/26 subjects. Neurologic deficits were found on 10 subjects, most prominent being headache (7), seizures, and cranial nerve pareses. LP were performed with the indication of diagnosis based on neurologic deficits (5 with leukemia and 4 lymphoma), therapy (2 with lymphoma) and prophylaxis mainly on leukemias (14). Of 10 subjects with neurologic deficits, 3 had positive cytology. Conversely, positive cytology was found on 2 out of 16 subjects without neurologic deficits. Three positive-cytology subjects displayed leptomeningeal contrast enhancement. Negative cytology was found in one subject with enhancement, 3 with parenchymal mass lesion, and 3 with non-specific MRI features. Conclusion: CSF analysis among patients with hematologic malignancy yield positive results mainly when there is clinical correlation. Nevertheless, when prophylaxis is considered necessary, CSF analysis should be performed to raise awareness regarding CNS involvement, especially among leukemia patients.
P10.14 Long-term impact of Temozolomide on 1p19q codeleted oligodendrogliomas growth kinetics
Authors: C. Izquierdo, A. Alentorn, M. Simó, A. Idbaih, D. Ricard, G. Kaloshi, J. Bruna, J. Honnorat, J. Delattre, F. Ducray
Journal: Neuro-Oncology (2017)

BACKGROUND: Growth kinetics studies have shown that most 1p/19q co-deleted low-grade oligodendrogliomas (OII) present an initial volume decrease when treated with upfront temozolomide (TMZ). However, the duration of this volumetric response has not been precisely studied. Herein, we evaluated the long-term impact of upfront TMZ on OII growth kinetics. MATERIAL AND METHODS: The growth kinetics of 36 OII was evaluated on serial magnetic resonance images before (n=20), during and after treatment (n=36) with upfront TMZ. Results: Median follow-up was 6.5 years (range: 2.07-11.56), median age at TMZ onset was 45.2 years (range: 2.07-11.56) and the median number of TMZ cycles was 18 (range: 2-29). After TMZ onset, all but two patients (94.4%) presented a volume decrease that lasted for a median duration of 17.9 months (range: 2.7-103.9). In 12 patients volume regrowth occurred during TMZ treatment and in 22 patients after TMZ discontinuation. In patients in whom TMZ was discontinued in the absence of progression, a prolonged (>2 years) ongoing volume decrease was observed in 9 patients. However, at 3 and 5 years after TMZ onset, an ongoing volume decrease was only observed in 4 patients (11%) and 2 patients (5.9 %). In contrast to the 17.9 months median duration of volumetric response the median progression free survival as evaluated by the treating neuro-oncologists was 45.7 months. Conclusions: Long-term analysis of growth kinetics shows that in OII, upfront TMZ results in a prolonged volumetric response in only a limited number of patients and that the impact of this chemotherapy regimen may be overestimated in the absence of precise volumetric analysis.
The landscape of BRAF transcript and protein variants in human cancer
Authors: Andrea Marranci, Zhijie Jiang, Marianna Vitiello, Elena Guzzolino, Laura Comelli, Samanta Sarti, Simone Lubrano, Cinzia Franchin, Ileabett Echevarría-Vargas, Andrea Tuccoli, Alberto Mercatanti, Monica Evangelista, Paolo Sportoletti, Giorgio Cozza, Ettore Luzi, Enrico Capobianco, Jessie Villanueva, Giorgio Arrigoni, Giovanni Signore, Silvia Rocchiccioli, Letizia Pitto, Nicholas Tsinoremas, Laura Poliseno
Journal: Molecular Cancer (2017)

The BRAF protein kinase is widely studied as a cancer driver and therapeutic target. However, the regulation of its expression is not completely understood. Taking advantage of the RNA-seq data of more than 4800 patients belonging to 9 different cancer types, we show that BRAF mRNA exists as a pool of 3 isoforms (reference BRAF, BRAF-X1, and BRAF-X2) that differ in the last part of their coding sequences, as well as in the length (BRAF-ref: 76 nt; BRAF-X1 and BRAF-X2: up to 7 kb) and in the sequence of their 3'UTRs. The expression levels of BRAF-ref and BRAF-X1/X2 are inversely correlated, while the most prevalent among the three isoforms varies from cancer type to cancer type. In melanoma cells, the X1 isoform is expressed at the highest level in both therapy-naïve cells and cells with acquired resistance to vemurafenib driven by BRAF gene amplification or expression of the Δ[3–10] splicing variant. In addition to the BRAF-ref protein, the BRAF-X1 protein (the full length as well as the Δ[3–10] variant) is also translated. The expression levels of the BRAF-ref and BRAF-X1 proteins are similar, and together they account for BRAF functional activities. In contrast, the endogenous BRAF-X2 protein is hard to detect because the C-terminal domain is selectively recognized by the ubiquitin-proteasome pathway and targeted for degradation. By shedding light on the repertoire of BRAF mRNA and protein variants, and on the complex regulation of their expression, our work paves the way to a deeper understanding of a crucially important player in human cancer and to a more informed development of new therapeutic strategies.
Apolipoprotein A-IV–Associated Cardiac Amyloidosis
Authors: Melanie C. Bois, Surendra Dasari, John R. Mills, Jason Theis, William E. Highsmith, Julie A. Vrana, Martha Grogan, Angela Dispenzieri, Paul J. Kurtin, Joseph J. Maleszewski
Journal: Journal of the American College of Cardiology (2017)
P13.03 Profiling protease activities in cerebrospinal fluids: a novel method for detection of neoplastic meningitis?
Authors: C. Conrad, K. Dorzweiler, M. Thanisch, J. Bartsch, H. M. Strik
Journal: Neuro-Oncology (2017)

Background: Neoplastic meningitis (NM) is fatal with a poor median survival of 2-4 month. Early discrimination between benign and malignant CSF alterations has crucial prognostic and treatment implications. By degradation of extracellular matrix (ECM) components and adhesion molecules, Matrix Metalloproteases (MMPs) and A Disintegrin and Metalloproteases (ADAMs) are essential for break-down of the blood-brain-barrier and metastatic invasion of tumor cells into the CSF. The Proteolytic activity matrix assay (PrAMA) is a multiplex, real-time approach that allows for sensitive detection of proteases in low-volume clinical samples such as CSF. In this pilot study, we performed PrAMA analyses in CSF samples of patients with NM to gain insights into context-dependent protease function. Methods: Cell-free CSF from controls (n=10), NM (n=10), and patients with intracranial neoplasia but no CSF involvement (tumor, n=10) underwent PrAMA analysis to detect activities of zinc-dependent proteases (Matrix Metalloproteinases, MMPs, and A Disintegrin and Metalloproteinases, ADAMs) in 50 microlitres of CSF. Protease activities in CSF samples were compared in the absence and presence of a broad-range MMP/ADAM inhibitor, batimastat (BB-94), to verify MMP activities. Specific MMP/ADAM activities were inferred using an algorithm developed previously (Miller et al., 2011) using MatLab (version 8.4.0.150421 (R2014b)). Results: In NM patients, four out of five peptides indicated increased cleavage rates compared to control and tumor samples. PrAMA inference revealed the contribution of MMP-2, MMP-9, ADAM8 and ADAM17 to the observed activities, also confirmed by the use of batimastat. For the mentioned proteases, neoplastic meningitis caused 4-5-fold higher protease activities relative to control and tumor samples. Whilst for MMP-2 and ADAM8, changes were not significant (p>0.1), the values for MMP-9 were 1.54x10-11 [s-1] for controls, 2.04x10-11 for tumor and 6.96x10-11 for NM (p<0.001) and for ADAM17 5.66x10-12 for controls, 5.91x10-12 for tumor and 2.71x10-11 for NM (p<0.001). Thus, MMP-9 and ADAM17 in the CSF appear to be suitable marker enzymes to detect NM. Conclusion: A multiplex approach to determine protease activities in the CSF is a promising method for sensitive and clearcut detection of neoplastic meningitis. Rapid and sensitive assessment of context-dependent protease profiles in small volumes of CSF with PrAMA may be suitable for clinical routine.
US drug regulators should consider adding adults to SSRI suicide warning, says campaigner
Authors: Ed Silverman
Journal: BMJ (2017)

A British doctor who campaigned for the public to be warned about increased suicide risk in young people taking antidepressants has said that US drug regulators should consider including adults in warnings.

David Healy, a psychiatry professor at Bangor University, called for the warnings after GlaxoSmithKline (GSK) was ordered to pay $3m (£2.34m; €2.75m) to the widow of a US man who killed himself shortly after starting generic paroxetine.

The jury in the case of Stewart Dolin, a 57 year old attorney, concluded that GSK had failed to properly warn the public about the increased risk of suicide when taking paroxetine. The jury reached its verdict after lawyers for Dolin’s widow, Wendy, presented evidence in the Chicago federal court suggesting that GSK knew that paroxetine posed a risk to adults but had concealed …
Endoscopic sphincterotomy in pediatric patients: do we know enough?
Authors: Jaya Agarwal, Sundeep Lakhtakia
Journal: Endoscopy (2017)

The first successful endoscopic sphincterotomies were reported in adults, more than 40 years ago, independently by Classen & Demling [1] and by Kawai et al. [2], when they removed impacted biliary stones, thereby transforming endoscopic retrograde cholangiopancreatography (ERCP) from a diagnostic to a therapeutic procedure. Since then ERCP with endoscopic sphincterotomy has become the preferred minimally invasive method for the treatment of pancreaticobiliary diseases in adults. Extrapolation into the pediatric population occurred a decade later, when Cotton & Laage performed pancreatic sphincterotomy in an adolescent child with chronic pancreatitis [3]. Later, Buckley & Connon described successful biliary sphincterotomy in five children [4]. Biliary endoscopic sphincterotomy is usually performed to remove bile duct stones and to facilitate the placement of a stent, often across a biliary stricture. Pancreatic endoscopic sphincterotomy is usually performed to place a pancreatic stent. Widespread use of therapeutic ERCP in children has led to a better understanding of its indications as well as of expected technical and clinical outcomes.